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FacultyofMedicineUniversityofOttawa
EPI7999:Thesis
Title:
ThePharmacologicProphylaxisofPediatricMigraine:ASystematicReview,SurveyandDesignofaRandomizedControlledTrial
(AthesissubmittedinpartialfulfillmentoftherequirementsforthedegreeofMScEpidemiology)
By:
SerenaOrr,MD,MScCandidate
ThesisAdvisoryCommittee:DarDowlatshahi,MD,PhD,FRCPC(ThesisSupervisor)
TimothyRamsay,PhD(ThesisCo-Supervisor)SuzanneN.Christie,MD,FRCPC(ContentExpert)
Preparedfor:TheGraduateStudiesCommittee
DegreeSought:MScEpidemiology
©SerenaOrr,Ottawa,Canada,2016
ii
TableofContents
TABLEOFCONTENTS....................................................................................................................IILISTOFTABLES.............................................................................................................................VILISTOFFIGURES...........................................................................................................................VILEGEND.............................................................................................................................................VIENGLISHTHESISABSTRACT...................................................................................................VIIIFRENCHTHESISABSTRACT.......................................................................................................IXACKNOWLEDGEMENTS.................................................................................................................XTHESISPARTI:SYSTEMATICREVIEW.....................................................................................11. BACKGROUND............................................................................................................................................11.1. Theprevalenceandimpactofpediatricmigraine.............................................................11.2. Thepathophysiologyofmigraine..............................................................................................11.3. Generalapproachtothetreatmentofpediatricmigraine.............................................31.4. Educationandlifestylechangesforthemanagementofpediatricmigraine........31.5. Psychologicalinterventionsforpediatricmigraine..........................................................41.6. Complimentaryandalternativemedicineforpediatricmigraine..............................51.7. Nutraceuticalsforpediatricmigraine.....................................................................................71.7.1. Butterbur....................................................................................................................................................................71.7.2. Riboflavin...................................................................................................................................................................71.7.3. Magnesium................................................................................................................................................................81.7.4. CoenzymeQ10...........................................................................................................................................................81.7.5. FishOils.......................................................................................................................................................................81.7.6. L-5-Hydroxytryptophan......................................................................................................................................81.7.7. CombinationTherapies........................................................................................................................................8
1.8. PharmaceuticalsforPediatricMigraine................................................................................91.8.1. AntiepilepticMedications...................................................................................................................................91.8.2. Calcium-ChannelBlockersandBeta-Blockers.........................................................................................111.8.3. Antidepressants....................................................................................................................................................121.8.4. Antiemetics..............................................................................................................................................................131.8.5. Others........................................................................................................................................................................13
1.9. Conclusions.......................................................................................................................................142. METHODS.............................................................................................................................................152.1. Objectives..........................................................................................................................................152.2. StudyDesign.....................................................................................................................................152.3. CriteriaforConsideringStudiesforthisReview..............................................................162.3.1 TypesofStudies.....................................................................................................................................................162.3.2 TypesofParticipants...........................................................................................................................................162.3.3. TypesofInterventions.......................................................................................................................................172.3.4 TypesofComparisons.........................................................................................................................................182.3.5 TypesofOutcomes................................................................................................................................................182.3.6 LanguageofStudies..............................................................................................................................................18
2.4. SearchMethodsforIdentificationofStudies.....................................................................192.5. ScreeningProcess..........................................................................................................................202.5.1 FirstScreenMethodology..................................................................................................................................202.5.2 SecondScreenMethodology.............................................................................................................................21
2.6. DataExtraction..............................................................................................................................222.7. Meta-Analyses.................................................................................................................................23
iii
3. RESULTS...............................................................................................................................................253.1. CharacteristicsofIncludedStudies........................................................................................253.2. NutraceuticalInterventions......................................................................................................343.2.1 Butterbur(Petasiteshybridus).......................................................................................................................343.2.2 Riboflavin(VitaminB2).......................................................................................................................................36
3.3. Pharmaceuticals............................................................................................................................383.3.1 Topiramate...............................................................................................................................................................383.3.2 ValproicAcid............................................................................................................................................................433.3.3. Flunarizine...............................................................................................................................................................443.3.4 Timolol.......................................................................................................................................................................473.3.5 Clonidine....................................................................................................................................................................483.3.6 Trazodone.................................................................................................................................................................503.3.7 Nimodipine...............................................................................................................................................................513.3.8 Cinnarizine...............................................................................................................................................................523.3.9 Dimethothiazine.....................................................................................................................................................533.3.10 Papaverine.............................................................................................................................................................54
3.4. UnpublishedTrials........................................................................................................................553.5. Meta-Analyses.................................................................................................................................553.5.1 Riboflavinvs.Placebo..........................................................................................................................................553.5.2 Topiramatevs.Placebo.......................................................................................................................................563.5.3 Flunarizinevs.Placebo........................................................................................................................................583.5.4 OtherInterventions..............................................................................................................................................58
4. DISCUSSION.........................................................................................................................................58THESISPARTII:SURVEYONNON-INFERIORITYMARGINSFORMIGRAINETRIALS:
DETERMININGANON-INFERIORITYMARGINFORMIGRAINETRIALS:THENON-INFERIORITYMARGINSINMIGRAINERESEARCH(NIMM)SURVEY...................................61
1. BACKGROUND.........................................................................................................................................612. OBJECTIVES.............................................................................................................................................652.1. Primaryobjectives.........................................................................................................................652.2. Secondaryobjectives....................................................................................................................65
3. METHODS................................................................................................................................................663.1. StudyDesign&Protocol.............................................................................................................663.2. Inclusion&ExclusionCriteria..................................................................................................683.2.1 InclusionCriteria...................................................................................................................................................683.2.2 ExclusionCriteria..................................................................................................................................................68
3.3. Statistics.............................................................................................................................................684. HUMANPROTECTION............................................................................................................................684.1. TimeCommitment.........................................................................................................................684.2. RisksInvolvedinParticipatingintheStudy......................................................................684.3. BenefitsAssociatedwithParticipatingintheStudy......................................................69
5. RESULTS..................................................................................................................................................696. DISCUSSION.............................................................................................................................................74
THESISPARTIII:DESIGNOFARANDOMIZEDCONTROLLEDTRIAL...........................771. BACKGROUND....................................................................................................................................772. METHODS.............................................................................................................................................812.1. StudyObjectives..............................................................................................................................812.1.1. PrimaryObjective.................................................................................................................................................812.1.2 SecondaryObjectives...........................................................................................................................................81
2.2. StudyDesign.....................................................................................................................................822.3. EligibilityCriteria..........................................................................................................................832.3.1 InclusionCriteria...................................................................................................................................................832.3.2 ExclusionCriteria..................................................................................................................................................84
2.4. Interventions....................................................................................................................................86
iv
2.5. Outcomes...........................................................................................................................................882.6. Randomization................................................................................................................................912.7. StudyVisits........................................................................................................................................92
3. PROTECTINGAGAINSTSOURCESOFBIAS.........................................................................................933.1. SelectionBias...................................................................................................................................933.2. PerformanceBias...........................................................................................................................933.3. AttritionBias...................................................................................................................................933.4. DetectionBias.................................................................................................................................94
4. STATISTICS..........................................................................................................................................944.1. SampleSizeCalculations............................................................................................................944.2. PlannedStatisticalAnalyses.....................................................................................................964.2.1 PrimaryHypotheses.............................................................................................................................................964.2.2 PrimaryOutcomeAnalysisPlan......................................................................................................................974.2.3 SecondaryOutcomeAnalysisPlan.................................................................................................................974.2.4 DealingwithMissingDataandApproachtoDataAnalysis.................................................................984.2.5 InterimDataAnalyses.........................................................................................................................................98
5. TRIALMANAGEMENTISSUES.....................................................................................................995.1. RecruitmentProcess.....................................................................................................................995.1.1 RecruitmentTargets............................................................................................................................................995.1.2 StrategiestoMaximizeRecruitmentandFollow-Up..........................................................................100
6. PERSONNELANDROLES.............................................................................................................1016.1. StudyPersonnel...........................................................................................................................1016.1.1 SiteResearchCoordinators............................................................................................................................1016.1.2 SiteInvestigators................................................................................................................................................1026.1.3 SiteResearchPharmacists..............................................................................................................................1036.1.4 LeadSiteResearchCoordinator...................................................................................................................1036.1.5 LeadSitePrincipalInvestigator...................................................................................................................1036.1.6 LeadSiteResearchPharmacists...................................................................................................................1046.1.7 LeadSiteBiostatistician...................................................................................................................................104
6.2. DataandSafetyMonitoringBoard.....................................................................................1046.3. TrialSteeringCommittee........................................................................................................105
7. ETHICALCONSIDERATIONS......................................................................................................1057.1. ClinicalEquipoiseRegardingLevetiracetamforPediatricMigraineProphylaxis
1057.2. InformedConsent........................................................................................................................1067.3. SpecialConsiderationsinthePediatricPopulation....................................................1077.4. PrivacyandConfidentiality....................................................................................................107
REFERENCES................................................................................................................................109THESISAPPENDIX......................................................................................................................1208. APPENDIXA.ELECTRONICSEARCHSTRATEGIESFORIDENTIFICATIONOFSTUDIES...............1209. APPENDIXB.SYSTEMATICREVIEWINCLUDEDSTUDIESELIGIBILITYFORMS.........................12310. APPENDIXC.SYSTEMATICREVIEWINCLUDEDSTUDIES‘CHARACTERISTICSOFSTUDIES’
TABLES 14211. APPENDIXD.SYSTEMATICREVIEWINCLUDEDSTUDIES‘RISKOFBIASASSESSMENT’TABLES
16412. APPENDIXE.EMAILINVITATIONTOPOTENTIALPARTICIPANTS............................................18613. APPENDIXG.NON-INFERIORITYMARGINSINMIGRAINERESEARCH(NIMM)SURVEY....18814. APPENDIXH.NIMMRESPONSESIN“OTHER”CATEGORY.......................................................19315. APPENDIXI.RCTELIGIBILITYCRITERIARATIONALE...............................................................19616. APPENDIXJ.RCTHEADACHEDIARYTEMPLATE.......................................................................19817. APPENDIXK.PEDMIDASQUESTIONNAIRE................................................................................200
v
18. APPENDIXL.TRIALINFORMEDCONSENTFORMFORPARENTSANDPARTICIPANTSAGED16ANDOVER........................................................................................................................................................201
19. APPENDIXM.TRIALASSENTFORMFORPARTICIPANTSAGEDLESS16YEARS..................20720. APPENDIXN.BROCHURETOEXPLAINSTUDYPROCEDURESTOPARTICIPANTS..................21021. APPENDIXO.PASSREPORT1–SUPERIORITYHYPOTHESISSAMPLESIZECALCULATION
21222. APPENDIXP.PASSREPORT2–NON-INFERIORITYHYPOTHESISSAMPLESIZE
CALCULATION........................................................................................................................................................214
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LISTOFTABLES
1. Table1.Eligibilitycriteriaforstudies…………………………………………………………………..........27-282. Table2.Summaryofincludedstudies………………………………………………………………………..34-403. Table3.CharacteristicsofNIMMrespondents…………………………………………………………...77-784. Table4.Non-inferioritymarginresponsesforprophylacticmigrainetrials…………………78-795. Table5.Non-inferioritymarginresponsesforacutemigrainetrials……………………………79-806. Table6.Expertopiniononappropriatenon-inferioritymarginsforcommonlyused
migraineoutcomes…………………………………………………………………………………………………...80-817. Table7.ICHDcriteriaforpediatricmigrainewithoutaura………………………………………………918. Table8.ICHDcriteriaforpediatricmigrainewithaura………………………………………………91-92
LISTOFFIGURES1. Figure1.PRISMADiagram……………………………………………………………………………………………..342. Figure2.Riskofbiasgraph:reviewauthors'judgementsabouteachriskofbiasitem
presentedaspercentagesacrossallincludedstudies………………………………………………………403. Figure3.Riskofbiassummary:reviewauthors'judgmentsabouteachriskofbiasitemfor
eachincludedstudy…………………………………………………………………………………………………….…414. Figure4.Topiramatevs.placebo:pooledanalysisofthepercentage(%)reductionin
migrainefrequencycomparingbaselinetothetreatmentperiod……………………………………..655. Figure5.Illustrationofthedifferencebetweenasuperiorityandnon-inferiority
hypothesis……………………………………………………………………………………………………………………..716. Figure6.Studytimelines………………………………………………………………………………………………..89
LEGENDχ2:ChisquareAHS:AmericanHeadacheSocietyANOVA:AnalysisofvarianceCAM:ComplimentaryandalternativemedicineCANTAB:CambridgeNeuropsychologicalTestAutomatedBatteryCBT:CognitivebehaviortherapyCHS:CanadianHeadacheSocietyCI:ConfidenceintervalDSMB:DataandSafetyMonitoringBoardFDA:FoodandDrugAdministrationICHD:InternationalClassificationofHeadacheDisordersIHS:InternationalHeadacheSocietyKg:KilogramsMCID:MinimalclinicallyimportantdifferenceMedDRA:MedicalDictionaryforRegulatoryActivityMcg:Micrograms
vii
Mg:MilligramsN:NumberNIH:NationalInstitutesofHealthNIMM:Non-InferiorityMarginsinMigraineResearchOHSN-REB:OttawaHealthScienceNetworkResearchEthicsBoardOR:OddsratioPDF:PortableDocumentFormatPedMIDAS:PediatricMigraineDisabilityAssessmentScalePRN:Prorenata(asneeded)qAM:Quaquedieantemeridiem(everydaybeforenoon)qHS:Quaquehorasomne(everynightatbedtime)REDCap:ResearchElectronicDataCaptureRevMan:ReviewManagerRCT:RandomizedcontrolledtrialSAS:StatisticalAnalysisSystemSD:StandarddeviationWHO:WorldHealthOrganization
viii
ENGLISHTHESISABSTRACT
Objectives:1)Todescribethestateoftheevidenceforinterventionsinpediatricmigraine,2)to
surveyexpertsregardingnon-inferioritymarginsinmigraineresearchand3)todesignaclinical
trialinthisareaofresearch.
Methods:Asystematicreviewwascarriedouttoidentifyrandomized,placebo-controlledtrialsof
pharmaceuticalandnutraceuticalinterventionsusedtopreventmigraineinchildrenand
adolescents,usingCochranemethods.Secondly,neurologistswithexpertiseinHeadacheMedicine
wereinvitedtoparticipateinasurveyregardingtheiropinionsonnon-inferioritymarginsfor
outcomesusedinclinicaltrialsofmigraineinterventions.Thirdly,aprotocolwaswrittenfora
three-arm,parallel-group,randomizedtrialcomparingtheefficacyandsafetyoftopiramate,
levetiracetamandplacebofortheprophylaxisofpediatricmigraine.
Results:Thesystematicreviewidentified19articlesof12interventionsforpediatricmigraine.The
qualityoftheevidencewaspoorandfewconclusionscouldbemade.Ninety-nineeligible
respondentscompletedthesurveyandnon-inferioritymarginsforsixoutcomesweredetermined.
Arandomizedcontrolledtrialprotocolwasdevelopedtodetermineiftopiramateandlevetiracetam
aresuperiortoplacebo,andiflevetiracetamisnon-inferiortotopiramateforthepreventionof
migrainesinchildrenandadolescents.
Conclusions:Itishopedthattheresultsofthisthesiscanbeappliedtofurthertheevidenceinthis
areaofclinicalresearch.
ix
FRENCHTHESISABSTRACT
Objectifs:1)Décrirel’étatdelarecherchesurlamigrainechezlesenfants,2)faireunsondage
parmilesexpertsparrapportauxseuilsdenon-inférioritépourlesessaiscliniquessurlamigraine
and3)fairelaconceptiond’unessaicliniquesurdesinterventionspréventifspourlamigrainechez
lesenfants.
Méthodes:Unerevuesystématiqueaétéexecutéeafind’identifierdesessaiscliniquessurlesujet
d’interventionspharmaceutiquesetnutraceutiquespourprévenirlamigrainechezlesenfants,en
utilisantlesméthodesCochrane.Desneurologuesavecexpertiseparrapportauxmauxdetêtesont
étéinvitésàparticiperdansunsondagesurlesujetdesseuilsdenon-inférioritéutiliséspourla
recherchesurlamigraine.Unprotocolaétédeveloppépourdécrireunessaicliniquequi
compareral’efficacitéetlatolérabilitédetopiramate,levetiracetametd’unplacebopourla
préventiondesmigraineschezlesenfants.
Résultats:Larevuesystématiqueaidentifiée19articlessurlesujetde12interventionspourla
migrainechezlesenfants.Laqualitédelarechercheétaitfaibleetpeudeconclusionsétaient
possibles.Quatre-vingt-dix-neufrépondentsontcompletéslesondageetsixseuilsdenon-
inférioritéontétéspecifiés.Unessaicliniqueaétédéveloppéafindedeterminersitopiramateet
levetiracetamsontsupérieursauplacebo,etsilevetiracetamestnon-inférieuràtopiramatepourla
préventiondesmigraineschezlesenfants.
Conclusions:Lesrésultatsdecettethèsepeuventêtreappliquéspouraméliorerlaqualitédela
recherchedanscedomaine.
x
ACKNOWLEDGEMENTSIwouldliketoacknowledgetheCanadianInstitutesofHealthResearchfortheirroleinfundingthis
workthroughtheCanadianGraduateScholarshipandtheOntarioGovernment,fortheirrolein
fundingthisworkthroughtheOntarioGraduateScholarship.
IwouldalsoliketothanktheOttawaHealthScienceNetworkResearchEthicsBoardforreviewing
theprotocolfortheNon-InferiorityMarginsinMigraineResearch(NIMM)survey(protocol
#20150651-01H).
Forthesystematicreview:IwouldliketothankMargaretSampson,MLIS,PhD,AHIPforherrolein
designingtheelectronicsearchstrategiesforthesystematicreviewandJanetJoyce,MLIS,forher
roleinpeerreviewingtheelectronicsearchstrategies.IwouldalsoliketothankDr.SuzanneN.
Christie,MD,FRCPCforherroleinscreeningtheresultsofthesystematicreviewasasecond
screener,andDr.ErickSell,MD,FRCPC,forhisroleintranslatingPortugueseandSpanisharticles.I
wouldliketothankDrs.Ramsay,ChristieandDowlatshahifortheirrolesinassistingmewith
questionsaboutsystematicreviewdesignandimplementation.
Forthesurvey:IwouldliketothanktheAmericanHeadacheSocietyandtheCanadianHeadache
SocietyfordistributingtheNon-InferiorityMarginsinMigraineResearch(NIMM)surveytotheir
members.Thisprojectwasacollaborationbetweenmyself,SerenaOrr,MDandDrs.Dariush
Dowlatshahi,MD,PhD,FRCPC,SuzanneN.Christie,MD,FRCPC,TimothyRamsay,PhD,Jonathan
Gladstone,MD,FRCPCandDavidDodick,MD,FRCPC,FACP,FAHS.Theroleofeachauthoris
outlinedbelow:
xi
• SerenaOrr:Conceptualizedthesurvey,designedthesurvey,wrotetheprotocol,submitted
theprotocoltotheOHSN-REB,carriedouttheanalysesandwrotethemanuscript.
• DariushDowlatshahi:HelpedDr.Orrindesigningthesurvey,planningsurveydistribution
andreviewedtheprotocolandmanuscript.
• SuzanneN.Christie:HelpedDr.Orrindesigningthesurvey,planningsurveydistribution
andreviewedtheprotocolandmanuscript.
• TimothyRamsay:HelpedDr.Orrindesigningthesurvey,planningsurveydistributionand
reviewedtheprotocolandmanuscript.
• JonathanGladstone:HelpedDr.Orrinplanningsurveydistribution,distributedthesurvey
tomembersoftheCanadianHeadacheSociety,reviewedtheprotocolandmanuscript.
• DavidDodick:HelpedDr.Orrinplanningsurveydistributionandreviewedtheprotocoland
manuscript.
Fortherandomizedtrialprotocol:IwouldliketothankDr.TimothyRamsayforhisassistancein
samplesizecalculationsandplanningstatisticalanalysesforthetrial.IwouldliketothankDrs.
DowlatshahiandChristiefortheirrolesinassistingmewithquestionsabouttrialdesign.
1
THESISPARTI:SYSTEMATICREVIEW
1. Background
1.1. Theprevalenceandimpactofpediatricmigraine
Migraineisoneofthemostcommondiagnosesencounteredbythepediatricneurologist.Ithas
beenestimatedthattheworldwideprevalenceofmigraineis7.7%inthepediatricagegroup,with
considerablevariationwithage,wherebytheprevalenceincreasessignificantlyinadolescence1.
Notonlyismigrainecommon,butitalsohasanimportantimpactontheindividualandsocietyin
termsofdisability.Inthe2010GlobalBurdenofDiseases,InjuriesandRiskFactorsStudy,migraine
wastheeighthmostcommoncauseofglobalyearsoflifelivedwithdisabilityamongstthemost
commonlyreporteddiseasesandinjuries2.Amultitudeofstudieshavefoundthatchildrenand
adolescentswithmigrainesufferfromimpairedhealth-relatedqualityoflife3–5.Furthermore,
childrenandadolescentswithmigraineexperienceasignificantamountofdisabilityrelatedtotheir
headaches6–8,whichengendersimportantfunctionalconsequencesontheirday-to-daylives.For
example,childrenandadolescentswithmigrainehaveinferioracademicperformanceascompared
totheirpeers9,10.Therefore,migraineisnotonlycommoninthepediatricagegroupbuthas
importantconsequencesforday-to-dayfunctioningandqualityoflife.
1.2. Thepathophysiologyofmigraine
Migraineismostoftenconceptualizedasaneurovasculardisorder,althoughits
pathophysiologyisnotcompletelyunderstood.Thepainarisingfrommigraineoriginatesinthe
trigeminovascularsystem:nociceptorsresidinginmeningealbloodvessels,cranialsinusesand
proximalcerebralbloodvesselsbecomeactivatedandsendafferentpainsignalstothespinal
trigeminalnucleusinthebrainstemandtotheuppercervicalspinalcord11.Itisunclearhowthese
nociceptorsbecomeactivatedattheonsetofmigraine,althoughaleadingtheoryimplicates
2
peripheralsensitizationprovokedbysterilemeningealinflammation.Itisthoughtthatapro-
inflammatorystateexistsinthemeningesduringmigraineandthatthisstatecausesalower
thresholdfornociceptoractivationorperhapsevensustainedactivationofthenociceptors12.
Fromthespinaltrigeminalnucleus,secondorderneuronsprojecttoamultitudeofbrainareas,
includingtheparabrachialnucleus,andseveralthalamicandhypothalamicnuclei.Thesecond
orderneuronslocatedintheuppercervicalspinalcordalsoprojecttoseveraltargetsinthe
thalamusandhypothalamusaswellastargetsinbrainstemincludingtheperiaquedualgrayinthe
midbrain,thereticularformationandthesuperiorsalivatorynucleus12.Theseprojectionsfrom
secondorderspinaltrigeminalanduppercervicalneuronsarethoughttoplayaroleingenerating
someofthesymptomsassociatedwithmigraine(eg.nausea,anorexiaandfatigue)11.
Asisdescribedabove,manyofthesecondorderneuronsfromthespinaltrigeminalnucleusand
uppercervicalspinalcordprojecttothalamicnuclei.Inturn,thirdorderneuronsinthethalamus
sendprojectionstovariouscorticalareas,withindividualnucleiprojectingtospecificcortical
regions(eg.dura-sensitiveneuronsintheventroposteromedialnucleusofthethalamusprojectto
theprimarysomatosensoryandinsularcortices).Thesethirdorderthalamicneuronsarethought
tomodulatecorticalactivityintheirrespectivetargetregions,andsomeofthehigherorder
symptomsassociatedwithmigraine,suchasallodyniaanddifficultyconcentrating,maybe
explainedbyactivationofthesepathways11.
Inadditiontotheseascendingpathways,therearealsonumerousdescendingpathwaysthatact
tomodulatetheexperienceofpainandthatmayplayaroleincentralsensitization.Variouscortical
andbrainstemregionshaveadescendinginfluenceonthetrigeminovascularsystem,andrecent
evidencesuggeststhatthehypothalamusalsohasamodulatoryeffectontrigeminalnociception11.
Migraineursarethoughttohavealteredexcitabilityatthelevelofthecortexandperhapsalso
dysfunctionofmodulatorybrainstemregionssuchastheperiaqueducalgrayareaofthe
midbrain11.
3
Becauseofthecomplexityofmigrainepathophysiology,migraineinterventionsarenumerous,
varied,andhavediversetheoreticalmechanismsofaction.
1.3. Generalapproachtothetreatmentofpediatricmigraine
Giventheimpacttheyhavenotonlyonpatients’lives,butonsocietyasawhole,theoptimal
treatmentofmigrainesisvital.Treatmentrequiresamultiprongedapproach.Therearetwobroad
classesofinterventionsformigraines:pharmacologicalandnon-pharmacological.Thereisalsoa
seriesofinterventionsthatfallundertheumbrellaofcomplimentaryandalternativemedicines
(CAM).Avarietyofnon-pharmacologicalinterventionshavebeenstudiedformigraine.
1.4. Educationandlifestylechangesforthemanagementofpediatricmigraine
Firstly,patienteducationisnecessary.Manyfactorsunderthepatient’scontrolcaninfluence
thefrequencyofmigraines.Lifestylefactorsappeartohaveanimportantimpactonprimary
headaches.Adolescentswithlowphysicalactivityaremorelikelytoreportrecurrent
headaches13,14,andamongstthosewithmigraine,lowphysicalactivityisassociatedwithhigher
levelsofmigraine-relateddisability15.Otherlifestylefactorsincludingdiet14,16andsleep-related
problems17–22havebeenshowntohaveanimportantrelationshipwithmigraineinthepediatric
agegroup.Inaddition,studiesamongstadultmigraineurshaveshownthatdysfunctionalcoping
withstressisprevalentinthispopulation23–25.Onestudyamongstchildrenwithprimary
headaches,includingmigraine,foundthatpoorcopingskillswereassociatedwithlowerqualityof
lifescores26.
Inadditiontoresearchdocumentingtheassociationsabove,afewstudieshaveexploredthe
efficacyoflifestyleinterventionsforpediatricmigraineprevention.Arandomizedtrialcarriedout
amongstpediatricmigrainepatientswithknownsleephygieneproblemsdemonstratedthat
educationaboutsleephygieneguidelinessignificantlyimprovedtheirmigrainesinregardsto
severalparametersascomparedtothecontrolcondition27.Acoupleofstudieshavealsotriedto
assesstheeffectofremovingdietarymigrainetriggersonmigraineparametersinthepediatric
4
population.Onerandomizedtrialcomparedahighfiberdiettoahighfiberdietpluseliminationof
foodshighinvasoactiveaminesinasampleofchildrenwithmigrainesandfoundnodifference
betweeninterventionarms28.However,anon-randomized,uncontrolledstudyfoundthat
eliminationofavarietyofcommontriggerfoodsfromthedietsofchildrenwithmigrainesresulted
in93%ofparticipantsreportingsignificantimprovementintheirmigraines29.Therefore,in
addressingthetreatmentofmigraines,itiscrucialtocounselthepatientonlifestylefactorsthat
canimpacttheirheadaches,priortoanydiscussionsofactiveinterventionsforthemigraines.
1.5. Psychologicalinterventionsforpediatricmigraine
Thereareseveralotherclassesofnon-pharmacologicinterventionstoconsiderinthispatient
population,whichfallundertheumbrellaofpsychologicalinterventions.Giventhefactthat
childrenandadolescentswithmigrainearethoughttohaveissueswithstresscoping,relaxation
therapyhasbeenstudiedasaprophylactictherapyformigraine.Asystematicreviewpublishedin
2006identifiedthreestudiesonrelaxationtherapyforthisindication.Theresultsofthestudies
wereinconsistent,andthereviewersconcludedthatrelaxationtherapymightbesuperiortoawait
listcondition30.Sincepublicationofthisreview,twostudieshaveexploredrelaxationtherapy
techniquesinthispopulationandhaveshownpromisingpreliminaryresultsinregardstothe
potentialofrelaxationtherapyforpediatricmigraineprophylaxis31,32.Thesame2006systematic
reviewalsopooledtheevidenceforbiofeedback,andfoundthatitdidnotdiffersignificantlyfrom
placeboforthepreventionofmigrainesinchildrenandadolescents30.Onesmallstudypublished
sincethenfoundthatbiofeedbackwaseffectiveinyieldingareductioninmigrainefrequencyand
severityinagroupofchildrenwithmigrainewithoutaura33.Despitethescarceevidence,
biofeedbackisusedfrequentlyincertainpediatricheadachepracticesandhasbeenrecommended
forselectpatientsinpediatricmigrainemanagementguidelines34.Cognitivebehaviortherapy
(CBT)hasalsobeenassessedforpreventionofmigrainesinchildrenandadolescents.Priorto
2006,twostudieshadassessedCBTinthispopulationandfoundnosignificantdifferencesinits
5
efficacyascomparedtoplacebo,additionalpainbehavioralmanagementoraprogressive
relaxationtechnique30.In2013,arandomizedcontrolledtrialcomparingamitriptylineplus
headacheeducationtoamitriptylineplusCBTinagroupofchildrenandadolescentswithchronic
migraineshowedthatthearmreceivingCBThadsignificantlygreaterimprovementinthe
frequencyoftheirmigrainesandintheirmigraine-relateddisabilityscores35.A2009Cochrane
reviewcarriedoutapooledanalysisofallpsychologicaltreatmentsforpediatricheadache,which
includedstudiesonrelaxationtherapy,biofeedbackandCBTandalsoincludedchildrenwithnon-
migrainousprimaryheadaches.Intotal,15studiesassessedtheefficacyofpsychological
interventionsforpediatricheadacheimmediatelyaftertreatment,andfoundastrongeffecton
immediatepainreduction(OR=5.51,95%CI:3.28-9.24).Sixofthestudiesassessedpainatfollow-
up,andresultswerealsoverypromisinginregardstotheefficacyofpsychologicalinterventionsin
reducingheadache-relatedpain(OR=9.91,95%CI:3.73-26.33)36.A2006meta-analysisof
psychologicalinterventionsforrecurrentheadachesinchildrenandadolescentscametosimilar
conclusionsabouttheefficacyoftheseinterventionsasthe2009Cochranereview37.Thus,thereare
severalnon-pharmacologicinterventionswithvaryingdegreesofevidenceforefficacyinthe
treatmentofpediatricmigraine.
1.6. Complimentaryandalternativemedicineforpediatricmigraine
Thenextcategoryofinterventionsforpediatricmigrainepertainstocomplimentaryand
alternativetherapies(CAM).TheNationalInstitutesofHealthhasdefinedCAMasa:“groupof
diversemedicalandhealthcaresystems,practices,andproductsthatarenotpresentlyconsidered
tobepartofconventionalmedicine”38.TheuseofCAMisincreasing39,anditiscurrentlya
multibillion-dollarperyearindustryintheUS40.Inthepediatricworld,headacheisthemost
commonreasonforCAMuse,alongwithpain41.Acoupleofstudieshavehighlightedtheprevalence
ofCAMuseamongstpediatricheadachepatients.AstudycarriedoutinanItalianheadacheclinic
foundthat76%ofthechildrenwithheadaches,mostofwhomhadmigraines,reportedusingCAM,
6
withthemostcommonmodalitiesbeingherbalremediesorvitaminandmineralsupplements42.
ThisstudymayhaveoverestimatedtheuseofCAMgiventhehighlyselectedpopulation,butastudy
amongstapopulation-basedsampleofUSchildrenfoundthat30%ofthechildrenreporting
headacheswerealsousingCAM43.Therefore,itindeedappearsthatCAMuseforheadachesis
commoninchildrenandadolescents,thoughanaccurateestimateoftheprevalenceisnotcurrently
available.AvarietyofCAMmodalitieshavebeenstudiedforpediatricheadache:acupuncture,
homeopathy,nutritionalsupplements,vitamins,herbalpreparationsandmanualtherapies
includingosteopathyandchiropractictechniques44.Twostudieshavefoundacupuncturetobe
effectiveinpediatricmigraineprophylaxis.Inonestudy,asmallgroupofchildrenwithmigraine
wererandomizedtoacupunctureorshamacupuncture.Theacupuncturegrouphadsignificantly
greaterreductionsinthefrequencyandintensityoftheirmigraines45.Thesecondstudywasamore
recentrandomizedtrialcomparinglaseracupuncturetoshamlaseracupunctureinagroupof
childrenandadolescentswithprimaryheadaches.Thoserandomizedtolaseracupuncturehad
significantlygreaterdecreasesinmigrainefrequencyandintensityascomparedtothesham
group46.Homeopathyhasonlybeenstudiedforthisindicationinoneinstance.Amulticenter,open-
label,non-randomized,prospectivestudyassessedavarietyofindividualizedhomeopathic
remediesforthepreventionofmigrainesinchildrenaged5to15years47.Although209
participantswererecruited,only168wereincludedintheanalysesandnointention-to-treat
analyseswereattempted.Duringthefirstthreemonthsoftreatment,alloutcomeschanged
favorably.Migrainefrequency,intensityanddurationdecreasedsignificantlyovertimeandthe
percentageofchildrenwithabsenteeismfromschoolwassignificantlyreduced.However,thelack
ofacontrolgroupandthediversityoftreatmentsusedmakesitdifficulttodrawconclusionsabout
theefficacyofhomeopathyforthisindicationfromthisstudy.Althoughosteopathyhasbeen
assessedforcervicogenicheadacheinchildren,nostudieshaveexamineditspotentialefficacyfor
pediatricmigraine44.Thus,someevidenceexistsinrelationtotheefficacyofacupunctureand
7
homeopathyforpediatricmigraineprophylaxis,butotherCAMmodalitiessuchasosteopathyand
energymedicinehavenotyetbeenexploredforthisindication.
1.7. Nutraceuticalsforpediatricmigraine
Nutraceuticals,definedas“anysubstancethatmaybeconsideredafoodorpartofafoodand
providesmedicalorhealthbenefits,includingthepreventionandtreatmentofdisease”48,comprise
nutritionalsupplements,vitaminsandherbalpreparations.Avarietyofnutraceuticalshavebeen
assessedfortheprophylaxisofpediatricmigraine.Inthissystematicreview,evidencederivedfrom
eligiblerandomizedcontrolledtrialsontheefficacyofnutraceuticalsforthisindicationwillbe
reviewed.However,themagnitudeofevidencefromnon-randomizedstudiesisnotnegligible.The
mainnutraceuticalsthathavebeenstudiedforpediatricmigraineprophylaxisare:butterbur,
riboflavin,magnesium,coenzymeQ10,fishoilsandcombinationtherapies49.
1.7.1. Butterbur
Oneopen-labelstudyamongstasampleofchildrenandadolescentswithmigrainefound
Petadolex®,aformulationofbutterbur,tobeeffectiveformigraineprevention,withresults
showingthatafter4monthsoftreatmentthefrequencyofmigraineswassignificantlyreduced,
withnomajoradverseeventsreported50.
1.7.2. Riboflavin
Twonon-randomizedstudieshaveexploredthepotentialforriboflavinasaninterventionin
pediatricmigraineprevention.Inaretrospectivechartreviewinvolvingasmallseriesofchildren
withavarietyofheadachedisorders,themajorityofwhomhadmigraine,riboflavinwasfoundto
significantlydecreasemigrainefrequencyinthefirst4monthsoftreatment,butnotbeyondthat
initialtreatmentperiod51.Riboflavinwasalsostudiedretrospectivelyinagroupofadolescentswith
chronicheadaches,mostofwhomhadchronicmigraine,andwasfoundtoyieldimprovementin
73%ofthesubsetofparticipantswithchronicmigraine52.Thus,basedonnon-randomized
8
evidence,itappearsthatriboflavinisapromisingprophylactictherapyformigraineinchildrenand
adolescents.
1.7.3. Magnesium
Onlyonenon-randomizedstudyhasevaluatedmagnesiumfortheprophylaxisofpediatric
migraine.Thissmallopen-labelstudyassessedmagnesiuminavarietyofchildhoodperiodic
syndromesincludingmigraine.Overall,77.5%oftheparticipants,ofwhommosthadmigraine,had
agoodclinicalresponsewherebytheirattackswereeliminatedorreducedtolessthanonethirdof
thebaselinefrequency53.Thesizeofthestudyandheterogeneityoftheparticipantsrendersitlow
qualityevidenceforthequestionofinterest.
1.7.4. CoenzymeQ10
Onenon-randomizedstudyevaluatedtheuseofcoenzymeQ10formigraineprophylaxisina
relativelylargesampleofchildrenandadolescentswhowerefoundtobedeficientincoenzymeQ10.
Aftervariabletreatmentperiods,participantsbenefitedfromastatisticallysignificantreductionin
migrainefrequencyandmigrainedisabilityscores54.Thisstudythereforeshowspromisefor
coenzymeQ10asatargetedinterventioninpediatricmigraineprevention.
1.7.5. FishOils
Inchildrenandadolescents,onlyonestudyassessedtheefficacyoffishoilsinmigraine
preventionanditwasrandomizedbydesign55.Therefore,itwillnotbesummarizedhere.
1.7.6. L-5-Hydroxytryptophan
L-5-hydroxytryptophanisanaturallyoccurringaminoacidwithantidepressantpropertiesthat
hasalsobeenstudiedformigraine,butthereisonlyonestudythatwascarriedoutinthepediatric
populationanditwasrandomized56.Therefore,itwillnotbereviewedhere.
1.7.7. CombinationTherapies
9
Therearethreenon-randomizedstudiesontheefficacyofcombinationnutraceuticaltherapies
formigraineinthepediatricpopulation.Eachofthesestudiesassessedtheefficacyofthesame
combinationofginkgolideB,coenzymeQ10,magnesiumandriboflavinovertime57–59,withonlyone
ofthestudieshavingacomparisonintervention59:acombinationofL-tryptophan,5-
hydroxytryptophan,vitaminPPandvitaminB6.Allthreestudiesdemonstratedthatthe
combinationtherapyyieldedstatisticallysignificantdecreasesinmigrainefrequencyovertime,and
thestudywithacomparisongroupdemonstratedthattheginkgolide-containingcombination
therapywassuperiortothealternatetherapy.Therefore,thiscombinationofginkgolideB,
coenzymeQ10,magnesiumandriboflavinmaybeeffectiveforthepreventionofmigrainesin
childrenandadolescentsbasedonnon-randomizedpreliminaryfindings.
1.8. PharmaceuticalsforPediatricMigraine
Ahostofpharmaceuticalmedicationshavebeenstudiedforpediatricmigraineprophylaxis.In
thissystematicreview,wewillsummarizetheevidencefromeligiblerandomizedcontrolledtrials
forpharmaceuticalagentsinpediatricmigraineprophylaxis.However,manynon-randomized
studiesalsoexist.Here,abriefoverviewofthenon-randomizedliteratureinthisareawillbe
provided.
1.8.1. AntiepilepticMedications
Topiramateisoneofthebest-studiedmedicationsformigraineprophylaxisinbothadultsand
children.Theefficacyandsafetyoftopiramateforthepreventionofmigrainesinchildrenand
adolescentshasbeenassessedinfournon-randomizedstudies.Threeretrospectivechartreviews
havebeencarriedout.Twoofthechartreviewsdidnothaveacomparisongroup,andfoundthat
overtime,topiramateyieldedsignificantreductionsinmigrainefrequencyandotherheadache
parameters60,61.Theotherretrospectivestudycomparedtopiramateprophylaxistoflunarizine
prophylaxisinarelativelylargegroupofpediatricpatients,andfoundthatbothinterventions
10
resultedinreductionsinmigrainefrequency,withnosignificantgroupdifferencesnoted62.One
prospectiveopen-labelstudyevaluatedtheefficacyoftopiramateinthepreventionofmigrainesfor
childrenwithmigrainesrefractorytoothertreatments.Thissmallstudy,whichincludedonly24
participants,didnotyieldanysignificantdifferencesinmigrainefrequencyovertime,though
migraineseverityandassociatedsymptomsdidsignificantlyabatewithtopiramate63.Adverse
eventsratesvariedbetween10%and33%inthesefourstudies,withthemostcommonsideeffects
reportedbeingweightchanges,anorexia,cognitivesideeffects,paresthesiasanddrowsiness60–63.
Evidencefromnon-randomizedstudiesthereforesupportstheefficacyandtolerabilityof
topiramatefortheprophylaxisofpediatricmigraine.
Valproicacidhasalsobeenfrequentlystudiedasapotentialinterventionforthepreventionof
migrainesinthisagegroup.Thenon-randomizedliteratureonvalproicacidasaprophylacticagent
forpediatricmigraineiscomprisedoffivestudies.Twoofthesestudieswereretrospectivechart
reviews,encompassingatotalofonly67patients64,65.Bothofthesestudieshintedatafavorable
responsetodivalproex,whichistheenteric-coatedcounterpartofvalproicacid.Theotherthree
non-randomizedvalproicacidstudieshadopen-labelprospectivedesigns,withamuchlarger
numberofparticipants:intotal,368childrenandadolescentswithmigrainewereincludedinthese
studies66–68.Oneofthestudiesdidnotassessefficacy,butonlysafetyandtolerabilityofdivalproex
forthisindication67.Thetwostudiesthatreportedonefficacyfoundthatdivalproexandsodium
valproatebothsignificantlydecreasedmigrainefrequencyovertimeandleadtoimprovementin
otherclinicaloutcomes66,68.Thesafetystudyuncoveredahighrateofsideeffects:88%ofthe
participantsreportedatleastonesideeffect,withthemostcommonbeingweightgain,nausea,
somnolenceandupperrespiratorytractinfections.Fiveseriousadverseeventswerereported,of
whichonlyone,hyperammonemia,wasdeemedrelatedtodivalproexsodiumextended-release.
Theinvestigatorsalsofoundthat,overall,ammonialevelsincreasedduringtreatment66.Theother
studiesreportedsimilarsideeffectprofilesandoverallratesofsideeffectsbetween48and84%64–
11
66,68.Basedonthisnon-randomizeddata,itisevidentthatvalproicacidmightbeeffectivefor
pediatricmigraineprophylaxis,butthatitisassociatedwithasignificantrateofsideeffects,notto
mentionitsquestionableuseinteenagedfemalesgivenitsknownteratogeniceffects,whichhas
leadtorecommendationstoavoiditsuseinwomenofchildbearingpotentialwheneverpossible69.
Althoughtraditionally,theonlytwoantiepilepticmedicationsthathavebeencommonlyused
clinicallyandstudiedforpediatricmigraineprophylaxisaretopiramateandvalproicacid,interest
inthepotentialuseoflevetiracetamforthisindicationisemerging.Twoverysmallstudies
prospectivelyassessedtheefficacyandsafetyoflevetiracetamforpediatricmigraine70,71.Migraine
frequencydecreasedsignificantlyovertimeinbothstudiesandtolerabilitywasfavorable.Ineach
study,approximately10%ofthepatientsexperiencedbehavioralorpsychiatricadverseevents,
whichhavebeenwelldocumentedwiththismedication.Moreevidenceisrequiredpriorto
drawingconclusionsabouttheefficacyandsafetyoflevetiracetamforthepreventionofmigraines
inpediatrics,butthepreliminary,verylimiteddataispromising.
1.8.2. Calcium-ChannelBlockersandBeta-Blockers
Threemedicationsclassifiedascalcium-channelblockers,flunarizine,nimodipineand
cinnarizine,andtwomedicationsclassifiedasbeta-adrenergicblockers,propranololandtimolol,
havebeenstudiedinthispopulation.Infact,propranololwasthemostcommonlyprescribed
migraineprophylacticmedicationamongstagroupofUSpediatriciansbasedinMichiganina
surveyonpediatricmigrainemanagementpatterns72.
Threenon-randomizedstudieshavelookedatflunarizineasaprophylacticagentforpediatric
migraine.Oneofthestudieswasarelativelylargeretrospectivechartreview62,andtwoofthe
studiesweresmall,prospective-openlabelstudies73,74.Theretrospectivestudycomparedthe
efficacyofflunarizinetothatoftopiramatein261childrenandadolescentswithmigraineand
foundnodifferenceinresponderratescomparingthetwomedications;bothgroupshadfavorable
responses62.Bothoftheprospectivestudiesfoundpreliminaryevidencefortheefficacyof
12
flunarizineinpediatricmigraineprophylaxis:inonestudy,66%ofthepatientsimproved74,andin
theotherstudy,allpatientshadsomeresponsetoflunarizine73.Intwoofthestudies,noadverse
eventswerereported73,74.Intheretrospectivestudy,6%oftheparticipantstakingflunarizine
reportedadverseevents,withweightgain,drowsinessanddizzinessbeingthemostcommon.Thus,
flunarizinedoesappeartohavesomepotentialforpediatricmigraineprophylaxisbasedonnon-
randomizedevidence.Nimodipineandcinnarizehavenotbeenassessedinanynon-randomized
studiesinthispopulation.
Theliteratureisdevoidofevidencefromnon-randomizedstudiesfortheuseoftimololin
pediatricmigraineprophylaxis.Onenon-randomizedstudy,witharetrospectivechartreview
design,assessedtheefficacyofpropranololforthepreventionofmigrainesinasampleofchildren
andadolescents.Inthisstudy,bothpropranololandamitriptylineyieldedsignificantresponder
rates,withnodifferencesbetweenthegroupsexceptforhigherratesofsideeffectsreportedinthe
amitriptylinegroup75.Thisonestudythereforesupportstheuseofpropranololinthispopulation.
1.8.3. Antidepressants
Amitriptylineandtrazadonearethetwoantidepressantsthathavebeencommonlyusedand
studiedforthepreventionofmigrainesinthepediatricagegroup.Infact,inmanycenters,
practitionersuseamitriptylineasafirstlinepharmacologicprophylacticagentforthisindication76.
Tworetrospectivechartreviews75,76andoneprospective,open-labelstudy77haveexploredthe
efficacyandsafetyofamitriptylineforpreventionofmigrainesinchildrenandadolescents.Both
retrospectivestudiesfoundfavorableefficacyresultsforamitriptyline:oneofthestudies
demonstratedthat89%ofparticipantshadapositiveresponsetoamitriptylinewithasignificant
decreaseinmigrainefrequency76andtheotherfoundthatbothamitriptylineandpropranolol
yieldedsignificantdecreasesinmigrainefrequencyovertime75.Migrainefrequencydecreased
significantlyand84.2%ofchildrendemonstratedimprovementintheirheadacheswith
amitriptylineprophylaxisintheprospectivestudy77.Althoughtwoofthesestudiesdidnotreport
13
onsideeffects,oneofthestudiesfoundthatamitriptylineresultedinhigheradverseeventrates
thanpropranolol,withweightgain,fainting,drowsinessandtremorbeingthemostcommonly
reportedsideeffects75.Evidencefromnon-randomizedtrialssupportsthecurrentwidespreaduse
ofamitriptylinetopreventmigrainesinchildrenandadolescents.Therearenonon-randomized
studiesthathaveexploredtheefficacyoftrazadoneforthisindication.
1.8.4. Antiemetics
Severalantiemeticsmightbeusefulinpediatricmigraineprophylaxis:domperidone,
metoclopramideandcyproheptadine.Domperidoneandmetoclopramidehavenotbeenassessedin
anynon-randomizedstudies.Theefficacyofcyproheptadineforpediatricmigraineprophylaxishas
onlybeentestedinonenon-randomizedstudy.Aretrospectivechartreviewshowedthat
cyproheptadinesignificantlyreducedmigrainefrequencyandwasassociatedwithan83%
responserateinasmallsampleofpediatricmigraineurs76.Cyproheptadinewasassociatedwith
sedationandincreasedappetite,thoughtheproportionofpatientswithsideeffectswasnot
specified.Thus,thereislittleevidencefromnon-randomizedstudiestoassesstheuseof
antiemeticsinpediatricmigraineprophylaxis.
1.8.5. Others
Thereareseveralotherpharmacologicagentsusedinthiscontextbeyondthosedescribedin
theclassesabove:Botox,clonidine,papaverineandpizotifen.Twochartreviewsretrospectively
evaluatedtheefficacyandsafetyofOnabotulinumtoxinA(Botox)forthepreventionofchronic
headaches,includingchronicmigraine.Onesmallretrospectivecaseseriesof6adolescentswith
chronicheadachesfoundthatallpatientsrespondedtoBotoxinjectionsgivenevery3months,with
threepatientsreportingtransientsideeffects:ptosis,neckinjectionsitehematomaandburningat
injectionsites78.ThesecondretrospectivestudyassessedtheefficacyofBotoxin45childrenand
adolescentswithchronicheadaches.Therewasastatisticallysignificantdecreaseinmigraine
14
frequencywiththeinjections.Sevenpatientshadadverseevents,includingpainattheinjection
sites,eyelidinflammation,eyelidpainandneckandshouldermyalgias79.Inadditiontothese
studies,thereisarandomizedcontrolledtrialcurrentlyunderwaythataimstoassesstheefficacy
andsafetyofBotoxformigrainepreventioninadolescentswithchronicmigraine(clinicaltrials.gov
identifier:NCT01662492)80.Basedonthislimitedretrospectiveevidence,thereispromisefor
Botoxinpediatricchronicmigrainepreventionandresultsfromtherandomizedstudywillaidin
assessingitsefficacymoredefinitively.
Clonidinehasbeenusedformigraineprophylaxisinthepast,buthasfallenoutoffavorbothin
theclinicalandresearchcommunitiesinthelastcoupleofdecades.Ithasonlybeenassessedinone
non-randomizedstudyinthepediatricpopulation.Aprospectiveopen-labelpilotstudyamongst
childrenwithmigrainerevealedthat50%ofparticipantshadmeaningfulreductionsintheir
migrainefrequencies,with40%benefitingfromcompleteandlastingremissionfromtheir
headaches81.Inthisgroupof50children,sixdevelopedsideeffects:threerasheswerereported,
twochildrenhaddrowsinessandonechildhadcontinuousheadaches.Thereislittleevidenceto
supporttheuseofclonidineforpediatricmigraineprophylaxis,thoughthisonestudydoessuggest
somepotential.
Papaverineandpizotifenhavenotbeenassessedinnon-randomizedstudiesthisindication.
1.9. Conclusions
Asisevidencedfromtheoverviewabove,thereisawiderangeoftherapeuticoptionsfor
pediatricmigraine,noneofwhichhavebeenparticularlyrigorouslyorwellstudied.Mostofthe
evidenceforpediatricmigraineinterventionsisderivedfromlowquality,non-randomizedstudies.
Pharmaceuticalsremainthemainstayofallopathicmedicaltreatmentsofferedbypractitioners
lookingafterchildrenandadolescentswithmigraine.However,nutraceuticalsareanimportant
partofthegrowingCAMmovement,whichcurrentlyrepresentsamultibilliondollarperyear
industryintheUS40.InoneItalianstudy,76%ofchildrenandadolescentsinatertiarycare
15
headacheclinicwereusingherbaltherapiesand40%wereusingvitaminandmineralsupplements
fortheirheadaches42.IntheUS,30%ofchildrenwithheadachesreportedusingCAMtherapies,
includingnutraceuticals,intoanationallyrepresentativesurvey82.Thus,nutraceuticalsare
increasinglypopular,andthisiscompellingpractitionersofallopathicmedicinetoeducate
themselvesaboutnutraceuticaloptions.
Inthissystematicreview,wewillaimtosummarizetheevidencefromthehighestquality
randomizedstudiesfortheefficacyandsafetyofpharmaceuticalandnutraceuticaloptionsinthe
prophylaxisofpediatricmigraine.
2. METHODS
2.1. Objectives
Theprimaryobjectiveofthissystematicreviewistosummarize,evaluateandquantifythe
evidencefortheefficacyofnutraceuticalandpharmaceuticalinterventionsintheprophylaxisof
pediatricmigraine.
Thesecondaryobjectiveofthissystematicreviewistosummarize,evaluateandquantifythe
evidenceforthesafetyandtolerabilityofnutraceuticalandpharmaceuticalinterventionsinthe
prophylaxisofpediatricmigraine.
2.2. StudyDesign
Themethodologyfollowedinthissystematicreviewadherestotheguidelinessetoutinthe
CochraneCollaboration’sHandbookforSystematicReviewsofInterventions83.Thismethodological
approachiscomplimentedbyconsiderationoftheGuidelinesforControlledTrialsofDrugsin
Migraine,whichweredevelopedin2012bytheInternationalHeadacheSociety,theleading
authorityonprimaryheadaches84.Stipulationsintheseguidelineswereusedtorefinetheeligibility
criteriaforstudiesinthissystematicreview.Thegoalofusingtheguidelinestoestablisheligibility
16
criteriawastoensurethatonlythemostmethodologicallyrigorousrandomizedstudieswouldbe
includedinthisreview,soastomaintainasummaryofthehighestqualityofevidence.
Inadditiontothesystematicreview,meta-analyseswerecarriedoutonbodiesofevidencethat
wereamenabletopooling.Again,themethodologylaidoutintheCochraneHandbookisadheredto
forthepurposesofthemeta-analyses.
2.3. CriteriaforConsideringStudiesforthisReview
2.3.1 TypesofStudies
Theaimofthissystematicreviewistosummarizethehighestqualityevidencefortheefficacy
andsafetyofprophylacticnutraceuticalandpharmaceuticalpediatricmigraineinterventions.In
ordertolimitincludedstudiestothoseofhighmethodologicalquality,onlyrandomized,placebo-
controlledtrialswereconsidered.Parallel-groupandcross-overdesignswereeligible.Inorderto
complywiththerecommendationssetforthintheInternationalHeadacheSocietyGuidelinesfor
ControlledTrialsofDrugsinMigraine84,cross-overstudieswererequiredtohaveaminimum
washoutperiodof4weeksbetweenstudyinterventions.Thepurposeofsettingaminimum
washoutperiodwastoavoidtheinclusionofstudieswithbiasedresultsduetocarry-overeffects.
Theunitofrandomizationwasrequiredtobetheindividualandcluster-randomizedtrialswere
excluded.Limitingeligiblestudiestothoserandomizedbyindividualreducesthechanceof
selectionbias,whichisoftenasignificantproblemwithclusterrandomizedtrials85.
Inordertominimizeperformancebias,includedstudieswererequiredtoblindparticipants,
suchthateithersingle-blindordouble-blindtrialswereeligible.Unblindedstudieswereexcluded.
2.3.2 TypesofParticipants
Onlystudieslimitedtopediatricpatients,aged18yearsandunder,wereincluded.Studiesthat
includedadultswereconsideredonlyifresultsofasubgroupanalysisonpatientsundertheageof
18yearswereavailable.Participantswererequiredtohavemigraineorasubtypeofmigraine(eg.
17
migrainewithaura,chronicmigraine,probablemigraine)asperasetofvalidatedcriteria.The
threemostcommonlyusedmigrainecriteriainthepediatricliteraturearetheInternational
ClassificationofHeadacheDisorders(ICHD)criteria,nowintheirthirditeration86,theAdHoc
criteria87andtheVahlquistcriteria88;thelattertwosetsofcriteriaweremostlyusedpriortothe
firstiterationoftheICHDcriteriain1988.Currently,theICHDcriteriaareconsideredthegold
standardforthediagnosisofmigraine.TheICHDandVahlquistcriteriahavebothbeenshowntobe
valid89andthetwosetsofcriteriaareconsistentwithanoverallkappaof0.57reportedinone
pediatricstudy90.TheAdHoccriteriawerecreatedin1962andareconsideredtobethe
predecessoroftheICHDcriteria87.AlthoughtheyaremorevaguethantheICHDcriteria,oneadult
studyshowedthattheAdHoccriteriaagreedwiththeICHDcriteria91.7%ofthetime91,indicating
highconsistencybetweenthetwoclassificationsystems,andsupportingthevalidityofusingtheAd
HoccriteriaagainstthegoldstandardoftheICHDcriteria.Therehasalsobeenapediatricstudy
publishedthatfoundremarkableconsistencyinmigraineprevalenceratesregardlessofwhether
theICHD,AdHocorVahlquistcriteriawereusedfordiagnosis,especiallyinthecaseofmigraine
withoutaura92.Therefore,studiesusingICHD,VahlquistorAdHoccriteriawereeligible,andother
criteriahadtobevalidatedinordertobeconsideredforinclusion.
2.3.3. TypesofInterventions
Asisdescribedindetailintheintroduction,thereisawidevarietyofinterventionsaimedat
preventingmigrainesinchildrenandadolescents.Inordertolimitthescopeofthisreview,only
pharmacologicandnutraceuticalinterventionswereincluded.Pharmacologicinterventionsfor
pediatricmigraineprophylaxisaremedicationsusedinallopathicmedicinethatfallintoavarietyof
categories,listedabove(ie.antiepilepticmedications,antidepressants,etc).Asdescribedabove,
nutraceuticalsarefoodderivativesthatareusedformedicalpurposesandhavebeendefinedas:
“anysubstancethatmaybeconsideredafoodorpartofafoodandprovidesmedicalorhealth
benefits,includingthepreventionandtreatmentofdisease”48.Interventionsfallingoutofthescope
18
ofpharmaceuticalsornutraceuticals,suchaslifestyleinterventionsandpsychologicaltreatments,
wereexcluded.
2.3.4 TypesofComparisons
Allincludedstudieswererequiredtohaveatleastonestudyarmcomprisingaplacebocontrol.
Theplacebocontrolisnecessarygiventhatnoneoftheseinterventionshavebeenadequately
studiedandthereforeassaysensitivitymustbeestablished.Inaddition,theInternationalHeadache
SocietyGuidelinesforControlledTrialsofDrugsinMigraine84statethatprophylactictrialsfor
migraineshouldincludeaplacebocontrolandtheyspecifythatevenstudieswithactive
comparatorsshouldincludeaplaceboarm.
Norestrictionswereplacedonactivecomparators:anytypeofactivecomparatorwaseligible
aslongastherewasalsoaplacebocomparatorarm.
2.3.5 TypesofOutcomes
Studieswerenotexcludedbasedonoutcomes.TheCochraneCollaborationrecommendsthat
priorityoutcomesbeestablishedbutstates:“reportingofoutcomesshouldrarelydetermine
eligibilityofstudies”83.Forthepurposesofthisreview,anytrialwithanoutcomepertainingto
migraineprophylaxiswaseligibleforinclusion.Theprimaryoutcomeofinterestrelatestomigraine
frequency.TheInternationalHeadacheSocietyGuidelinesforControlledTrialsofDrugsin
Migraine84stipulatethattheprimaryoutcomeinmigraineprophylaxistrialsshouldbethe
differencebetweenmigrainefrequencyattheendoftreatmentorthroughouttreatmentand
migrainefrequencyatbaseline.Thus,whenavailable,thisoutcomewashighlightedandusedfor
poolingtheresultsinmeta-analyses.
2.3.6 LanguageofStudies
19
Eligibilityofthestudieswasnotrestrictedbylanguageofpublication.Articlesdeemed
potentiallyeligibleandwritteninlanguagesotherthanEnglishorFrenchweretranslatedto
Englishandincludediftheymetalleligibilitycriteria.
Table1.Eligibilitycriteriaforstudies
ComponentofStudy InclusionCriteria ExclusionCriteriaStudytype • Randomizedat
individuallevel• Parallel-groupdesign• Crossoverdesignwith
minimumwashoutperiodof4weeks
• Singleblind• Doubleblind
• Non-randomized• Clusterrandomized• Crossoverdesignwith
washoutperiodlessthan4weeks
• Unblinded
Participants • Aged18yearsorless• Migraineormigraine
subtypeasperICHDcriteria,Vahlquistcriteriaorothervalidatedcriteria
• Studieswithparticipantsover18yearswithnosubgroupanalysisonthoseunder18years
• Non-migraineheadaches
• Migrainediagnosedwithunvalidatedcriteria
Interventions • Pharmaceuticalinterventions
• Nutraceuticalsinterventions
• Lifestyleinterventions• Psychological
interventions• CAMinterventions
otherthannutraceuticals(eg.acupuncture)
Comparisons • Placebo• Activecomparatorif
placeboarmincluded
• Activecomparatorifnoplaceboarm
Outcomes • Oneoutcomemustpertaintomigraineprophylaxis
• Primaryoutcomeofinterestischangeinmigrainefrequencyovertreatmentperiod
• Nooutcomesrelatingtomigraineprophylaxis
2.4. SearchMethodsforIdentificationofStudies
20
Thefollowingdatabasesweresearched:MEDLINEincludingIn-Process&OtherNon-Indexed
Citations(1946-May19,2015),Embase(1947toWeek20,2015)andCochraneCentralRegisterof
ControlledTrials(CENTRAL,April2015).AllweresearchedusingtheOvidinterface.TheMEDLINE
searchstrategywasdevelopedbyalibrarianexperiencedinsystematicreviewsearching(Margaret
Sampson),andpeerreviewedbyanotherlibrarian(JanetJoyce),usingthePRESSstandard93.The
MEDLINEsearchwasthenadaptedfortheotherdatabases.Nolanguagelimitswereappliedbutthe
searchwaslimitedtorandomizedcontrolledtrialsandthepediatricagegroupusingvalidated
filters.Includedreferencelistswerescreenedforadditionalreferences.Thedetailedelectronic
searchstrategiesarepresentedinAppendixA.
Aswell,theInternationalClinicalTrialsRegistryPlatformSearchPortalandClinicalTrials.gov
weresearchedonJuly2nd2015forongoingorrecentlycompletedtrials.Authorsofpotentially
eligibleunpublishedtrialswerecontactedinordertoinquireabouttimingofmanuscript
publicationandaccesstotheunpublisheddata.
2.5. ScreeningProcess
2.5.1 FirstScreenMethodology
Twoscreeners(SerenaOrrandSuzanneNadineChristie)completedthefirsteligibilityscreen.
ThesearchresultswereuploadedintotheAbstrackrsoftware,whichwasusedtofacilitatethefirst
screenofstudies.Abstrackrisanopen-sourcedweb-basedapplicationavailabletousersatno
charge94.Itisdesignedtoassistresearchersintheprocessofscreeningreferencesforasystematic
review.ReferencesareuploadedtoAbstrackrandmultiplescreenerscanthenusetheapplication
torapidlyandefficientlyscreenthetitlesandabstractsresultingfromthesearch.Thistoolallows
userstokeeptrackofeligibilitydecisionsmadeduringthefirstscreen.Eachreferencecanbe
assignedadescriptivetagthatsummarizeswhyaparticulareligibilitydecisionwasmadeaboutthe
givenstudy(eg.excludedbecausenotrandomized).Abstrackrstoresalleligibilitydecisionsand
21
tags,andtheresultsofthescreencanbeexportedoncecomplete.Inaddition,theapplicationwill
automaticallyidentifyconflictsbetweenscreenersinregardstoeligibilitydecisionsandallows
userstoenteradecisionreconciliationmodewhereconflictscanberesolved.Anotherfeaturethat
allowsAbstrackrtomaximizescreeningefficiencyisitsabilitytohighlightkeywordsinabstracts
andtitles.Userscandefinekeywordsthatindicateeitherweakorstrongpotentialforinclusionor
exclusion.Abstrackrwillsearcheachsubsequentreference’stitleandabstractforthesekeywords,
highlightingwordsassociatedwithinclusioningreenandwordsassociatedwithexclusioninred.
2.5.2 SecondScreenMethodology
AfterthefirstscreenwascompleteinAbstrackr,twoscreeners(SerenaOrrandSuzanne
NadineChristie)undertookthesecondeligibilityscreen.Mendeleywasusedtomanagethesecond
eligibilityscreen.Mendeley(www.mendeley.com)isafreereferencemanagerthatallowstheuser
touploadreferenceswithPortableDocumentFormat(PDF)filesintotheapplication,organizethe
referencesintofolders,highlightandannotatethePDFfilesandcreategroupswherereferences
canbesharedbetweenusers.
Forthepurposesofthisreview,oncethefirsteligibilityscreenwascompleteinAbstrackr,the
referenceswereuploadedtoMendeley.ResultsoftheAbstrackrscreenwereexportedintoanExcel
file.EligibilitydecisionsandtagsintheExcelfilewerereviewedandusedtoorganizethe
referencesintofoldersinMendeley.Allreferencesthatpassedthefirsteligibilityscreenwere
includedinthesecondscreenandtheirassociatedPDFfileswereuploadedintoMendeley.ThePDF
fileswerereadduringthesecondscreeninordertomakefinaleligibilitydecisions.Eligibility
decisionswererecordedbyorganizingthefilesintofolders(eg.“includedaftersecondscreen”,
“excludedaftersecondscreenbecausemigrainecriterianotvalidated”,etc).Conflictsbetweenthe
twoscreenerswereresolvedinaconsensustelephonemeeting,heldonJanuary4th2016,onceboth
screenershadcompletedthesecondscreen.
22
2.6. DataExtraction
Foreachincludedstudy,aneligibilityscreeningformwascompletedinordertoensurethatthe
studyindeedmetallinclusioncriteriaandnoneoftheexclusioncriteria(seeAppendixB).
Datafromincludedstudieswereextractedusingastandardizedformcalledthe“Characteristics
ofStudiesTable”(seeAppendixC),whichwasmodeledbasedontherecommendedformatinthe
CochraneHandbook83.The“CharacteristicsofStudiesTables”areorganizedintofivesections
designedtocomprisetheentiretyofthemostpertinentdatafromeachstudy:methods,
participants,interventions,outcomesandnotes.Inthe“Methods”section,thedesignofthetrial
wasdescribed,includingwhetherthestudywasparallel-grouporcrossover,howmanystudyarms
wereincluded,theblindingstatusofthestudyanddetailsonrecruitmentandstudyduration.The
“Participants”sectionprovideddetailsaboutthenumberofparticipantsandthemostimportant
definingcharacteristicsoftheparticipantpopulation,thatistheageoftheparticipants,the
migrainedefinitionusedinthestudy,thedurationandfrequencyofthemigrainesatbaselineand
whetherornotimportantgroupdifferencesexistedintermsofbaselinecharacteristicsinthe
interventiongroups.Theactiveintervention(s)andplaceboarmweredescribedindetailinthe
“Interventions”sectionofthetable,wherebythenumberofparticipantsassignedtoeachgroup
wasgiven,inadditiontothename,route,dose,frequency,andifavailable,theappearanceand
smellofeachintervention.Theprimaryandsecondaryoutcomes,aswellastheadverseevents,
weredescribedindetailinthe“Outcomes”section,withpointestimates,varianceestimates,and
testsofsignificancereportedfortheprimaryoutcomewhenavailable.The“Notes”sectionwas
usedtodocumentparticularitiesaboutthestudyinquestionthatmayimpactinterpretationofits
results,thequalityratingofthestudyandanyothersalientdetails.
Qualityratingswerecompletedoneachstudy.The“CochraneRiskofBiasTool”isatoolthat
wasdevelopedbytheCochranecollaborationtomakeadeterminationontheinternalvalidityofa
particularstudy83.Inthissystematicreview,the“CochraneRiskofBiasTool”wasusedtomake
23
determinationsabouttheriskofbiasinsixdifferentdomains(seeAppendixD):selectionbias
(randomsequencegenerationandallocationconcealment),performancebias(blindingof
participantsandpersonnel),detectionbias(blindingofoutcomeassessmentforself-reportedand
objectiveoutcomes),attritionbias(incompleteoutcomedata),reportingbias(selectivereporting)
andotherbias.Eachdomainwasgivenariskofbiasratingbasedontheinformationinthe
manuscript:1)“highriskofbias”whenthemethodusedclearlycouldhaveledtobiasedresults,2)
“unclearriskofbias”whenthemethodusedwasinadequatelydescribedtomakeajudgmentonthe
qualityrating,3)“lowriskofbias”whenthemethodusedwasadequateandtheriskofbiasforthat
domainwasconsideredtobenegligible.InaccordancewiththeCochraneguidelines83,astudywas
givenanoverall“highriskofbias”ifatleastonedomainwasratedashavinga“highriskofbias”,
whereasthequalityratingwas“unclearriskofbias”ifatleastonedomainwasratedashavingan
“unclearriskofbias”andtherewerenodomainswith“highriskofbias”,andastudyhadtohave
“lowriskofbias”throughoutalldomainsinordertobegivenanoverallratingof“lowriskofbias”.
2.7. Meta-Analyses
Whenseveralstudieswereavailableforoneintervention,theoutcomesineachstudywere
reviewedindetail.Wheregroupsofstudieshadoverlapinoutcomeswithsufficientdataavailable
forpoolingtheresults,ameta-analysiswasconsidered.Meta-analyseswerecarriedoutif:1)
outcomesoverlappedasabove,2)theinterventionswerethesame,2)thecomparatorswerethe
same(ie.placebo),3)thestudieswerenotexcessivelyclinicallyheterogeneous.Ifastudywithin
oneinterventioncategorywaslackingtheoutcomeusedtopoolthedataorlackingcomponentsof
thedatanecessaryforthemeta-analysis,theauthorswerecontactedinordertorequestthe
missingdata.Uptothreeattemptsweremadetocontactauthorstoobtainsupplementaldata.Ifthe
authorsdidnotrespondorwereunwillingtosharethedata,thenthestudyinquestionwas
excludedfromthemeta-analysis.
24
Allmeta-analyseswerecarriedoutusingtheCochraneCollaborations’ReviewManager5.3.5
software(RevMan:http://tech.cochrane.org/revman).RevManisasoftwarepackageendorsedby
theCochraneCollaborationthathastheabilitytoconvertrawdatafromagroupofstudiesinto
pooledestimatesofeffectsusingavarietyofstatisticaltechniquesformeta-analysis.Therawdata
forthemeta-analyseswereentereddirectlyintoRevManandappropriateanalysisoptionswere
selecteddependingontheoutcomeinquestionandthecharacteristicsofthestudiesbeingpooled.
Alloutcomesamenabletopoolingwerecontinuousandthuspointestimates,standard
deviationsandsamplesizeswereenteredforeachstudy’sinterventionandcomparator.Ifthescale
usedtomeasurethecontinuousoutcomewasidenticalacrossstudies,thenanestimateofthemean
differencewith95%confidenceintervals(CI)wasgenerated.Ifthescaleusedtomeasurethe
continuousoutcomewasdifferentacrossstudies,thenanestimateofthestandardizedmean
differencewith95%CIwasgenerated.Arandomeffectsinverse-variancemethodwasusedasthe
defaultmodeltogenerateestimatesofthemeandifferenceorstandardizedmeandifference.In
decidingbetweenusingafixedorarandomeffectsmodel,statisticalandclinicalheterogeneityof
thestudieswereconsidered,withclinicalheterogeneitybeinggivengreaterweightinthedecision.
Statisticalheterogeneitywasassessedusingtwostatistics:1)thechisquaretestofheterogeneity,
wherethebodyofevidencewasdeemedstatisticallyheterogeneousifthepvaluewaslowerthan
0.1and,2)theI2statistic,wherestatisticalheterogeneitywasdefinedasanI2inexcessof30%.
Eachofthesedefinitionsofstatisticalheterogeneitywaschosenbasedonrecommendationsinthe
CochraneHandbookforSystematicReviewsofInterventions83:1)thep=0.1cutoffisrecommended
forthechisquaretestofheterogeneitygiventhelackofpowerofthetesttodetectstatistical
homogeneitywiththetypicalsmallsamplesizesseeninmeta-analyses,2)the30%cut-offfortheI2
statisticwaschosenbasedonthecut-offformoderateheterogeneitylistedintheHandbook.Inno
casewerethedatafrompooledstudiesconsideredclinicallyhomogeneousenoughtojustifyusinga
fixedeffectsmodel.
25
3. RESULTS
3.1. CharacteristicsofIncludedStudies
ThePRISMAdiagraminFigure1illustratestheresultsofthesystematicreviewthrougheach
stageofscreening.Intotal19articleswereeligibleforinclusion,comprising27studies.Detailson
eachstudyaresummarizedinTable2.Twelveinterventionswerereviewedinthesestudies:
butterbur,riboflavin,topiramate,valproicacid,flunarizine,timolol,clonidine,trazadone,
nimodipine,cinnarizine,dimethothiazineandpapaverine.Allofthestudieshadaplacebo
comparator,andthreeofthestudieshadanotherarminvolvinganactivecomparator.Fiveofthe
studieshadacrossoverdesign,andtheremainingarticlesreportedonparallel-grouptrials.Twoof
thearticlescomprisedpooledanalysesfromgroupsoftrials.TwelveofthearticlesusedICHD
criteria,fiveusedVahlquistcriteriaandtwousedAdHoccriteriatodiagnosemigraine.Outcomes
variedsignificantlybetweenstudies,renderingitachallengetopooldataintometa-analyses.
Sevenofthestudiesweregivenahighriskofbias,eightofthestudieshadanunclearriskofbias
andfourstudieshadalowriskofbias.Theoverallriskofbiasforthisbodyofliteratureis
summarizedinFigure2andtheriskofbiasresultsforeachindividualstudyaredisplayedinFigure
3.
26
Figure1.PRISMADiagram
Table2.Summaryofincludedstudies
Intervention Study Design Participants Interventions Efficacy Safety RiskofBias
Butterbur Oelkers-Ax2008
Randomized,partlydouble-blind,3-arm,parallel-grouptrialwith12weektreatmentphaseand8weekfollow-upphase
39childrenaged8-12yearswithmigraineasperICHDcriteria
20randomizedtoPetadolex®50mg/dayif8-9yoor50mgbidif10-12yo(doseincreasedto75mg/dayor75mgbidrespectivelyPRNat8weeks)vs.19randomizedto
Allthreegroupshadasignificantreductioninheadachefrequencywithmusicsuperiortoplaceboatpost-treatment(p=0.042)andbothmusicandPetadolex®superiortoplaceboat6mthfollow-up
Petadolex®groupreportedGIsymptoms,allergicsymptomsanddermalsymptoms;nosignificantdifferences
High
27
placebovs.24randomizedtomusictherapy
comparingthegroups
Riboflavin Bruijn2010
Randomized,double-blind,crossoverstudywith4weekbaseline,12weektreatment,4weekwashoutandsecond12weektreatmentperiod
42childrenaged6-13yearswithmigraineasperICHDcriteria
20randomizedtoriboflavin50mgdailyforthefirstperiodvs.22randomizedtomatchedplaceboforthefirstperiod
Nogroupdifferencesintermsofthechangeinmigrainefrequency(p=0.44)
Noadverseeventsineithergroup
Unclear
MacLennan2008
Randomized,double-blind,2-arm,parallel-grouptrialwith4weekbaselineperiodand12weektreatmentperiod
48childrenaged5-15yearswithmigraineasperICHDcriteria
27randomizedtoriboflavin200mgdailyvs.21randomizedtoplacebo
Nodifferenceintheproportionofparticipantsachievinga50%+reductioninmigrainefrequency:thetrialwasstoppedearlyduetolowlikelihoodofdetectingadifference
Oneparticipantonriboflavinhadanincreaseinthenumberoftensionheadaches,4childrentakingriboflavinhadachangeintheirurinecolor
Low
Topiramate Ford2014 Pooledanalysisofpediatricdatafrom5differentrandomized,double-blind,placebo-controlled,parallel-grouptrialswithtreatmentperiodsrangingfrom16-26weeks
309childrenaged6-17yearswithmigraineasperICHDcriteria
Thenumberofpatientsrandomizedtoeachgroupisnotgiven:somewererandomizedtotopiramate2-3mg/kg/day,50mgdaily,100mgdailyor200mgdaily,somewererandomizedtoplaceboandonestudyhadanactivecomparatorarminvolvingpropranolol160mgdaily
Intermsofthe%reductioninmigraines:inTOPMAT-MIG3006thetopiramate100mgdailywassuperiortoplacebo(p=0.0164);inCAPS-122thetopiramateandplacebogroupsdidnotdiffer;inTOPMAT-MIGR-001/002/003therewasatrendtowardstopiramate100mgdailybeingsuperiortoplacebo
Somepatientsinthetopiramategroupsreportedinfluenza-likesymptoms,languageproblemsandparesthesias
Unclear
Lakshmi2007
Randomized,double-blind,placebo-controlled,2-arm,parallelgroupstudy
44childrenaged8-14yearswithmigraineasperICHDcriteria
22randomizedtotopiramate25mgdailywithweeklyincreasesof25mgtoamax
Thetopiramategrouphadagreaterdecreaseinmigrainefrequencyfrombaselinetotheendofthestudy
Moreadverseeventswithtopiramatewithmost
Low
28
with4weektitrationperiodand12weekmaintenanceperiod
of50mgbidvs.22randomizedtoplacebo
(from16.14+9.35to4.27+1.95vs.from13.38+7.48to7.48+5.94,p=0.025)
commonbeing:weightloss,lossofappetite,paresthesiasandlackofconcentrationinschoolbeingthemostcommon
Lewis2009
Randomized,double-blind,placebo-controlled,3-arm,parallel-grouptrialwith9weekbaseline,16weektreatmentand6weektaperandexitphase
103adolescentsaged12-17yearswithmigraineasperICHDcriteria
35randomizedtolowdosetopiramate(25mg/dayuptoamaximumof25mgbid)vs.35randomizedtohighdosetopiramate(25mg/dayuptoamaximumof50mgbid)vs.33randomizedtoplacebo
Highdosetopiramategrouphadalargerdecreaseinmigrainefrequencyascomparedtoplacebo(72.2%vs.44.4%,p=0.016),butnosignificantdifferencecomparinglowdosetopiramatetoplacebo(p=0.798)
Moreadverseeventswithtopiramate(74%vs.48%)withmostcommon:upperrespiratorytractinfections,paresthesiasanddecreasedappetite
Low
Pandina2010
Randomized,double-blind,placebo-controlled,3-arm,parallel-grouptrialwith9weekbaseline,16weektreatmentand6weektaperandexitphase(analysisofsubsetofdatafromLewis2009)
103adolescentsaged12-17yearswithmigraineasperICHDcriteria
35randomizedtolowdosetopiramate(25mg/dayuptoamaximumof25mgbid)vs.35randomizedtohighdosetopiramate(25mg/dayuptoamaximumof50mgbid)vs.33randomizedtoplacebo
N/A–analysisofsubsetofthedatarelatedtocognitiveadverseevents
Oncognitivetesting,highdosetopiramateassociatedwithsmallincreasesinpsychomotorreactiontimesanddecreaseinthenumberofuniquewordstheycouldgenerate
Low
Winner2005
Randomized,double-blind,placebo-controlled,parallel-grouptrialwith2:1assignmenttotheinterventiongroupand4
162childrenaged6-15yearswithmigraineasperICHDcriteria
112randomizedtotopiramate15mgdailytitrateduptomaxof2-3mg/kgdailyor200mgdailyvs.50randomizedtoplacebo
Greaterreductioninmigrainefrequencyinthetopiramategroupinper-protocolanalysisandtrendinintention-to-treatanalysis(2.8+2.4vs.2.2+2.1,p=0.033forPPand2.6+2.6
Nodifferenceinsideeffectsoverall;4seriousadverseeventswithtopiramate
Unclear
29
weekbaselineperiod,8weektitrationperiodand12weekmaintenanceperiod
daysvs.2.0+3.1days,p=0.061forITT)
Winner2006
Pooledanalysisofpediatricdatafromthreerandomized,double-blind,placebo-controlled,parallel-grouptrialswith2weekwashout,4weekbaseline,8weektitrationand18weekmaintenanceperiods
49adolescentsaged12-18withmigraineasperICHDcriteria
11randomizedtolowdosetopiramate(50mgdaily)vs.13randomizedtomediumdosetopiramate(100mgdaily)vs.13randomizedtohighdosetopiramate(200mgdaily)vs.12randomizedtoplacebo
Greaterreductionsinmigrainefrequencyinthemediumandhighdosetopiramategroupsascomparedtoplacebo(63%and65%comparedto13%reductions,p<0.04)
Nooveralldifferenceinadverseevents;moreweightlossandcognitivesideeffectswithtopiramate;mostcommonadverseeventswithtopiramate:upperrespiratorytractinfections,paresthesiasandweightloss
Unclear
Valproicacid Apostol2008
Randomized,double-blind,placebo-controlled,4-armparallelgrouptrialwith2weekwashoutperiod,4weekbaselineperiod,2weektitrationperiodand10weektreatmentperiod
305adolescentsaged12-17yearswithmigraineasperICHDcriteria
83randomizedtolowdosedivalproex(250mgdaily)vs.74randomizedtomediumdosedivalproex(startedat250mgdailyandincreasedto500mgdaily)vs.75randomizedtohighdosedivalproex(startedat500mgdailyandincreasedto1000mgdaily)
Nodifferencebetweenanydoseofdivalproexandplacebointermsofdecreaseinmigrainefrequency
Nooveralldifferencesinadverseevents;mostcommonwithdivalproex:upperrespiratorytractinfections,somnolenceandfatigue
Unclear
Flunarizine MachínAltueña1987
Randomized,double-blind,placebo-controlled,3-arm,parallel-groupstudywith16weektreatmentperiod
45childrenaged5-13yearswithmigraineasperAdHoccriteria
15randomizedtoflunarizine0.15mg/kgdailyvs.15randomizedtodimethothiazine1mg/kgdailyvs.15randomizedto
Nodifferencesinratesofclinicalimprovementbetweenthegroups(93.3%fordimethothiazinevs.86.7%forflunarizinevs.80%forplacebo,
23.1%offlunarizinepatientsgainedweight
High
30
placebo p>0.05)Sorge1985 Randomized,
double-blind,placebo-controlled,2-arm,parallel-grouptrialwith12weektreatmentperiod
48childrenunderage18yearswithmigraineasperVahlquistcriteria
24randomizedtoflunarizine5mgdailyvs.24randomizedtoplacbeo
Lowerheadachefrequencyattrialcompletionintheflunarizinegroup(p<0.001)
Lackingdetailsonadverseevents;3patientswithdrewfromtheflunarizinegroupduetosideeffects(GIsymptoms,drowsinessandfatigue)
High
Sorge1988 Randomized,double-blind,placebo-controlled,crossovertrialwith4weekbaseline,12weektreatment,4weekwashoutandsecond12weektreatmentperiod
70childrenaged5-11yearswithmigraineasperVahlquistcriteria
35randomizedtoflunarizine5mgdailyforfirsttreatmentperiodvs.35randomizedtoplaceboforfirsttreatmentperiod
Greaterreductioninmigrainefrequencyduringflunarizinetreatmentperiodascomparedtoplacebotreatmentperiod(p<0.001)
Mostcommonlyweightgainanddrowsinessbutgroupcomparisonsnotmade
High
Timolol Noronha1985
Randomized,double-blind,placebo-controlled,crossoverstudywith4weekbaseline,8weektreatment,4weekwashoutand8weeksecondtreatmentphase
17patientsaged5-16yearswithmigraineasperVahlquistcriteria
9randomizedtotimolol5mgdailyforfirsttreatmentperiodand8randomizedtoplaceboforfirsttreatmentperiod
Therewerenogroupdifferencesinanyoftheoutcomes,includingmigrainefrequency
Lackingdetailonadverseevents;twopatientswithdrewfromtimololduetoheadacheandvomiting
High
Clonidine Sillanpää1977
Randomized,double-blind,placebo-controlled,2-armparallelgroupstudywith8weektreatmentperiod
57children15yearsandunderwithmigraineorvascularheadacheasperVahlquistcriteria
28randomizedtoclonidine25micrograms(mcg)dailyifunder40kgorand25mcgbidifover40kgvs.29randomizedtoplacebo
Lackofdetailwithreportingofresults(mosthypothesistestsnotgiven):1/3oftheparticipantswereheadache-freeduringtreatmentineachgroup,57%ofclonidineparticipantsand42%ofplaceboparticipantshad
Adverseeventsin11clonidineparticipantsvs.6placebo;mostcommonwithclonidinewasfatigueand
High
31
only1or2headachesduringtheentirestudy
nausea
Trazodone Battistella1993
Randomized,double-blind,placebo-controlled,crossoverstudywith12weektreatment,4weekwashoutandsecond12weektreatmentperiod
40childrenaged7-18yearswithmigraineasperICHDcriteria
20randomizedtotrazadone1mg/kgdailyforfirsttreatmentperiodvs.20randomizedtoplaceboforfirsttreatmentperiod
Nogroupdifferencesinthefirsttreatmentphase;inthesecondphasethetrazodonegrouphadagreaterdecreaseinmigrainefrequency(trazadonereducedfrom2.1+0.2attacks/monthto1.8+0.2vs.placeboincreasedfrom1.8+0.1to2.1+0.2,p<0.005)
Lackingdetailsonadverseevents;noseriousadverseeventsoccurred
Unclear
Nimodipine Battistella1990
Randomized,double-blind,placebo-controlled,crossoverstudywith4weekbaseline,12weektreatment,4weekwashoutandsecond12weektreatmentperiod
37patientsaged7-18yearswithmigraineasperAdHoccriteria
18patientsrandomizedtonimodipine10-20mgtidforfirsttreatmentperiodvs.19randomizedtomatchedplaceboforfirsttreatmentperiod
Nogroupdifferencesinthefirsttreatmentphase;inthesecondphasethenimodipinegrouphadagreaterdecreaseinmigrainefrequencythantheplacebogroup(from2.7+0.8attacks/monthto1.9+1.7vs.from2.6+0.8to2.8+0.6,p<0.01)
Lackingdetailsonadverseevents
Unclear
Cinnarizine Ashrafi2014
Randomized,double-blind,placebo-controlled,2-armparallelgroupstudywith4weekbaselineand12weektreatmentperiod
62children5-17yearswithmigraineasperICHDcriteria
30randomizedtocinnarizine1.5mg/kgdailyifweightlessthan30kgand50mgdailyif30kgormorevs.32randomizedtoplacebo
Cinnarizineyieldedahigherproportionachieving50%orgreaterreductioninmigraines(60%vs.31.3%,p=0.023);nodifferencesingroupsforchangeinmigrainefrequency
3cinnarizineparticipantsvs1placeboparticipanthaddrowsiness;1incinnarizinegrouphadsignificantweightgain
Unclear
Dimetho-thiazine
MachínAltueña1987
Randomized,double-blind,placebo-controlled,3-arm,parallel-groupstudywith16weektreatmentperiod
45childrenaged5-13yearswithmigraineasperAdHoccriteria
15randomizedtodimethothiazine1mg/kgdailyvs.15randomizedtoflunarizine0.15mg/kgdailyvs.15randomizedtoplacebo
Nodifferencesinratesofclinicalimprovementbetweenthegroups(93.3%fordimethothiazinevs.86.7%forflunarizinevs.80%forplacebo,p>0.05)
23.1%offlunarizinepatientsgainedweight
High
Papaverine Sillanpää Randomized, 37children 19randomized Morepatientsin Adverse High
32
1978 double-blind,placebo-controlled,2-armparallel-groupwith
aged6-15yearswithmigraineasperVahlquistcriteria
topapaverine5-10mg/kgdaily(startedat5mg/kgdaily)vs.18randomizedtoplacebo
thepapaverinegroupwerepain-freeontreatment(6vs.0,p<0.001)andheadachefrequencywaslowerinthepapaverinegroup(p<0.001)
eventsnotreported
Figure2.Riskofbiasgraph:reviewauthors'judgementsabouteachriskofbiasitempresentedaspercentagesacrossallincludedstudies.
33
Figure3.Riskofbiassummary:reviewauthors'judgmentsabouteachriskofbiasitemforeachincludedstudy.
*NB.Redcirclesindicatehighriskofbias,greencirclesindicatelowriskofbiasandwhitesquaresindicateunknownriskofbias
34
3.2. NutraceuticalInterventions
3.2.1 Butterbur(Petasiteshybridus)
Butterbur(Petasiteshybridus)isaperennialshrubthatgrowsinseveraldifferentcontinents.Its
medicinalpotentialhasbeenrecognizedforcenturies95.Althoughithashadmanyusesthroughout
theyears,itiscurrentlytoutedasaremedyformigraines,asthma,rhinitisandchroniccough95,96.
Themechanismthroughwhichitmayexertaneffectonmigraineisunclear.Ithasbeenshownto
haveanti-inflammatorypropertiesthroughitsselectiveinhibitionoftheenzymecyclooxygenase-
297,andinthiswayitcouldrelievemigraineswithamechanismsimilartothatofthenon-steroidal
anti-inflammatorydrugs,whicharecommonlyusedinpediatricmigraine.Leukotrieneproduction
fromprimedgranulocytesalsoappearstobeinhibitedbyPetasites,furthercontributingtoitsanti-
inflammatoryactivity98.Petasiteshasanotherpropertythatcouldrenderitefficaciousinmigraine:
ithasbeenshowntoinhibitL-typevoltage-gatedcalciumchannels99,inamanneranalogousto
calciumchannelblockerslikeflunarizine,whichisrecommendedforpediatricmigraine
prophylaxis100.
Unfortunately,Petasitescontainspyrrolizidinealkaloids,whicharecompoundswithknown
hepatotoxicity.Arecentstudyfounddetectablelevelsofpyrrolizidinealkaloidsinalmosthalfofthe
samplesofPetasitescommercialproductsthatitassayed101.AformulationcalledPetadolex®,with
supposedlyundetectableamountsofpyrrolizidinealkaloids,hasbeendevelopedandwasoriginally
foundtobesafeforhumanuse102.However,post-marketingsurveillancehasidentifiedcasesof
hepatoxicitylinkedtoPetadolex®.Thishaspromptedregulatoryauthorities,includingtheGerman
FederalInstituteofMedicalDevicesandtheSwissAgencyforTherapeuticProducts,tobanitsuse
intheirrespectivecountries103.Therefore,althoughtheevidencefortheuseofPetadolex®from
placebo-controlledtrialswillbereviewedhere,itisnolongeraviableoptionforpediatricmigraine
prophylaxis.
35
Onlyonestudyassessingtheefficacyofbutterburforthisindicationmetinclusioncriteria.
Oelkers-Axetalcarriedoutapartlydouble-blind,randomized,3-armparallelgrouptrialinagroup
of63childrenwithmigraineaged8to12years104.Patientswererandomizedtoreceiveoneof
threetherapies:butterbur,placeboormusictherapy.ThebutterburgroupwasgivenPetadolex®,a
regulatedformulationofbutterbur,atastartingdoseof50mgdailyforchildrenaged8and9years,
or50mgtwicedailyforchildrenaged10-12years.Thestartingdosewasadministeredforthefirst
8weeks.Subsequently,childrenwithasuboptimalresponsehadtheirdoseincreasedby50%for
thenext4weeksoftreatment.Theplacebogroupwasgivenplacebopillsforthefirst8weeks,with
adoseadjustmentat8weeksifnecessary.Finally,themusictherapygroup,whocouldnotbe
blindedtotheirassignmentgiventhenatureofthetreatment,received12weeklysessionsofmusic
therapy,focusedonavarietyoftechniquesincludingmusic-aidedrelaxationtraining,body
awarenesstechniquesandconflicttraininginamusicalrole.Atthepost-treatmentassessment,
bothas-treatedandintention-to-treatanalysesshowedthatthegroupsallhadasignificant
decreaseintheirmigrainefrequencyascomparedtobaseline,whichwastheprimaryoutcome.At
thisstage,musictherapywassuperiortoplacebowithregardstotheprimaryoutcome,whereas
Petadolex®wasnot.However,atthe6monthfollow-upassessment,bothmusictherapyand
Petadolex®weresuperiortoplacebo.Furthermore,therewerenodifferencesinadverseevents
betweenthegroups.Thebutterburgroupprimarilyexperiencedgastrointestinal,cutaneousand
allergicsymptomsassideeffects.TwopatientsinthePetadolex®groupandandthreepatientsin
theplacebogrouphadtransientmildtransaminitis.Thisstudywasdeemedtohaveahighriskof
biasbasedonseveralkeyweaknesses.Namely,completeimplementationofadouble-blind
protocolwasnotpossiblegiventhatmusictherapycannotbeblindedtothepatients.Thisposeda
highriskforperformancebiasanddetectionbias.Inaddition,randomizationdidnotsucceedin
makingthegroupsbalancedonallbaselinecharacteristics:thePetadolex®grouphadalmost
doublethebaselinemigrainefrequencyascomparedtotheothergroups(9.8+7.6vs.5.5+4.4vs.
36
5.0+2.5,p=0.409),andthoughthisdidnotreachstatisticalsignificance,itisclinicallymeaningful.
Finally,therewasahighriskofattritionbiasgivenahigherrateofdrop-outsinthemusictherapy
andPetadolex®groupsascomparedtoplacebo(29%formusictherapyvs.25%inPetadolex®
groupvs.5%inplacebogroup,p=0.113).Thoughthedifferenceswerenotstatisticallysignificant,
theywereclinicallysignificantandthereforelikelycreatebiasintheresults.Thus,onlyonestudy
assessedtheefficacyofbutterburinchildrenandthisstudyisofinferiormethodologicalquality
givenseveralkeyareaswithahighriskofbias.This,coupledwithsafetyconcernsaboutbutterbur,
precludesrecommendationsforitsuseinpediatricmigraineprophylaxis.
Therefore,onlyonesmalltrialwithahighriskofbiaslendssomeevidenceinfavorof
Petadolex®.Giventhisandtheevidencesuggestingthatbutterburcompoundsmaybehepatotoxic,
itwouldbeunwisetorecommendtheuseofbutterburforpediatricmigraineprophylaxis.
3.2.2 Riboflavin(VitaminB2)
Unlikebutterbur,riboflavindoesnothavealonghistoryofmedicinaluse.Itwasonlyisolated
inthe1930sandsynthesizedshortlythereafter.Riboflavinisderivedfromamultitudeofdietary
sources.Itplaysavitalroleinmitochondrialenergymetabolismthroughitstwoactivecoenzymes:
riboflavin5’-phosphateandflavinadeninedinucleotide.Bothofthesecompoundsparticipateina
multitudeofmetabolicprocesses105.Itispreciselyitsroleinmitochondrialenergymetabolismthat
givesriboflavinsomecredibilityasapotentialtherapyformigraines.Thereisanaccumulating
bodyofevidencesuggestingthatmigraineursmaybeinastateofmitochondrialenergy
depletion106–113.Therefore,compoundslikeriboflavin,whichplayaroleinmitochondrialenergy
production,mayhelptopreventmigraines.
Twostudiesontheefficacyofriboflavinforpediatricmigraineprophylaxiswereincludedinthe
systematicreview.Thefirststudy,byMacLennonetal,randomized48childrenbetweentheagesof
5and15yearstoreceiveeither12weeksofriboflavin200mgdailyoramatchedplacebofortheir
migraines114.Effortsweremadetomaintainblindingamongstbothparticipantsandstudy
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personnel.After12monthsofrecruitmentandattainmentof86%oftheplannedsamplesize,the
trialwasstoppedgiventhataninterimdataanalysisshowedthattherewasaverylowprobability
offindingefficacyfortheriboflavinintervention.Theexactstoppingruleusedfortheinterim
analysisisnotclear.Therewerenogroupdifferencesintheprimaryoutcome,thatis,the
proportionofparticipantsachievinga50%orgreaterreductioninmonthlymigrainefrequency.
Also,noneofthesecondaryoutcomesfavoredriboflavin.Overall,however,riboflavinwaswell
tolerated:onechildhadanincreaseintheirtension-typeheadachesandfourchildrenreporteda
changeintheirurinecolorbutotherwisetherewerenoreportedadverseeventsforthetreatment
group.Thestudywaspoweredtodetecta40%differencebetweenplaceboandriboflavin,whichis
ambitiousandthereforethestudywaslikelyunderpowered.Thestudywasmethodologically
soundwithalowriskofbiasacrossallofthecoredomains.
ThesecondstudyonriboflavinwascarriedoutbyBruijnandcolleagues,andinvolved
randomizing42childrentoreceiveeitherriboflavin50mgdailyorplacebo,consistingof100mgof
carotene,inadouble-blind,cross-overdesign115.Eachtreatmentwasadministeredfor16weeks
andtherewasa4-weekwashoutperiodinbetweentheinterventions.Intheend,intention-to-treat
analysesdidnotuncoveranydifferencesbetweenthegroupsineithertheprimaryorsecondary
outcomes.Thestudywasonlypoweredtodetectadifferenceof0.6standarddeviationsbetween
thegroupsrelativetothechangeinmigrainefrequency.Thisminimalclinicallyimportant
differenceislikelytoolarge,andthestudywasthereforearguablyunderpowered.Also,thedoseof
riboflavinismuchlowerthanthatusedinotherstudiesandthanthetypicaldoseusedclinically.
Hence,itispossiblethatthelackofefficacywasduetounder-dosing.Anotherconcernrelatesto
theuseofcaroteneintheplacebo;althoughtherationaleforitsusewassound(riboflavincolors
theurineorangeandcarotenemimicsthissideeffect),itispossiblethatthecarotenecouldhavea
migraineprophylacticeffectrenderingitanactivecomparatorasopposedtoatrueplacebo.The
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studywasratedashavinganunclearriskofbiasgiventhattherewerenodetailsavailableonthe
methodofrandomization.Otherwise,thestudywasmethodologicallysound.
Therearethereforetwosmalltrialsthathavefoundnodifferencebetweenplaceboand
riboflavinforpediatricmigraineprophylaxis.Bothstudieswerelikelyunderpowered.TheBruijnet
alstudyhadseveralothermethodologicalshortcomingsaswell.Hence,itisdifficulttomake
conclusionsaboutriboflavin’sefficacybasedonthecurrentstateoftheevidence.Givenits
favorabletolerability,furtherhighqualitystudies,involvinglargergroupsofpatients,are
warranted.
3.3. Pharmaceuticals
3.3.1 Topiramate
Topiramateisacommonlyusedantiepilepticmedicationwithabroadanticonvulsantprofile
comprisingamultitudeofpotentialmechanismsofactionforseizureprophylaxis116.Itisunclear
howitmightoperateinmigraineprevention.Therationaleforitsuseinmigrainepertainstothe
beliefthatmigraineandepilepsymayoverlapintheirpathophysiologies,andthatmigraine,like
epilepsy,involvesastateofbrainhyperexcitability117.In2014,topiramatewasapprovedbythe
FoodandDrugAdministration(FDA)fortheprophylaxisofmigraineinadolescents.Itisthefirst
andonlydrugtoreceiveFDAapprovalforthisindicationinthepediatricagegroup118.Health
Canadacurrentlyhasnotapprovedanydrugsforpediatricmigraineprophylaxis,buttopiramateis
approvedformigraineprophylaxisinadults119.
Sixstudiesontheefficacyoftopiramateformigraineprophylaxisinchildrenandadolescents
wereincluded.Inadouble-blind,parallel-grouptrial,Winneretalrandomizedchildrenaged6to
15yearstoreceiveeithertopiramateintitratingdosesupto2-3mg/kg/dayortitratingdosesof
placeboina2:1ratio120.Afterthe4-weekbaselineperiod,an8-weektitrationperiodwasinitiated
foreachgroup,withthetopiramateparticipantsstartingatadoseof15mgdaily,followedbyaslow
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titrationuptoamaximumof200mgdailyor2-3mg/kg/dayasneeded,andtheplaceboparticipants
havinganartificialtitrationschedule.Afterthetitration,eachgroupentereda12-week
maintenancephase.During20weeksoftreatment,thetopiramategrouphadahighermean
reductionintheirheadachefrequencyintheper-protocolanalysis(2.6+2.6daysforthetopiramate
groupvs.2.0+3.1daysfortheplacebogroup,p=0.033),butthedifferencebetweentopiramateand
placeboonlyapproachedsignificanceintheintention-to-treatanalysis(2.8+2.4daysforthe
topiramategroupvs.2.2+2.1daysfortheplacebogroupp=0.061).Becausenosamplesize
calculationsarereported,itisunclearwhatminimalclinicallyimportantdifferencethetrialwas
poweredtodetect.Intention-to-treatanalysesforallsecondaryoutcomesfavoredtopiramateina
statisticallysignificantmannerexceptfortheanalysiscomparingtheproportionofpatientswitha
50%orgreaterreductioninmigrainefrequencyoverthetreatmentperiod:here,therewasno
differencewhencomparingplacebototopiramate(p=0.18).Topiramatewaswelltoleratedwithno
significantdifferenceintheincidenceofadverseeventsascomparedtoplacebo.Therewere4
seriousadverseeventsinthetopiramategroup.Thisstudywasratedashavingunclearriskofbias,
simplybecauseofalackofdescriptionastohowtherandomizationcodewasgenerated.Otherwise,
allotherdomainsofthestudyhadalowriskofbiasandoverallthemethodologicalqualityofthe
trialwasstrong.
Lakshmietalcarriedoutadouble-blind,placebo-controlled,parallel-grouprandomizedtrialin
44childrenaged8-14yearswithmigraine121.Theyrandomized22participantstotopiramate,
whichwasinitiatedatadoseof25mgdailyandtitratedupto50mgbidover4weeksfollowedby
maintenanceatthisdosefor12weeks,and22participantstomatchedplacebofor16weeks.
Topiramatewassignificantlybetterthanplaceboatreducingthefrequencyofmigraineswhen
comparingbaselinetotheendoftreatment(thetopiramategroupwentfromameanof16.14+9.35
migrainedays/monthto4.27+1.95days/monthvs.theplacebogroupthatwentfrom13.38+7.48
days/monthto7.48+5.94days/month,p=0.025).Topiramatewasalsosignificantlybetterthan
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placebointermsoftheproportionofpatientsachievinga50%orgreaterreductioninmigraine
frequency,inreducingdisabilityscoresonthePedMIDASandinreducingschoolabsenteeismas
comparedtoplacebo,butwasnodifferentfromplacebointermsofchangesinmigrainedurationor
intensity.Thereweremoreadverseeventswithtopiramate,withweightloss,reducedappetite,
paresthesiasanddecreasedconcentrationbeingthemostprevalent.Althoughthetrialwassmall,it
wasmethodologicallyrigorous,receivingajudgmentoflowriskofbiasforalloftheCochranerisk
ofbiasdomains.
Lewisetalrandomizedagroupof106adolescentsaged12to17yearswithmigrainetoeither
highdosetopiramate,lowdosetopiramateorplaceboinadouble-blind,3-arm,parallel-grouptrial
ina1:1:1fashion122.Thestudycompriseda9-weekbaselineperiod,duringwhichthefirstweek
wasdedicatedtoscreening,thenext4weeksinvolvedawash-outperiodforanyprophylactic
migrainemedicationsinuseandthelast4weeksconsistedofthebaselineperiod.Afterthese9
weeks,theparticipantsentereda16-weektreatmentperiod,whichwasfollowedbya6weektaper
andendofstudyperiod.Thetopiramategroupsbothstartedatadoseof25mgdaily,andthelow
dosegroupwasthentitratedupto25mgbidastolerated,whereasthehighdosegroupwastitrated
upto50mgbidastolerated.Theplacebogroupwasgivenmatchingplacebopills.Eachpatient
received4identical-appearingpillsperday,comprisedof25mgoftopiramateorplacebo,ora
combinationthereof.Theprimaryoutcome,thatis,thepercentreductioninmigrainefrequency
comparingthelast12weeksoftreatmenttobaseline,wasachievedinsignificantlymorepatients
takinghighdosetopiramateascomparedtoplacebo(72.2%vs.44.4%,p=0.016),whereasthere
wasnodifferencecomparinglowdosetopiramatetoplacebo(p=0.798).Mostofthesecondary
outcomesyieldedsimilarresultswithonlythehighdosetopiramatetreatmentbeingfavoredover
placebo.Thestudywaspoweredtodetectadifferenceof43%betweenthetopiramategroupsand
placebointermsoftheprimaryoutcome,thatisthepercentagereductioninmigrainefrequencyin
thelast12weeksoftreatmentcomparedtobaseline,atapowerof80%withaprobabilityoftypeI
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errorof5%usinga2-sidedMann-Whitneytest.Therefore,itispossiblethattherewasaclinically
meaningfuldifferencebetweenlowdosetopiramateandplacebothatwasnotdetectedgiventhe
relativelylowpowerofthestudy.Thisstudywasmethodologicallysoundwithalowriskofbias
acrossalldomainsofpotentialbias.
Inasubsequentpublication,Pandinaetal123reportedonneurocognitiveandmoodoutcomes
observedintheLewisetalstudy.ThesamepatientshadalsocompletedaCambridge
NeuropsychologicalTestAutomatedBattery(CANTAB)andaProfileofMoodStates.Thehighdose
topiramategrouphadsignificantincreasesintheirreactiontimesontheCANTABascomparedto
placebo,butlowdosetopiramateandplacebodidnotdifferintheirreactiontimes.Thelowdose
topiramategrouphadasignificantreductionintheirtotalnumberofuniquewordsascomparedto
placebo.However,changesseeninCANTABmemory,visualinformationprocessingandlearning
scoresdidnotdiffersignificantlybetweenthegroups,nordidtheProfileofMoodStateschanges
overtime.
Winneretalalsocarriedoutapooledanalysisontheefficacyandsafetyoftopiramatefor
adolescentmigraineprophylaxisusingdatafromthreeadultrandomizedcontrolledtrials124.
Fourty-nineadolescentswereincludedfromthethreetrials.Allthreetrialshadsimilar
methodologywhereparticipantswererandomizedinequalproportionstooneoffourtreatment
groups:topiramate50mgdailyorinonetrialpropranolol,topiramate100mgdaily,topiramate
200mgdailyorplacebo.Eachgroupunderwenta2-weekwashoutperiodandthena4-week
baselineperiod.Subsequently,thegroupsenteredan8-weektitrationphase,wherepatients
randomizedtotopiramatestartedadoseof25mgdaily,whichwassubsequentlyincreasedby
25mgweeklyuntilthetargetdosewasachieved.Followingthetitrationphase,participantsentered
an18-weekmaintenancephase.The100mgand200mgtopiramategroupsweresignificantly
betterthanplacebowithregardstotheprimaryoutcome:theyhadagreaterreductioninmigraine
frequencyduringtreatmentascomparedtobaseline(63%fortopiramate100mggroupand65%
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fortopiramate200mggroupcomparedto13%reductionforplacebogroup,p<0.04).However,the
treatmentgroupsdidnotdifferfromplacebointermsofthesecondaryoutcomes.Overall,
topiramatewaswelltoleratedwithnoseriousadverseeventsandnodifferencefromplaceboin
termsoftheincidenceofadverseevents.Cognitivesideeffectsweremorecommonwithtopiramate
thanwithplacebo.Themostcommonsideeffectsreportedwereupperrespiratorytractinfections,
weightlossandparesthesias.Thestudiesthatwereusedforthepooledanalysiswere
methodologicallystrong,butthisanalysiswasratedashavingunclearriskofbiasgiventhatitis
unclearwhetherallocationtotherandomsequencewasconcealedinanyofthestudies,evenafter
accessingtheoriginaladulttrials.
Finally,similarlytoWinneretal124,Fordetallookedatthesubsetofpediatricpatients
participatinginfivelarge,multicenterRCTs125.Thetrialswerealldouble-blind,placebo-controlled
parallel-groupdesignswithtreatmentperiodsrangingfrom16-26weeks.Dosingregimensfor
topiramatevariedfrom50mgdailyto200mgdailyandinonetrialthedosingwasflexibleat2-3
mg/kgdaily.Onestudyhadapropranolol160mgdailyactivecomparatorarminadditiontothe
placeboandtopiramatearms.Thisanalysisisonlypublishedinconferenceabstractformandthe
numbersrandomizedtoeacharmarenotgiven,butatotalof309pediatricparticipantswere
included.Twoefficacyoutcomeswereanalyzed:thepercentchangeinmonthlymigrainefrequency
andtheresponderrate,thatis,thepercentageofparticipantsachievinga50%orgreaterreduction
inmigrainefrequency.Withregardstothepercentreductioninmigrainefrequency,onlyonetrial
foundasignificantdifferencebetweentopiramateandplacebo:intheTOPMAT-MIG-3006trial,
topiramate100mgdailywassuperiortoplaceboforthisoutcome(p=0.0164).Similarly,onlythe
TOPMAT-MIG-3006trialyieldedasignificantdifferenceinresponderratescomparingtopiramate
withplacebo,withtopiramate100mgdailyoutperformingplaceboforthisoutcome(p=0.0048).
Sideeffectsarenotreportedonindetail,butthemostcommoneventswereflu-likesymptoms,
languageproblemsandparesthesias.Itisimportanttonotethatthreeoutofthefivetrials
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comprisedbothpediatricandadultpatientsandmaynothavebeenpoweredtodetectdifferences
intheoutcomesforthepediatricsubsetofparticipants.OnlytheTOPMAT-MIG-3006andCAPSS-
122trialsrecruitedexclusivelypediatricparticipantsandthusonlythosetrialsweredefinitely
adequatelypoweredfortheirprimaryoutcomes.Thisanalysiswasonlydescribedinconference
abstractformandtherewasunclearriskofbiasintermsofallocationconcealmentandattrition
bias.Thus,theanalysishadanunclearriskofbiasoverall.Theauthorsconcludedthattopiramate
100mgdailywasefficaciousinadolescents,giventhattheTOPMAT-MIG-3006study,which
supportedtheefficacyoftopiramateatthisdose,recruitedonlyadolescentsages12to17years.
Thereisconsistentevidencefromthesesixstudiesthattopiramateiseffectiveinpreventing
migrainesinchildrenandadolescents.Italsoappearedtobewelltoleratedamongstthesepatients,
thoughthepooledanalysisbyPandinaetal123confirmedwhatmanycliniciansobserveanecdotally
intheirpatients:thattopiramatehasadverseeffectsoncognition.Becauseofitssideeffects,
primarilythoserelatedtocognition,topiramatemustbeusedjudiciouslyinthispopulationgiven
thatcognitiveperformanceiskeyinthechildoradolescent’ssuccessinschoolandintheir
transitiontoemployment.
3.3.2 ValproicAcid
Valproicacid,liketopiramate,isabroad-spectrumantiepilepticdrugwithmultiplemechanisms
ofaction116thathasbeenusedoff-labelforpediatricmigraineprophylaxis.ValproicacidhasFDA
approvalforuseinmigraineprophylaxisinadults,whereasHealthCanadahasnotapproveditfor
thisindication.Again,therationaleforusingvalproicacidinmigrainepertainstothetheorythat
migraineandepilepsyhavesimilarunderlyingmechanisms126.
Theefficacyofvalproicacidforpediatricmigraineprophylaxishasonlybeenassessedinone
eligibletrial.InastudysponsoredbyAbbottPharmaceuticals,Apostoletalrandomized305
adolescentswithmigrainetoeitherdivalproex250mgdaily,divalproex500mgdaily,divalproex
1000mgdailyormatchedplaceboinadouble-blind,4-armparallel-grouptrial127.Participantsfirst
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hada2-weekwashoutperiod,followedbya4-weekbaselineperiod.Eligibleparticipantswerethen
randomizedtooneofthe4groupsanda2-weektitrationperiodstarted.Duringtitration,thosein
the250mgand500mgdivalproexgroupsstarteddivalproexatdoseof250mgdaily,whereasthose
inthe1000mgdivalproexgroupstarteddivalproexatadoseof500mgdaily.Followingthe2-week
titration,targetdoseswerestartedandmaintainedfor10weeks.Therewerenosignificant
differencesbetweenthegroupsintermsoftheprimaryoutcome,thatis,thechangeinmigraine
frequencycomparingbaselinetothe12-weektreatmentperiod.Inaddition,noneofthedivalproex
groupsweresignificantlydifferentfromplaceboinanyofthesecondaryoutcomes.Overall,there
wasnodifferenceinthefrequencyofadverseeventratesbetweenthegroups.Themostcommon
adverseeventswithdivalproexwereupperrespiratorytractinfection,somnolenceandfatigue.The
effectsizeusedtopowerthestudywasbasedonresultsofasimilartrialinadults.Theauthors
acknowledgethattheplaceboresponsewasmuchstrongerintheirtrialthanthatobservedinthe
adulttrial,whichisunsurprisinggiventhatpediatricstudiestendtoseehigherplaceboresponse
rates,especiallyinparallel-grouptrialsasopposedtocross-overtrials128.Therefore,itispossible
thatthetrialwasunderpoweredinthissetting.Thedescriptionofhowtherandomsequencewas
generatedlacksdetailanditisuncleariftheallocationwasconcealed.Hence,thisstudywasrated
ashavinganoverallunclearriskofbias,despiteotherdomainsofpotentialbiashavingalowriskof
bias.
Basedonthefactthatonlyonevalproatestudyhadenoughmethodologicalrigortobeincluded
inthisreviewandgiventheextensivesideeffectprofileofthismedication,valproatecertainlydoes
notappeartobeareasonablefirstlineagentforpediatricmigraineprophylaxis,althoughstrong
conclusionscannotbemadegiventhelimitedevidence.
3.3.3. Flunarizine
Flunarizinebelongstotheclassofmedicationsbythenameofcalcium-channelblockers.Its
mechanismofactioninmigraineisalsounknown.Onestudycarriedoutusingpatchclamp
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recordingsintrigeminalganglionneuronsshowedthatflunarizineinhibitedsodiumandcalcium
currents,resultinginhyperpolarizingneuronalmembranepotentials129.Thus,flunarizinelikely
inhibitsneuronaltransmissioninthetrigeminalganglion,whichplaysacrucialroleinmigraine
pathogenesis.Anotherstudyshowedthatflunarizinewasabletoreducethedegreeofcerebral
mitochondrialinjurythatoccursduringcorticalspreadingdepression130,whichisbelievedtobethe
underlyingpathophysiologicalcorrelateofmigraineaura131.Therefore,somepreliminaryevidence
suggeststhatflunarizinecouldhaveplausiblemechanismsofactioninpreventingmigraine.Inthe
mostcurrentAmericanAcademyofNeurology(AAN)practiceparameteronthetreatmentof
migraineinchildrenandadolescents,flunarizineistheonlymedicationthatreceiveda
recommendationtousebasedonevidencethatitis“probablyeffective”forthepreventionof
migrainesinthispopulation100.
Therewerethreeincludedstudiesthatassessedtheefficacyofflunarizinefortheprophylaxisof
migraineinchildrenandadolescents,twoofwhichwerebythesameauthorgroup.Adouble-blind,
placebo-controlled,2-arm,parallel-grouptrialwascarriedoutbySorgeetalinordertoassessthe
efficacyofflunarizineforthepreventionofpediatricmigraines132.Forty-eightchildrenwith
migrainewererandomizedtoreceivethreemonthsofeitherflunarizine5mgqHSorplacebo.
Duringthetreatmentperiod,theparticipantsonflunarizinehadasignificantlylowermean
migrainefrequencyascomparedtoplacebo(p<0.001)andhadasignificantlylowermeanmigraine
duration(p<0.05)aswell.However,thelattermayhavebeenanartifactofthefactthatthe
flunarizinegrouphadalowermigrainedurationatbaseline(p<0.05).Thereislittlementionofside
effectsinthemanuscript.Theauthorsdostatethatweightlossandsleepinesswerethemost
commonadverseevents,butdonotreportfrequenciesineachgroup.Also,threepatientswithdrew
fromtheflunarizinegroupduetosideeffects(gastrointestinalsymptoms,drowsinessandfatigue)
whereasthreepatientswithdrewfromtheplacebogroupduetolackofefficacy.Nointention-to-
treatanalyseswereused.Thetrialoverallhadahighriskofbiasduetothisattritionbias,withthe
46
twogroupshavingclearlydistinctreasonsfordrop-outs.Therewasalsounclearriskofbiasin
relationtothepossibilityofselectionbias,giventhatrandomizationandallocationconcealment
werenotdescribed.
Afewyearslater,Sorgeetalcarriedoutadouble-blind,placebo-controlled,crossovertrialina
groupof70childrenaged5to11yearswithmigraine133.Thetimelineofthetrialinvolveda4-week
baselineperiod,followedbya12-weektreatmentperiod,followedbya4-weekwashoutperiod,
andfinallyanother12-weektreatmentperiod.ParticipantsrandomizedtoGroupAreceived
flunarizine5mgdailyforthefirsttreatmentperiodandthenwerecrossedovertoplacebo,whereas
participantsinGroupBhadtheoppositetreatmentorder.Duringtheflunarizinetreatmentperiod,
bothgroupshadastatisticallysignificantdecreaseintheirmigrainefrequency(p<0.001inboth
cases).Inaddition,duringtheflunarizineperiod,bothgroupshadastatisticallysignificant
reductioninthedurationoftheirmigraines,startingatmonth3offlunarizineingroupAand
startingatmonth2offlunarizineingroupB(p<0.001inbothcases).Thereportingofsideeffectsis
vagueandonlymakesmentionoftheoverallfrequencyofthemostcommonsideeffects:22.2%of
participantsexperiencedweightgainand9.5%experienceddrowsiness.Itisunclearastowhether
therecouldhavebeenselectionbiasinthestudygiventhelackofdetailgivenwithregardsto
randomizationandallocationconcealment.Therewasahighriskofattritionbiasgiventhat2
patientswithdrewfromtheflunarizinegroupand5patientswithdrewfromplacebo,withno
intention-to-treatanalysesused.Therefore,thetrialwasgivenahighriskofbiasoverall.
AsmallstudycarriedoutbyMachínAltueñaetalrandomized45childrenaged5to13years
withmigrainetoeitherflunarizine,dimethothiazineorplaceboina4-monthdouble-blind,3-arm,
parallel-groupinterventionstudy134.Therewerenogroupdifferencesintermsoftheprimary
outcome:93.3%ofthedimethothiazinegrouphadclinicalimprovementvs.86.7%ofthe
flunarizinegroupvs.80%oftheplacebogroup(p>0.05).Inaddition,nogroupdifferenceswere
seeninanyofthesecondaryoutcomes.Weightgainoccurredin23.1%oftheflunarizinegroupbut
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noothersignificantsideeffectswerenotedinthemanuscript.Therewasahighriskofbiasinthis
studyinthatnosamplesizecalculationsweregivenandthestudywasverylikelyunderpoweredto
detectclinicallyimportantdifferencesintheefficacyoftheinterventions.Therewasalsounclear
riskofbiasrelatedtoallocationconcealment,thusintroducingthepotentialforselectionbias.This
studywasthereforeathighriskofbiasanditisdifficulttodrawanyconclusionsonflunarizine’s
efficacyfromtheseresults.
ThetwoSorgeetalstudies132,133,bothofwhichhadhighriskofbias,supporttheuseof
flunarizineinpediatricmigraineprophylaxisandtheMachínAltueñaisdifficulttointerpret134.
Becauseofthelowqualityofevidenceandthesmallnumberofparticipantsinthestudies,astrong
recommendationforitsuseshouldnotbemade.ThisislikelywhytheAANpracticeparameter
labeledflunarizineas“probablyeffective”forthisindication100,ratherthanmakingastronger
statementaboutitsuseinpediatricmigraineprophylaxis.
3.3.4 Timolol
Timololbelongstotheclassofmedicationscalledbeta-blockers,whichareantihypertensive
medicationsthatreducevasculartonebyinhibitingbeta-adrenergicreceptors.Howbeta-blockers
mightworktopreventmigrainesisunclear.Ithasbeenhypothesizedthattheircentralinhibitionof
beta-adrenergicreceptorsandtheirinteractionwithserotoninreceptorsmaymediatetheir
mechanismofactioninmigraine135,136.Timololisapprovedforuseinadultmigraineprophylaxisby
HealthCanadaandtheFDA.
Onestudyassessedtheefficacyoftimololforpediatricmigraineprophylaxis.Noronha
describedasmalldouble-blind,placebo-controlled,cross-overtrialthathecarriedout,whereby9
patientswererandomizedtoreceivedtimolol5mgdailyforthefirsttreatmentperiodthencrossed-
overtoplacebo,and8patientswererandomizedtoreceiveplaceboforthefirsttreatmentperiod
thencrossed-overtotimolol5mgdaily137.Therewasa4-weekbaselineperiodinthistrial,followed
by8weeksoftreatment,thena4-weekwashoutperiod,andthenfinallyanother8-weektreatment
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period.Therearefewdetailsgivenabouttheresults.Theauthordoesreportthattherewereno
differencesbetweenthegroupsintermsofmigrainefrequency,severitynorduration.Theonly
mentionofadverseeventspertainstotheauthordescribinghowtwopatientswithdrewduetoside
effectsoftimolol,namelyheadacheandvomiting.Nosamplesizecalculationsaredescribedand
giventhattherewereonly17patientsinthetrial,itisverylikelythatthestudywasunderpowered.
Therewasahighriskofattritionbiasinthisstudygiventhat2patientswithdrewfordrug-specific
reasons(ie.duetotimololsideeffects).Therewasunclearriskofbiasrelatedtoselectionbiasgiven
aninadequatedescriptionofrandomizationandallocationconcealment.Therefore,thistrialwas
consideredtohaveahighriskofbias.
Basedontheavailableevidence,thereisnotenoughinformationtocommentontheefficacyof
timololforpediatricmigraineprophylaxis.Onlyonesmall,underpoweredtrialisavailable;future
studiesarethereforerequiredpriortodrawingconclusionsabouttimolol’suseforthisindication.
3.3.5 Clonidine
Clonidineisanalpha-2adrenergicagonistwithseveralpostulatedmechanismsofactioninpain
modulation.Alpha-2adrenergicagonistslikeclonidinemayhavearoleinalleviatingpainthrough
theiranti-inflammatorypropertiesandthroughtheirabilitytomodulatedescendingpainpathways
inthecentralnervoussystem:theycaninhibitnitricoxideandglutamatereleaseincentralpain
pathwaysandcanincreasedescendinginhibitionintherostralventromedialmedulla,whichplays
animportantroleindescendingpaininhibition138.Animalexperimentshaveleadtosome
interestinginsightsaboutthepotentialrolethatclonidineplaysinmodulatingpainassociatedwith
migraine.Itappearsthatclonidinemightinhibittrigeminalreferredpaininmigrainebyinhibiting
C1spinalneuronsthatreceiveinputsfromstructuresbelievedtobeinvolvedinreferredpain139.
Also,clonidinehasbeenshowntoinhibitNMDA-evokedresponsesinnociceptiveneuronslocated
inthetrigeminalnucleuscaudalis140,whichisabrainareaofcentralimportanceinmigraine
pathogenesis.Inanotheranimalexperiment,clonidineinhibitedthemigrationofcorticalspreading
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depression141,aphenomenonthatisbelievedtounderliemigraineaura131.Therefore,clonidinehas
severalplausiblemechanismsofactionthatcouldleadtoitsefficacyinmigraineprevention.
AlthoughitisnotcurrentlyapprovedforuseinmigrainebytheFDAnorHealthCanada,itisused
off-labelforthisindication.
Sillanpääreportedtheresultsofadouble-blind,placebo-controlled,2-armparallel-groupstudy
involvingthecomparisonofclonidinetoplaceboformigraineprophylaxisinchildrenwith
migraineupto15yearsofage142.Althoughitseemsimpliedthatthetrialwasrandomized,itisnot
explicitlystatedinthetext.Becausethepaperwaspublishedin1977withasingleauthorforwhom
nocurrentcontactinformationwastraceable,thestudywasincludedinthesystematicreview
despitetheunclearrandomizationstatus.Inthisstudy,28childrenreceivedclonidineatadoseof
25micrograms(mcg)dailyforthoseweighinglessthan40kgand25mcgbidforthoseweighing
over40kg,and29childrenreceivedplaceboforthe2-monthtreatmentperiod.Intheclonidine
group,thedosewasincreasedby25mcgforeachparticipantafterthefirstmonthoftreatment.The
reportingofoutcomesissuboptimalasitisunclearwhichoutcome(s)wereprimary.Also,insome
instanceshypothesistestsarereportedandinotherstheyarenot.Forthefrequencyofmigraines
outcome,whichisnormallytheprimaryoutcomeinsuchtrials,theredidnotappeartobe
significantdifferencesbetweenthegroups.Thegroupsalsodidnotdifferwithrespecttomigraine
intensitynorduration.Inthesubgroupsofpatientshavingafamilyhistoryofmigraineormigraine
withaura,thosetreatedwithclonidinehadsignificantlylowermigrainefrequenciesduringthe
treatmentperiod.Thoseintheclonidinegroupreportedmoreadverseevents:11participantson
clonidinevs.6participantsonplaceboreportedadverseevents.Intheclonidinegroup,themost
commonadverseeventwasfatigue,followedbynausea.Inthisstudy,nosamplesizecalculations
arereportedandgiventhesmallsamplesize,thetrialwaslikelyunderpoweredtodetectsmallbut
meaningfulclinicaldifferenceswhencomparingclonidinetoplacebo.Therewasahighriskof
reportingbiasgiventhathypothesistestswereonlyreportedforsomeoutcomes.Therewasalsoa
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highriskofattritionbiasgiventhat3patientswithdrewfromthestudyandallwereinthe
clonidinegroup.Theriskofselectionbiaswasuncleargiventhelackofclaritysurrounding
randomizationandallocationconcealment.Therefore,overall,thetrialhadahighriskofbias.
Basedonthisonestudywithhighriskofbias,itisdifficulttodrawconclusionsontheefficacy
ofclonidineforpediatricmigraineprevention.
3.3.6 Trazodone
Trazodoneisananti-depressantmedicationthatinhibitsthereuptakeofserotoninatthe
neuronalsynapse.Itsmechanismofactioninmigraineisunclear,thoughithasbeenpostulatedthat
theincreasedavailabilityofserotonincouldberelatedtoitsanti-migrainepotential143.Itis
currentlyonlyapprovedforuseinmajordepressivedisorderinbothCanadaandtheUSanditsuse
inmigraineisthereforeofflabel,evenintheadultpopulation.
Trazodonehasonlybeenassessedinonerandomizedstudyforthisindicationinthepediatric
population.Theefficacyoftrazodoneforthepreventionofmigraineinchildrenandadolescentshas
beenassessedinonesmallrandomized,double-blind,placebo-controlledcrossovertrialinvolving
40participantsaged7to18years144.Battistellaetalrandomizedparticipantstoreceivetrazodone
1mg/kg/daydividedtidorcolor-matchedplacebodailyfor12weeks.Awashoutperiodwasthen
initiatedandmaintainedfor4weeks,andparticipantswerethencrossedovertotheother
intervention.Afterthefirsttreatmentperiod,therewasnodifferencecomparingtrazodoneto
placebointermsofmigrainefrequency,andmigrainedurationwasinfactlongerinthetrazodone
group(16.1+1.4hrsvs.10.2+1.0,p<0.01).Inthesecondtreatmentphase,thetrazodonegrouphad
agreaterreductioninmigrainefrequency(trazodonereducedfrom2.1+0.2attacks/monthto
1.8+0.2vs.placeboincreasedfrom1.8+0.1to2.1+0.2,p<0.005)andduration(from10.7+1.3to
4.9+0.7vs.from11.9+1.3to13.1+1.3,p<0.001)ascomparedtotheplacebogroup.Noadverse
eventsarereportedinthemanuscriptandtheauthorsstatethatnoseriousadverseevents
occurred.Twopatientswithdrewfromthegroupinitiallyrandomizedtotrazodoneandthree
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patientswithdrewfromthegroupinitiallyrandomizedtoplacebo,duetoerrorsinmedication
administrationandonsetofnewillnesses.Nosamplesizecalculationsaregivenandthereforeitis
unclearhowthestudywaspoweredandforwhichoutcome.Themethodofrandomizationwasnot
describedandallocationconcealmentisnotmentionedinthetext,thereforeintroducinganunclear
riskofselectionbias.Thestudywasthusgivenaratingofunclearriskofbias.
Giventhatthisistheonlystudyontrazodoneforpediatricmigraineprophylaxisandgivenits
somewhatunusualresults(ie.superiorityoftrazodoneoverplaceboonlyseenduringsecond
treatmentphase),itwouldbeimprudenttodrawconclusionsontheefficacyoftrazodoneforthis
indication.
3.3.7 Nimodipine
Nimodipineisacalcium-channelblocker,inthesamecategoryasflunarizineandcinnarizine.As
withothermigraineinterventions,itsexactmechanismofactionisunclear.Arecentanimalstudy
foundthatnimodipineadministrationresultedindownregulationofcalcitoningene-related
peptide(CGRP)expressioninthetrigeminalnucleuscaudalis145.CGRPisthoughttoplayan
importantroleinmigrainepathophysiology:itslevelsriseduringmigraine,CGRPadministration
cantriggermigraines,andanewclassofmedicationscalledtheCGRPreceptorantagonistshold
promiseformigraineprophylaxis146.Therefore,thepotentialefficacyofnimodipineinmigraine
prophylaxiscouldbeexplainedbydownregulationofCGRPinthetrigeminalnucleuscaudalis,a
brainareathatiscriticalinmigrainepathogenesis.Inaddition,researchhasshownthatinhibition
ofL-typevoltage-gatedcalciumchannels,whichoccurswithnimodipine,decreasestherateof
corticalspreadingdepression147,whichisbelievedtounderliemigraineaura131.Therefore,there
areacoupleofpotentialmechanismsbywhichnimodipinemayeffectivelypreventmigraines.
NeitherHealthCanadanortheFDAapprovedtheuseofnimodipineformigrainepreventionin
adultsorchildren.
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Onlyonerandomizedstudyhasinvestigatedthepotentialrolefornimodipineinpediatric
migraineprophylaxis.TheBattistellaetalgrouprandomized37participantsaged7to18yearsto
nimodipine10-20mgdailytidortocolor-matchedplaceboinadouble-blind,2-arm,placebo-
controlled,crossovertrial148.SimilarlytotheotherBattistellaetaltrial,a4-weekwashoutperiod
occurredbetweenthetwotreatmentperiodsandeachtreatmentperiodwas12weeksinduration.
Afterthefirsttreatmentphase,thegroupsdidnotdifferintermsofmigrainefrequencynor
migraineduration.However,migrainefrequencywasreducedtoagreaterextentinparticipants
takingnimodipineduringthesecondtreatmentphase(from2.7+0.8attacks/monthto1.9+1.7vs.
from2.6+0.8to2.8+0.6,p<0.01),thoughnodifferencewasseenformigrainedurationinthatphase.
Threepatientsexperiencedmildtransientgastrointestinalsymptomsduringtheinitialdaysof
nimodipinetreatment,thoughnootheradverseeventswerereported.Themethodsof
randomizationandallocationconcealmentwerenotdescribed,introducingthepotentialfor
selectionbias.Theremayhavealsobeenattritionbiasas18.9%oftheparticipantswithdrewfrom
thestudyanditwasnotmadeclearforwhatreason(s)andwhichgroup(s)theseparticipants
belongedto.Therefore,theriskofbiaswasratedasunclearforthistrial.
Basedonthisonestudy,theefficacyandtolerabilityofnimodipineforpediatricmigraine
prophylaxiscannotbeestablished.
3.3.8 Cinnarizine
Cinnarizinehastwoprimarymechanismsofaction:itactsasacalcium-channelblockerandalso
hasantihistaminergicproperties149.Itspotentialmechanismofactionismigraineisnotknown.One
smallstudyfoundthatcinnarizineinducedserotoninreleasefromplateletsandinhibitedplatelet
aggregationinbothhealthyvolunteersaswellasmigraineurs150.However,giventhecomplex
pathophysiologyofmigraine,whichisstillnotfullyunderstood,itisunclearastowhetherthese
effectsseeninthissmallstudycouldunderliecinnarizine’spotentialmechanismofactionin
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migraine.Atthepresenttime,cinnarizinedoesnothaveHealthCanadanorFDAapprovalforusein
anyconditionincludingmigraine.
Onerandomizedtrialoncinnarizinewasincludedinthisreview.Ashrafietalrandomized62
childrenaged5to17yearstoreceiveeithercinnarizine1.5mg/kgdailyor50mgforthoseweighing
above30kg,orplacebofora12-weektreatmentperiod151.Therewasahigherresponserateinthe
cinnarizinegroupwith60%ofthecinnarizineparticipantsachievinga50%orgreaterreductionin
attackfrequencyascomparedtoonly31.3%oftheplaceboparticipants(p=0.023).Bothgroupshad
statisticallysignificantreductionsinheadachefrequencyovertimebutnogroupdifferenceswere
seen.Itappearsthatcinnarizinewasmoreeffectivethanplaceboinseveralofthesecondary
outcomes,includinginreducingmigraineintensityandduration.Threeparticipantsinthe
cinnarizinegrouphaddrowsinessascomparedtooneintheplacebogroupandonecinnarizine
participantgained2.5kgonthemedication.Giventhelackofdescriptionofallocationconcealment
inthemanuscript,thestudywasgivenanunclearriskofselectionbias,andthusanunclearriskof
biasoverall.Therefore,overall,thissmallstudyfoundevidencefortheefficacyandtolerabilityof
cinnarizineinthispatientpopulation,thoughfindingsneedtobereplicatedpriortodrawing
conclusionsonitsefficacy.
3.3.9 Dimethothiazine
Dimethothiazineisaphenothiazinemedicationinthecategoryofneurolepticantipsychotic
medications.ItisnotapprovedbyHealthCanadanortheFDAandisnotavailableinNorthAmerica,
thoughitisavailableinsomecountriesworldwide.Itspotentialmechanismofactioninmigraineis
unknown.
Asdescribedabove,MachínAltueñaetalcomparedtheefficacyofflunarizine,dimethothiazine
andplaceboinagroupof45childrenaged5to13years134.Thestudywasarandomized,double-
blind,parallel-grouptrialcarriedoutinSpain.Allofthegroupshadsimilarratesofimprovement:
93.3%ofthedimethothiazinegrouphadclinicalimprovementvs.86.7%oftheflunarizinegroupvs.
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80%oftheplacebogroup(p>0.05)andtherewerenosignificantdifferencesinthesecondary
outcomes.Themostcommonsideeffectwasweightgain,occurringin23.1%oftheflunarizine
group.Thestudywasratedashavingahighriskofbiasgivenhowsmallthegroupswereandthe
lackofsamplesizecalculations,introducingthepotentialforasignificantlackofpowertodetect
clinicallymeaningfulgroupdifferences.Nomentionismadeofallocationconcealmentinthe
manuscript,andthustherewasanunclearriskofselectionbias.Givenmethodologicalissueswith
thetrial,onecannotdrawconclusionsontheuseofdimethothiazineforthisindicationfromthis
onestudy.
3.3.10 Papaverine
Papaverineisavasoactivecompoundthathasbeenstudiedaspotentialinterventionfor
preventingmigraines.Inrats,papaverineappearstorevertcorticalspreadingischemiatotheless
severephenomenonofcorticalspreadingdepression152.Ashasbeenmentionedpreviously,
migraineauraisbelievedtobecausedbycorticalspreadingdepression131,andifpapaverine
lessensthisprocess,itcouldperhapsplayaroleinmitigatingmigraine.Papaverinedoesnothave
HealthCanadanorFDAapprovalforuseinmigraine.
Sillanpääetalcarriedouttheonlyrandomizedcontrolledtrialassessingtheefficacyof
papaverineinchildrenandadolescentswithmigraine153.Thirty-sevenparticipantsagedbetween6
and15yearswithmigraineorvascularheadacheswererandomizedtoreceiveeitherpapaverine,
startingatadoseof5mg/kgdailydividedbidortidanddoublingto10mg/kgdayinonemonthif
tolerated,orplacebo,fora2monthtreatmentperiod.Significantlymoreparticipantstaking
papaverinehadpainfreedomduringthetreatmentperiodascomparedtoplacebo(6participants
outof19randomizedtopapaverinevs.0participantsoutof18randomizedtoplacebo,p<0.001).
Althoughspecificnumericalresultsarenotgiveninthemanuscript,afigureandasentenceinthe
textalludetosignificantlybetterimprovementinmigrainefrequency,durationandintensityinthe
papaverinegroupascomparedtoplacebo(p<0.001).Theadverseeventprofilesarenotreportedin
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themanuscript.Thisstudyhadanoverallunknownriskofbiasgiventheprobabilityofselection
bias:nomentionwasmadeofallocationconcealment.Inaddition,therewasapotentialforattrition
bias,giventhatfiveparticipantswereexcluded:twoforadverseeventsthatwerenotdescribedand
threeduetoinadequatecompliancewiththeintervention.Thereisnomentionofwhichgroup(s)
theybelongedto,andthereforetheriskofattritionbiasisunknown.Basedonthisonesmalltrial,it
isnotpossibletomakeaconclusionontheefficacy,andespeciallythesafety,ofpapaverineasa
pediatricmigrainepreventativeintervention.
3.4. UnpublishedTrials
Aftersearchingtheclinicaltrialregistries,threeunpublishedrandomizedcontrolledtrialswith
potentialforeligibilitywereidentified(clinicaltrialregistrynumbers:IRCT2013092914809N1,
EUCTR2010-019947-21-ESandIRCT2013020412361N1).Theauthorswerecontactedabouttheir
trials,toinquireabouteligibilityandpublicationstatus:Dr.AfshinFayyazi,Dr.LalaJarinandDrs.
AhmadTalebianandBabakSoltani,forclinicaltrialsIRCT2013092914809N1,EUCTR2010-
019947-21-ESandIRCT2013020412361N1,respectively.Attemptsatcontactingtheauthorswere
madeelectronicallyviae-mailonthefollowingdates:July2nd2015,July14th2015andOctober22nd
2015.Unfortunately,noneoftheauthorsrepliedtothee-mails,andcontactwasthereforenot
made.Becauseoftheimpossibilityofknowingwhetherthesetrialswereindeedeligibleornot
basedonthelimitedinformationontheclinicaltrialregistries,andbecausetheresultsofthese
studieswereunavailable,thesetrialscouldnotbeincludedinthissystematicreview.Their
existenceintroducesthepossibilityofpublicationbiasintothisbodyofliterature.
3.5. Meta-Analyses
3.5.1 Riboflavinvs.Placebo
Twostudiesassessedtheefficacyofriboflavinforthepreventionofmigrainesinchildrenand
adolescents114,115.However,thestudiesweretooclinicallyheterogeneoustoallowforpoolingina
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meta-analysis.Themainpointsofdissentwererelatedto:1)thedosing:riboflavinwasdosedat
200mg/dayintheMacLennanetaltrial114andat50mg/dayintheBruijnetaltrial115,2)the
outcomes:therewasinadequateoverlapinthemeasuredoutcomesforpoolingofthedata.
Therefore,theresultsofthesestudiesaredescribedqualitativelyabove,butnostatisticalpooling
wascarriedoutontheriboflavindata.
3.5.2 Topiramatevs.Placebo
Althoughsixstudiesontopiramateforpediatricmigraineprophylaxiswereincluded,onlyfive
ofthesestudies120–122,124,125includedefficacydataandonlythreeofthesestudies120–122had
substantialenoughoverlapintheirreportedoutcomestoallowforpoolinginameta-analysis.Inan
attempttoincludetheothertwotopiramatestudies124,125withefficacydatainthemeta-analysis,
theauthors(LisaM.Ford125andPaulWinner124)werecontactedwithinquiriesaboutaccessto
potentiallyunpublisheddatathatwouldpermitinclusionoftheirtrialsinthemeta-analysis.Dr.
Fordindicatedtomethatthemanuscriptassociatedwiththepublishedabstract125doescontainthe
requesteddata,butthatitcouldnotbesharedatthistimegiventhatthemanuscriptisin
preparationforpublication(LisaFord,personalcommunicationoveremail,July15th2015).Three
attemptstocontactDr.Winner(July2nd2015,August11th2015andOctober22nd2015)were
unsuccessfulandthedatarequiredtoaddthatstudy124tothemeta-analysiswerenotobtained.In
thisway,themeta-analysisdoesnotfullyreflecttheextentofthedataontopiramateforpediatric
migraineprophylaxis.Eachofthestudieswithmissingdataconsistedofapooledanalysisofdata
frompreviouslypublishedtrials:theFordetal125pooledanalysiscomprised260childrenaged6to
17yearsfrom5separatetrialsandtheWinneretal124pooledanalysiscomprised49adolescents
aged12to17yearsfrom3separatetrials.Thus,thenumberofparticipantsfromthesetwostudies
waslargeandfailuretoincludethisdatainthemeta-analysiscertainlycompromisedtheprecision
oftheestimateoftheeffectsize.However,bothofthesestudiesexcludedfromthemeta-analysis
alsoshowedfavorableefficacyresultsfortopiramate,anditisnotexpectedthattheirinclusionin
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themeta-analysiswouldhaveresultedinachangeindirectionintheestimateoftheeffectsizenor
wouldweexpectadramaticallydifferentpointestimateoftheeffectsize.
Thethreestudies120–122includedinthemeta-analysiswereamenabletopoolinggiventhateach
ofthestudiesreportedonthepercentagechangeinthefrequencyofmigrainescomparingbaseline
tothetreatmentperiod.Becauseofsignificantclinicalheterogeneityinthedatafromthethree
includedstudies,arandomeffectsinversevariancemethodwasusedtoestimatetheestimateof
theeffectsize.Apooledpointestimateofthemeandifferencewith95%confidenceintervalswas
generatedusingRevMan.Themeandifferencewaschosentoestimatetheeffectgiventhatall
studiesusedthesamescaletomeasuretheoutcomeofchangeinmigrainefrequency,thatis,the
percentageona100-pointscale.
Theresultsofthemeta-analysiscomparingtheefficacyoftopiramatetoplacebointermsofthe
percentagereductioninmigrainefrequencyaredisplayedinFigure4.Theestimateofthemean
differenceis21.4%(95%CI:9.7-33.0%),whichcanbeinterpretedassuch:basedontheresultsof
thesethreetrials,topiramateisexpectedtoreducemigrainefrequency21.4%morethanplacebo
overthecourseoftreatment,andthisresultisstatisticallysignificant.
Figure4.Topiramatevs.placebo:pooledanalysisofthepercentage(%)reductioninmigrainefrequencycomparingbaselinetothetreatmentperiod
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3.5.3 Flunarizinevs.Placebo
Althoughthreetrialscomparedflunarizinetoplaceboforpediatricmigraineprophylaxis132–134,
therewerenosharedoutcomesbetweenthetrials.Therefore,itwasnotpossibletopoolresults
fromthesethreestudiesintoameta-analysis.
3.5.4 OtherInterventions
Alloftheotherinterventionsincludedinthissystematicreviewwereonlyassessedinisolated
studies,therebyprecludingtheuseofmeta-analysistopooldata.
4. DISCUSSION
Inthissystematicreviewandmeta-analysis,19eligiblearticleswereidentified,comprising12
interventionsforpediatricmigraineprophylaxis:butterbur,riboflavin,topiramate,valproicacid,
flunarizine,timolol,clonidine,trazadone,nimodipine,cinnarizine,dimethothiazineandpapaverine.
Onlythreeinterventionswereassessedinmorethanoneeligiblestudy:riboflavin,topiramateand
flunarizine.Theremaininginterventionswereonlystudiedinsingletrials,oftenofpoorquality
witheitherunclearorhighriskofbias.Giventhisandgivenexcessiveclinicalheterogeneityforthe
interventionsthatwerestudiedinmultipletrials,onlyonemeta-analysiswaspossible:topiramate
vs.placebo.Thismeta-analysisislimitedbythefactthatonlyhalfoftheeligiblestudieswere
amenabletopooling,givenalackofoverlappingoutcomesandhighclinicalheterogeneity.
Therefore,theresultsofthismeta-analysismustbeinterpretedinlightofthefactthatthepooled
resultsdonotreflecttheentirebodyofliterature.
Giventhelimitationsinvolumeandqualityofevidence,fewconclusionscanbedrawnfromthis
systematicreview.Asdescribedabove,topiramateappearstobesafeandeffectiveforthe
preventionofmigraineinthepediatricpopulation,basedonsixeligiblestudiesandonemeta-
analysiscomprisedofthreeofthesetrials.Bothbutterburandvalproicacidappeartohavelimited
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tolerabilityinthispopulationbasedonlimitedevidence.Theremaininginterventionsincludedin
thissystematicreview(ie.riboflavin,flunarizine,timolol,clonidine,trazadone,nimodipine,
cinnarizine,dimethothiazineandpapaverine)lackedthevolumeandqualityofevidencerequired
formakingconclusionsaboutefficacyandsafety.
Themostsignificantconclusionthatcanbedrawnfromthissystematicreviewpertainstothe
paucityofevidenceforinterventionsaimedatpreventingmigraineinchildrenandadolescents.
Tworelatedprojects,onesystematicreview154andonemeta-analysis155,withcomparable
objectivesandscopeotherthanthefactthatonlypharmaceuticalinterventionswereeligible,have
drawnsimilarconclusionsabouttheevidenceforpediatricmigraineprophylaxis.Thereisadire
needforhighquality,adequatelypoweredandwell-justifiedclinicaltrialsinthisbodyofliterature.
Oneofthechallengesincarryingouttrialsofinterventionsinthepediatricpopulationpertains
totheethicsoftreatingchildrenwithplacebo.Althoughitisgenerallyacceptedthatinterventions
mustbecomparedtoplaceboinordertoestablishefficacy,somegroupshavecalledthisphilosophy
intoquestion.Ithasbeenarguedthat,inthepediatricpopulation,itmaybemoreethicaltouseoff-
labelinterventionsthatarecommonlyprescribedinclinicalpracticeasactivecomparators,rather
thanusingplacebocomparators156.Inthiscontext,non-inferiorityhypothesesmaybemore
appropriatethansuperiorityhypotheses.Unfortunately,therearenoestablishednon-inferiority
marginsforcommonoutcomesusedinmigraineresearch.Onlyafewpublishedmigrainetrials
withadultparticipantshaveusednon-inferiorityhypotheses157–159,andneitheremployedawell-
justifiednon-inferioritymargin.Inordertoaddressthisgapintheliterature,theNon-Inferiority
MarginsinMigraine(NIMM)Researchsurveywasconceived.TheNIMMsurvey’srationale,
methodsandresultsaredescribedbelowinPartII.
Giventheneedforhighqualityevidenceinthisbodyofliterature,aclinicaltrialwithlowriskof
biasandadequatepowerwasdesigned.TheresultsoftheNIMMsurveywereusedtodeterminethe
samplesizeforthistrial,giventhatitiscomprisedofbothasuperiorityhypothesisandanon-
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inferiorityhypothesis.ThetrialprotocolisdescribedbelowinPartIII.WiththeNIMMsurveyand
theproposedclinicaltrial,weaimtostrengthenthebodyofevidenceontheefficacyof
interventionsforthepreventionofmigraineinchildrenandadolescents.
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THESISPARTII:SURVEYONNON-INFERIORITYMARGINSFORMIGRAINETRIALS:DeterminingaNon-InferiorityMarginforMigraineTrials:TheNon-InferiorityMarginsinMigraineResearch(NIMM)Survey
1. Background
Traditionally,clinicaltrialshavebeendesignedaroundwhatisreferredtoassuperiority
hypotheses160.Whensettingasuperiorityhypothesis,theinvestigatorsareattemptingtodisprove
thenullhypothesisthattwointerventionsdonotsignificantlydiffer,thatis,thegoalistoshowthat
oneinterventionissuperiortotheother.Superiorityhypothesesareestablishedbasedonsettinga
minimalclinicallyimportantdifference(MCID).TheMCIDisthedifferencebetweenthe
interventionsthatisfelttobesufficienttocallthenewinterventionclinicallysuperiortothe
comparativeintervention.
Althoughsuperiorityhypothesesarethemostwidelyusedindesigningclinicaltrialsandare
thusthemostfamiliartothescientificcommunity,theyarenotalwaysthemostappropriatetypeof
hypothesistoemployfortheclinicalquestion.Asthemedicalliteraturegrowsandtherangeof
evidence-basedtreatmentoptionsexpands,poweringastudybasedonthehypothesisthatone
interventionissuperiortothenextisnotalwaysthemostclinicallyrelevantorappropriateoption.
Forexample,inmanyareasofmedicine,thereareinterventionsthatareknowntobesafeand
effectivebasedonpriorevidence,andinvestigatorsmaywishtocomparetheseinterventionsto
newinterventionsthatarelessexpensive,easiertouseoraccess,orperhapsmoretolerableto
patients161.Inthesetypesofscenarios,themedicalcommunitywouldlikelyadoptthenew
interventionifitwasshowntobenolesseffectivethantheestablishedintervention,asopposedto
requiringittohaveevidenceforsuperioritytotheestablishedintervention.Theneedtoshow
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superiorityisobviatedbytherelativeadvantagesthatthenewinterventionhasoverthe
establishedintervention(e.g.cost,easeofuse,sideeffectprofile,etc).Therefore,designingthetrial
withthegoalofestablishingsuperiorityofthenewinterventionovertheestablishedintervention
wouldbeinappropriate,becauseifsuperiorityisnotshownstatistically,thenewinterventionmay
berejectedbythemedicalandscientificcommunities,eventhoughitmayfactbeaseffectiveasthe
establishedinterventionwhilstofferingrelativeadvantagesbeyondefficacy.Inthistypeof
situation,anon-inferiorityhypothesisismoreappropriatethanasuperiorityhypothesistothe
goalsofthetrialandismoreclinicallyrelevant.
Non-inferiorityhypothesesareusedwhentheobjectiveofthetrialistoshowthatanew
interventionisnoworsethantheestablishedinterventionrelativetoitsefficacyortolerability162.
Inordertoestablishanon-inferiorityhypothesisandgenerateanestimateofanappropriate
samplesizetotestthishypothesis,investigatorsmustdesignateanon-inferioritymargin(delta).
Essentially,non-inferiorityisbasedonshowingthatthedifferencefoundbetweentheestablished
interventionandthenewinterventionissmallerthanapre-definedmargin,thenon-inferiority
margin(seefigure5).Therefore,thenullhypothesisinanon-inferioritytrialisthatthenew
interventionisinferiortotheestablishedinterventiongivenadifferencebetweentheinterventions
thatisequaltothenon-inferioritymarginorlargerthanthenon-inferioritymargin.
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Figure5.Illustrationofthedifferencebetweenasuperiorityandnon-inferiorityhypothesis
Figure5.Illustrationoftheconceptofanon-inferiorityhypothesis.Aninterventionisconsiderednon-inferiorwhentheconfidenceintervalfortheestimateofitseffectdoesnotincludevaluesbelowthenon-inferioritymargin(–delta).Asthefigureillustrates,aconclusionofsuperioritycanstillbedrawnwithanon-inferiorityhypothesiswhentheconfidenceintervalfortheestimateoftheeffectofaninterventionisrestrictedtovaluesabovezero.
Theprocessofestablishinganon-inferioritymarginrequirescarefulconsideration.Choosingan
excessivemarginwillresultinclinicallyinferiorinterventionsbeingdeemednon-inferiorto
establishinginterventions,whereaschoosingtoosmallamarginwillresultinrejectionofan
interventionthatmaybeclinicallynon-inferior,andwillunnecessarilyinflatethesamplesizeofthe
trial160.Inaddition,non-inferioritymarginsshouldnotexceedtheMCID,forobviousethicaland
intuitivereasons.Guidelinesrecommendchoosingthemarginbasedonbothstatisticalandclinical
considerations163.Severaltechniquesforsettinganon-inferioritymarginhavebeendescribed.For
example,avarietyoftechniqueshavebeenproposedbasedontheuseofhistoricaldata162.One
suchtechniqueinvolvesretrievingdatafromtrialsthathavecomparedtheestablishedintervention
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toplacebo.Thedifferencebetweentheestablishedinterventionandplacebocanthusbeobtained,
andonecandetermineapercentageofthatdifferencethatwillbecalledthenon-inferiority
margin160.Althoughthishistoricalapproachtheoreticallyallowsonetoconcludethatanon-inferior
interventionisalsosuperiortoplacebo,amajorassumptionismadeintheprocess:thatthe
establishedinterventionwillhaveasimilareffectinthecurrenttrialstoitseffectinpriortrials162.
Thisassumptioncanneverbecompletelytrue,giventhatstudypopulations,trialset-upanddesign
issueswillalwayscreateheterogeneitybetweentrials.Anotherapproachisbasedontheopinions
ofexpertsand/orstakeholders.Inthisway,individualswithexpertiseinthefieldand/or
stakeholdersareconsultedabouttheiropinionsonanappropriatenon-inferioritymargin163.This
approach,whilesubjective,isarguablypreferableinthatthehypothesisofthetrialwillbedriven
byexpertorstakeholderconsensus,andtheresultsofthetrialarethereforemorelikelytobe
pertinenttotheknowledgeusersandconsequentlymorelikelytobeappliedintheclinicalcontext.
Unfortunately,itappearsthatthemajorityofnon-inferioritytrialsarepublishedwithoutan
adequatedescriptionorjustificationforthechoiceofthenon-inferioritymargin.Arecent
systematicreviewfoundthatonly23%ofnon-inferioritytrialsjustifiedtheirchoiceofanon-
inferioritymargin164.Thisflawintheliterature,coupledwiththeincreasingprevalenceofnon-
inferioritytrials161,164,isalarming.Severalreasonscouldexplainthisdeficiency:inadequate
trainingofinvestigatorsregardingtheconductandreportingofnon-inferioritytrials164,journals
notenforcingadherencetotrialreportingguidelines164,orperhaps,investigatorschoosingtoset
thenon-inferioritymarginthemselvesratherthanconsultinghistoricaldataorexpertcolleagues
giventhetimeandresourcerequirementsassociatedwiththeseapproaches.
Non-inferioritytrialsappeartobeunderusedintheareaofmigraineresearch.Onlyafew
publishedtrialsinthisareahavetestednon-inferiorityhypotheses157–159.Toourknowledge,none
ofthesetrialsprovidedajustificationforthechoiceofthemargin.Therefore,itappearsthat
headacheexpertshavenotyetbeensurveyedfortheiropinionsonclinicallyacceptablenon-
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inferioritymarginsforoutcomesusedinmigrainetrials.Resultsofsuchasurveywouldbevery
usefulinthedesignoffuturenon-inferioritytrials,giventhattheywouldprovideareferencefor
investigatorstouseinchoosingtheirnon-inferioritymargins.Furthermore,becausethe
InternationalHeadacheSocietyhaspublishedGuidelinesforControlledTrialsofDrugsin
Migraine165,thereareestablishedandacceptedstandardprimaryoutcomesthatshouldbeusedin
migrainedrugtrials,thusfacilitatingtheuseofnotonlyuniversalprimaryoutcomesbutalso
associatednon-inferioritymargins.
TheaimofthisstudyistosurveyNorthAmericanheadacheexpertsregardingtheiropinionson
acceptablenon-inferioritymarginsforprimaryoutcomesinmigrainetrials.
2. Objectives
2.1. Primaryobjectives
a. Toestablishaclinicallyacceptablenon-inferioritymarginfortherecommended
primaryoutcomeintrialsofmigraineprophylaxis165,thatis,thechangeinthe
numberofmigraineattackscomparingbaselinetothetreatmentperiod,througha
surveyofheadacheexpertsinNorthAmerica.
b. Toestablishaclinicallyacceptablenon-inferioritymarginfortherecommended
primaryoutcomeintrialsofacutemigrainetreatment165,thatis,thepercentageof
patientswhoareheadachefree2hoursaftertreatment,throughasurveyof
headacheexpertsinNorthAmerica.
2.2. Secondaryobjectives
c. Toestablishclinicallyacceptablenon-inferioritymarginsforimportantsecondary
outcomesintrialsofmigraineprophylaxis165throughasurveyofheadacheexperts
inNorthAmerica.Secondaryoutcomesofinterestwillbe:
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• Thechangeinthenumberofmigrainedayscomparingbaselinetothe
treatmentperiod
• Theintensityoftheheadacheasmeasuredbythe4-pointseverityscale
(0=noheadache,1=mildheadache,2=moderateheadache,3=severe
headache)
d. Toestablishclinicallyacceptablenon-inferioritymarginsforimportantsecondary
outcomesintrialsofacutemigrainetreatment165throughasurveyofheadache
expertsinNorthAmerica.Secondaryoutcomesofinterestwillbe:
• Thepercentageofpatientswhohaveamigrainerelapsewithin48hoursof
treatment
• Thepercentageofpatientswithsustainedpainfreedom(ie.painfreedom
2hoursaftertreatmentandmaintained48hoursaftertreatment)
3. Methods
3.1. StudyDesign&Protocol
TheNon-InferiorityMarginsinMigraineResearch(NIMM)surveywasdesignedtoestablish
clinicallyrelevantnon-inferioritymarginsthroughexpertopinionforoutcomescommonlyusedin
migraineclinicaltrialsandendorsedbytheInternationalHeadacheSociety’sGuidelinesfor
ControlledTrialsofDrugsinMigraine165.TheNIMMsurveycomprised11questions.Thefirstfive
questionspertainedtodeterminingparticipants’eligibilitytocompletethesurveyandto
characterizingparticipants(eg.adultvs.childneurologist,percentageofpracticedevotedto
research,etc–seeAppendixG).Theremainingsixquestionsaimedtodetermineparticipants’
opinionsaboutnon-inferioritymarginsforoutcomesusedinmigrainetrials.Theoutcomesof
interestforprophylactictreatmenttrialswere:thechangeinthenumberofmonthlymigraine
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attackscomparingbaselinetothetreatmentperiod,thechangeinthenumberofmonthlymigraine
dayscomparingbaselinetothetreatmentperiodandthechangeintheaveragemigraineintensity
comparingbaselinetothetreatmentperiod.Theoutcomesofinterestforacutetreatmenttrials
were:theabsolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention,the
absolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatmentand
theabsolutepercentageofpatientswithsustainedpainfreedom.Withintheinitialfivequestions,
branchinglogicwasusedtonotifyparticipantsoftheirnon-eligibilitywhereapplicable.For
example,inquestion1,participantswereaskedwhatkindofpractitionertheyidentifyas:anadult
neurologist,achildneurologistor‘other’.Forparticipantsselecting‘other’,branchinglogicwas
usedtodisplayanotificationofnon-eligibility(seeAppendixG).
TheAmericanHeadacheSociety(AHS)andtheCanadianHeadacheSociety(CHS)were
contactedandaskedtodistributethesurveytotheirmembersviaemail.Thesurveywasapproved
fordistributionbybothsocieties.TheinitialemailsinvitingAHSandCHSmemberstocompletethe
surveyweredistributedinNovember2015.Follow-upemailsremindingpotentialparticipants
aboutthesurveyweresentonemonth(December2015)andtwomonths(January2016)following
theinitialinvitationemail.
ThesurveyswereadministeredanonymouslytoparticipantsusingResearchElectronicData
Capture(REDCap™).REDCap™isasecurewebapplicationwithasurveymodulethatallowsfor
bothsurveydesignanddistributioninthecontextofasecureplatform.Potentialparticipantswere
presentedwithanemail(seeAppendixE)thatbrieflyexplainsthesurveyandwereprovidedwitha
linktotheREDCap™survey(seeAppendixG).Anintroductionandconsentscriptwaspresentedto
interestedpartiesatthebeginningofthesurvey,andprovideddetailspertinenttotheconsent
process.Essentially,theintroductionscriptexplainedconceptspertinenttothestudyandthe
consentscriptexplainedthatcompletionofthesurveyisnotexpectedtoengenderanyspecific
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harmsorbenefits,thatidentifyinginformationwillnotbecollectedinthecontextofthisstudy,and
thatparticipationinthesurveyisprovidingimpliedconsentforparticipationinthestudy.
TheOttawaHealthScienceNetworkResearchEthicsBoardapprovedthestudyprotocol
(OHSN-REBProtocol#20150651-01H).
3.2. Inclusion&ExclusionCriteria
3.2.1 InclusionCriteria
a. Practicingadultorchildneurologist
b. Expertiseinheadachemedicine
3.2.2 ExclusionCriteria
c. CannotreadandunderstandEnglish
3.3. Statistics
DatawereexportedfromREDCap™intoSAS®4.0.Descriptivestatisticsweregeneratedfor
eachitem(frequenciesandpercentages).Chisquare(χ2)testsofgoodnessoffitwereemployedto
assessiftherewasasignificantdifferencebetweentheproportionsofresponseitemsforeach
question.
4. HumanProtection
4.1. TimeCommitment
Thetimecommitmentinvolvedinparticipatinginthesurveywastheonlyethicalconsideration
thatpertainstothisproject.Participantscompletedaten-itemsurvey,requiringatime
commitmentof5-10minutesforcompletion.
4.2. RisksInvolvedinParticipatingintheStudy
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Itwasnotanticipatedthatanyriskswouldbeassociatedwithstudyparticipation.Theonly
actionassociatedwithparticipationwassurveycompletion.Therewasnoexperimental
manipulation,treatmentnorphysicaltestingofstudyparticipants.
4.3. BenefitsAssociatedwithParticipatingintheStudy
Therewerenoanticipatedbenefitsassociatedwithstudyparticipation.Studyparticipantswere
notofferedanyincentivesforparticipationandwerenotexpectedtodirectlybenefitfrom
publicationofitsresults.Theremotebenefitofimprovingfuturenon-inferioritytrialdesignsmay
beconstruedasabenefittosomeparticipants.
5. Results
Intotal,120individualscompletedtheNIMMsurvey.Twentyonerespondentswereineligible
toparticipateinthesurveybasedontheirresponsestotheinitialscreeningquestions:20
individualsdidnotidentifyasaneurologist,andoneindividualindicatedthattheyhadno
experiencepracticingHeadacheMedicine.Afterexcludingtheseineligibleparticipants,thefinal
samplesizeforthesurveycomprised99respondents.
RespondentcharacteristicsaredisplayedinTable3.Themajorityofthesample(84.9%)was
comprisedofadultneurologistsand74%ofrespondentsreportedpracticingintheUSA.Themost
commontypeofpracticewasacademic,with47.5%ofrespondentsclaimingtopracticeinthis
setting,while34.3%oftherespondentsreportedpracticinginthecommunityandtheremainder
reportedpracticinginamixedmodel.Respondentshadvaryingdegreesofexperiencepracticing
HeadacheMedicine(seeTable1);interestingly,alargenumberofrespondents(44.9%)reported
over20yearsofpracticeexperience.Themajorityofrespondentsreportedspendinglessthan10%
oftheirtimeonresearchactivities(59.6%),while23.2%reportedspending10-25%oftheirtime
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onresearch,andtheremainderofthesamplereportedthatover25%oftheirtimewasspenton
research(seeTable3).
Table3.CharacteristicsofNIMMrespondents
Characteristic Totalnumberofrespondents(missing)
N(percentage)
TypeofNeurologistAdultNeurologistChildNeurologist
99(0)
84(84.9)15(15.1)
LocationofPracticeUSACanada
96(3)
71(74)25(26)
TypeofPracticeAcademicCommunityMixedacademic/communitymodel
99(0)
47(47.5)34(34.3)18(18.2)
YearsPracticingHeadacheMedicine0-5years5-10years10-15years15-20yearsOver20years
98(1)
16(16.3)17(17.4)7(7.1)14(14.3)44(44.9)
PercentageofTimeDevotedtoResearch<10%10-25%25-50%50-75%>75%
99(0)
59(59.6)23(23.2)9(9.1)4(4.0)4(4.0)
Themostcommonlyselectednon-inferioritymarginforthechangeinthenumberof
monthlymigraineattackscomparingbaselinetothetreatmentperiodwas1attackpermonth,with
39.4%oftherespondentschoosingthismargin(seeTable4).Theresponsesfortheoutcomeof
monthlyattackswerenotevenlydistributed(p<0.0001).Forthechangeinthenumberofmonthly
migrainedays,44.4%oftherespondentsselected1dayastheirpreferrednon-inferioritymargin
andthiswasthemostcommonlyselectedmargin,withtheresponsesforthisoutcomebeing
unevenlydistributed(p<0.0001).Respondentsmostcommonlyselected1.0astheirpreferrednon-
inferioritymarginforthechangeinmigraineintensityonthe4-pointratingscale,with31.3%
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indicatingthismarginastheirchoice.Onceagain,theresponsestothisquestionwereunevenly
distributed(p<0.0001).
Table4.Non-inferioritymarginresponsesforprophylacticmigrainetrials
Outcome Totalnumberofrespondents(missing)
Margin Frequencyofrespondentsselectingmargin(percentage)
Changeinthenumberofmonthlymigraineattackscomparingbaselinetothetreatmentperiod
99(0) 0.25 8(8.1)0.5 28(28.3)0.75 6(6.0)1.0 39(39.4)1.25 8(8.1)Other* 10(10.1)
Changeinthenumberofmonthlymigrainedayscomparingbaselinetothetreatmentperiod
99(0) 0.5 20(20.2)0.75 7(7.1)1.0 44(44.4)1.25 4(4.0)1.5 16(16.2)Other* 8(8.1)
Changeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)
99(0) 0.2 9(9.1)0.4 28(28.3)0.6 18(18.2)0.8 8(8.1)1.0 31(31.3)Other* 5(5.0)
*SeeAppendixH
Forthefirstacuteoutcome,theabsolutepercentageofparticipantswhoarepain-free2
hoursaftertheintervention,41.4%ofrespondentsfeltthat5%wasthemostappropriatenon-
inferioritymargin(seeTable5).Thelattermarginwasthemostpopularselection,andthe
responsestothisquestionwereunevenlydistributed(p<0.0001).Themostcommonlychosennon-
inferioritymarginforthepercentageofpatientswithamigrainerelapsewithin48hoursof
treatmentwas5%,with42.4%ofrespondentsindicatingthatthisoptionwastheirpreference.
Again,theresponsestothisitemwerenotevenlydistributed(p<0.0001).Finally,forthe
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percentageofpatientswithsustainedpainfreedomat48hours,5%wasonceagainthemost
popularresponseitem,with42.4%oftherespondentsselectingthismargin.Theresponsestothis
questionwerenotevenlydistributed(p<0.0001).
Table5.Non-inferioritymarginresponsesforacutemigrainetrials
Outcome Totalnumberofrespondents(missing)
Margin Frequencyofrespondentsselectingmargin(percentage)
Absolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention
99(0) 2.5 17(17.2)5 41(41.4)7.5 5(5.0)10 25(25.3)12.5 7(7.1)Other* 4(4.0)
Absolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatment
99(0) 2.5 20(20.2)5 42(42.4)7.5 9(9.1)10 21(21.2)12.5 4(4.1)Other* 3(3.0)
Absolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionandremainpain-free48hoursaftertheintervention)
99(0) 2.5 18(18.2)5 42(42.4)7.5 8(8.1)10 22(22.2)12.5 5(5.1)Other* 4(4.0)
*SeeAppendixH
Basedonthemostcommonresponsesselectedforeachitem,expertopiniononappropriate
non-inferioritymarginsfortheoutcomesstudiedissummarizedinTable6.
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Table6.Expertopiniononappropriatenon-inferioritymarginsforcommonlyusedmigraineoutcomesProphylacticTrialOutcomesOutcome Margin Percentageofexperts
selectingmarginChangeinthenumberofmonthlymigraineattackscomparingbaselinetothetreatmentperiod
1day 39.4%
Changeinthenumberofmonthlymigrainedayscomparingbaselinetothetreatmentperiod
1day 44.4%
Changeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)
1.0point 31.3%
AcuteTrialOutcomesOutcome Margin Percentageofexperts
selectingmarginAbsolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention
5% 41.4%
Absolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatment
5% 42.4%
Absolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionandremainpain-free48hoursaftertheintervention)
5% 42.4%
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6. Discussion
TheNIMMsurveysummarizestheopinionsofneurologistswithexpertiseinHeadache
Medicineonappropriatenon-inferioritymarginsforoutcomescommonlyusedinclinicaltrialsof
interventionsformigraine.Thissurveyisuniqueinprovidingthemigraineresearchcommunity
withexpertopinionfromalargenumberofHeadacheMedicinespecialistsonoptimalnon-
inferioritymarginsformigrainetrialoutcomes.
Itisinterestingtonotethatthemajorityoftherespondents(59.6%)reportedspendingless
than10%oftheirtimeonresearchactivities.Thus,oursamplewascomprisedofparticipantswho
areprimarilyengagedinclinicalHeadacheMedicine.Webelievethatthisisastrengthofthestudy,
giventhatclinicalHeadacheMedicinespecialistsaretheprimaryknowledgeusersvis-à-visclinical
trialsonmigrainetreatments.Anotherinterestingfeatureofoursamplepertainstotheexperience
levelofparticipants:59.2%ofparticipantsreported15ormoreyearsofexperienceinpracticing
HeadacheMedicine.Inaddition,thevarioustypesofpracticemodels(ie.academicvs.community
vs.mixedmodel)wereeachwellrepresentedinthesample.Therefore,webelievethatoursample
ofparticipantswasoptimalinthatitwasdiverseandthecollectivedegreeofclinicalexperience
wassignificant,therebymakingtheconclusionsdrawnmorecredibletoawiderangeofend
knowledgeusers.
Weusedseveralevidence-basedstrategiesinordertomaximizeparticipation166.Weusedsocial
exchangetheoryindesigningtheemailinvitationbyhighlightingtheminimalcoststoparticipants
(ie.brevityofthesurvey)andthepotentialbenefitstofutureresearchstudies.Wedidnotcollect
anypersonalorsensitiveinformation.Wealsoattemptedtooptimizerecruitmentbysendingtwo
follow-upcommunicationstopotentialparticipants.Finally,itisknownthatsendingsurveys
throughrespectedorganizationscancontributetooptimizingparticipation166,andwewereableto
havetheNIMMsurveysentoutthroughtheAHSandCHS.
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Respondentsselectedmultiple-choiceoptionsinordertoindicatetheiropinionsonthenon-
inferioritymargins.Onecouldarguethatthepre-specificationofmultiplechoiceoptionsleadsto
biasedresults,bylimitingrespondentstoavailableoptions.However,eachsurveyitemhadan
“Other”responseoption,wherebyparticipantscouldselectamarginoutsideofthoselistedinthe
multiplechoiceoptions.Giventhelownumberofrespondentsselecting“Other”asanoption(range
from3.0-10.1%),andgiventheheterogeneityofthewrittenresponsesassociatedwiththe“Other”
option(seeAppendixH),itmaybereasonabletoconcludethatdesigningthesurveydifferently,for
example,withfreetextentryasopposedtomultiplechoiceoptions,wouldnothaveyielded
drasticallydifferentresults.Thedecisionwasmadetousemultiplechoiceoptionssoastosimplify
thesurveyforrespondentsandensurethatthesurveywouldyieldasetmarginforeachoutcome.
Designingthesurveywithfree-textentryofmarginsmayhaveavoidedthepotentialproblemof
biasingrespondentsintoselectingparticularmargins,butinterpretationoftheresultswouldhave
beencomplicatedinthatitlikelywouldnothavebeenpossibletoselectonepreferredmarginfor
eachoutcomeinavalidmanner.Asurveywithsimilaraimssampledexpertopiniononnon-
inferioritymarginsforanticoagulantstopreventvenousthromboembolismpost-orthopedic
surgeryusingfree-textentryasameansofselectingthepreferredmargins,andtheresultsshowed
averywiderangeofresponsesthatwouldbedifficulttoapplytopractice167.
Severaladditionallimitationsofthissurveyshouldbenoted.Therewasahighlikelihoodof
coveragebiasgiventhatAHSandCHSmembershiplistswereusedasthesamplingframe.Itislikely
thatHeadacheMedicinespecialistswhoaremembersoftheseorganizationsdiffersystematically
fromHeadacheMedicinespecialistswhoarenotmembersoftheseorganizations.Membersare
likelymoreinvolvedinacademicactivitiesgiventhattheseorganizationspromoteandsupport
academicendeavorssuchasscientificmeetingsandresearchcollaborations.Languageminorities
arelikelysystematicallyunderrepresentedintheAHSandCHSasallcommunicationsandmeetings
areheldinEnglish.Thesurveyalsohadasignificantpotentialfornon-responsebiasforseveral
76
reasons.Firstly,althoughitwasnotpossibletodeterminethetotalnumberofeligibleHeadache
MedicinespecialistswithintheAHSandCHS,wesuspectthatourresponseratewaslowbasedon
thetotalnumberofmemberswhoweresentthesurvey(eg.1,211AHSmembersweresentthe
survey).BecausethesurveywasonlysentinEnglish,languageminoritieswerelikelysystematically
underrepresentedamongstsurveyrespondents.Therewasalsoasignificantpotentialfor
measurementerrorinthissurvey.Thesurveytopicwascomplexandalthoughanattemptwas
madeatformulatingtheclearestpossiblequestions,thesurveywasnotpilotedanditistherefore
possiblethatsomerespondentsfoundthequestionschallengingtoanswer.Althoughoutcomes
wereselectedjudiciously,throughconsultationofinternationalguidelines,patientswerenot
consultedonthechoiceofoutcomes.Thepatientperspectiveisthereforelackinginthissurveyand
thisisanimportantlimitationofthestudy.Therecommendednon-inferioritymarginswere
selectedusingthemodeoftheresponses.Althoughusingthemodeallowedustosimplytranslate
theresultsofoursurvey,itarguablymaynotprovidetheidealrepresentationoftherangeof
responses.
Astheliteratureonmigrainetreatmentexpandsandmoreinterventionsareconsistently
showntohavesuperiorefficacytoplacebo,non-inferioritytrialswillplayanincreasinglyimportant
roleinexpandingourknowledgeofsafeandeffectivetreatmentsformigraine.Thisstudyprovides
auniqueperspectivefromalargeandexperiencedgroupofHeadacheMedicinespecialistsontheir
opinionsregardingnon-inferioritymarginsforoutcomesusedinmigraineclinicaltrials.Itishoped
thattheseresultsmaybeusedinthedesignoffutureclinicaltrials,sothatappropriatesamplesizes
maybecalculatedbasedinpartontherecommendednon-inferioritymarginsderivedfromthis
survey.
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THESISPARTIII:DESIGNOFARANDOMIZEDCONTROLLEDTRIAL
1. BACKGROUND
Aswassummarizedabove,migraineisexceedinglycommoninchildren,affecting
approximately8%ofallchildrenandadolescentsworldwide1.Migraineisalsoasignificantcauseof
disabilityinadults2andchildren6–8.Theliteraturereviewpresentedinthebackgroundsection
above(seethesispartI)combinedwiththedataobtainedthroughthesystematicreview(seethesis
partI)provideacomprehensiveoverviewoftheevidencebaseformigrainemanagementin
pediatrics.
Severalconclusionscanbereachedafterreviewingtheevidenceforpediatricmigraine
prophylaxis.Firstly,amongstallcategoriesofinterventions,thepharmaceuticalshavebeenthebest
studied.Thisisunsurprisinggiventhatfundingforpharmaceuticalresearchismorereadily
availablethanfundingfornon-pharmaceuticalresearch,whichtendstohavelesscommercial
value168.Amongstthepharmaceuticals,themostextensivebodyofliteraturepertainstotheefficacy
andsafetyoftopiramateforthepreventionofmigrainesinchildrenandadolescents.Sixstudies
haveexploredthisquestion120–125,andtopiramateappearstobemoreefficaciousthanplacebofor
thisindicationbasedonbothaqualitativeandquantitativereviewoftheevidence.However,
topiramatealsoappearstobelesstolerabletopatientsthanplacebo,withahostofrelatively
commonsideeffectsincludingcognitivesideeffects,weightlossandanorexia,paresthesiasand
upperrespiratorytractinfections.Inadditiontothesixtopiramatestudies,thesystematicreview
identifiedelevenothernutraceuticalorpharmaceuticalinterventionsthathavebeenstudiedin
randomizedtrialsforthisindication:butterbur104,riboflavin114,115,valproicacid127,flunarizine132–
134,timolol137,clonidine142,trazadone144,nimodipine148,cinnarizine169,dimethothiazine134and
papaverine170.Inadditiontotheseinterventionswithevidencefromrandomizedstudies,ahostof
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pharmaceuticalandnutraceuticalinterventionshaveonlybeenassessedinnon-randomized
studiesorlowqualityrandomizedstudiesthatdidnotqualifyforthesystematicreview:
magnesium53,coenzymeQ1054,fishoils55,combinationnutraceuticalinterventions57–59,
levetiracetam70,71,amitriptyline75–77,L-5-hydroxytryptophan56,cyproheptadine76,pizotifen171and
Botox78,79.
Oftheinterventionswithanevidencebaseotherthantopiramate,fewholdpromiseaspotential
first-lineinterventionsforthepreventionofmigraineinchildrenandadolescents.Avarietyof
limitationsexistforsomeoftheseinterventions.Severaloftheinterventionsarenotavailablein
Canada:nimodipine,cinnarizineanddimethothiazine.Nutraceuticalsareconsideredtobenatural
healthproductsandareregulateddifferentlybyHealthCanadathanpharmaceuticals172withless
stringentregulationsandsurveillanceascomparedtopharmaceuticals.Therefore,theroutine
clinicaluseofnutraceuticalsforthepreventionofpediatricmigraineislimitedbythelackof
stringencyinregulationsandqualitycontrol,withthefollowinginterventionsfallingintothis
category:butterbur,riboflavin,magnesiumcoenzymeQ10,fishoils,L-5-hydroxytryptophanand
combinationnutraceuticalagents.Afewoftheinterventionsthathavebeenstudiedforthis
indicationareassociatedwithsignificantsideeffectprofilesthatmaketheiruseasfirst-lineagents
lessappealingtobothphysiciansandpatients,namelyvalproicacid,pizotifenandflunarizine.Most
often,pediatriciansorpediatricneurologistsareprescribingprophylaxisforpediatricmigraine.
Severaloftheinterventionsthathavebeenstudiedareoflimitedfamiliaritytothesepractitioners,
andarethereforelesslikelytohavesuccessfuluptakeasfirst-lineinterventions:timolol,
papaverineandpizotifen.AlthoughpreliminaryevidenceforBotoxsuggeststhatitmightbe
efficaciousinchronicmigraine78,79,ithasnotbeenstudiedforprophylaxisofepisodicheadaches.
Manypractitionersuseamitriptylineasafirst-lineinterventionformigrainepreventioninthe
pediatricagegroup76.Itisthereforequitesurprisingthattheevidenceforitsuseisderived
exclusivelyfromnon-randomizedstudies75–77,withtheexceptionofonerandomizedstudy
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comparingitsefficacyalonetoitsefficacyincombinationwithcognitivebehaviortherapy35.This
lackofevidenceandthecommonalityofitsuserenderitanexcellentcandidateinterventionforthe
nextrandomizedcontrolledtrialinthearea.Infact,theChildhoodandAdolescentMigraine
Preventionstudy(CHAMP),currentlyunderway,iscomparingtheefficacyofamitriptyline,
topiramateandplaceboinarandomized,double-blind,parallel-groupdesign173.Giventhat
amitriptylineisalreadybeingstudiedinalarge,well-designedclinicaltrial,itwouldbedifficultto
justifythedesignofasecondrandomizedtrialaimingtoanswerthesamequestionwhenthereare
somanyotherimportantandunansweredquestionsinthisareaofresearch.
Oftheremaininginterventionswithoutlimitationstosuccessfuluptakeasdescribedaboveand
whichlackconsistentevidenceforefficacythusjustifyingstudyinarandomizedtrial,thatis,
clonidine,trazadone,papaverine,levetiracetam,andcyproheptadine,levetiracetamisthemost
likelytobedeemedclinicallyacceptabletothemedicalcommunityandtopatients.Aspreviously
mentioned,clonidinehasfallenoutoffavourasamigrainepreventiveagent,withrecentdatafrom
oneNorthAmericancentersuggestingthatitisveryinfrequentlyprescribedforthisindication174.
Additionally,thedatafromtheonerandomizedstudyonitsefficacyisunconvincing142anditwould
thereforenotbetheidealinterventiontoinvestresourcesintofurtherstudying.Trazodonealso
lackspromiseasafirst-linemigrainepreventiveagent,giventhatitappearstobeusedvery
infrequentlyincurrentclinicalpractice174,andgiventhattheonlystudyonitsefficacyforthis
indicationfailedtodemonstratethatithaspotentialbeyondplacebo144.TheFDAhasnotapproved
useofpapaverineandHealthCanadaisregulatingpapaverineasanewdrug175,acategorythat
appliestointerventionswithlimiteddataonefficacyandsafetyinCanadaduetoashortperiodof
saleorminimalsales.Giventhisandtheminimaldatafoundduringthissystematicreview,
papaverineisnotanauspiciousagenttobestudiedasamigrainepreventive.Cyproheptadine,
althoughrelativelycommonlyusedinmanycenters,tendstobeusedprimarilyinyoungerchildren,
andmuchlesscommonlyinadolescents76,174.Thereasonforitsminimaluseintheadolescentage
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grouplikelypertainsinparttoconventionalpracticepatterns,andinparttodatafromasmall
randomizedstudythatfoundittobelesseffectivebeyond9yearsofageascomparedtoitsefficacy
inyoungerchildren176.Therefore,cyproheptadineislesslikelytobeusedintheadolescentage
group,andgiventhatmigraineisthemostprevalentinthispediatricsubsetofpatients1,itwouldbe
wisertostudyanotherinterventionthatismorelikelytobeeffectiveinadolescentswithmigraine.
Incontrast,levetiracetamhasdemonstratedpromiseformigraineprophylaxisinnon-randomized
studies70,71,andhasarelativelystrongtolerabilityprofile.Asidefromtheapproximately10%rate
ofbehavioralandpsychiatricsideeffects,itisrelativelysafetouse,doesnotrequireregularblood
worksurveillanceandhasthelowesttoxicityrankingofallofthenewanticonvulsantmedications
onthemarket177.Inaddition,pediatriciansandpediatricneurologistsarefamiliarwith
levetiracetambecauseitiscommonlyusedforthetreatmentofepilepsy178.
Asisdescribedabove,onlytwonon-randomizedstudieshaveassessedtheefficacyof
levetiracetamforthepreventionofmigrainesinthepediatricpopulation70,71.Becauseofitsrelative
promisebasedonthispreliminarydataandbecauseofalackofsignificantbarrierstouptakeas
comparedtotheotherinterventionsidentifiedinthisreview,itisofinteresttoinvestigateits
efficacyandtolerabilityforthisindication.Inordertoavoidduplicationandtoensurethatno
currentstudiesareunderwaytoanswerthisquestion,clinicaltrialregistriesweresearchedfor
relevantprotocolsonJuly15th2015(theNationalInstitutesofHealth(NIH)clinicaltrialregistry:
clinicaltrials.govandtheWorldHealthOrganization(WHO)InternationalClinicalTrialRegistry
Program:http://www.who.int/ictrp/en/).Nopediatricstudieswerefound.Onlyonestudywas
identifiedthroughclinicaltrialregistrysearches(registrationnumber:NCT00203216)andthe
clinicalquestionwaslimitedtotheadultpopulationaged18yearsandover.Therefore,
levetiracetamshowspromiseformigrainepreventionbasedonnon-randomizeddata,islikelyto
havesignificantuptakeclinicallyiffoundtobeeffectiveforthisindication,andnocompeting
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randomizedstudiesarecurrentlyunderwaytoassessitsefficacyandtolerabilityintheprevention
ofpediatricmigraine.
Thegoaloftheproposedstudywillbetocomparetheefficacyandsafetyoflevetiracetamto
thatoftopiramateandplaceboforthepreventionofmigrainesinchildrenandadolescents,usinga
randomized,double-blind,placebo-controlled,3-arm,parallel-grouptrialdesign.
2. METHODS
2.1. StudyObjectives
Theprimaryandsecondaryobjectiveshavebeenchoseninordertocomplywiththe
recommendationsdetailedintheInternationalHeadacheSocietyGuidelinesforControlledTrialsof
DrugsinMigraine84.
2.1.1. PrimaryObjective
• Tocomparetheefficacyoflevetiracetam,topiramateandplacebofor
reducingthenumberofmigraineattacksfrombaselineascomparedtothe
final4-weektreatmentintervalinchildrenandadolescentswithmigraine.
2.1.2 SecondaryObjectives
• Tocomparetheefficacyoflevetiracetam,topiramateandplacebofor
reducingthenumberofmigrainedaysfrombaselineascomparedtothe
final4-weektreatmentintervalinchildrenandadolescentswithmigraine.
• Tocomparetheefficacyoflevetiracetam,topiramateandplacebofor
reducingtheaverageintensityofmigraineattacksinchildrenand
adolescentswithmigraine.
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• Tocomparetheresponderrates,definedastheproportionofpatients
withatleasta50%reductioninmigrainefrequencyduringthetreatment
period,oflevetiracetam,topiramateandplaceboinchildrenand
adolescentswithmigraine.
• Tocomparetheefficacyoflevetiracetam,topiramateandplacebofor
reducingthedisabilityassociatedwithmigrainesinchildrenand
adolescents.
• Tocomparethesafetyoflevetiracetam,topiramateandplaceboin
childrenandadolescentswithmigraine.
2.2. StudyDesign
Thisstudywillconstitutearandomized,double-blind,placebo-controlled,3-arm,parallel-group
trial.Thestudywillbeamulticentertrialgiventhatitwillnotbefeasibletorecruitadequate
numbersofpatientsfromonecenter.Anticipatingthateachcenterwillrecruitanaverageof15
patientsperyear,withatotalsamplesizeof328(seebelow),theplanwillbetohave11centers
recruitingpatientsfortwoyears.Eachcenterwillhavearesearchcoordinatorassignedtothe
project,whowillberesponsibleforpatientrecruitment,enrollment,schedulingpatientfollow-ups,
carryingouttelephonefollow-ups,dataentryandcommunicationwiththesiteinvestigator,the
steeringcommitteeandthedataandsafetymonitoringboard.Participantswillberecruitedovera
periodoftwoyears.Aftera1-monthbaselineperiod,participantswillberandomizedtoreceive
eitherlevetiracetam,topiramateorplaceboina1:1:1allocation.Thetreatmentperiodwillbegin
withan8-weektitrationperiod,followedbya16-weekmaintenanceperiod,followedbya4-week
weaningperiod.Thetrialwillterminateaftera4-weekpost-treatmentobservationperiod
followingtheweaningperiod.Telephonevisitswilloccurwiththesitestudycoordinatorandclinic
visitswilloccurwiththesiteinvestigator.Boththeclinicvisitsandthetelephonevisitswilloccur
monthlyandtheywillbeseparatedby2-weekintervals,suchthatpatientshaveapointofcontact
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withthestudyevery2weeks.Theonlyexceptiontothisalternatingschedulewillbeforthelast
visit,whichwillbeatelephonevisitratherthanaclinicvisit.Thestudyscheduletemplateis
displayedinfigure6.
Figure6.Studytimelines
*NB.Bluetimepointsareclinicvisitsandredtimepointsaretelephonevisits
2.3. EligibilityCriteria
Theeligibilitycriteriahavebeenchosenbasedontherecommendationsmadebythe
InternationalHeadacheSocietyintheirGuidelinesforControlledTrialsofDrugsinMigraine84.The
rationalefortheeligibilitycriteriaarelistedinAppendixI.
2.3.1 InclusionCriteria
1. MigrainewithoutauraormigrainewithauraasperInternational
ClassificationofHeadacheDisordersThirdEdition,BetaVersion(ICHD)
criteria86(seeTables7and8)
2. Age8.0-18.0years
BaselineTitration Maintenance WeanPost-Rx
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3. Migrainefrequencyof2-8attackspermonthinthreemonthretrospective
periodand1monthbaselineperiod,withdefinitionofattackasfollows:
i. Attacksareseparatedbyatleasta48hourheadache-freeinterval
4. Migraineshavebeenpresentforatleastoneyear
5. Abletocommunicatesufficientlywithparentsinordertoaccuratelycomplete
aheadachediaryandstudyquestionnaires
2.3.2 ExclusionCriteria
1. Otherheadachetypesarepresentandtheparticipantcannotdifferentiate
migrainefromtheotherheadache(s)
2. Fifteenormoreheadachedayspermonth(ie.chronicmigraine)
3. Overusingacutemigrainemedications:
i. Takingatriptanontenormoredayspermonth
ii. Takingacetaminophenoranon-steroidalanti-inflammatorymedicationon
fifteenormoredayspermonth
4. Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment
5. Takinganantipsychoticorantidepressantmedicationwithinthreemonthsof
enrollment
6. ReceivedBotoxinjectionsformigrainewithinthepastthreemonths
7. Previoustrialoftopiramateorlevetiracetamformigraineprophylaxiswith:
i. Adequatedosing
ii. Atleastthreemonthsofprophylaxis
8. Historyofanaphylaxisorallergytotopiramateorlevetiracetam
9. Pregnant,lactatingorpositivepregnancytest
10. Sexuallyactiveandnotusingareliablebirthcontrolmethod
11. Historyofrenalcalculi
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12. Significanthepaticorrenalimpairment
13. Ontheketogenicdiet
14. Historyofepilepsy
15. HasapsychiatricdisorderasdefinedintheDiagnosticandStatisticalManual
ofMentalDisorders5thedition(DSMV)
16. Hasalcoholordrugdependence
17. Historyofsignificantbehavioralproblems
18. Historyofanotherchronicpaindisorder
Table7.ICHDcriteriaforpediatricmigrainewithoutaura
Criterion DescriptionA Atleast5attacksthatfulfillcriteriaB-DB Attackslasting2-72hours*C Twoofthefollowingfourcharacteristicsarepresent:
• Unilateralorbilaterallocation• Pulsatingquality• Moderateorseverepainintensity• Aggravatedbyorcausingavoidanceofphysicalactivity
D Duringattacks,atleastoneofthefollowingcriteriaaremet:• Nauseaand/orvomiting• Photophobiaandphonophobia
E NotbetterexplainedbyanotherICHDdiagnosis
*Untreatedorunsuccessfullytreated
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Table8.ICHDcriteriaforpediatricmigrainewithaura
Criterion DescriptionA Atleast2attacksmeetingcriteriaBandCB Oneormoreofthefollowingfullyreversiblesymptomsofaura:
• Visual• Sensory• Speechand/orlanguage• Motor• Brainstem• Retinal
C Twoofthefollowingfourcharacteristicsarepresent:• Atleastonesymptomofauraspreadsgraduallyoverfiveminutes
ormore,and/ortwoormoresymptomsoccurinsuccession• Eachindividualsymptomofauralastsbetweenfiveandsixty
minutes• Atleastonesymptomofauraisunilateral• Theauraisaccompaniedbyaheadacheorfollowedbyaheadache
withinsixtyminutesD NotbetterexplainedbyanotherICHDdiagnosisandtransientischemic
attackhasbeenexcluded
2.4. Interventions
Participantsmeetingalleligibilitycriteriaaftertheonemonthbaselineperiodwillbe
randomizedina1:1:1fashiontoeitherlevetiracetam,topiramateorplacebo.Allinterventionswill
beadministeredinanoralsolutionform,whichwillbepreparedbythesitepharmacy.The
solutionswillbematchedintasteandcolor,soastoensurethatblindingismaintainedbasedon
theappearanceoftheintervention.Theinterventionswillbetitratedinastandardwayduringthe
courseofthe8-weektitrationperiodfollowingrandomization.
Levetiracetamwillbeadministeredinanoralsolutionform,withaconcentrationof
100mg/mL.Participantsinthelevetiracetamgroupwillbetreatedwithatargetdoseof20-
40mg/kg/day,toamaximumof3000mg/day.Thistargetdosagewaschosenbasedonprescription
recommendations179andbasedonapreviousprospectiveopen-labelstudyontheefficacyof
levetiracetamforpediatricmigraineprophylaxis71.Thetitrationschedulewillbeasfollows:initiate
levetiracetamat5mg/kg/dayqHSforoneweek,thendoubleto10mg/kg/daydividedbidforone
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week,theincreaseto15mg/kg/daydividedbidforoneweek(ie.5mg/kgqAMand10mg/kgqHS),
thenincreasetotargetof20mg/kg/dayandifrequired,canthenincreasein5mg/kg/day
incrementsweeklyuptoamaximumdoseof40mg/kg/daydividedbid.Ifthepatientisresponding
welltotheintervention,thenthedoseoflevetiracetamwillbeheldat20mg/kg/day;increases
beyond20mg/kg/daywillonlybecarriedoutifnecessary.Althoughlevetiracetamisusually
initiatedat10mg/kg/dayandincreasedbiweeklyby10mg/kg/day,thedecisionwasmadeto
initiatethedoseat5mg/kg/dayandincreaseby5mg/kg/dayweeklyinordertoreflecttheweekly
titrationscheduleoftopiramate.Thesimilarweeklytitrationscheduleswillhelptomaintain
participantandphysicianblinding.
Topiramatewillbeadministeredinoralsolutionform,withaconcentrationof6mg/mL.
Participantsassignedtotopiramatewillhavetheirdosagetitratedupto2-3mg/kg/day,toa
maximumof200mgdaily,inaccordancewithdosingrecommendations179andpreviouspediatric
topiramatetrials120,173.Thetitrationwillcorrespondtothefollowing:1)forchildren8-12years:
initiateat15mgqHSforoneweek,thendoubleto15mgbidforoneweek,thenincreaseto25mg
bidforoneweek,thencontinuewith25mg/weekincreasesinthedose,upto2-3mg/kg/dayor
200mgmaximum,2)forchildrenagedover12years:initiateat25mgqHSforoneweek,then
doubleto25mgbidforoneweek,thenincreaseto25mgqAMand50mgqHSforoneweek,and
continuetitrationby25mgweeklyincreasesupto2-3mg/kg/dayorthe200mgdailymaximum(ie.
100mgbid)179.
Theplacebogroupwillbegivenamatchedplacebooralsolution.Theplacebogroupwillfollow
asimilartitrationscheduletotheinterventiongroups.Theywillbeinitiallygiven3mLofthe
placebosolutionqHS,whichwillbedoubledto3mLbidafteroneweek,andtheywillsubsequently
have3mL/weekincreasesupto6mLbid,or,ifrequired,theywillcontinuetohave3mL/week
increasesthroughoutthetitrationperiodtoamaximumof12mLbid.
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Iftolerabilityissuesariseforanyoftheinterventions,thentheinvestigatoronsitewillhavethe
libertytodeviatefromthetitrationscheduleasrequiredclinically.Theinvestigatorwillbeableto
holdoffadoseincrease,decreaseacurrentdoseorrecommenddiscontinuationshouldintolerable
adverseeventsoccur.Theinvestigatorwillremainblindedthroughout,andwillmakedecisions
basedontheclinicalscenariowhileremainingblinded.However,ifaseriousadverseeventoccurs
orifaclinicalscenarioarisesthatrequiresunblinding,thesiteinvestigatorwillcontactthe
pharmacydepartmenttobreaktheirblinding.
Eachinterventionwillbeweanedoverthecourseof4weeks,indecrementsof25%perweek.
Blindingwillbemaintainedduringtheweaningphaseandbeyond.Thestudyinvestigatorwillhave
theauthoritytodeviatefromtheweaningscheduleattheirdiscretion,shouldtheybelievethatitis
inthebestinterestofthepatienttodoso.Uponcompletionofthewean,atweek32,therewillbea
studyvisitwiththesiteinvestigator.Atthisvisit,thesiteinvestigatorwilldiscusstheneedfor
ongoingprophylaxiswiththepatientandfamily,andwillhavetheabilitytostartaprophylactic
interventionatthispointintime,ifclinicallyindicated.Follow-upforthemigraineswillbe
arrangedeitherwithachildneurologistatthatcenter,orwiththepatient’sfamilydoctor,as
appropriateanddependingonthepatientandfamily’spreference.
2.5. Outcomes
Apaper-basedheadachediarywillbemaintainedbyparticipantsfromthebeginningofthe
baselineperioduntiltheendofthefollow-upperiod.TheInternationalHeadacheSociety
GuidelinesforControlledTrialsofDrugsinMigrainerecommendthatheadachediariesbeusedto
trackalloutcomesinmigraineprophylaxistrials,andrecommendsimpleformatseitherin
electronicorpaperformthatonlytrackprimaryandsecondaryoutcomesandavoidextraneous
informationsoastonotoverwhelmparticipants84.Theheadachediarytemplatethatwillbe
employedforthepurposesofthistrialcanbefoundinAppendixJ.Asrecommendedbythe
InternationalHeadacheSociety,itonlymeasurestheprimaryandsecondaryoutcomes,withthe
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exceptionofalsoaskingparticipantstoreportontheuseofacuteabortivemedications.Although
theInternationalHeadacheSocietyrecommendsagainstacutemedicationusageasanoutcomein
parallel-grouptrials,theydostatethatthisoutcomeshouldbeincludedinheadachediaries84,and
thisiswhythiselementwasincludedinthetemplateheadachediary.
Thechoiceofprimaryandsecondaryoutcomeswasbasedontherecommendationsmadeby
theInternationalHeadacheSociety84.Theprimaryoutcomewillbethechangeinmonthlymigraine
attackscomparingthebaselineperiodtothefinal4weeksoftreatment.Migraineattackfrequency
waschosenastheprimaryoutcomegiventhatitislikelymoreaccuratethanmeasuringmigraine
days.Theproblemwithusingmigrainedaysforthefrequencyoutcomeliesinthefactthatthe
numberofdaysdependsonattackduration,whichismultifactorial(eg.acutetreatment
administered,timeofdayofattackonset).Thus,giventhatmigrainedaysareinfluencedby
migraineduration,thisisacompositeoutcome,makingmigraineattacksbettersuitedasthe
primaryoutcome.However,thechangeinmigrainedayscomparingbaselinetothefinal4-weeksof
treatmentwillbemeasuredasasecondaryoutcome,giventhattheInternationalHeadacheSociety
suggeststhatbothmigraineattackfrequencyandmigrainedaysshouldbemeasured84.
Othersecondaryoutcomesofinterestwerealsochosenbasedontherecommendationsmade
bytheInternationalHeadacheSociety84.Migraineintensitywillbemeasuredusinga4-pointscale,
asrecommendedintheguidelines:
• 0–noheadache
• 1–mildheadache
• 2–moderateheadache
• 3–severeheadache
Theintensityofthemigrainesinboththebaselineperiodsandthefinal4weeksoftreatment
willbeaveragedandcompared,suchthatachangeinaveragemigraineintensitywillconstitutethe
outcomemeasuredinthiscase.
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Inadditiontomeasuringthechangeinmigraineattackfrequencyandmigrainedayfrequency,
theresponderrateforeachgroupwillbecalculated.Theresponderrateisarecommended
outcomebytheInternationalHeadacheSociety,andcomprisesthepercentageofpatientsachieving
a50%orgreaterreductioninmigraineattackfrequencywhencomparingthebaselineperiodto
thefinal4weeksoftreatment84.Itisbelievedtobeapatient-centeredoutcome,giventhatpatients
oftenvaluetheabilityofamigraineprophylacticagenttoreducetheirmigrainefrequencybyat
leasthalf84.However,thereisnodatatosupportwhichmigraineoutcomesarethemostpatient-
centered,andintheabsenceofthisdata,relianceontheInternationalHeadacheSocietyGuidelines
ismostappropriate.
TheInternationalHeadacheSocietyGuidelinesalsohighlightthatmigraine-relateddisabilityor
qualityoflifecanbeusedassecondaryoutcomesinordertocapturetheglobalburdenofmigraine
onthepatient’slife.Thereisawell-validatedandwidelyusedmigraine-specificinstrument
availabletomeasuremigraine-relateddisabilityinthepediatricpopulation:thePediatricMigraine
DisabilityAssessmentScale(PedMIDAS)180.ThePedMIDASwasmodeledafteritsadultcounterpart:
theMIDAS.Itwasdevelopedtobesimpletouse,rapidtocompleteandsensitivetotheunique
lifestyleofchildrenandadolescents.ThePedMIDASiscomprisedof6questionsthatevaluatethe
patient’sabilitytofunctioninthepast90days.ScoresonthePedMIDASrangefrom0toa
theoreticalmaximumof540.Disabilityisassessedacrossthreecoredomains:schoolfunctioning,
homefunctioningandfunctioninginthesocialandplaydomains.PedMIDAShasgoodinternal
consistencyandreliability,withaCronbach’sαscoreof0.78andaPearsoncorrelationscoreof0.8
ontest-retest180.Inadditiontoitsvalidationintheoriginalclinicalsample,thePedMIDAShasalso
beenvalidatedinapopulation-basedsample8.ThePedMIDASalsohasapatient-basedgrading
systemdevelopedbytheoriginalgroupwhocreatedthequestionnaires:1)GradeI:scoresof0-10
indicatelittletonodisability,2)GradeII:scoresof11-30indicatemilddisability,3)GradeIII:
scoresof31-50indicatemoderatedisabilityand4)GradeIV:scoresabove51indicatesevere
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disability7.PedMIDASscoreswillbemeasuredatbaselineandattheendoftreatment,andthe
changeinthescorewillbecomparedbetweenthegroups.ThePedMIDASwillbeadministeredat
thebaselinevisit,atthecompletionofthemaintenanceperiod(atweek28)andattheendofthe
follow-upperiod(atweek36),overthetelephone.ThePedMIDASatbaselinewillbecomparedto
boththePedMIDASatweek28andatweek36.ThePedMIDASquestionnairecanbefoundin
AppendixK.
Adverseeventswillberecordedintheheadachediary.Theywillsubsequentlybecodedusing
theMedicalDictionaryforRegulatoryActivity(MeDRA®),whichisaninternationalmedical
terminologysystemdevelopedbytheInternationalConferenceonHarmonisationofTechnical
RequirementsforRegistrationofPharmaceuticalsforHumanUse.Adverseeventswillbeclassified
basedonthefollowingcategories:seriousornon-serious,expectedorunexpected,resolved,study-
related,possiblystudy-relatedorunrelatedtothestudy.Recordswillbekeptonparticipants
withdrawingfromthetrialduetoanadverseeventandonparticipantshavingtheirmedication
dosereducedortheirtitrationheldduetoadverseevents.
2.6. Randomization
Patientswhoareeligibleforparticipationandwhoconsenttoparticipationwillberandomly
assignedtoreceiveeitherlevetiracetam,topiramateorplaceboina1:1:1fashion.Thesiteresearch
pharmacistwillcontactacentralrandomizationserviceinordertocarryoutrandomization.The
centralrandomizationservicewillbeutilizedinordertoensurethatallsitesarerandomizinginthe
sameway,andinordertofacilitateallocationconcealment.Thecentralrandomizationservicewill
employacomputerrandomnumbergeneratortoassignparticipantstoaninterventiongroup.
Randomizationwillbestratifiedbycenterandbyage(8-13years,>13yearsto18years).Within
eachstratum,randomizationwilltakeplaceinblocksof4,6or8,withthesizeoftheblockbeing
randomlyselected.
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Theallocationwillonlybeknowntothecentralrandomizationserviceandtothesiteresearch
pharmacist,whowillhavenocontactwiththeinvestigators,researchpersonnelnorwiththe
participants.Thesiteresearchpharmacistwillmaintainapassword-protected,encrypted
electroniclistofpatientallocations.Thislistwillbemaintainedinordertohavetheinformation
accessibleonsiteforthepurposesofrapidaccessintheeventwhereaseriousadverseevent
occursandunblindingisrequired.
2.7. StudyVisits
Thestudyvisitscheduleisillustratedinfigure6.Eachhospitalvisitwillinvolveinteractionof
theparticipantwiththestudysiteinvestigator.Theinitialstudyvisitatweek0willcomprisea
completehistoryandphysicalexambythestudyinvestigator.Eligibilitycriteriawillbereviewedat
theinitialvisit.Ifapatientiseligibleforthestudy,thesiteinvestigatorwillcontactthesiteresearch
coordinatortofurtherdiscusstheprojectwiththepatientandfamily.Theresearchcoordinatorwill
explainstudyprocedurestothepatientandfamilyandwillseekinformedconsentfromeligible
participantsaged16yearsandoverandtheparentorguardian(seeAppendixL).Assentwillbe
soughtfromeligibleparticipantsunder16years(seeAppendixM).Consentingparticipantswillbe
senthomewithabrochureexplainingthestudy(seeAppendixN).Theresearchcoordinatorwill
explainthemigrainediaryindetailandwillgooverexamplesofhowtocompleteit.Participants
willbeinstructedtocompletethemigrainediaryonadailybasis,andwillbegiventipsonhowto
remembertocompletethediary(eg.setalarmonphone,leavediaryatthebedsideandcomplete
priortogoingtosleep,etc).
Subsequentstudyvisitswillinvolveweightmeasurements,physicalexamsasnecessary(eg.if
patientisexperiencingconcerningsideeffects)andintervalhistories.Anemphasiswillbeplaced
onreviewingtheheadachediary,interventioncomplianceandaddressinganyconcernsfromthe
patientorfamily.
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Duringthemonthlytelephonevisits,thesitestudycoordinatorwillreviewtheintervalhistory,
reviewcompliancewiththeheadachediaryandinterventionanddiscusssideeffectswiththe
patientandfamily.Wheresignificantconcernsarisewithsideeffectsorthepatient’shealth,the
studycoordinatorwillliaisewiththesiteinvestigatortoscheduleamoreexpedientfollow-up.
3. ProtectingAgainstSourcesofBias
3.1. SelectionBias
Inordertodecreasethepotentialforselectionbias,patientswillberandomizedusingacentral
randomizationservicethatbasesrandomizationonrandomnumbergeneration.Thismethodof
randomizationisconsideredtohavelowriskofselectionbias83.Inaddition,thereisalowriskof
selectionbiasrelatedtoallocationconcealmentwhenacentralrandomizationserviceisusedfor
thepurposesofrandomization83.Toensurethatthemostimportantcovariatesarebalanced
betweenthegroups,stratificationbasedoncenterandage(8-13years,>13yearsto18years)will
occurduringtherandomizationprocess.Othercovariates(ie.gender,baselinemigrainefrequency)
willbeaccountedforinlinearregressionmodels.
3.2. PerformanceBias
Thistrialwillbedouble-blind;onlythepharmacistswillknowthegroupassignment,whilethe
patients,families,studypersonnelandoutcomeassessorswillremainblinded.Thethree
interventionswillallbeadministeredinsolutionform,andthesolutionswillbematchedfortaste
andcolor.Inaddition,solutionvolumeswillbekeptrelativelyhomogeneousaswillthetitration
schedulesforeachintervention.Clinicalcarewillbeidenticalforallthreegroups.Inthisway,
severalattemptshavebeenmadetoensurethatblindingisbothestablishedandmaintained,in
ordertolimitthepotentialforperformancebias.
3.3. AttritionBias
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Participantswillhaveregularcontactwithstudypersonnel,withfollow-upsevery2weeks.
Thiswillensurethatanypatientandparentalconcernsarepromptlyaddressed.Inaddition,the
frequencyofin-hospitalfollow-upvisitswillbeminimizedbyprovidingtelephonefollow-upfor
50%ofthevisits,thusminimizingthenecessityforparticipantstodisplacethemselvesand
hopefullyoptimizingretention.Missingdatawillbeimputedusingmultipleimputation,which
shouldalsocontributetotheminimizationofattritionbias83.
3.4. DetectionBias
Theoutcomeswillprimarilybederivedfromtheparticipants’headachediaries.Giventhatthe
participantswillbeblindedandthateffortshavebeenmadetoensurethattheyremainblinded,
detectionbiasshouldbeminimized.Thesitestudycoordinatorswillassistincollectingsomeofthe
outcomes(eg.administrationofPedMIDASoverthetelephoneatthelastfollow-up).Study
coordinatorswillalsoremainblindedthroughoutthetrial.Therefore,theriskofdetectionbiasin
thisstudyshouldbelow,basedonhowtheoutcomesarebeingascertained.
4. STATISTICS
4.1. SampleSizeCalculations
Threeprimaryhypothesesofdifferingnaturesarebeingexploredintheproposedstudy:two
superiorityhypotheses,wherebytopiramateandlevetiracetamarehypothesizedtobesuperiorto
placebo,andanon-inferiorityhypothesis,wherebylevetiracetamishypothesizedtobenon-inferior
totopiramatewithrespecttotheprimaryoutcome.Giventhethreeprimaryhypotheses,two
separatesamplesizecalculationswerecarriedoutandthefinalsamplesizewaschosenbasedon
thelargerofthetworesults.
Theprimaryoutcomeinthistrialconsistsofthedifferencebetweentheaveragenumberof
monthlymigraineattacksatbaselineandtheaveragenumberofmonthlymigraineattacksinthe
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final4weeksoftreatment.Thisisacontinuousoutcome,characterizedbystandarddeviationasthe
measureofvariation.Allsamplesizecalculationswerecarriedoutusingapower(1–β)of0.8and
analpha(α)valueof0.05.Analyseswerecarriedouttakingintoaccounttheplannedgroup
sequentialdesignwithk=4intervals(seebelow).Thefollowingdatawereusedforthesamplesize
calculations:
• Topiramatevs.placebohypothesis:Theonlypediatricmigrainetrialcomparing
topiramateandplacebowithsimilareligibilitycriteriaandthesameprimaryoutcomeis
theWinneretaltrial120.Inthistrial,topiramateyieldedameanreductioninmigraine
attacksof2.6days,withastandarddeviation(SD)of2.6days,andplaceboyieldeda
meanreductionof2.0days,withaSDof3.1days.Nosamplesizecalculationswere
providedinthispediatrictrial.Adultrandomizedcontrolledtrialswithsimilareligibility
criteriaandassessingtheefficacyoftopiramatevs.placeboformigraineprophylaxis
usingthesameprimaryoutcomehavesetaminimalclinicallyimportantdifferenceof
1.19dayspermonth,withastandarddeviationof2.5daysfortheirsamplesize
calculations,basedonpilotdata181–183.Intheabsenceofdataonstakeholderopinion
regardingtheoptimalMCIDforthisoutcome,thedecisionwasmadetousethe
followingvaluesforthesamplesizecalculation,basedonthedatafromtheWinneretal
trialandtheadulttrials:1)topiramatemean:2.6,2)placebomean:1.41,3)SD:2.5.
Usingthesevalues,withatwo-tailedhypothesis,anαof0.05andapowerof0.8,a
samplesizeofN=71pergroupwascalculatedusingthePASS14software184(see
AppendixOforPASSreport).Planningforadrop-outrateof25%,thefinalsamplesize
topowerthetrialforthesuperiorityhypothesisis284.
• Levetiracetamvs.placebohypothesis:Asdescribedabove,twonon-randomizedstudies
evaluatedtheefficacyoflevetiracetamforpediatricmigraineprophylaxis70,71.Neitherof
thesestudiesusedacomparator,andbothwereobservational.Neitherusedreasonably
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similarinclusioncriteriatotheproposedstudy.Inlinewiththethirdhypothesis,
levetiracetamisexpectedtohavesimilarefficacytotopiramateforthisoutcome.
Therefore,aseparatesamplesizecalculationwasnotcarriedoutforthissecond
hypothesisasitwasassumedthattherequiredsamplesizewouldbesimilartothat
requiredforthefirstsuperiorityhypothesis.
• Topiramatevs.levetiracetamhypothesis:Inordertocalculateavalidsamplesizeforthis
thirdhypothesis,theNon-InferiorityMarginsinMigraineResearch(NIMM)surveywas
carriedout(seeabove).TheNIMMsurveyaskedexpertstoexpresstheiropinionson
optimalnon-inferioritymarginsforavarietyofcommonlyusedmigraineoutcomes.The
mostcommonlychosenresponseitemforthequestionregardingthenon-inferiority
marginfortheprimaryoutcomeinthistrial(ie.thechangeinthenumberofmigraine
attacks),was1attack,thatis,expertsfeltthatifaninterventionyielded1additional
attackpermonthorlessascomparedtothestandardintervention,thenitwouldbe
reasonabletoconsideritnon-inferior.Therefore,inordertocalculateasamplesizefor
thisnon-inferiorityhypothesis,thefollowingvalueswereused:1)non-inferiority
margin(delta):1,2)SD:2.5(asabove).Usingthesevalues,withanon-inferiority
hypothesis,whichisbydefinitionaone-tailedhypothesis,anαof0.05andapowerof
0.8,asamplesizeofN=82pergroupwascalculatedusingthePASS14software184(see
AppendixP).Planningforadrop-outrateof25%,thefinalsamplesizetopowerthe
trialforthenon-inferiorityhypothesisis328.Giventhatthiscalculationyieldedalarger
samplesizethanthesuperiorityhypothesiscalculation,thefinalsamplesizewillbe
328,soastomaintainadequatepowerforbothhypotheses.
4.2. PlannedStatisticalAnalyses
4.2.1 PrimaryHypotheses
97
Therewillbethreeprimaryhypothesesintheproposedtrial:
1. Topiramatewillyieldagreaterdecreaseinthefrequencyofmigraineattackscomparing
baselinetothefinal4weeksoftreatmentascomparedtoplacebo.
2. Levetiracetamwillyieldagreaterdecreaseinthefrequencyofmigraineattackscomparing
baselinetothefinal4weeksoftreatmentascomparedtoplacebo.
3. Levetiracetamwillbenon-inferiortotopiramatewithregardstothechangeinmigraine
attackfrequencycomparingbaselinetothefinal4weeksoftreatmentascomparedto
placebo.
4.2.2 PrimaryOutcomeAnalysisPlan
AllanalyseswillbeperformedusingSAS®4.0.Demographiccharacteristicsforeachgroupwill
bepresenteddescriptivelyintabularform.
Theprimaryoutcomeinthisstudyisacontinuousoutcome:thechangeinmonthlymigraine
attackscomparingthebaselineperiodtothefinal4weeksoftreatment.Thegroupmeansforthis
outcomewillbecomparedusingusingaone-wayANCOVA.TheresponsevariablefortheANCOVA
willbethenumberofmonthlymigraineattacksinthefinal4weeksoftreatment,andanalysiswill
adjustforthenumberofmonthlymigraineattacksatbaselineasthecovariateofinterest.A
Bonferronicorrectionwillbeappliedinordertoaccountforthemultiplecomparisonscarriedout
post-hocintheeventwheretheinitialANCOVAissignificant(ie.topiramatevs.levetiracetam,
topiramatevs.placeboandlevetiracetamvs.placebo).
Inordertofurtherexploretheimpactofcovariatesontheprimaryoutcome,alinearregression
modelwillbeusedtomodeltheimpactofgroup,age,genderandbaselinemigrainefrequencyon
thechangeinmigrainefrequency.
4.2.3 SecondaryOutcomeAnalysisPlan
98
Thefollowingcontinuoussecondaryoutcomeswillbeanalyzedinthesamewayastheprimary
outcome,withone-wayANCOVAscombinedwithBonferronicorrections(whereapplicablepost-
hoc)inordertocomparetopiramatevs.placebo,levetiracetamvs.placeboandtopiramatevs.
levetiracetam:
1. Thechangeinfrequencyinmigrainedayscomparingbaselinetothefinal4weeksof
treatment
2. Thechangeintheaveragemigraineintensitycomparingbaselinetothefinal4weeksof
treatment
3. ThechangeinPedMIDASscorecomparingbaselinetoweek28.
4. ThechangeinPedMIDASscorecomparingbaselinetoweek36.
ThefollowingdiscreteoutcomeswillbeanalyzedusingchisquaretestswithBonferroni
correctionsappliedinordertocomparetopiramatevs.placebo,levetiracetamvs.placeboand
topiramatevs.levetiracetam:
1. Theproportionofparticipantsachievinga50%orgreaterreductioninmigrainefrequency
whencomparingbaselinetothefinal4weeksoftreatment
2. Theproportionofparticipantswithanyadverseeventduringthetrial
3. Theproportionofparticipantswhowithdrewfromthetrialduetoadverseevents
4. Theproportionofparticipantswhohadtheirdosereducedortitrationheldduetoadverse
events
4.2.4 DealingwithMissingDataandApproachtoDataAnalysis
Missingdatawillbeimputedusingmultipleimputationtechniques.Becauseoneoftheprimary
hypothesesofthetrialisanon-inferiorityhypothesis,bothper-protocolandintention-to-treat
analyseswillbecarriedout.
4.2.5 InterimDataAnalyses
99
Threeinterimdataanalyseswillbeplannedusingagroup-sequentialdesign:1)thefirst
analysiswilloccurwhen25%ofparticipantshavebeenrecruited;2)thesecondanalysiswilloccur
when50%oftheparticipantshavebeenrecruited;3)thethirdanalysiswilloccurwhen75%ofthe
participantshavebeenrecruited;4)thefinalanalysiswilloccurwhen100%oftheparticipants
havebeenrecruited.Intheinterimanalyses,onlytheprimaryoutcomeandthethreeoutcomes
relatedtoadverseeventswillbeanalyzed(ie.theproportionofparticipantswithadverseevents,
theproportionofparticipantswhowithdrewfromthetrialduetoadverseeventsandthe
proportionofparticipantswhohadtheirdosereducedortitrationheldduetoadverseevents).
TheO’BrienandFlemingmethod185willbeusedtocontroltheleveloftypeIerror(α)inthe
proposedtrial.Thealphawillbespentinthefollowingway,withpvaluecut-offsforeachanalysis
asfollows,given4plannedanalyses(k=4)atintervalsik(seeAppendixPforsourceofpvalues):
• Firstinterimanalysis(i1):p=0.00116
• Secondinterimanalysis(i2):p=0.00529
• Thirdinterimanalysis(i3):p=0.02532
• Finalanalysis(i4):p=0.04643
DetailsregardingtheboundariesusedforthetrialstoppingrulesareincludedinAppendixP.
5. TRIALMANAGEMENTISSUES
5.1. RecruitmentProcess
5.1.1 RecruitmentTargets
Eachoftheelevensiteswillbeexpectedtorecruitanaverageof15patientsperyearand
recruitmentwillproceedovertwoyears,sothateachsiterecruitsanaverageof30patients.
Siteresearchcoordinatorswillmaintainarecruitmentlogdetailingthenumberofpatients
assessedforstudyeligibility,thenumberexcludedwithstandardizedreasonsforexclusion,the
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numberwhoconsentedtoparticipationandthenumberwhowererandomizedtoanintervention.
Siteresearchcoordinatorswillsendrecruitmentlogstothetrial’ssteeringcommitteeonamonthly
basis.Inthisway,therewillbeanongoingassessmentastowhetherrecruitmenttargetsarebeing
met.Ifparticularsitesarestrugglingwithrecruitment,thetrialsteeringcommitteewillreachoutto
theaffectedsite(s)andworkonsolutionsaimedatimprovingtherecruitmentrate.
5.1.2 StrategiestoMaximizeRecruitmentandFollow-Up
Sitecoordinatorswillhostapresentationforallclinicalpersonnelinparticipatingclinicsafew
weekspriortoinitiatingsiterecruitment.Clinicalpersonnelwillbeinformedaboutthestudy,its
purpose,itsoveralldesignaswellasitsrecruitmentmethods.Posterswithconciseinformation
aboutthestudyandthesitecoordinator’scontactinformationwillbeplacedineveryclinicroom
andinmultiplelocationsineachparticipatingclinic.Thesitecoordinatorwillsendanemailto
clinicalpersonnelevery3months,whichwillbrieflydescribehowrecruitmentatthesiteis
proceedingrelativetothesite’srecruitmenttarget.Whereproblemswithrecruitmentarise,thesite
coordinatorwillliaisewiththetrialsteeringcommitteetodiscusssolutionstowardsimprovingsite
recruitment.
Participantswillbegivenbrochures(AppendixN)thatdetailstudyproceduresandwhatto
expectasthestudyunfolds.Havingthisinformationatthetimeofrecruitmentshouldimprove
participants’understandingoftheirroleinthestudyandhopefullyimproveretentionand
adherencelongterm.Biweeklyfollow-upswillbeinplace,thusgivingparticipantsthechanceto
havetheirconcernsaddressedexpediently.Ateachfollow-up,participantswillberemindedabout
studyproceduresandtheimportanceofadheringtotheirinterventionasprescribed.Thus,every
attemptwillbemadetokeeptheparticipantsinformedaboutthestudyandtheimportanceof
adherence.Maximizingparticipants’informationinthiswayisthoughttoimproveadherencein
clinicaltrials185.Also,only50%ofthevisitswillbeinclinic,whiletheother50%willbeconducted
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overthephone.Thisshouldplacealesserburdenoftransportationandtimeonparticipants,and
alsohopefullycontributetooptimalretention.
Atthe4-weekclinicvisit,whenpatientswillreceivetheirintervention,thesitestudy
investigatorwilldiscussmeansofensuringmedicationadherencewithparticipants(eg.settingan
alarmontheirphone,placingthemedicationbottleinanopportunelocationthatwillprovidea
visualremindertotakethemedication,etc).Ateachfollow-up,medicationcompliancewillbe
addressedwithparticipants.Ifissuesarise,thestudycoordinatororinvestigatorwillre-explore
meansofmaximizingadherencewiththeparticipant.
6. PERSONNELANDROLES
6.1. StudyPersonnel
6.1.1 SiteResearchCoordinators
Eachsitewillhaveasiteresearchcoordinator.Thetimecommitmentoftheresearch
coordinatorwillvaryasafunctionofthesiterecruitmenttarget:theresearchcoordinatorwillhave
anywherefrom0.1-0.4full-timeequivalents(FTE)devotedtothisparticularstudyandthenumber
ofFTEswilldependontherecruitmenttarget.Thesiteresearchcoordinatorwillhaveavarietyof
rolesinthestudy:1)participantrecruitment,2)enrollmentofeligibleandconsentingparticipants,
3)maintenanceofrecruitmentlogs,4)hostingapresentationforclinicpersonnelpriortoinitiating
thestudyinordertoinformstaffabouttheproject,5)settingupandmaintainingpostersinthe
clinicareawithinformationaboutthestudy,6)sendingemailstoclinicstaffevery3monthswith
studyandrecruitmentupdates,7)schedulingpatientfollow-upsandclinicvisits,8)carryingout
telephonefollow-ups,9)dataentry,10)documentingandclassifyingadverseevents,11)notifying
thetrialsponsorofanyseriousandunexpectedadverseeventsthatrequireexpeditedreportingto
HealthCanada,12)communicationwiththesiteinvestigator,13)communicationwiththesteering
102
committee,14)communicationwiththedataandsafetymonitoringboard,and15)communication
withtheleadsitebiostatistician.Siteresearchcoordinatorswillmeetwithsiteinvestigatorsona
monthlybasis.Monthlyreportsdetailingsiterecruitmentstatistics,drop-outstatistics,adverse
eventsandissuesarisingwillbepreparedbythesitecoordinatorsandsenttothetrialsteering
committee.Thisinformationwillalsobecompiledandsenttothedataandsafetymonitoringboard
every3monthsandtotheleadsitebiostatisticianonamonthlybasis.Whentheleadsite
biostatisticianhasdeterminedthataninterimdataanalysisisrequired(ie.whenrecruitment
numbershavereachedthethresholdforinterimanalysis),siteresearchcoordinatorswillbe
requiredtocompletedataentryforrecruitedparticipants.Allsiteresearchcoordinatorswillenter
dataintoREDCaP™,whichisasecure,encryptedwebapplicationthatallowsresearcherstocollect
data,storedataandhasamultitudeofotherfunctions.TheuseofREDCaP™byallsiteswillallow
foralldatatobestoredinonelocation,whichwillfacilitateanalysesfortheleadsitebiostatistician.
6.1.2 SiteInvestigators
Siteinvestigatorswillberesponsibleforfilingresearchethicsboardapplicationsattheir
respectivesites.Siteinvestigatorswillalsocarryoutallclinicvisitswithparticipants,whichwill
involveweighingthepatients,carryingoutphysicalexamsasrequired,takinginterimhistories,
discussinginterventioncompliance,addressingpatientconcerns,inquiringaboutadverseevents,
andaddressinganyclinicalconcernsorissuesarising.Thedocumentationofadverseevents,and
notificationofthetrialsponsorofseriousandunexpectedadverseeventsthatrequireexpedited
reportingtoHealthCanada,willnotonlybetheresponsibilityoftheresearchcoordinator,butalso
ofthesiteinvestigator,giventhattheymaybeinformedofadverseeventsduringclinicvisits.Site
investigatorswillbeinregularcommunicationwithsiteresearchcoordinatorsaboutissuesarising
fromthestudy.Monthlymeetingsbetweenthesiteresearchcoordinatorandsiteinvestigatorwill
bearrangedinordertoensurethatissuesareaddressedandthatthecoresiteteamisworking
togethertomaximizerecruitmentandfollow-up.
103
6.1.3 SiteResearchPharmacists
Thesiteresearchpharmacistswillberesponsibleforcoordinatingrandomization.Atthetime
ofrandomization,theresearchpharmacistwillcontactacentralrandomizationservice.Once
randomizedbythisservice,thesiteresearchpharmacistwillrecordtheparticipant’sallocationinto
apassword-protected,encryptedelectronicdocument.Thepharmacistwillprepareandpackage
thestudyinterventionsforparticipants.Participantswillvisitthesitepharmacyonamonthlybasis
andthesiteresearchpharmacistwilldispensetheinterventiontotheparticipantsatthistime.
6.1.4 LeadSiteResearchCoordinator
Theleadsiteresearchcoordinatorwillbeassignedallofthesamerolesasthesiteresearch
coordinators,inadditiontoseveralothertasks:1)servingastheprimarycontactpersonforthe
siteresearchcoordinatorsshouldquestionsabouttheprotocolortroubleshootingarise,2)
assistingtheprincipalinvestigatorwiththeleadsiteresearchethicsboardapplication,theHealth
CanadaClinicalTrialApplication,preparationofthetrialprotocolandotherrequired
documentationand3)sittingonthetrialsteeringcommittee.Giventhesignificanttime
commitmentrequiredtofulfillallofthesetasks,theleadsiteresearchcoordinatorwillhave1.0
FTEsdevotedtothisproject.
6.1.5 LeadSitePrincipalInvestigator
Theleadsiteprincipalinvestigatorwillhavethesameresponsibilitiesasthesiteinvestigators,
inadditiontotheirroleasprincipalinvestigatorandtrialsponsor.Inadditiontotheseroles,the
leadsiteprincipalinvestigatorwill:1)writethetrialprotocolandcreateprotocolbindersforall
siteswiththeassistanceoftheleadsiteresearchcoordinator,2)actasthetrialsponsorandobtain
fundingforthetrial,giventhatthiswillbeaninvestigator-initiatedtrial3)prepareandsubmita
ClinicalTrialApplicationtoHealthCanadaalongwiththeleadsiteresearchcoordinator,4)serveas
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theprimarycontactpointforsiteinvestigatorsshouldquestionsariseaboutresearchethicsboard
applications,thetrialprotocolortroubleshootingariseand5)sitonthetrialsteeringcommittee.
6.1.6 LeadSiteResearchPharmacists
Theleadsiteresearchpharmacistswillhavethesamerolesasthesiteresearchpharmacists.
6.1.7 LeadSiteBiostatistician
TheREDCaP™databasewillbedesignedbytheleadsitebiostatistician,inconsultationwiththe
leadsiteprincipalinvestigator.Theleadsitebiostatisticianwillbeinchargeofcarryingoutallof
thedataanalyses,forboththeinterimanalysesandthefinalanalysis.Monthlyreportswillbesent
totheleadsitebiostatisticianfromthesiteresearchcoordinatorsaboutrecruitmentstatistics,
drop-outstatistics,adverseeventsandissuesarisingatindividualsites.Theleadsitebiostatistician
willmergethedatafromthevarioussitesinordertoprepareacompiledreportforthemonthly
steeringcommitteemeetings.Inaddition,interimanalyseswillbetheresponsibilityoftheleadsite
biostatistician.Whenrecruitmenttargetsforinterimanalyseshavebeenreached,theleadsite
biostatisticianwillcontactthesiteresearchcoordinatorstoaskforalldataentrytobecompleted
onenrolledparticipants.Thisdatawillthenbeusedtocarryouttheinterimanalyses,andthe
biostatisticianwillprepareareportoninterimresultstobesubmittedtothedatasafetymonitoring
board.
6.2. DataandSafetyMonitoringBoard
Thedataandsafetymonitoringboard(DSMB)willcomprisethreeindividuals:1)a
biostatistician(notthesameindividualastheleadbiostatistician),2)aneurologist(notthesame
individualastheleadsiteprincipalinvestigator),3)anepidemiologistwithexpertiseinclinicaltrial
designandimplementation.TheDSMBwillmeetevery3months,duringwhichtimethereports
fromthesiteresearchcoordinatorswillbereviewed.ThiswillgivetheDSMBtheopportunityto
reviewadverseeventsandissuesarisingatthevarioussites.Inadditiontothescheduledmeetings,
105
meetingswilloccuronceinterimdataanalyseshavebeencompleted.Theleadsitebiostatistician
willprovidetheinterimdataanalysisreportstotheDSMB,andaninterimmeetingwillbe
scheduled.Atthesetimes,theDSMBwillreviewtheinterimefficacyandsafetydata.
Ifconcerningtrendsinadverseeventsarise,orifseriousadverseeventsoccur,theDSMBwill
contacttheresearchpharmacistsattheinvolvedsite(s)tobreakblindingoninvolvedparticipants
whennecessary.TheDSMBwillhavetheauthoritytorecommendearlytrialtermination,should
majorconcernsarisewithregardstoadverseeventsoratinterimanalyses.Intheeventwherethe
DSMBdoesrecommendearlytrialtermination,areportwillbepreparedbytheDSMB
biostatistician,whowillcommunicatetherecommendationverballyandinwritingtothetrial
steeringcommittee.
6.3. TrialSteeringCommittee
Thetrialsteeringcommitteewillcomprisetheleadsiteprincipalinvestigator,theleadsite
researchcoordinatorandtheleadsitebiostatistician.Thesteeringcommitteewillmeetmonthlyin
ordertoreviewtrialprogress.Themonthlyreportfromthebiostatistician,consistingofa
compilationofthesiteresearchcoordinatorreports,willbereviewed.Recruitmentnumbers,drop-
outs,adverseeventsandissuesarisingatthesiteswillbediscussedandreviewed.Where
necessary,actionpointswillbedevelopedinordertoimprovetrialimplementation.Asabove,
recommendationsfromtheDSBMwillbecommunicatedtothesteeringcommitteethroughthe
DSBM’sbiostatistician.
7. ETHICALCONSIDERATIONS
7.1. ClinicalEquipoiseRegardingLevetiracetamforPediatricMigraineProphylaxis
Asisdescribedabove,thereisclearuncertaintyintheliteratureregardingtheefficacyof
levetiracetamfortheprophylaxisofpediatricmigraine.Onlytwonon-randomizedstudies70,71have
106
assessedthesafetyandefficacyoflevetiracetamforthisindication.Levetiracetamhasneverbeen
comparedtoplacebonortotopiramateintheliterature.Inordertoestablishassaysensitivityfor
levetiracetamascomparedtoplacebo,whichhasnotyetbeendeterminedintheliterature,itis
necessarytocompareittoplaceboinadouble-blind,randomizedfashion.Inaddition,the
comparisonoflevetiracetamtotopiramatewillhelptoestablishitsnon-inferioritywithregardsto
efficacyandsafetyrelativetotheinterventionwiththehighestlevelofevidenceintheliterature.
Thetwointerventionshaveneverbeencomparedinthepast,andthereisthusuncertaintyasto
whetherlevetiracetamisnon-inferiortotopiramateforthepreventionofpediatricmigraine.
Therefore,thereisdefiniteclinicalequipoiseintheliteratureregardingthetwoprimary
hypothesesofthistrial,thatis:1)levetiracetamwillyieldagreaterdecreaseinthefrequencyof
migraineattackscomparingbaselinetothefinal4weeksoftreatmentascomparedtoplacebo,2)
levetiracetamwillbenon-inferiortotopiramatewithregardstothechangeinmigraineattack
frequencycomparingbaselinetothefinal4weeksoftreatmentascomparedtoplacebo.
7.2. InformedConsent
Informedconsentwillbeobtainedinwritten(seeAppendixL)andverbalformfromboth
participantsaged16yearsandoverandtheparent(s)orguardian(s)oftheparticipant.For
participantsyoungerthan16yearsofage,verbalandwritten(seeAppendixM)assentwillbe
obtained.Ifaparticipantovertheageof16yearsisdeemedcognitivelyunabletoprovideinformed
consent,thenassentwillbesoughtinlieuofconsent,andtheparent(s)orguardian(s)willprovide
informedconsent.TheconsentandassentformshavebeenwritteninaccordancewiththeTri-
CouncilPolicyStatement:EthicalConductforResearchInvolvingHumans186.Theresearch
coordinatorwillexplainimportantelementsoftheconsentprocesstotheparticipantandtheir
parent(s)orguardian(s)andwillbepresenttoanswerquestionsabouttheconsentform.
Participantsandtheirparent(s)orguardian(s)willalsobegiventheopportunitytotakethe
consentformhometofurtherdiscussthestudyandtheirpossibleinvolvement.Contact
107
informationfortheprincipalinvestigatorisavailableontheconsentform(seeAppendixL)andthe
principalinvestigatorwillbeavailabletoparticipantsandtheirparent(s)orguardian(s)for
questionsrelatedtoconsentshouldtheyarise.
7.3. SpecialConsiderationsinthePediatricPopulation
Inordertoimprovemigrainecareinchildrenandadolescents,itisnecessarytocarryoutwell-
designedclinicaltrialsofinterventionsforpediatricmigraine.Thisstudywilladdsignificantlyto
thebodyofevidenceinthepediatricmigraineprophylaxisliterature.Becausethisisastudy
involvingchildrenandadolescents,specialconsiderationswillbetakentoaddressconcernsrelated
tocarryingoutresearchonthisvulnerablepopulation.Therisk/benefitratiointhisstudyhasbeen
carefullyconsidered.Thereisasignificantanticipatedbenefittoparticipantsthroughparticipation
inthistrial:participantsfromallthreeinterventiongroupsareexpectedtobenefitfromreduced
migrainefrequencyovertime.Althoughtherearerisksofadverseeventsforbothtopiramateand
levetiracetam,theparticipantsandtheirparent(s)orguardian(s)willbenotifiedaboutthese
potentialrisksduringtheconsentprocess.Also,theriskofseriousadverseeventsforeachofthese
interventionsisverylow.
Becauseoftheyoungageoftheparticipants,bothaconsentandanassentprocesswillbe
available.Participantsundertheageof16yearsorthosewhoarenotcognitivelyabletoprovide
informedconsentwillbeguidedthroughanassentprocess.Theassentformwillbetailoredfor
youngerchildren,withamoreconcisepresentationandtheuseofsimplifiedlanguage.
7.4. PrivacyandConfidentiality
Theprivacyandconfidentialityofparticipantswillbeprotectedinavarietyofways.Contact
informationforparticipantswillbestoredinaseparatefiletothedatacollectionfiles.Storageof
contactinformationisrequiredinorderfortheresearchcoordinatortohavetheabilitytocontact
participantsfortelephonefollow-ups.Thisinformationwillbestoredinanencrypted,password-
protectedelectronicfilethatwillbedivorcedfromanyoftheotherstudydata.Inaddition,the
108
researchpharmacistswillmaintainanencrypted,password-protectedelectronicfileofparticipant
groupassignments,whichwillincludeparticipantnamesandcontactinformation.Thisisnecessary
inordertoensurethatunblindingcanoccurshouldaseriousadverseeventbereported.The
remainingstudydatawillbeenteredbythesiteresearchcoordinatorsintoREDCaP™,which,as
describedabove,isaweb-based,secureandencrypteddatastoragesoftwarethatiswidelyusedfor
researchpurposes.TheREDCaP™databasewillcontainonlyde-identifieddata:studyidentification
numbers,generatedatrandom,willbeusedfordatastorage.Noidentifierswillbeincludedinthe
database.
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173. HersheyA,PowersS,CoffeyC,etal.ChildhoodandAdolescentMigrainePrevention(CHAMP)study:adouble-blinded,placebo-controlled,comparativeeffectivenessstudyofamitriptyline,topiramate,andplacebointhepreventionofchildhoodandadolescentmigraine.Headache.2013;53(5):799–816.
174. JohnsonA,BickelJ,LebelA.PediatricMigrainePrescriptionPatternsataLargeAcademicHospital.PediatrNeurol2014;51(5):706–12.
175. HealthCanada.ListingofDrugsCurrentlyRegulatedasNewDrugs(TheNewDrugsList).HealthCanadaDrugsandHealthProducts.2012;Availablefrom:http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/newdrug-drognouv/ndrugs_ndrogue-eng.php
176. LavensteinB.Acomparativestudyofcyproheptadine,amitriptyline,andpropranololinthetreatmentofpreadolescentmigraine.Cephalalgia1991;11:122–4.
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181. BrandesJ,SaperJ,DiamondM,etal.Topiramateformigraineprevention.Pharmacotherapy2006;26(3):375–87.
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184. PASS14PowerAnalysisandSampleSizeSoftware(2015).2015;Availablefrom:ncss.com/software/pass
185. FriedmanL,FurbergC,DeMetsD.FundamentalsofClinicalTrials.4thEdition.NewYork,USA:Springer;2010.
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120
ThesisAppendix
8. AppendixA.Electronicsearchstrategiesforidentificationofstudies
MEDLINESearchStrategy:1.expMigraineDisorders/2.statusmigra*.mp.3.migraine*.tw.4.or/1-35.pc.fs.6.prophyl*.mp.orprevent*.ti,ab.7.Amitriptyline/8.expBotulinumToxins/9.Clonidine/10.expCyproheptadine/11.Domperidone/12.flunarizine/ortrazodone/13.Piracetam/14.Metoclopramide/15.Nimodipine/16.Papaverine/17.Pizotyline/18.Propranolol/19.Timolol/20.Topiramate.mp.21.ValproicAcid/22.5-Hydroxytryptophan/23.expFattyAcids,Omega-3/24.Q10.ti,ab.25.Coenzyme.mp.26.Riboflavin/27.Magnesium/28.Petasites/orbutterbur*.tw.29.expGinkgolides/30.or/5-2931.4and3032.((randomizedcontrolledtrialorcontrolledclinicaltrial).pt.orrandomized.ab.or
placebo.ab.orclinicaltrialsastopic.sh.orrandomly.ab.ortrial.ti.)not(expanimals/nothumans.sh.)
33.(child*oradolescent*orinfan*).mp.34.31and32and3335.removeduplicatesfrom34EmbaseSearchStrategy:
121
1.expmigraine/2.statusmigrainosus.mp.3.migrain*.tw,kw.4.AliceinWonderlandSyndrome.tw.5.or/1-46.prophyl*.mp.orprevent*.ti,ab.7.prophylaxis/8.amitriptyline/9.botulinumtoxin/10.clonidine/11.cyproheptadine/12.domperidone/13.flunarizine/14.trazodone/15.piracetam/16.metoclopramide/17.nimodipine/18.papaverine/19.pizotifen/20.propranolol/21.timolol/22.topiramate/23.valproicacid/24.5hydroxytryptophan/25.omega3fattyacid/26.ubidecarenone/27.riboflavin/28.magnesium/29.butterbur/30.ginkgolide/31.or/6-3032.5and3133.(random$orfactorial$orcrossover$orcross-over$orplacebo$or(doubl$adjblind$)or
(singl$adjblind$)orassign$orallocat$orvolunteer$).mp.orcrossover-procedure/ordouble-blindprocedure/orrandomizedcontrolledtrial/orsingle-blindprocedure/
34.limit32to(childorpreschoolchild<1to6years>orschoolchild<7to12years>oradolescent<13to17years>)
35.(pediatricorpaediatricorchild$ornewborn$oradolescen$orinfan$orneonat$oryouth$orteen$orbaby$orbabies$orpreschool$orpre-school$orelementaryschool$orelementarystudent$orkindergartenornurseryschool$orgradeschool$orpublicschool$orhighschool$orhighschool$orschoolchild$).mp.
36.32and33and(34or35)37.limit36toembase38.removeduplicatesfrom37CENTRALSearchStrategy:1.migrain*.tw,kw.2.prophyl*.mp.orprevent*.ti,ab.
122
3.(AmitriptylineorBotoxorClonidineorCyproheptadineorDomperidoneorFlunarizineorTrazadoneorLevetiracetamorMetoclopramideorNimodipineorPapaverineorPizotifenorPropranololorTimololorTopiramateorValproicAcidorL-5-hydroxytryptophanorOmega-3orCoenzymeQ10starthereorRiboflavinorMagnesiumorButterburorGinkgolide).tw.
4.1and(2or3)5.(pediatricorpaediatricorchild$ornewborn$oradolescen$orinfan$orneonat$oryouth$
orteen$orbaby$orbabies$orpreschool$orpre-school$orelementaryschool$orelementarystudent$orkindergartenornurseryschool$orgradeschool$orpublicschool$orhighschool$orhighschool$orschoolchild$).mp.
6.4and57.removeduplicatesfrom6
123
9. AppendixB.SystematicReviewIncludedStudiesEligibilityForms
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Oelkers-Ax2008Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes
(Exclude)No
(Include)Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
124
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:MacLennan2008Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
125
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Bruijn2010Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
x
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
126
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Winner2005Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
127
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Lakshmi2007Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? X Wasthestudyrandomized? X Wasthestudyeithersingleordoubleblind? X ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?X
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
X
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
128
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Lewis2009Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? X Wasthestudyrandomized? X Wasthestudyeithersingleordoubleblind? X ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?X
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
X
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
129
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Pandina2010Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? X Wasthestudyrandomized? X Wasthestudyeithersingleordoubleblind? X ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?X
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
X
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicintervention(or
interventions)takendailytopreventmigraines?x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
130
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Winner2006PooledAnalysisScreenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
131
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Apostol2008Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? X Wasthestudyrandomized? X Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?X
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
X
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
X
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
132
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Sorge1988Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
133
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Sorge1985Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
x
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
134
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Noronha1985Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
x
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
135
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Sillanpää1977Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
136
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Battistella1993Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
x
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
137
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Battistella1990Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
x
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
138
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Ford2014Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
139
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Ashrafi2014Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclud
e)
No(Inclu
de)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
140
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:MachínAltueña1987Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
141
ProphylacticInterventionsforPediatricMigraine:StudyEligibilityChecklist
StudyID#:Sillanpää1978Screenedby:SLO
Table1:InclusionCriteria
Characteristic Yes(Include)
No(Exclude)
Unsure(Discuss)
StudyDesignIsthestudyaclinicaltrial? x Wasthestudyrandomized? x Wasthestudyeithersingleordoubleblind? x ParticipantsWasthestudylimitedchildrenand/oradolescents,aged18
andunder?x
Wasthestudylimitedtoparticipantswithoneormoreofthefollowing:episodicmigraine,chronicmigraine,migrainewithauraormigrainewithoutaura?
x
WasthediagnosisofmigrainemadeusingICHDcriteria(1988andlater)orothervalidateddiagnosticcriteria(before1988)?
x
InterventionsWasthetreatmentapharmacologicornutraceutical
intervention(orinterventions)takendailytopreventmigraines?
x
Comparison Wasthereaplaceboascomparison? x
Table2:ExclusionCriteria
Characteristic Yes(Exclude)
No(Include)
Unsure(Discuss)
StudyDesignWasthestudyrandomizedinclusters(ie.aclusterRCT*)?
x
Forcross-overtrialsonly:Wasthewashoutperiodlessthan4weeks?
*ClusterRCT:AclusterRCTisatrialinwhichindividualsarerandomizedingroups(i.e.thegroupisrandomized,nottheindividual).
Shouldthisstudybeincludedinthereview?☐Include☐Exclude☐Unsure
142
10. AppendixC.SystematicReviewIncludedStudies‘CharacteristicsofStudies’
Tables
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Oelkers-Ax2008StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,partlydouble-blind,3-armparallel-grouptrial
• 8weekbaselineperiodfollowedby12weektreatmentphasefollowedby8weekpost-treatment/follow-upphase
• PatientswererecruitedusingadvertisementsfromthecatchmentareaoftheHeidelbergUniversityhospital
Participants • Childrenaged8-12withmigrainemeetingICHDcriteria• Allhadatleast1yrhistoryofmigraine• Hadtoreport2ormoremigraines/monthin3months
precedingenrollmentandduringthebaselineperiod• Higherbaselinemigrainefrequencyinthebutterburgroup
(9.8+7.6vs.5.5+4.4vs.5.0+2.5,p=0.409)Interventions • Petadolex®:20patientsrandomizedtoreceive50mg/dayif
8-9yoor50mgbidif10-12yowithadoseincreaseto75mg/dayfor8-9yoorif10-12yo75mgbidat8weeksifsuboptimalresponseinthefirst8weeksoftreatment
• Placebo:19patientsrandomizedtoplacebo,witha“doseincrease”at8weeksifsuboptimalresponse
• Musictherapy:24patientsrandomizedto12weeklysessionsofmusictherapyinvolvingmusic-aidedrelaxationtraining,bodyawarenesstechniquesandconflicttraining
Outcomes • Primaryoutcome:Allthreegroupshadastatisticallysignificantreductioninheadachefrequencycomparingbaselinetopost-treatmentandfollow-upinbothas-treatedandintention-to-treatanalyses(ITT)(seeTable3).Inpost-treatment,musictherapywassuperiortoplacebo(p=0.042inITT)buttherewasnodifferencebetweenplaceboandbutterbur.At6monthspost-treatment,bothmusictherapy(p=0.018)andbutterbur(p=0.042)weresuperiortoplacebo.
• Secondaryoutcome:Responderrates,thatisthoseachievinga50%orgreaterreductioninmigrainefrequency,werehighestinthemusicgroupatpost-treatment(p=0.01),butdidnotdifferbetweenthegroupsatthe6monthfollow-up.
• Adverseevents:Nodifferenceinadverseeventsbetweengroupsnorstudyperiods;butterburgroupmostlyreported
143
gastrointestinalsymptoms,dermalorallergicsymptomsNotes • Higherdrop-outrateininterventiongroups:5%inthe
placebogroupvs.25%inbutterburgroupvs.29%inthemusictherapygroup
144
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:MacLennan2008StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,2-arm,parallelgroupclinicaltrial
• Patientswerefollowedfora4-weekbaselineperiodandtreatedfor12weeks
• Recruitmentthroughlocalschools,theEDortheoutpatientdepartmentoftheChildren’sHospitalofWestmead,Australia
Participants • Childrenaged5-15yearswithmigrainemeetingICHDcriteria• Participantshadtohavemigraineforatleast3monthswith
monthlymigrainefrequencybetween2and8attacks/month• Participantsalsohadtohaveatleastonemigrainein4week
baselineperiod• Nosignificantdifferencesfoundbetweenthegroupsat
baselineInterventions • Riboflavin:27participantswererandomizedtoriboflavin
200mgdaily• Placebo:21participantswererandomizedtoplacebo
Outcomes • Thetrialwasstoppedaftera12monthinterimdataanalysisduetolackofevidenceforadifferencebetweenthegroups
• Primaryoutcome:Therewerenogroupdifferenceintheproportionofparticipantsachievinga50%orgreaterreductioninmigrainefrequency(66.6%ofplacebovs.44.4%ofriboflavin,p=0.125)
• Secondaryoutcomes:Nochangeinmigraineintensityineithergroup,meannumberofdayswithassociatedsymptomsdecreasedforplacebobutnotforriboflavin,bothgroupshadadecreaseinnumberoftreatedmigraineattacks
• Adverseevents:Onechildtakingriboflavinhadanincreaseinthenumberoftensionheadaches,and4childrenintheriboflavingroupnotedachangeintheirurinecolor
Notes • Thereisnonoteaboutwhattypeofstoppingruletheyusedintheinterimdataanalysisanditisquestionableastowhetherearlyterminationwaswarranted.
145
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Bruijn2010StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,cross-overstudy
• 4weekbaselineperiodfollowedby16weektreatmentperiodfollowedby4weekwashoutperiodfollowedbyanother16weektreatmentperiod
• Recruitmentfrom2hospitalsintheNetherlandsParticipants • Childrenaged6-13yearswithmigrainemeetingICHDcriteria
• Participantshadtohaveatleast2migrainespermonthatbaseline
• Therewerenosignificantbaselinedifferencesbetweenthegroups
Interventions • Riboflavin:20patientsrandomizedtoreceiveriboflavin50mgdailyforfirsttreatmentperiod
• Placebo:22patientsrandomizedtoreceivematchedplacebo(containingcarotene)capsulesforfirsttreatmentperiod
Outcomes • Primaryoutcome:Thegroupsdidnotdifferwithregardstochangeinmigrainefrequency(p=0.44)
• Secondaryoutcomes:Noothermeasuredoutcomessignificantlydifferedbetweenthegroups
• Noadverseeventswerereportedineithergroup• Analysisforperiodofcarry-overeffectwasinconclusive
Notes • Thestudywaspoweredtodetectadifferenceof0.6SDbetweenthegroupsintermsoftheprimaryoutcome
146
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Winner2005StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,placebo-controlled,2-armparallel
grouptrialwith2:1assignmenttotheinterventiongroup• Comprisedof4weekbaselineperiodfollowedby8week
medicationtitrationperiodfollowedby12weekmaintenanceperiod
• Recruitmentfrom17medicalcenterintheUSParticipants • Childrenaged6-15yearswithmigrainemeetingICHDcriteria
• Required3-10migrainedays/monthin4weekbaselineperiodand3monthsprecedingstudyentry
• Chronicmigraineexcluded• Therewerenosignificantdifferencesbetweenthegroupsat
baselineInterventions • Topiramate:112patientsrandomizedtotopiramate,ata
startingdoseof15mgdaily,whichwastitratedupasneededto200mgdailyor2-3mg/kg/day,whicheverwasachievedfirst
• Placebo:50patientsrandomizedtoplacebowithidentical“titration”scheduletotopiramate
Outcomes • Primaryoutcome:Intheintention-to-treatanalysis,thetopiramategroupshowedatrendtowardsagreatermeanreductioninmigrainefrequencyduringthetreatmentperiodascomparedtotheplacebogroup(2.6+2.6daysvs.2.0+3.1days,p=0.061);thedifferencebetweenthegroupswasstatisticallysignificantintheper-protocolanalysis(2.8+2.4vs.2.2+2.1,p=0.033)
• Secondaryoutcomes:thetopiramategrouphadagreaterreductionthanplaceboinmigrainedaysduringthelasttreatmentmonthascomparedtothebaselineperiod;nodifferenceinproportionofparticipantshaving50%orgreaterreductioninmigrainefrequency,buthigherproportionoftopiramategroupwith75%orgreaterreductioninmigrainefrequency;
• Adverseevents:nosignificantdifferenceinincidenceofadverseeventsinplacebovs.topiramategroup;4seriousadverseeventsintopiramategroup
Notes • 16%ofpatientsintheplacebogroupvs.20.5%ofpatientsinthetopiramategroupdroppedoutofthestudy
147
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Lakshmi2007StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,placebo-controlled,2-arm
parallel-groupstudy• Comprisedofa4-weektitrationperiodfollowedbya12-week
maintenanceperiod• CarriedoutinoutpatientdepartmentofthePostgraduate
InstituteofMedicalEducationandResearchinIndiaParticipants • Childrenaged8-14yearswithmigrainemeetingICHDcriteria
• Participantshadtohave2ormoremigrainespermonthinthe3monthsprecedingenrollment
Interventions • Topiramate:22randomizedtotopiramateatastartingdoseof25mgdailywithweekly25mgincreasestoamaximumof50mgbid
• Placebo:22randomizedtoplaceboOutcomes • Primaryoutcome:Thetopiramategrouphadagreater
decreaseinmigrainefrequencycomparingbaselinetotheendofthestudy(from16.14+9.35to4.27+1.95vs.from13.38+7.48to7.48+5.94,p=0.025)
• Secondaryoutcomes:Therewasahigherproportionofpatientsinthetopiramategroupshowinga50%orgreaterreductioninmigrainefrequencyfollowingtreatmentascomparedtoplacebo;nodifferenceinthemeanchangeinmigrainedurationormeanmigraineseverity;nodifferenceinrescuemedicationusebetweenthegroups;greaterdecreaseinPedMIDASdisabilityscoreinthetopiramategroup;greaterimprovementinschoolabsenteeisminthetopiramategroup
• Adverseevents:Thereweremoreadverseeventsinthetopiramategroup,withweightloss,lossofappetite,paresthesiasandlackofconcentrationinschoolbeingthemostcommon
Notes • Onlyonepatientlosttofollow-upineachgroup
148
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Lewis2009StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,placebo-controlled,double-blind,3-arm,
parallel-groupstudy• Comprised9weekbaseline(1weekscreening,4week
washoutofprophylacticmedicationsand4weekbaselineperiod)followedby16weektreatmentperiodfollowedby2weektaperandthen4weekexitphase
• Recruitmentfrom31USandnon-USsitesParticipants • Adolescentsaged12-17yearswithmigrainemeetingICHD
criteria• Participantshadtohavemigrainesforaminimumof6
months• Participantshadtohave3-12migrainedays/monthinthe3
monthsprecedingenrollmentInterventions • Lowdosetopiramate:35patientsrandomizedtotopiramate
initiatedat25mg/dayuptoamaximumof25mgbidasneededover4weeksandthenmaintainedfor12weeks
• Highdosetopiramate:35patientsrandomizedtotopiramateinitiatedat25mg/dayuptoamaximumof50mgbidasneededover4weeksandthenmaintainedfor12weeks
• Placebo:33patientsrandomizedtoplaceboforthetreatmentperiod
• NB.Allpatientsreceived4tablets/daythroughout,withthetabletsconsistingofeitherplacebo,25mgtopiramateoracombinationthereof
Outcomes • Primaryoutcome:Thehighdosetopiramategrouphadasignificantlargerdecreaseinmigrainefrequencywhencomparingthelast12weeksoftreatmenttobaselineascomparedtoplacebo(72.2%vs.444%,p=0.016),buttherewasnosignificantdifferencecomparinglowdosetopiramateandplacebo(p=0.798)
• Secondaryoutcomes:Morethan50%ofparticipantstreatedwithhighdosetopiramateweremigraine-freeduringthelast4weeksoftreatment;highdosetopiramatebutnotlowdosetopiramatewassuperiortoplaceboinreducingmigrainefrequencyduringthelast4weeksoftreatmentascomparedtobaseline;mostsecondaryanalysesalsofoundthathighdosetopiramatewassuperiortoplacebobutnotlowdosetopiramate
• Adverseevents:Thereweremoreadverseeventsinthetopiramategroupsascomparedtotheplacebogroup(74%
149
vs.48%),withthemostcommonadverseeventsinthetopiramategroupsbeingupperrespiratorytractinfections,paresthesiasanddecreasedappetite;therewere2seriousadverseeventsinthehighdosetopiramategroupthatweredeemedunlikelytoberelatedtotreatmentbytheinvestigators
Notes • None
150
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Pandina2010(analysisofsubsetofthedatafromLewis2009)StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,placebo-controlled,double-blind,3-arm,
parallel-groupstudy• Comprised9weekbaseline(1weekscreening,4week
washoutofprophylacticmedicationsand4weekbaselineperiod)followedby16weektreatmentperiodfollowedby2weektaperandthen4weekexitphase
• Recruitmentfrom31USandnon-USsitesParticipants • Adolescentsaged12-17yearswithmigrainemeetingICHD
criteria• Participantshadtohavemigrainesforaminimumof6
months• Participantshadtohave3-12migrainedays/monthinthe3
monthsprecedingenrollmentInterventions • Lowdosetopiramate:35patientsrandomizedtotopiramate
initiatedat25mg/dayuptoamaximumof25mgbidasneededover4weeksandthenmaintainedfor12weeks
• Highdosetopiramate:35patientsrandomizedtotopiramateinitiatedat25mg/dayuptoamaximumof50mgbidasneededover4weeksandthenmaintainedfor12weeks
• Placebo:33patientsrandomizedtoplaceboforthetreatmentperiod
• NB.Allpatientsreceived4tablets/daythroughout,withthetabletsconsistingofeitherplacebo,25mgtopiramateoracombinationthereof
Outcomes • Primaryoutcome:ThiswasreportedintheLewisetal2009publication.Inthispaper,thefocuswasoncognitiveandmoodsideeffects.
• Outcomesforthispublication:Ascomparedtoplacebo,thehighdosetopiramategrouphadsmallincreasesintheirpsychomotorreactiontimes;thehighdosetopiramategroupalsohadadecreaseinthenumberofuniquewordstheycouldgenerate;nootherchangeswereseenincognitivescoresontheCANTABassessment(ie.memory,learning,visualprocessing);noneofthegroupsdifferedsignificantlyinthechangesseenintheirProfileofMoodStatesscores
Notes • None
151
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Winner2006PooledAnalysisStudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Analysisfrom3adultsstudieswheredataonadolescent
participantsaged12-18yearswaspooled• Allthreeadulttrialsweredouble-blind,randomized,parallel-
group,placebo-controlledstudies• Recruitmentfrom150differentsitesinNorthAmerica,
EuropeandAsia• Compriseda2-weekwashoutperiod,followedbya4-week
baselineperiod,followedbyan8-weektitrationphaseandthenan18-weekmaintenancephase
Participants • Analysisisrestrictedtoadolescentparticipantsaged12-18yearswithmigrainemeetingICHDcriteria
• Participantshadtohave3-12migraines/monthinthe3monthspriortoenrollmentandinthebaselineperiod
• TherewerenomajorbaselinedifferencesbetweenthegroupsInterventions • Lowdosetopiramate:Twoofthestudiesrandomizedatotal
of11participantstotopiramate50mgdaily• Mediumdosetopiramate:Allthreestudieshadagroup
randomizedtotopiramate100mgdaily,comprising13participants
• Highdosetopiramate:Allthreestudieshadagrouprandomizedtotopiramate200mgdaily,comprising13participants
• Placebo:Allthreestudieshadaplaceboarm,comprising12participants
• Propranolol:Onestudyusedpropranololasanactivecomparatorinsteadofthelowdosetopiramate
• NB.Allgroupsontopiramatestartedatadoseof25mgdaily,with25mg/weekincreasesuntilthemaximumdosefortheirassignedgroupwasreached
Outcomes • Primaryoutcome:Thetopiramate100mgdailyand200mgdailygroupshadsignificantlygreaterreductionsinmigrainefrequencycomparingthetreatmentperiodtobaselineascomparedwithplacebo(63%and65%comparedto13%reductions,p<0.04)
• Secondaryoutcomes:Nosignificantdifferenceswereseenforthesecondaryoutcomes
• Adverseevents:Therewerenomeaningfuldifferencesinthefrequencyofadverseeventsbetweenthegroups;therewerenoseriousadverseeventsinanyofthetopiramategroups;weightlossappearedtobemorecommonfortopiramate;the
152
mostcommonadverseeventswereupperrespiratorytractinfections,paresthesiasandweightloss;7patientsontopiramatevs.2patientsonplacebohadcognitivesideeffects
Notes • None
153
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Apostol2008StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,placebo-controlled,4-armparallel
grouptrial• Comprisedof2weekwashoutperiod,followedbya4week
baselineperiodfollowedby2weektitrationperiodfollowedby10weeksofmaintenancetreatment
• Recruitmentfrom38differentUScentersParticipants • Adolescentsaged12-17withmigrainemeetingICHDcriteria
• Participantshadtohave3-12migraines/monthin3monthperiodpriortostudyentry
• Nostatisticallyorclinicallysignificantbaselinedifferencesbetweenthegroups
Interventions • Lowdosedivalproex:83participantsrandomizedtodivalproex250mgdaily,whichwasmaintainedthroughouttitrationandmaintenance
• Mediumdosedivalproex:74participantsrandomizedtodivalproex500mgdaily,whichstartedatadoseof250mgdailyduringthe2-weektitrationanddoublesubsequentlyforthe10-weekmaintenance
• Highdosedivalproex:75participantsrandomizedtodivalproex1000mgdaily,whichstartedatadoseof500mgdailyduringthe2-weektitrationanddoubledsubsequentlyforthe10-weekmaintenance
• Placebo:73participantsrandomizedtoplaceboOutcomes • Primaryoutcome:Therewasnodifferencebetweenanyof
thedivalproexdosesandplacebointermsofthechangeinmigrainefrequencycomparingbaselinetothe12weektreatmentperiod
• Secondaryoutcomes:Noneofthesecondaryoutcomesshowedanydifferencewhencomparinganyofthedivalproexdosestoplacebo
• Adverseevents:Therewerenogroupsdifferencesinthefrequencyofadverseevents;themostcommonsideeffectsforthedivalproexgroupswereupperrespiratorytractinfections,somnolenceandfatigue
Notes • Usedaneffectsizederivedfromanadultstudy,whichisperhapsnotappropriategiventhatchildrenareknowntohaveamoredramaticplaceboresponsethanadults.
154
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Sorge1988StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebo-controlledcrossovertrial
• RecruitmentfromHeadacheCenterat11ndMedicalSchoolofNaples
• Comprised4-weekbaseline,followedby12-weektreatmentperiod,followedby4-weekwashoutperiod,followedbycross-overtoanother12-weektreatmentperiod
Participants • Childrenaged5-11yearsofagewithmigrainemeetingVahlquist’scriteria
• Participantshadtohaveminimumof6monthsofmigraines• Therewerenosignificantdifferencesbetweenthegroupsat
baselineInterventions • Flunarizine:35patientswererandomizedtofirstreceive
flunarizine5mgdailyfortheinitialtreatmentperiod,andthentheyreceivedmatchedplacebo
• Placebo:35patientswererandomizedtofirstreceivedmatchedplacebofortheinitialtreatmentperiod,andthentheyreceivedflunarizine5mgdaily
Outcomes • Primaryoutcome:Bothgroupshadastatisticallysignificantreductioninmigrainefrequencyduringtheirtreatmentwithflunarizine(p<0.001inbothgroups)ascomparedtotheplacebophases
• Secondaryoutcomes:Thedurationofmigraineattackswasreducedby3monthsofflunarizineingroupAandby2monthsofflunarizineingroupBandthiswassignificantlydifferentfromtheplacebophases(p<0.001inbothgroups)
• Adverseevents:Thereisnodetailaboutwhichadverseeventsoccurredinwhichgroups;themostcommonsideeffectsweredrowsinessandweightgain,whichoccurredin9.5%and22.2%,respectively
Notes • 7patientswithdrewfromthestudy;2duringtheflunarizinephaseand5duringtheplacebophase
155
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Sorge1985StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebocontrolled,2-arm,parallel-groupstudy
• RecruitmentfromtheHeadacheCenteroftheNaplesIIedMedicalSchool
• Baselineperiodfollowedbyrandomizationtoaninterventionfor3months
Participants • Childrenundertheageof18yearswithmigrainemeetingtheVahlquistcriteria
• Baselinecharacteristicsweresimilarbetweenthegroups,exceptthattheflunarizinegrouphadshortermigrainesatbaseline(2.76+1.13hours/migrainevs.2.95+2.47hours/migraine)
Interventions • Flunarizine:24participantswererandomizedto3monthsofflunarizine5mgqHS
• Placebo:24participantswererandomizedto3monthsofplacebo
Outcomes • Primaryoutcomenotexplicitlydefined• Attrialcompletion,theflunarizinegrouphadsignificantly
lessfrequentheadachesthantheplacebogroup(p<0.001)duringthetreatmentperiod
• Theflunarizinegrouphadsignificantlyshortermigrainesduringthetreatmentperiodascomparedtoplacebo(p<0.05),buttheyalsohadshortermigrainesatbaseline
• Adverseevents:Thereisnodetaileddescriptionofadverseevents,onlyamentionthat3patientswithdrewfromtheflunarizinegroupduetosideeffects,namelygastrointestinalsymptoms,drowsinessandfatigue)andamentionthatthemostcommonsideeffectswereweightgainandsleepiness(butnodetailsaboutfrequencypergroup)
Notes • 3participantswithdrewfromflunarizinegroupbecauseofsideeffectsand3participantswithdrewfromplacebogroupduetolackofefficacy
156
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Noronha1985StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Thiswasadouble-blind,randomizedcross-overstudy
• Thesiteofrecruitmentisnotlisted,butpresumablyrecruitmentwasfromasiteinEnglandgiventheauthor’slocation
• Comprised4-weekbaselineperiod,followedby8weeksoftreatment,followedby4-weekwashoutperiod,followedby8weeksoftreatmentwithalternateagent
Participants • Childrenaged5to16yearswithmigrainemeetingtheVahlquistcriteria
• Participantshadtohaveahistoryofatleast2attacks/month,thoughitisunclearhowlongofahistorywasrequired
• ParticipantshadsimilarbaselinemigrainefrequenciesInterventions • Timolol:9patientswererandomizedtofirstreceivetimolol
5mgdailyandthenwerecrossedovertoplacebo• Placebo:8patientswererandomizedtofirstreceiveplacebo
thentimolol5mgdailyOutcomes • Itisunclearwhichoutcome(s)wereprimary
• Therewasnodifferencebetweentimololandplaceborelativetoreducingmigrainefrequency,migraineseveritynorduration
• Therewasasimilarprogressivedecreaseinthefrequencyofmigrainesinbothgroups
• Adverseeventsarenotdetailedbeyondthestatementmadeabout2patientsdroppingoutduringthetimololphaseduetosideeffects,namelyheadacheandvomiting
Notes • 2patientsexcludedgiventhattheydroppedoutfromtimololsideeffects
157
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Sillanpää1977StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebo-controlled,2-arm,parallel-grouptrial
• Althoughitseemsimpliedthatthetrialwasrandomized,itisnotclear
• Patientsweretreatedfor2months,andthenhadameanfollow-upof7.9months
• PatientswererecruitedfromthePediatricOutpatientDepartmentsinTurkuorTempere,Finland
Participants • Childrenuptoage15yearswithmigraineorotherparoxysmalvascularheadaches(categorizedassuchifonemigrainecriterionwasmissing;ie.analogoustoprobablemigraineinICHDcriteria)accordingtoVahlquist’scriteria
• Thegroupshadsimilarbaselineheadachetypesandheadachefrequencies
Interventions • Clonidine:28participantsrandomizedtoclonidine25microgramsdailyforchildren<40kgand25microgramsbidforchildren>40kg;after1month,thedosewasincreasedby25microgramsforallpatientsinthisgroup
• Placebo:29participantsrandomizedtoplaceboOutcomes • Itisunclearwhichoutcome(s)wereprimary
• Hypothesistestingresultsarenotreportedformostoftheoutcomes
• Inbothgroups,1/3oftheparticipantswereheadache-freeduringtreatment
• 57%ofclonidineparticipantsand42%ofplaceboparticipantshadonly1or2headachesduringtheentirestudy(nopgiven)
• Therewerenostatisticallysignificantdifferencesbetweenthegroupsintermsofheadacheintensityorduration(nopgiven)
• Participantswithmigrainewithaurawhoreceivedclonidinehadlessfrequentandlessintenseheadachesduringtreatmentascomparedtoplacebo(p<0.05)
• 14participantsonclonidinevs.10participantsonplacebohadlessneedforrescuemedication(nopgiven)
• 11participantsonclonidinevs.6participantsonplaceboreportedadverseevents;themostcommonsideeffectsforclonidinewerefatigueandnausea
Notes • Nosamplesizecalculationsarereported;3drop-outsarereported,allfromtheclonidinegroup
158
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Battistella1993StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized*,double-blind,placebo-controlled,2-arm,
crossovertrial• 4weekrun-inperiod,followedby12weektreatmentperiod,
followedby4weekwashoutperiod,followedbysecond12weektreatmentperiod(withotherintervention)
Participants • 40childrenaged7-18yearswithmigrainewithoutauraasperICHDcriteria
• Allhadmigraineforatleast6months• Hadtoreportatleast3migrainespermonth
Interventions • Trazodone:20patientsrandomizedtoreceivetrazadone1mg/kg/daydividedtidforfirstphaseoftreatment
• Placebo:20patientsrandomizedtoreceiveplaceboforthefirstphaseoftreatment
Outcomes • Primaryoutcome:Therewasnodifferencebetweenthegroupsinreductionofmigrainefrequencyinthefirsttreatmentphase;inthesecondtreatmentphase,thetrazadonegrouphadagreaterreductioninfrequencythantheplacebogroup(trazodonereducedfrom2.1+0.2attacks/monthto1.8+0.2vs.placeboincreasedfrom1.8+0.1to2.1+0.2,p<0.005)
• Secondaryoutcome:Attheendofthefirsttreatmentphase,thetrazodonegrouphadahigherdurationofmigrainethanplacebo(16.1+1.4hrsvs.10.2+1.0,p<0.01);attheendofthesecondtreatmentphase,thetrazodonegrouphadagreaterreductioninmigrainedurationthanplacebo(from10.7+1.3to4.9+0.7vs.from11.9+1.3to13.1+1.3,p<0.001)
• Adverseevents:Noseriousadverseeventsreported;nodetailsgivenaboutpotentialnon-serioussideeffects
Notes • 5patientswithdrew(2fromonegroupand3fromtheother)*NB.Authorcontactedtoensurethatthetrialwasrandomizedasmanuscriptwasvague
159
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Battistella1990StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized*,double-blind,placebo-controlled,2-arm,
crossovertrial• 4weekrun-inperiod,followedby12weektreatmentperiod,
followedby4weekwashoutperiod,followedbysecond12weektreatmentperiod(withotherintervention)
Participants • 37patientsaged7to18yearswithmigrainewithorwithoutauraaccordingtotheAdHoccriteria
• Patientswererequiredtohaveatleast1migraine/monthinthe6monthsprecedingthetrial
Interventions • Nimodipine:18patientsrandomizedtonimodipine10mgto20mgtidforthefirsttreatmentperiod
• Placebo:19patientsrandomizedtocolour-matchedplaceboforthefirsttreatmentperiod
Outcomes • Primaryoutcome:Therewasnodifferencebetweenthegroupsinreductionofmigrainefrequencyinthefirsttreatmentphase;inthesecondtreatmentphase,thenimodipinegrouphadagreaterreductioninfrequencythantheplacebogroup(from2.7+0.8attacks/monthto1.9+1.7vs.from2.6+0.8to2.8+0.6,p<0.01)
• Secondaryoutcome:Therewasnodifferencebetweenthegroupsinreductionofmigrainefrequencyineithertreatmentphase
• Adverseevents:3patientshadmildabdominaldiscomfortwithnimodipineininitialdaysoftreatment
Notes • 7patientswithdrewforreasonsnotrelatedtotheinterventions;theauthorsdonotspecifywhichgroup(s)theybelongedto
*NB.Authorcontactedtoensurethatthetrialwasrandomizedasmanuscriptwasvague
160
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Ford2014StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Analysisfrom5studieswheredataonparticipatingchildren
aged6-17yearswereanalyzed(ie.onlypediatricpatientsanalyzed)
• Allthreetrialsthatinvolvedarandomized,double-blind,placebo-controlled,parallel-groupdesign
• Alltrialsweremulticenter• Thetrialsrangedfrom16-26weektreatmentperiods,
including4-8weektitrationperiods• NB.Manydetailsarelackingasthisanalysiswasonly
availableinconferenceabstractformParticipants • Analysiswasrestrictedtopediatricpatientsaged6-17years
meetingICHDcriteriaformigraineInterventions • Atotalof309patientswereanalyzed,buttheabstractdoes
notreporthowmanybelongedtoeachgroup• Topiramate:Varioustopiramatedosinggroupswere
included:topiramate2-3mg/kg/day,50mgdaily,100mgdailyor200mgdaily
• Placebo:Allstudieshadaplaceboarm• Propranolol:Oneofthestudieshadanactivecomparatorarm
involvingpropranolol160mgdailyOutcomes • Noprimaryoutcomesspecified
• Percentreductioninmigraineattackrate:inTOPMAT-MIG-3006trialthetopiramate100mgdailywassuperiortoplacebo(p=0.0164);inCAPS-122thetopiramateandplacebogroupsdidnotdiffer;inTOPMAT-MIGR-001/002/003therewasatrendtowardstopiramate100mgdailybeingsuperiortoplacebo
• 50%responderrate:inTOPMAT-MIG-3006thetopiramate100mgdailyhadasignificantlyhigherresponderrate(p=0.0048),butnodifferencesinresponderratescomparingtopiramatewithplacebointheotherstudies
• Adverseevents:Mostcommonsideeffectswereinfluenza-likesymptoms,languageproblemsandparesthesias
Notes •
161
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Ashrafi2014StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Double-blind,placebo-controlled,2-arm,parallel-groupRCT
• 4weekpre-randomizationphaseand12weeksforthetreatmentphase
• ParticipantswererecruitedfromtheChildren’sMedicalCenterinTehran,Iran
Participants • Children5-17yearswithmigraineaspertheICHDcriteria• Allhadatleast6monthsofmigraine• Allhadatleast4attackspermonthinthe6monthspreceding
enrollment• Noclinicallysignificantdifferencesbetweenthegroupsin
baselinecharacteristicsInterventions • Cinnarizine:30participantsrandomizedtocinnarizine
1.5mg/kg/dayforthoseweighinglessthan30kgand50mgdailyforthoseweighing30kgormore
• Placebo:32participantswererandomizedtoplaceboOutcomes • Primaryoutcomes:Thereweremoreparticipantsachievinga
50%ormorereductioninheadachefrequencyinthecinnarizinegroupascomparedwithplacebo(60%vs.31.3%,p=0.023);bothcinnarizineandplaceboyieldedsignificantdecreasesinthemonthlymigrainefrequencyovertime,butnogroupdifferenceswerereported(cinnarizine:baseline8attacks/month,at1monthreducedto5,4.5at2monthsand4at3months,p<0.001;placebo:baseline8attacks/month,at1monthincreasedto12,reducedto6.5at2monthsand6at3months,p<0.001)
• Secondaryoutcomes:Headacheseveritywasreducedtoagreaterextentafter3monthsoftreatmentinthecinnarizinegroup(p<0.001);headachedurationwassignificantlyreducedinthecinnarizinegroupascomparedtotheplacebogroup(p=0.042)
• Adverseevents:Noseriousadverseeventsineithergroup;3cinnarizineparticipantvs1placeboparticipanthaddrowsiness;1cinnarizineparticipanthadsignificantweightgain(2.5kg)resultingintheneedtoreducethedose
Notes •
162
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:MachínAltueña1987StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Randomized,double-blind,three-arm,placebo-controlled
clinicaltrial• Nobaselineperiod,randomizedto4monthtreatmentperiod
Participants • Childrenaged5to13yearswithmigrainemeetingAdHoccriteria
• Noneofthechildrenhadbeenpreviouslytreated• Baselinedemographicsnotdescribed
Interventions • Flunarizine:15patientsrandomizedtoflunarizine0.15mg/kgoncedaily
• Dimethothiazine:15patientsrandomizedtodimethothiazine1mg/kg/daydividedbid
• Placebo:15patientsrandomizedtoplaceboOutcomes • Primaryoutcome:Clinicalimprovementwasseenin93.3%of
thedimethothiazinegroupvs.86.7%oftheflunarizinegroupvs.80%oftheplacebogroup(p>0.05)
• Secondaryoutcomes:Inthedimethothiazinegroup,35.7%hadcompleteimprovementand64.3%hadpartialimprovementvs.intheflunarizinegroup38.4%hadcompleteimprovementand61.5%hadpartialimprovementvs.intheplacebogroup41.7%hadcompleteimprovementand59.3%hadpartialimprovement(nosignificantdifferencesbetweenthegroups);41.3%reductioninmigrainefrequencyinthedimethothiazinegroupvs.46.8%influnarizinegroupvs.45.8%inplacebogroup(nosignificantdifferences);nosignificantdifferencesinchangeinmigraineintensitynorduration
• Adverseevents:23.1%offlunarizinepatientsgainedweight,1patient(groupnotmentioned)hadIgAdeficiencybutnootherbiochemicalabnormalitieswerenoted
Notes • TranslatedfromSpanish
163
ProphylacticInterventionsforPediatricMigraine:CharacteristicsofStudies
StudyID#:Sillanpää1978StudyStatus:� Included� Excluded� UncertainReviewedby:SLOCharacteristicsofStudyCharacteristic DescriptionofFindingsMethods • Thiswasadouble-blind,placebo-controlled,2-armparallel-
group,randomizedtrial• Thetreatmentperiodwas2monthsinduration;nobaseline
periodisdescribedinthetext• Patientswererecruitedfromtheoutpatientdepartmentsof
twohospitalsinFinlandParticipants • Patientsaged6-15yearswithmigraineasperVahlquist
criteriaorvascularheadache(meetingonlyoneVahlquistcriteria)
• Participantswererequiredtohaveatleast2headaches/month
• Therewerenosignificantdifferencescomparingbaselinecharacteristicsbetweenthegroups
Interventions • Papaverine:19participantsrandomizedtopapaverine5-10mg/kg/daydividedbidortid,startingatadoseof5mg/kg/dayanddoubledto10mg/kg/dayafter1month
• Placebo:18participantsrandomizedtoplaceboOutcomes • Noprimaryoutcomewasspecified
• 6/19papaverineparticipantsvs.0/18placeboparticipantswerepain-freeduringtreatment(p<0.001)
• Headachefrequency,intensityanddurationweresignificantlymorereducedinthepapaverinegroupascomparedtoplacebo(p<0.001)
• Adverseevents:notreportedNotes • 5patientswereexcluded(twobecauseofsideeffectsand
threeduetointerventioncomplianceissues;groupsnotspecified)
164
11. AppendixD.SystematicReviewIncludedStudies‘RiskofBiasAssessment’Tables
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Oelkers-Ax2008Reviewedby:SLOFinalqualityrating:Highriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Fromtext:“Patientswereallocatedtooneofthethreetreatmentgroupsafterbaselinebycomputerizedrandomization”
Allocationconcealment(selectionbias)
x Fromtext:“Randomizationwasaccomplishedbythefirstauthor(notinvolvedinpatientcontacts)whoassignedthesubjectnumbersinascendingnumericalsequence(blockrandomizationa9)tothesubjectswhoqualifiedforrandomization”
Blindingofparticipantsandpersonnel(performancebias)
x Thisstudywaspartiallydouble-blind,meaningthatthoseonplacebovs.butterburwereblinded,buttherewasnowayofmaintainingblindingforthemusicgroup.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Alloutcomeswereself-reportedinaheadachediary,exceptadverseeventsthatwerereportedatvisits.Again,themusictherapygroupwasunblinded.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectivemeasureswerestudied.
Incompleteoutcomedata(attritionbias)
x
Thereweremoredrop-outsinthemusictherapyandbutterburgroupsthanintheplacebogroup.TheydiddoanITTanalysis.
Selectivereporting(reportingbias)
x
Noconcernforthathere.
Otherbias x Therewasaclinicallymeaningful
165
differencebetweenthegroups.Butterburhadalmostdoublethebaselinemigrainefrequency.
166
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:MacLennan2008Reviewedby:SLOFinalqualityrating:Lowriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Fromtext:“Randomizationwasperformedbythebiasedcointechnique.ThecomputergeneratedlistofrandomnumberswascreatedandadministeredbythehospitalPharmacyDepartment”.
Allocationconcealment(selectionbias)
x GiventhatthePharmacydepartmentweretheonesusingtheallocationsequencesoftwarethereislowriskofbiasforallocationconcealment.
Blindingofparticipantsandpersonnel(performancebias)
x Thestudywasdoubleblindandeffortsweremadetomaintainblinding.Fromtext:“Theriboflavinandplacebocapsuleswereproducedbythesamemanufacturertoobtainanidenticalappearance.Asriboflavinisbrightorange,anorangefooddyewasusedinthemanufactureoftheplacebo”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x “EachfamilycollectedtheircapsulesdirectlyfromthePharmacy,andtreatmentallocationwasconcealedtotheparticipantsandinvestigatorsforthedurationofthestudy.Onlythedatamonitoringcommitteecouldviewunblindeddata,andtheydidnothaveanycontactwithstudyparticipants”
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectiveoutcomesassessed
Incompleteoutcomedata(attritionbias)
x
“Efficacyanalysiswasperformedonanintention-to-treatpopulationthatincludedallrandomizedpatients”
Selectivereporting(reportingbias)
Noneidentified
Otherbias x Itisunclearwhatkindofstoppingruletheyusedfortheirinterimanalysis.
167
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Bruijn2010Reviewedby:SLOFinalqualityrating:unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x Themethodofrandomizationisnotdetailedbeyondreferencetoa“randomizationkey”.
Allocationconcealment(selectionbias)
x Fromthetext:“Treatmentallocationwasconcealedfromtheparticipantsandinvestigatorsforthedurationofthestudy.Thehospitalpharmacistsguardedtherandomizationkey”
Blindingofparticipantsandpersonnel(performancebias)
x Effortsweremadetoblindandmaintainblinding.Forexample,becauseriboflavincandiscolortheurine,carotenewasaddedtoplacebo.Also,fromtext:”Toevaluateblinding,atthelastvisitparentswereaskedwhichtreatmenttheybelievedthattheirchildhadreceivedinwhichphase,andthereasonsfortheirassumptions”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove,effortsweremadetoblindthepatientswhoreportedtheoutcomesthroughtheirheadachediaries.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x Noobjectiveoutcomeswereassessed.
Incompleteoutcomedata(attritionbias)
x
4patientsdroppedoutofthegroupassignedtoplaceboinitiallyandnonedroppedoutofthegroupassignedtoriboflavininitially.However,intention-to-treatanalyseswereused.
Selectivereporting(reportingbias)
x Noevidenceforreportingbias.
168
Otherbias x Noneidentified
169
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Winner2005Reviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Fromtext:“medicationcodeschedulegeneratedbeforethetrial”.Itisunclearhowthecodewasgenerated.
Allocationconcealment(selectionbias)
x Itseemsasthoughtheallocationsequencewaskeptfromthoseinvolvedinthestudy:“Aphysiciandrugassignment/inventory(PDA)thatlistedtheuniquemedicationcodenumberwassuppliedtoeachinvestigator.Theinvestigatorenteredthesubject’sidentificationinformationinnumericalorder,therebyassigningthesubjectto1of2treatmentgroups”
Blindingofparticipantsandpersonnel(performancebias)
x Fromtext:“Treatmentassignmentswerenotrevealedtostudypatients,investigators,clinicalstaff,orstudymonitorsuntilallpatientshadcompletedthestudyandthedatabasehadbeenfinalized”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x
Noobjectiveoutcomes
Incompleteoutcomedata(attritionbias)
x
16%ofpatientsintheplacebogroupvs.20.5%ofpatientsinthetopiramategroupdroppedoutofthestudy.Also,ITTanalyseswereused.
Selectivereporting
x
Noneidentified
170
(reportingbias)Otherbias x Noneidentified
171
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Lakshmi2007Reviewedby:SLOFinalqualityrating:Lowriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Fromtext:“Arandomnumbertablewasusedtodrawuprandomizedblocksofsubjectsforallocationtoeacharmofthestudy,andarandomizationsequencewasgenerated.”
Allocationconcealment(selectionbias)
x Fromtext:“Theoriginalsequenceandthecodenumberswereplacedinsealedenvelopesandopenedonlyafterthedataanalysiswascompleted”
Blindingofparticipantsandpersonnel(performancebias)
x Fromthetext:“Thesubjectsthemselves,theirparents,thepersonengagedininterviewingandadministeringthedrugs,bothatenrollmentandfollow-up,wereallblindedtotheassignment.Dispensingboththedrugandtheplaceboinidenticalformswithsimilarappearance,pack-aging,taste,andotherfactorsfurtherensuredthisimplementation”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x
Therewerenoobjectiveoutcomes
Incompleteoutcomedata(attritionbias)
x
Therewasonlyonedrop-outineachgroupandbothwereattributedtofinanciallimitations.
Selectivereporting(reportingbias)
x
Noevidenceofselectivereporting.
Otherbias x Noneidentified
172
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Lewis2009Reviewedby:SLOFinalqualityrating:Lowriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Fromtext:“Subjectswereassignedrandomlybyusingpermutedblocksandacomputer-generatedschedule,withstratificationaccordingtoage(12–14yearsand15–17years).Centralrandomizationwasimplementedinthisstudy.”
Allocationconcealment(selectionbias)
x Therewaslowriskofallocationconcealmentfailuregiventhatcentralrandomizationwasused.
Blindingofparticipantsandpersonnel(performancebias)
x Thestudywasdouble-blindandeffortsweremadetomaintainblinding:“Treatmentwastakenintheformofidentical-appearingcapsulesattheendoftheprospectivebaselineperiod(day1)”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x Noobjectiveoutcomesinthisstudy
Incompleteoutcomedata(attritionbias)
x
Intention-to-treatanalyseswereusedanddrop-outratesweresimilaracrossgroups.
Selectivereporting(reportingbias)
x
Noneidentified
Otherbias x Noneidentified
173
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Pandina2010(analysisofsubsetofthedatafromLewis2009)Reviewedby:SLOFinalqualityrating:lowriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
FromLewis2009text:“Subjectswereassignedrandomlybyusingpermutedblocksandacomputer-generatedschedule,withstratificationaccordingtoage(12–14yearsand15–17years).Centralrandomizationwasimplementedinthisstudy.”
Allocationconcealment(selectionbias)
x Therewaslowriskofallocationconcealmentfailuregiventhatcentralrandomizationwasused.
Blindingofparticipantsandpersonnel(performancebias)
x Thestudywasdouble-blindandeffortsweremadetomaintainblinding(fromLewis2009text):“Treatmentwastakenintheformofidentical-appearingcapsulesattheendoftheprospectivebaselineperiod(day1)”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x SomeofthefeaturesoftheCANTABwereobjective(ie.reactiontime)andthetestwascompletedbytheparticipants,whowereblinded.
Incompleteoutcomedata(attritionbias)
x
Intention-to-treatanalyseswereusedanddrop-outratesweresimilaracrossgroups.
Selectivereporting(reportingbias)
x
Noneidentified
Otherbias x Noneidentified
174
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Winner2006PooledAnalysisReviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Fromtext:“randomizedinequalproportionsto1of4treatmentgroupsaccordingtoacomputer-generatedrandomizationschedule”
Allocationconcealment(selectionbias)
x Nomentionofallocationconcealment(originalstudiesaccessed)
Blindingofparticipantsandpersonnel(performancebias)
x Alltrialsweredouble-blindandthepatientsreportedtheoutcomes.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x
Noobjectiveoutcomes.
Incompleteoutcomedata(attritionbias)
x
Nineteenpatientsoutofthe51totalwithdrewfromthestudy.Thetextdoesnotsaywhichgroup(s)theybelongedto.However,intention-to-treatanalyseswereused.
Selectivereporting(reportingbias)
x Noneidentified.
Otherbias x Noneidentified
175
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Apostol2008Reviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thereisnodetaileddescriptionofhowtherandomsequencewascreated:“Therandomizationschedulewaspreparedbythesponsor’sstatisticsdepartmentpriortothestartofthestudy”
Allocationconcealment(selectionbias)
x Thereisnodescriptionastohowallocationwasconcealed.
Blindingofparticipantsandpersonnel(performancebias)
x Thetrialwasdouble-blindandeffortsweremadetomaintainblinding:“StudymedicationconsistedofunmarkedDVPXER250mgtabletsandmatchingplacebotabletsprovidedinsetsof4bottles”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove,participantswereblindedandtheyreportedalloutcomes.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x Therewerenoobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
Intention-to-treatanalyseswereused.
Selectivereporting(reportingbias)
x
Noevidenceofreportingbias
Otherbias x Noneidentified
176
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Sorge1988Reviewedby:SLOFinalqualityrating:Highriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Therearenodetailsabouthowtherandomsequencewascreated.
Allocationconcealment(selectionbias)
x Thereisnomentionastohowallocationwasconcealed.
Blindingofparticipantsandpersonnel(performancebias)
x Fromtext:‘Flunarizineandplacebowereidenticalinshapeandcolour.Bothpatientsandphysicianswereblindedwithregardtomedication.”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Thepatientsreportedontheoutcomesandtheywereblinded.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x
Therewerenoobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
2patientswithdrewfromtheflunarizinegroupand5withdrewfromtheplacebogroup.NoITTanalyseswereused.
Selectivereporting(reportingbias)
x Noneidentified.
Otherbias x Noneidentified
177
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Sorge1985Reviewedby:SLOFinalqualityrating:Highriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Nodescriptionofrandomsequencegeneration.
Allocationconcealment(selectionbias)
x Nomentionofallocationconcealment.
Blindingofparticipantsandpersonnel(performancebias)
x Thestudyislabeledasdouble-blindthoughnofurtherdetailsaregiven.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Giventhatthepatientsreportedtheoutcomesandthattheywereblinded,thereshouldbealowriskofdetectionbias.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
Threepatientswithdrewfromeachgroup:3fromplaceboforlackofefficacyand3fromtheflunarizinegroupforsideeffects.NoITTanalyseswereused.Giventhatthereasonsforwithdrawalweredifferent,therewashighriskofattritionbias.
Selectivereporting(reportingbias)
x
Noneevident.
Otherbias x Noneidentified.
178
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Noronha1985Reviewedby:SLOFinalqualityrating:Highriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thewaythatrandomizationwascarriedoutisnotdescribed.
Allocationconcealment(selectionbias)
x Allocationconcealmentisnotdescribed.
Blindingofparticipantsandpersonnel(performancebias)
x Thetrialisdescribedasbeing“double-blind”thoughnodetailsaregiven.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Thetrialwasdouble-blindandparticipantsreportedontheoutcomes.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
x
Therewerenoobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
Twopatientswithdrewduetosideeffectsdeemedtoberelatedtotimolol.Nointention-to-treatanalyseswereused.Althoughtwopatientsisasmallnumber,therewereonly17patientsinthetrialsoitisnotnegligible.
Selectivereporting(reportingbias)
x Noneidentified.
Otherbias x Noneidentified.
179
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Sillanpää1977Reviewedby:SLOFinalqualityrating:Highriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Itisunclearifthetrialwasrandomized.Itappearstobeimpliedinthefollowingsentence:“Whenthecodewasbrokenattheendofthestudy…”,butisneverexplicitlystated.
Allocationconcealment(selectionbias)
x Notdescribed
Blindingofparticipantsandpersonnel(performancebias)
x Thepatientswereblindedandreportedontheoutcomes.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
3drop-outsreported;allfromtheclonidinegroup
Selectivereporting(reportingbias)
x
Someofthehypothesistestingisnotreported(ie.nopvaluesgivenforsomeoutcomes).
Otherbias x Noneidentified
180
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Battistella1993Reviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thestudywasrandomizedbutthemethodofrandomizedisnotspecified
Allocationconcealment(selectionbias)
x Nomentionofallocationconcealment
Blindingofparticipantsandpersonnel(performancebias)
x Thetrialwasdouble-blindandeffortsweremadetomaintainblinding(eg.thecolorofplacebowasidenticaltotrazadone)
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Thetrialwasdouble-blindandpatientsreportedontheoutcomes
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Therewerenoobjectiveoutcomes
Incompleteoutcomedata(attritionbias)
x
12.5%ofpatientswithdrew(2/5fromgroupthatreceivedtrazadonefirstand3/5fromgroupthatreceivedplacebofirst;withdrawalsduetodrugadministrationerrorsoronsetofnewdiseases)
Selectivereporting(reportingbias)
x
Noneevident
Otherbias x Noneidentified
181
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Battistella1990Reviewedby:SLOFinalclassrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thetrialwasrandomizedbutthemethodofrandomizationisnotdescribed
Allocationconcealment(selectionbias)
x Thereisnomentionofallocationconcealment
Blindingofparticipantsandpersonnel(performancebias)
x Thestudywasdouble-blindandeffortsweremadetomaintainblinding(eg.theplacebowascolor-matchedtonimodipine)
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Asabove,thetrialwasdouble-blindandthepatientsreportedtheoutcomes
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Therewerenoobjectiveoutcomes
Incompleteoutcomedata(attritionbias)
x 18.9%ofthepatientswithdrewanditisnotmadeclearwhytheywithdrewandwhichgroup(s)theybelongedto
Selectivereporting(reportingbias)
x
Noneidentified
Otherbias x Noneidentified
182
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Ford2014Reviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Allstudieswererandomized.
Allocationconcealment(selectionbias)
x Unclearifallstudieshadallocationconcealment.
Blindingofparticipantsandpersonnel(performancebias)
x Allstudiesweredouble-blind
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Participantsreportedonalloutcomesandtheywereblinded
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Therewerenoobjectiveoutcomesinthesestudies
Incompleteoutcomedata(attritionbias)
x Nomentionofpediatric-specificdrop-outrates
Selectivereporting(reportingbias)
x
Noneidentified
Otherbias x Noneidentified
183
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Ashrafi2014Reviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thiswasarandomizedstudyusingarandomnumbertable
Allocationconcealment(selectionbias)
x Thereisnomentionofallocationconcealment
Blindingofparticipantsandpersonnel(performancebias)
x Thiswasadouble-blindstudyandeffortsweremadetomaintainblinding:“Bothcinnarizineandplaceboformulationsweredispensedtothepatientsinidenticalenvelopeswithsimilarappearance.Cinnarizineandplacebopillswereidenticalinshape,color,andtaste”
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Thepatientswereblindedandtheyreportedontheoutcomes.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
6patientslosttofollowupfromthestudy(4inthecinnarizinegroupand2intheplacebogroup)duetorelocationorearlydiscontinuationofthestudyintervention
Selectivereporting(reportingbias)
x
Noneidentified
Otherbias x Noneidentified
184
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:MachínAltueña1987Reviewedby:SLOFinalqualityrating:Highriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thiswasarandomizedstudy,thoughthemethodofrandomizationisnotdescribed.
Allocationconcealment(selectionbias)
x Nomentionofallocationconcealmentinthetext.
Blindingofparticipantsandpersonnel(performancebias)
x Itisunclearifthestudywasblindedornot,althoughitisimpliedtobeso.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Becausetheblindingstatuswasnotexplicitlydetailed,itisunclearifdetectionbiascouldexistforself-reportedoutcomes.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectiveoutcomesinthisstudy.
Incompleteoutcomedata(attritionbias)
x
Nodrop-outsreported.
Selectivereporting(reportingbias)
x
Noneidentified.
Otherbias x Therearenosamplesizecalculationsgivenandthestudywasverylikelyunderpoweredtodetectclinicallymeaningfulgroupdifferences
185
ProphylacticInterventionsforPediatricMigraine:RiskofBiasAssessment
StudyID#:Sillanpää1978Reviewedby:SLOFinalqualityrating:Unclearriskofbias
RiskofBiasTable
Bias Author’sjudgment Supportforjudgment Hig
hriskofbias
Lowriskofbias
Unclearriskofbias
Randomsequencegeneration(selectionbias)
x
Thisstudywasrandomizedbutthemethodofrandomizationisnotdescribed.
Allocationconcealment(selectionbias)
x Thereisnomentionofallocationconcealment.
Blindingofparticipantsandpersonnel(performancebias)
x Thestudywasdouble-blind.
Blindingofoutcomeassessment–self-reportedoutcomes(detectionbias)
x Theparticipantswereblindedandreportedontheoutcomes.
Blindingofoutcomeassessment–objectivemeasures(detectionbias)
Noobjectiveoutcomes.
Incompleteoutcomedata(attritionbias)
x Fivepatientswereexcluded(twobecauseofsideeffectsandthreeduetointerventioncomplianceissues).Thegroup(s)thattheybelongedtowerenotdescribed.
Selectivereporting(reportingbias)
x
Noneidentified
Otherbias x Noneidentified
186
12. AppendixE.EmailInvitationtoPotentialParticipants
Dear____________________, Youarereceivingthisemailbecauseyouhavesignificantexpertisein
HeadacheMedicine.WearecarryingoutabriefsurveyamongstHeadacheMedicinespecialistswiththegoalof
determiningclinicallyrelevantnon-inferioritymarginsforoutcomescommonlyusedinmigraineclinicaltrials.Wearehopingthattheresultsofthissurveycanbeappliedtothedesignoffuturenon-inferioritymigrainetrials,andthattheymayhelptoimprovethequalityofthedataandtheclinicalrelevanceofstudyresults.
Yourparticipationinthesurveyiscompletevoluntary.Thesurveywilltakenomorethan5-
10minutestocomplete.Youcanaccessthesurveythroughthefollowinglink:_________________________________________________________________________________________________
Weunderstandthatyouareverybusy,butweurgeyoutoconsidertakingthetimetocomplete
thissurveyasitmayhelptoimprovefutureresearchintheareaofmigrainetreatment.Thankyouforyourtimeandconsiderations.Sincerely,TheNIMMSurveyStudyGroupSerenaOrr,MD,MScCandidateDariushDowlatshahi,MD,PhD,FRCPCSuzanneChristie,MD,FRCPCTimothyRamsay,PhDDavidDodick,MD,FRCPC,FACP,FAHSJonathanGladstone,MD,FRCPC
187
AppendixF.EmailInvitationtoPotentialParticipants
Dear____________________, Thisisareminderemailregardingyourparticipationinabriefsurvey.You
arereceivingthisemailbecauseyouhavesignificantexpertiseinHeadacheMedicine.WearecarryingoutabriefsurveyamongstHeadacheMedicinespecialistswiththegoalof
determiningclinicallyrelevantnon-inferioritymarginsforoutcomescommonlyusedinmigraineclinicaltrials.Wearehopingthattheresultsofthissurveycanbeappliedtothedesignoffuturenon-inferioritymigrainetrials,andthattheymayhelptoimprovethequalityofthedataandtheclinicalrelevanceofstudyresults.
Yourparticipationinthesurveyiscompletevoluntary.Thesurveywilltakenomorethan5-
10minutestocomplete.Youcanaccessthesurveythroughthefollowinglink:_________________________________________________________________________________________________
Weunderstandthatyouareverybusy,butweurgeyoutoconsidertakingthetimetocomplete
thissurveyasitmayhelptoimprovefutureresearchintheareaofmigrainetreatment.Thankyouforyourtimeandconsiderations.Sincerely,TheNIMMSurveyStudyGroupSerenaOrr,MD,MScCandidateDariushDowlatshahi,MD,PhD,FRCPCSuzanneChristie,MD,FRCPCTimothyRamsay,PhDDavidDodick,MD,FRCPC,FACP,FAHSJonathanGladstone,MD,FRCPC
188
13. AppendixG.Non-InferiorityMarginsinMigraineResearch(NIMM)Survey
IntroductionScript:“Clinicaltrialscanbedesignedaroundavarietyofhypothesistypes.Traditionally,superiorityhypotheseshavebeenused,wherebytheaimistoshowthatoneinterventionissuperiortotheother.Non-inferiorityhypothesesareaimedatshowingthatanewinterventionisnotworsethananestablishedintervention.Non-inferiorityhypothesesaremoreappropriatewhenanewinterventionischeaper,easiertouseorhasabettersideeffectprofilethantheestablishedintervention,becauseadegreeofinferiorefficacycanbeacceptedinthecontextofotherrelativeadvantagesassociatedwiththenewintervention.Theuseofnon-inferiorityhypothesesinclinicaltrialsisincreasing.Todate,onlytwomigrainetrialshaveemployednon-inferiorityhypotheses.
Inordertoproperlydesignandpoweranon-inferioritystudy,anon-inferioritymarginmust
bedeterminedaprioriinordertocalculateasamplesize.Anon-inferioritymarginissetfortheprimaryoutcome.Itconstitutesanumberbelowwhichwewouldconsiderthenewinterventiontobeclinicallyinferiortotheestablishedintervention.Inotherwords,itisthemarginabovewhichthenewinterventionwouldbeconsiderednotworsethantheestablishedintervention,andabovewhichtheinterventionwouldbeclinicallyacceptabletopractitionersandpatients.Anacceptedwayofsettinganon-inferioritymarginisbysamplingopinionsfromexpertsinthefieldorotherstakeholders.Inthisprocess,expertsorstakeholdersareaskedtoexpresstheiropiniononanacceptablenon-inferioritymarginforaparticularclinicalquestion.
Youarebeingaskedtocompletethissurveybecauseyouhaveexpertiseintreatingmigraines.
Throughthissurvey,wearehopingtoestablishnon-inferioritymarginsforcommonlyusedandacceptedoutcomesinmigraineinterventiontrials,soastoimprovethedesignoffuturenon-inferioritytrialsinmigrainetherapeutics”.
ConsentScript:“Ifyouchoosetocompletethissurvey,youwillbeprovidingimplicitconsentfor
ustousethisdataforthepurposesofcompilingsurveyresults.Thisdatamayalsobeusedinfutureabstracts,publicationsand/oracademicpresentations.Yourresponsesarecompletelyanonymousandwillnotbetracedbacktoindividualrespondents.Wewillnotbecollectinganypersonalidentifyinginformationnorpersonalhealthinformationaspartofthisstudy.Researchrecordswillbekeptfor10years,asrequiredbytheOHSN-REB.Attheendofthestoragetime,allelectronicrecordswillbesecurelydeleted.Wedonotanticipatethatyouwillsufferanyharmfromparticipationinthisstudy.Wedonotforeseeanyrisksassociatedwiththisstudy.Youwillnotreceiveanydirectbenefitfromparticipation.Thesurveyconsistsof10multiplechoicequestionsandwillrequire5-10minutesofyourtimetocomplete.Youcanchoosetonotparticipate.Yourparticipationinthisstudyisvoluntary.Youmaydecidetocompletethesurveynowandwithdrawyourdataatalatertime,withoutaffectingyourcurrentorfutureemploymentatTheOttawaHospitalResearchInstitute.Therearenoconflictsofinteresttodeclarerelatedtothisstudy.Ifyouhaveanyquestionsaboutthisstudy,orifyoufeelthatyouhaveexperiencedastudy-relatedinjuryorillness,pleasecontactDr.SerenaOrrat(613)737-7600ext.1605.
TheOttawaHealthScienceNetworkResearchEthicsBoard(OHSN-REB)hasreviewedthis
protocol.TheBoardconsiderstheethicalaspectsofallresearchstudiesinvolvinghumanparticipantsatTheOttawaHospitalResearchInstitute.Ifyouhaveanyquestionsaboutyourrightsasastudyparticipant,youmaycontacttheChairpersonat613-798-5555,extension16719.”
189
Non-InferiorityMarginsinMigraineResearch(NIMM)Survey
1. Whatkindofpractitionerareyou?£ Adultneurologist£ Childneurologist£ Other*
If‘other’wasselected,branchinglogicwasusedtodisplaythefollowing: Youselected"Other"forpractitioner.Youarenoteligibleforthissurvey. Pleaseconfirm.
£ IamNOTaNeurologist(adultorchild)andIamNOTeligibleforthissurvey.£ IamaNeurologist(adultorchild)andIameligibleforthissurvey(eligible)
2. WheredoyoupracticeHeadacheMedicine?
£ Canada£ UnitedStates
3. InwhatsettingdoyoupracticeHeadacheMedicine?
£ Academicpractice£ Communitypractice£ Mixedacademic/communitypractice
4. ForhowmanyyearshaveyoubeenpracticingHeadacheMedicine?
£ 0-5years*£ 5-10years£ 10-15years£ 15-20years£ Over20years
*If‘0-5years’wasselected,branchinglogicwasusedtodisplaythefollowing:
“IfyouhavenotbeenpracticingHeadacheMedicine(i.e.practicing0years),thenyoumaynothavesufficientexpertiseintheareatomeeteligibilitycriteriaforthissurvey.Pleaseindicatewhichstatementappliestoyou”
£ IhaveNOTbeenpracticingHeadacheMedicineandIdoNOThaveHeadache
Medicineexpertisethroughotherexperience(eg.research,etc)(ineligible)£ IhaveNOTbeenpracticingHeadacheMedicinebutIhaveHeadacheMedicine
expertisethroughotherexperience(eg.research,etc)(eligible)£ IhavebeenpracticingHeadacheMedicine(eligible)
5. Whatpercentageofyourtimeisdevotedtoresearch?
£ Under10%£ 10-25%£ 25-50%£ 50-75%£ Over75%
190
6. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcomeusedinmigraineprophylaxistrials:thechangeinthenumberofmonthlymigraineattackscomparingbaselinetothetreatmentperiod?
£ Areductionof0.25attackspermonth(ie.ifthenewinterventionyields0.25attacks
permonthmorethantheestablishedintervention,oranythinglessthan0.25attacksmore,itisnon-inferior)
£ Areductionof0.5attackspermonth(ie.ifthenewinterventionyields0.5attackspermonthmorethantheestablishedintervention,oranythinglessthan0.5attacksmore,itisnon-inferior)
£ Areductionof0.75attackspermonth(ie.ifthenewinterventionyields0.75attackspermonthmorethantheestablishedintervention,oranythinglessthan0.75attacksmore,itisnon-inferior)
£ Areductionof1attackpermonth(ie.ifthenewinterventionyields1attackpermonthmorethantheestablishedintervention,oranythinglessthan1attacksmore,itisnon-inferior)
£ Areductionof1.25attackspermonth(ie.ifthenewinterventionyields1.25attackspermonthmorethantheestablishedintervention,oranythinglessthan1.25attacksmore,itisnon-inferior)
£ Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:____________________________________________________________________
7. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcome
usedinmigraineprophylaxistrials:thechangeinthenumberofmonthlymigrainedayscomparingbaselinetothetreatmentperiod?
£ Areductionof0.5dayspermonth(ie.ifthenewinterventionyields0.5daysper
monthmorethantheestablishedintervention,oranythinglessthan0.5daysmore,itisnon-inferior)
£ Areductionof0.75dayspermonth(ie.ifthenewinterventionyields0.75dayspermonthmorethantheestablishedintervention,oranythinglessthan0.75daysmore,itisnon-inferior)
£ Areductionof1daypermonth(ie.ifthenewinterventionyields1daypermonthmorethantheestablishedintervention,oranythinglessthan1daymore,itisnon-inferior)
£ Areductionof1.25dayspermonth(ie.ifthenewinterventionyields1.25dayspermonthmorethantheestablishedintervention,oranythinglessthan1.25daysmore,itisnon-inferior)
£ Areductionof1.5dayspermonth(ie.ifthenewinterventionyields1.5dayspermonthmorethantheestablishedintervention,oranythinglessthan1.5daysmore,itisnon-inferior)
£ Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:____________________________________________________________________
8. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcomeusedinmigraineprophylaxistrials:thechangeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)?
191
£ Areductionof0.2pointsinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.2pointslessthantheestablishedintervention,oranythinglessthan0.2pointsless,itisnon-inferior)
£ Areductionof0.4pointsinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.4pointslessthantheestablishedintervention,oranythinglessthan0.4pointsless,itisnon-inferior)
£ Areductionof0.6pointsinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.6pointslessthantheestablishedintervention,oranythinglessthan0.6pointsless,itisnon-inferior)
£ Areductionof0.8pointsinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.8pointslessthantheestablishedintervention,oranythinglessthan0.8pointsless,itisnon-inferior)
£ Areductionof1pointinaverageintensity(ie.ifthenewinterventionyieldsareductioninintensitythatis0.6pointslessthantheestablishedintervention,oranythinglessthan0.6pointsless,itisnon-inferior)
£ Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:____________________________________________________________________
9. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcomeusedintrialsofacutemigraineinterventions:theabsolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention?
£ 2.5%fewerparticipants(ie.if2.5%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder2.5%exists,itisnon-inferior)
£ 5%fewerparticipants(ie.if5%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder5%exists,itisnon-inferior)
£ 7.5%fewerparticipants(ie.if7.5%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder7.5%exists,itisnon-inferior)
£ 10%fewerparticipants(ie.if10%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder10%exists,itisnon-inferior)
£ 12.5%fewerparticipants(ie.if12.5%feweroftheparticipantsreceivingthenewinterventionarepain-freeascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder12.5%exists,itisnon-inferior)
£ Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:____________________________________________________________________
10. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcome
usedintrialsofacutemigraineinterventions:theabsolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatment?
£ 2.5%moreparticipants(ie.if2.5%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder2.5%exists,itisnon-inferior)
£ 5%moreparticipants(ie.if5%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder5%exists,itisnon-inferior)
192
£ 7.5%moreparticipants(ie.if7.5%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder7.5%exists,itisnon-inferior)
£ 10%moreparticipants(ie.if10%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder10%exists,itisnon-inferior)
£ 12.5%moreparticipants(ie.if12.5%moreoftheparticipantsreceivingthenewinterventionhavearecurrenceascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder12.5%exists,itisnon-inferior)
£ Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:____________________________________________________________________
11. Whatdoyouthinkwouldbeanacceptablenon-inferioritymarginforthefollowingoutcome
usedintrialsofacutemigraineinterventions:theabsolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionandremainpain-free48hoursaftertheintervention?
£ 2.5%fewerparticipants(ie.if2.5%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder2.5%exists,itisnon-inferior)
£ 5%fewerparticipants(ie.if5%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder5%exists,itisnon-inferior)
£ 7.5%fewerparticipants(ie.if7.5%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder7.5%exists,itisnon-inferior)
£ 10%fewerparticipants(ie.if10%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder10%exists,itisnon-inferior)
£ 12.5%fewerparticipants(ie.if12.5%feweroftheparticipantsreceivingthenewinterventionhavesustainedpain-freedomascomparedtothosereceivingtheestablishedintervention,oranydifferenceunder12.5%exists,itisnon-inferior)
Other–Pleasespecifyyoursuggestednon-inferioritymarginforthisoutcome:
___________________________________________________
193
14. AppendixH.NIMMResponsesin“Other”Category
Item Outcome “Other”Responses6 Changeinthenumberof
monthlymigraineattackscomparingbaselinetothetreatmentperiod
• “Areductionof1.5migrainedaypermonth(ie.ifthenewinterventionyields1daypermonthmorethantheestablishedintervention,oranythinglessthan1.5daymore,itisnon-inferior).Shouldalwaysusemigrainedaysandnotattacksorepisodes.Measuringattacksisinsensitivegiventhehighvariabilityinattackdurationbetweenandwithinindividuals”.
• “1ifepisodicmigraine”• “Idon'tthinkwehaveasufficientbodyofevidencein
themigraineprophylaxisliteraturetosupportnon-inferioritytrialsatall.Thatis,it'snotreallyanappropriatestudydesignwhensomanyofthestudiesofmedicationswecurrentlyuseproducedsuchaslightdecreaseinnumberofheadacheattacksordaysvsplacebo.ThePREEMPTstudyisagoodexample:thetreatmentgrouphad1.8migrainedayspermonthascomparedtoplacebo.Andwethinkthatonabotulinumtoxinisoneofthemosteffectivepreventivetreatmentswehave.Intermsoforaltreatments,itlookslikevalproateisthemosteffectwehave,andthatshowedareductionof2.4migrainedayspermonth.Giventhesenumberscomparedtoplacebo,Iwouldarguethatwedon'thaveatreatmentthat's'established'tothepointthatwecanuseitasthereferenceinanon-inferioritytrial.Ithinkwearestillatthestageofneedingtodoplacebo-controlledtrials.IwillalsopointoutthatthatIHSGuidelinesforcontrolledtrialsofdrugsinmigrainerecommendsincludingaplacebogroup”.
• “Achangein1attackpermonthisclinicallymeaningless.Lookforachangein2-4attackspermonth”
• “Iwouldgowithapercentagelike20%-Ithinkthequestionappliedbothtofrequentmigraineorchronicmigraine”
• “.2attackspermonth”• “50%orgreaterreductioninheadacheattack
frequency”• “Numberofattacksalonecannottellusifthereisa
differenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows.”
• “Areductionofatleast2attackspermonth”7 Changeinthenumberof
monthlymigrainedayscomparingbaselinetothetreatmentperiod
• “0.25”• “5”• “Pleaseseemyanswertothepreviousquestion”.
194
• “2-4days”• “Iwouldgowithapercentagelike20%-Ithinkthe
questionappliedbothtofrequentmigraineorchronicmigraine”
• “greaterthan4headachedays”• “50%orgreaterreductioninheadachedayfrequency”• “Numberofmigrainedaysalonecannottellusifthere
isadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.
8 Changeintheaveragemigraineintensitycomparingbaselinetothetreatmentperiod(wheretheintensityoftheheadacheismeasuredonthefollowing4-pointseverityscale:0=noheadache,1=mildheadache,2=moderateheadache,3=severeheadache)
• “Noprophylactictrialhasevershownasignificantreductioninmigraineintensity.Usinga4-pointordinalscaledoesnotprovidethesensitivitysufficienttodetectadifference.ItsameaninglessoutcomemeasureinprophylactictrialsusingthisGlaxoSmithKlinescaleforacutetherapytrials”.
• “Again,Idon'tthinkwehaveaconsistentenoughresponseinthetreatmentswecurrentlyuse,ascomparedtoplacebo,tobeabletorunanon-inferioritytrial”.
• “3pointsormore”• “intensitybyitselfwillnotmatter”• “Thechangeofaveragemigraineintensityalone
cannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.
Absolutepercentageofparticipantswhoarepain-free2hoursaftertheintervention
• “Iwouldhaveresultscomparedbyseverityattimethefirstdoseistaken.ThishasaneffectthatIrecallisaslargeasyourpercentagesabove.Youcannotassumethatrandomizationwillachieveequaldistributionofheadacheseverityatthetimeofheadachetreatment-oncethisiscontrolledfor-10%”
• “20%”• “25%fewer”• “Theabsolutepercentageofpainfreedomalone
cannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.
Absolutepercentageofpatientswhohaveamigrainerecurrencewithin48hoursoftreatment
• “20%”• “25%more”• “Theabsolutepercentageofmigrainerecurrencein
48halonecannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.
Absolutepercentageofpatientswithsustainedpainfreedom(ie.thepercentageofpatientswhoarepainfree2hoursaftertheinterventionand
• “20%”• “20%fewer”• “10%above.Overalldependsonwhetheryouinclude
placeborun-in(singleblindphasebeforerandomizationtoactivecomparators)”
195
remainpain-free48hoursaftertheintervention)
• “Theabsolutepercentageofpatientswithsustainedpainfreedomalonecannottellyouifthereisadifferenceorinourcasenon-inferiority.Itwilldependonwhatthestatisticalanalysisshows”.
196
15. AppendixI.RCTEligibilityCriteriaRationale
Theeligibilitycriteriafortheproposedrandomizedcontrolledtrialwerechosenforavarietyof
reasons,allofwhichfallintooneofthefollowingcategories(seeTable):1)compliancewiththe
InternationalHeadacheSocietyGuidelinesonControlledtrialsofDrugsinMigraine,2)safety,that
is,ensuringthatexposuretooneoftheactiveinterventionsdoesnotresultinanadverseevent,and
3)ensuringthatparticipantshaveabilitytoparticipateinthetrialandrespondtointerventions.
Theupperlimitoftheagecriterion,thatis,thatparticipantsmustbebetween8.0and18.0years,
waschoseninordertolimitthestudytopediatricpatients.Thelowerlimitoftheagecriterionwas
chosenbasedonthelowerlimitofasimilarlarge,well-designedpediatrictrialthatisunderway173
andbecauseitcanbemoredifficulttodiagnosemigraineaccuratelyinyoungerchildren.
Table.RationaleforSpecificInclusionandExclusionCriteria
Rationale InclusionCriteria ExclusionCriteriaCompliancewith
theInternationalHeadacheSocietyGuidelinesonControlledTrialsofDrugsinMigraine
• MigrainewithoutauraormigrainewithauraasperInternationalClassificationofHeadacheDisordersThirdEdition,BetaVersion(ICHD)criteria
• Migrainefrequencyof2-8attackspermonthinthreemonthretrospectiveperiodand1monthbaselineperiod
• Migraineshavebeenpresentforatleastoneyear
• Otherheadachetypesarepresentandtheparticipantcannotdifferentiatemigrainefromtheotherheadache(s)
• Fifteenormoreheadachedayspermonth(ie.chronicmigraine)
• Overusingacutemigrainemedications
• Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment
• Takinganantipsychoticorantidepressantmedicationwithinthreemonthsofenrollment
• Pregnant,lactatingorpositivepregnancytest
Safety N/A • Historyofanaphylaxisorallergytotopiramateorlevetiracetam
• Pregnant,lactatingorpositivepregnancytest
• Sexuallyactiveandnotusingareliablebirthcontrolmethod
• Historyofrenalcalculi• Significanthepaticorrenal
impairment• Ontheketogenicdiet
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• Hasalcoholordrugdependence• Historyofsignificantbehavioral
problems• Hasapsychiatricdisorderas
definedintheDiagnosticandStatisticalManualofMentalDisorders5thedition(DSMV)
Ensuringthatparticipantshaveabilitytoparticipateintrialandrespondtointerventions
• Abletocommunicatesufficientlywithparentsinordertoaccuratelycompleteaheadachediaryandstudyquestionnaires
• Overusingacutemigrainemedications
• Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment
• Takinganantipsychoticorantidepressantmedicationwithinthreemonthsofenrollment
• ReceivedBotoxinjectionsformigrainewithinthepastthreemonths
• Previoustrialoftopiramateorlevetiracetamformigraineprophylaxis
• Historyofepilepsy• Hasapsychiatricdisorderas
definedintheDiagnosticandStatisticalManualofMentalDisorders5thedition(DSMV)
• Hasalcoholordrugdependence• Historyofanotherchronicpain
disorderOther • Age8.0-18.0years
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16. AppendixJ.RCTHeadacheDiaryTemplate
Participantnumber:____________________Month:____________________Year:_____________________
Date 1 2 3 4 5 6 7 8 910 11 1213 14 1516 1718 19 2021 2223 24 2526 27 2829 3031
Didyouhaveaheadachetoday?
Yes
No
Wasthisheadacheamigraine?Ifyes,pleaseanswerquestionsbelow.
Yes
No
Howbadwasthemigraine?Pleaserecordtheworstpainthatyoufeltwiththismigraine.
Mild
Moderate
Severe
Atwhattimedidthemigrainestart?
StartTime
Atwhattimedidthemigraineend?Ifintonextday(s),extendarrowintodaywhereitendedandindicatetimeitendedthere.
EndTime
Didyouexperienceanyofthefollowingsymptomstoday?Tickallthatapply.
Increasedappetite
Decreasedappetite
Fatigue Problemsconcen-trating
Tinglingsensations
Changesinbehavior
Aggression Paranoia Problemsthinking
Other(pleaseindicatewhatthesymptomwas)
199
Didyoutakeanyofthesemedicationstorelievethemigrainetoday?Indicatehowmanydosesyoutooktodayinthebox.Acetamino-phen
Ibuprofen Naproxen Ketorolac Diclofenac Indo-methacin
Suma-triptan
Almotriptan Rizatriptan Eletriptan Naratriptan Frova-triptan
Zolmi-triptan
Other(pleaseindicatename)
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17. AppendixK.PedMIDASQuestionnaire
PedMIDAS
Thefollowingquestionstrytoassesshowmuchtheheadachesareaffectingday-to-dayactivity.
Youranswersshouldbebasedonthelastthreemonths.Thereareno“right”or“wrong”answersso
pleaseputdownyourbestguess.
1. Howmanyfullschooldaysofschoolweremissedinthelast3monthsduetoheadaches?
__________________
2.Howmanypartialdaysofschoolweremissedinthelast3monthsduetoheadaches(donot
includefulldayscountedinthefirstquestion)?___________________
3.Howmanydaysinthelast3monthsdidyoufunctionatlessthanhalfyourabilityinschool
becauseofaheadache(donotincludedayscountedinthefirsttwoquestions)?___________________
4.Howmanydayswereyounotabletodothingsathome(i.e.chores,homework,etc.)duetoa
headache?___________________
5.Howmanydaysdidyounotparticipateinotheractivitiesduetoheadaches(i.e.,play,goout,
sports,etc.)?____________________
6.Howmanydaysdidyouparticipateintheseactivities,butfunctionedatlessthanhalfyour
ability(donotincludedayscountedinthe5thquestion)?___________________
TotalPedMIDASScore:____________________
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18. AppendixL.TrialInformedConsentFormforParentsandParticipantsAged16
andOver
Title:OptimizingMigraineProphylaxisinPediatrics(OMPPTrial):ARandomizedControlled
TrialComparingtheEfficacyofLevetiracetam,TopiramateandPlaceboforPreventingMigrainesinChildrenandAdolescents
PrincipalInvestigator: Dr.SerenaOrr,MD,MScCandidate,PediatricNeurologyResident
Children’sHospitalofEasternOntario 401SmythRoad Ottawa,ON,Canada,K1H8L1 Phone:(613)737-7600ext.1605
1. IntroductionYouarebeinginvitedtoparticipateinaresearchstudy.Inthisstudy,wearetryingto
determineifthemedicationstopiramateandlevetiracetammighthelptopreventmigrainesinchildrenandadolescents.
Inordertoparticipateinanyresearchstudyyouhaveto:a)understandwhatisinvolvedin
participating,b)understandtherisksandbenefitsofparticipatingandc)makeaninformeddecisiontovoluntarilyacceptordeclineparticipation.Thisprocessiscalled‘informedconsent’.Thisformismeanttohelpyouunderstandthestudysothatyoucanmakeaninformeddecisiontotakepartinthestudyornot.
Youmaycomeacrosswordsinthisconsentformthatyoudonotunderstand.Pleaseaskthe
studyresearchcoordinatororstudyinvestigatortoexplainanythingthatyoudonotclearlyunderstand.Youcantaketimetoreadthroughanunsignedcopyofthisconsentformsothatyoucanthinkaboutit.Youcanalsodiscussitwithfamilyorfriendsbeforemakingadecision.
Youarebeingaskedtojointhisstudybecauseyouhavemigraineheadaches.Wearelooking
forinformationfromchildrenandadolescentswhoDOHAVEmigraineheadaches.Theresearchcoordinatorhasreviewedtheeligibilitycriteriaandhasdeterminedthatyouaresuitableforparticipationinthisstudy.
2. PurposeoftheStudy
Migrainesareverycommoninchildrenandadolescents,andcanhavealargeimpactontheir
day-to-daylives.Childrenandadolescentswithfrequentmigrainescanconsidertwotypesoftreatment:treatingtheheadacheswhentheycomeandtakingamedicationeverydaytopreventmigrainesinthefirstplace.Althoughseveraldifferentmedicationsareusedtopreventmigraines,wedon’thavealotofinformationaboutwhichonesarethemosteffective,becausetherearen’tverymanyresearchstudiesthathavebeendoneinthisarea.
Inthisstudy,wearetryingtocomparetwomedications,levetiracetamandtopiramate,toa
placebomedication,inordertodetermineifthesemedicationscanhelptopreventmigraines.
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3.OverviewoftheStudyPreventativemedicationsaregiventopatientstotryanddecreasethenumberofmigraines
theyarehaving.Notonlyshouldthesemedicationsworktodecreasethemigraines,buttheymustalsobetolerabletothepatients;thatis,theymustnothavetoomanyunpleasantsideeffects.
Severalstudiessuggestthattopiramateissafeandeffectiveinpreventingmigrainesinchildren
andadolescents.Levetiracetamhasnotbeenstudiedasmuchastopiramateformigraines,butpreliminarystudiessuggestthatitmighthelptopreventthem.Levetiracetamiscommonlyusedtotreatseizuresinchildrenandadolescents,andhasbeenfoundtobesafeinthatcontext.
Inthisstudy,wewouldliketocomparetopiramate,levetiracetamandplacebotodetermine
howwelltheseinterventionsworktopreventmigraines.Participantswillberandomlyassignedtobetreatedwitheithertopiramate,levetiracetamorplacebo.Aplaceboisamatchingpillthatdoesnotcontainanyactiveingredients.Whenresearchersaretryingtostudywhetheradrugworksornot,theymustcompareittoplacebo.Thishelpstoaccountforthefactthatmanypatientstendtodobetterjustbytakingapillorbyparticipatinginaresearchstudy.
Inordertocomparethesethreeinterventions,participantsinthisstudywillberandomly
assignedtoreceive24weeksoftreatmentwitheithertopiramate,levetiracetamorplacebo.Thismeansthateachpersonparticipatinginthisstudywillhaveanequalchanceofgettingeitheroftheinterventions,andthatthedecisionaboutwhoreceiveswhichinterventionisrandom.
4.StudyInclusion&ExclusionCriteriaA.InclusionCriteria
Inordertoparticipate,youmustmeetallofthefollowingcriteria:6. MigrainewithoutauraormigrainewithauraasperInternationalClassificationofHeadache
DisordersThirdEdition,BetaVersion(ICHD)criteria7. Age8.0-18.0years8. Migrainefrequencyof2-8attackspermonthinthreemonthretrospectiveperiodand1
monthbaselineperiod,withdefinitionofattackasfollows:a. Attacksareseparatedbyatleast48hourheadache-freeinterval
9. Migraineshavebeenpresentforatleastoneyear10. Abletocommunicatesufficientlywithparentsinordertoaccuratelycompleteaheadache
diaryandstudyquestionnaires
B.ExclusionCriteriaInordertoparticipate,youmustmeetNONEofthefollowingcriteria:19. Otherheadachetypesarepresentandtheparticipantcannotdifferentiatemigrainefrom
theotherheadache(s)20. Fifteenormoreheadachedayspermonth(ie.chronicmigraine)21. Overusingacutemigrainemedications:
a. Takingatriptanontenormoredayspermonthb. Takingacetaminophenoranon-steroidalanti-inflammatorymedicationonfifteen
ormoredayspermonth
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22. Takingamigraineprophylacticmedicationwithinthreemonthsofenrollment23. Takinganantipsychoticorantidepressantmedicationwithinthreemonthsofenrollment24. ReceivedBotoxinjectionsformigrainewithinthepastthreemonths25. Previoustrialoftopiramateorlevetiracetamformigraineprophylaxiswith:
a. Adequatedosingb. Atleastthreemonthsofprophylaxis
26. Historyofanaphylaxisorallergytotopiramateorlevetiracetam27. Pregnant,lactatingorpositivepregnancytest28. Sexuallyactiveandnotusingareliablebirthcontrolmethod29. Historyofrenalcalculi30. Significanthepaticorrenalimpairment31. Ontheketogenicdiet32. Historyofepilepsy33. HasapsychiatricdisorderasdefinedintheDiagnosticandStatisticalManualofMental
Disorders5thedition(DSMV)34. Hasalcoholordrugdependence35. Historyofsignificantbehavioralproblems36. Historyofanotherchronicpaindisorder5.StudyProceduresIfyoudecidetoparticipateinthisstudy,youwillfirstentera4weekbaselineperiod,during
whichyouwillcompleteaheadachediaryandhaveabaselineassessmentwiththestudydoctor.Ifyoucontinuetomeetoureligibilitycriteriaafterthat4weekperiod,youwillberandomlyassignedtoeitherreceivetopiramate,levetiracetamorplacebofor24weeks,followedbya4weekperiodduringwhichwewillslowlytakeyouoffthemedication.Neitheryou,thestudycoordinatornorthestudydoctorwillknowwhichmedicationyouaretaking.Theresearchpharmacistwillmaintainapassword-protectedlistwiththisinformationincasethereisaneedforyou,thestudycoordinatororthestudydoctortohaveaccesstothatinformationatanypointintime.Thepurposeofnotknowingwhichmedicationyouaretakingistomakesurethatanyeffectofthemedicationthatweobserveisduetothemedicationitselfandnotwhatyou,thestudydoctororthestudycoordinatorexpectthemedicationtobelike.
Duringthefirst8weeksofthestudy,thestudydoctorwilladjustthedoseofthemedicationto
reachadosethatworksbesttopreventyourmigrainesandistolerabletoyouintermsofsideeffects.Youwillthentakethemedicationfor16moreweeks.Afterthe16weeksarecomplete,themedicationwillbetaperedoffover4weeks.Onceyouareoffthemedication,therewillbeanother4weekperiodforfollow-up.Duringthestudy,youwillbeaskedtofilloutadailyheadachediaryinordertokeeptrackofyourmigraines.Youwillhavemonthlytelephonecheck-inswiththestudyresearchcoordinatorandmonthlyvisitswiththestudydoctorintheclinic.
Ateachstudyvisit,youwillseethestudydoctor.Yourweightwillbetakenandyouwillreport
onhowyouarefeeling(ie.howyourheadachesareandwhetheryouarehavinganynewsymptomsthatmightbesideeffects).Ifneeded,youwillhaveaphysicalexam.Thestudydoctorwillalsoreviewyourheadachediarytoseehowthingsaregoingwithyourmigraines.
Duringeachmonthlytelephonecheck-in,thestudyresearchcoordinatorwillcontactyoutoask
youhowthingsaregoingwiththemedicationandyourheadaches.Thecoordinatorwillreviewyouruseoftheheadachediaryandwillaskyouaboutprogresswithyourheadachesaswellasothersymptomsthatcouldberelatedtothemedication.
204
Throughoutthestudy,youwillbeabletotakemedicationslikeTylenolorAdviltotreat
migrainesastheycome.Youwillbeaskedtonottakeanyothermedicationeverydaytopreventmigraines,becauseitisimportantforustoseewhattheeffectsofthesemedicationsarealone,withouttheaddedeffectofotherdailymedicationstakentopreventmigraines.
6.PossibleRisksInvolvedinParticipatinginthisStudyTopiramateandlevetiracetamarebothcommonlyusedmedications,andbothhavebeenfound
tobesafetouseinchildrenandadolescents.Eachdoeshavepotentialsideeffects,someofwhichareweightloss,decreasedappetite,changesinbehaviororconcentrationandaverysmallincreaseintheriskofgettingkidneystones.Theplacebomedicationwillnotcontainactiveingredients.However,somepeoplestillexperiencerelieffromtheirheadacheswithplacebo,anditisalsopossibletohavesideeffectsfromplacebo.Throughoutthestudy,youwillbecloselymonitoredformedicationsideeffects,andthedosingofyourmedicationcanbeadjustedifyougetanysideeffectsthatyoucannottolerate.
7.PossibleBenefitsInvolvedinParticipatingintheStudyIfyouparticipateinthisstudy,youmightreceiveamedicationthatsignificantlyhelpsto
preventyourmigraines.Youwillreceivethismedicationfor24weeksatnocost.Theinformationgainedfromthisstudywillhelpustoimprovethecareofchildrenandadolescentswithmigraine.Yourinvolvementwillpotentiallybenefitmanychildrenandadolescentsinthefuture,becauseoftheinformationthatwewillgainfromthisstudy.
8.VoluntaryParticipationandWithdrawalYourdecisionaboutwhetherornottoparticipateinthisstudyisvoluntary.Youcanchooseto
participate,oryoucanchoosetowithdrawfromthestudyforanyreasonwithoutpenaltyorlossofbenefitstowhichyouareotherwiseentitledandwithoutanyeffectonyourfuturemedicalcare.
Therewillbenoconsequencesofyourdecisiontowithdrawfromthestudy.Youcandecidenottobeinthestudywithoutlosinganymedicalbenefitsyouwouldotherwise
receive.Ifyoudoenterthestudy,youcanleavethestudyatanytimewithoutlossofanymedicalbenefitsoranyotherpenalty.Ifyouleavethestudy,yourusualmedicalcarewillnotbeaffectedinanyway.
9.PaymentforInjuryandHarmIntheeventthatyousufferinjuryasadirectresultofparticipatinginthisstudy,normallegal
rulesofcompensationwillapply.Bysigningthisconsentform,youareinnowaywaivingyourlegalrightsorreleasingtheinvestigatorsfromtheirlegalandprofessionalresponsibilities.
10.CompensationIfyoutakepartinthisstudy,youwillnotbepaidorrewardedinanyway.Youwillnotbe
compensatedforanydiscoveriesmadeasaresultofthisstudy.11.Confidentiality
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Onlyyou,thestudydoctor,thestudycoordinatorandmembersoftheNeurologyclinicwhoare
treatingyouwillknowthatyouareinvolvedwiththisstudy.Becausethestudycoordinatorwillbecontactingyouonamonthlybasisoverthephone,wewillneedtocollectyourcontactinformation.Wewillstorethisinformationinapassword-protected,encryptedelectronicfile.Theremainingrecordskeptforthisstudywillidentifyyoubyanumber,notbyname,nordateofbirth.Allinformationobtainedduringthisstudy,includingyourmedicalrecords,personaldataandresearchdata,willbekeptstrictlyconfidentialexceptasrequiredbylaw.Yournameormaterialidentifyingyouasastudyparticipantwillnotbereleasedwithoutwrittenpermission,exceptwhenitisrequiredorpermittedbylaw.Anypersonalinformationthatleavesthehospitalorclinicwillbecodedsothatyoucannotbeidentifiedbyname.Youwillnotbeidentifiedinanypublicationorpresentationofthisstudy.Thestudyrecordswillberetainedforaperiodof7yearsasperCanadianregulations.CHEOinternalmonitoringresearchstaffmayreviewchartsandmedicalrecordsforqualityimprovementpurposes.
12.ContactPersonsTheCHEOResearchEthicsBoardsisacommitteeofthehospitalthatincludesindividualsfrom
differentbackgrounds.TheBoardreviewsallresearchthattakesplaceatthehospital.Itsgoalistoensurethattherightsandwelfareofpeopleparticipatinginresearchareprotected.TheBoard’sworkisnotintendedtoreplaceaparentorchild’sjudgmentaboutwhatdecisionsandchoicesarebestforthem.ThisstudyhasbeenreviewedandapprovedbytheCHEOResearchEthicsBoard.YoumaycontacttheChairoftheResearchEthicsBoard,forinformationregardingpatients’rightsinresearchstudiesat:(613)737-7600ext.3272,althoughthispersoncannotprovideanyhealth-relatedinformationaboutthestudy.Ifyouhaveanyquestionsaboutparticipationinthisstudy,orifyoufeelthatyouhaveexperiencedastudy-relatedinjury,pleasecallDr.Orrat(613)737-7600ext.1605.
206
CONSENTIhavereadthisconsentformanditscontentswereexplained.Myquestionshavebeen
answered.IgiveconsentvoluntarilytoparticipateinthisstudyandIwillreceiveasignedanddatedcopyofthisconsentformformyrecords.
BysigningthisinformedconsentformIamauthorizingsuchaccesstomypersonaldataas
describedinthiscontent.IamawarethatIcanrequestacopyoftheresultsofthisstudyuponitscompletion,ifIwishto
doso.NameofSubject(Printed)Date:mm/dd/yyyy_________________________________________________________________________________________________Signature
ofSubjectDate:mm/dd/yyyy(orParent/LegalGuardian)_________________________________________________________________________________________________Signature
ofParent/LegalGuardianDate:mm/dd/yyyy_________________________________________________________________________________________________SignatureofInvestigatorDate:mm/dd/yyyy_________________________________________________________________________________________________SignatureofPersonConductingConsentDiscussionDate:mm/dd/yyyy
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19. AppendixM.TrialAssentFormforParticipantsAgedLess16Years
Title:OptimizingMigraineProphylaxisinPediatrics(OMPPTrial):ARandomizedControlled
TrialComparingtheEfficacyofLevetiracetam,TopiramateandPlaceboforPreventingMigrainesinChildrenandAdolescents
PrincipalInvestigator: Dr.SerenaOrr,MD,MScCandidate,PediatricNeurologyResident
Children’sHospitalofEasternOntario 401SmythRoad Ottawa,ON,Canada,K1H8L1 Phone:(613)737-7600ext.1605Thisformmaycontainwordsyoudonotunderstand.Pleaseaskthestudydoctorto
explainanythingyoudonotunderstand.Ifyouwishtotalktothestudydoctorpleaseask.1.Whatisthisstudyabout?Thisisaresearchstudy.Researchstudiesaredonewhenwearetryingtofindoutmoreabout
something.Wearetryingtofindoutmoreabouthowtotreatheadachescalledmigraines.Youarebeingaskedtoparticipateinthisstudybecauseyouhavemigraines.Wearehopingtofigureoutifthemedicationstopiramateandlevetiracetamworktopreventmigrainesinkids.
2.DoIhavetobeinthisstudy?No.Youdonothavetobeinthisstudyifyoudon’twantto.Evenifyousaythatyouwanttobeinthisstudy,youcanchangeyourmindlater.Ifyouchange
yourmind,pleasetellyourdoctorortheresearchcoordinator.Theycananswerquestionsyouhaveaboutthestudybeforeyoumakeupyourmind.Youcantalktoyourmom,ordad,orthepersonwholooksafteryouaboutit.Theycanreadyoutheinformationtheresearchcoordinatorgavethemtohelpyoumakeupyourmind.
Ifyouwanttobeinthisstudy,youwillhavetosignthisform.3.Whatwillhappenduringthestudy?Inthisstudy,wearetryingtocomparetwomedications,levetiracetamandtopiramate,toa
placebomedication,tofigureoutifthesemedicationscanhelptopreventmigraineheadaches.Aplaceboisamatchingpillthathasnoactivedrugsinit.Whenwearetryingtostudyifadrugworksornot,wehavetocompareittoplacebo.
Ifyoujointhisstudy,youwillfilloutaheadachediaryeveryday.Afteronemonth,ifyoustillhaveenoughheadachesandstillwanttobeinthestudy,youwillstarttreatment.Youwillhaveanequalchanceofgettingtreatedwitheitherlevetiracetam,topiramateorplacebo.Thepharmacistwilluseacomputertofigureoutwhichtreatmentyouwillget.Youwillnotknowwhichtreatmentyouaregetting.Thestudydoctorandcoordinatorwillalsonotknowwhichtreatmentyouareon.Youwilltakethetreatmenteverydayfor24weeks.Afterthat,wewillslowlytakeyouoffthetreatmentover4weeks,andthenfollowyouforanother4weekstoseehowyouaredoing.
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Youwillhavemonthlycallsfromthestudyresearchcoordinatorandmonthlyvisitswiththestudydoctorintheclinic.Ateachvisit,youwillseethestudydoctor.Yourweightwillbetakenandyouwilltellthedoctorhowyouarefeelingwithyourheadachesandanyproblemsyouarehaving.Ifneeded,youwillhaveaphysicalexam.Thestudydoctorwillalsolookatyourheadachediarytoseehowthingsaregoing.Ateachmonthlytelephonecall,thestudycoordinatorwillcontactyoutoaskyouhowthingsaregoingwiththemedicationandyourheadaches.
4.ThegoodandthebadthingsaboutdoingthisstudyIfyoudecidetobeinthisstudy,goodthingsmighthappen.Themedicationthatyougetmight
helptopreventyourmigrainesandmakeyoubetterabletofunctioninschool,athomeandinactivities.Youwillgetthismedicationfor24weeksatnocost.Theinformationthatwegetfromthisstudymighthelpkidswithmigrainesinthefuture.
Ifyoudecidetobeinthisstudy,somebadthingscouldhappen.Themedicationcouldgiveyou
sideeffects.Someofthepossiblesideeffectswithlevetiracetamandtopiramateareweightloss,decreasedappetite,changesinbehaviororconcentrationandaverysmallincreaseinthechanceofgettingkidneystones.Theplacebomedicationwillnothaveactivedrugsinit.Somepeoplefeelbetterwithplacebo,andsomepeoplealsohavesideeffectsfromplacebo.
5.WillanyoneknowthatIdidthisstudy?Wewillnotshareanyinformationaboutyouwithanyoneoutsideofthestudy.Wewillnottell
anyoneoutsideofthisstudythatyouparticipated.6.DoIhavetodothis?Youdonothavetobeinthisstudy.Itisokaytosayno.Youcantellyourparentsorthestudy
doctorthatyoudonotwanttobeinthisstudyatanytime.Thatwillbeokay.ItwillnotaffectanycarethatyoureceiveorwillreceiveatCHEO.
Ifyoudecidetobeinthestudy,youcanchangeyourmindatanytimelater.Youcanstillsayno
andthatwillbeokay.7.WhocanItalktoaboutthestudy?Theresearchcoordinatorcanansweryourquestionsaboutthestudyatanytime.Youcanalso
talktoyourmom,yourdadorwhoeverlooksafteryou.8.Confidentiality
CHEOinternalmonitoringresearchstaffmayreviewtheresearchfilesforqualityimprovementpurposes.Yourcontactinformationwillbestoredinasafe,encryptedsoftwaresothatthestudycoordinatorcancontactyou.Therestofthestudydocumentswillnotcontainanyinformationthatcanbelinkedtoyouspecifically,likeyournameordateofbirth.Therestofthedocumentswillonlycontainyourstudyidentificationnumber.
209
ASSENTFORMDoyouwanttobeinthisstudy?Pleasecheckonebox: �Yes,Iwanttobeinthestudy. �No,Idonotwanttobeinthestudy._______________________________________NameofChild(Print) _______________________________________ _____________________________SignatureofChild Date: mm/dd/yyyy _______________________________________NameofParentorLegalGuardian(Print)Iattestthattheparticipanthadenoughtimetoconsiderthisinformation,hadanopportunityto
askquestionsandvoluntarilyagreedtobeinthestudy_________________________________________________NameofPersonExplainingAssent(Print) __________________________________________ _____________________________SignaturePersonExplainingAssent Date:mm/dd/yyyy
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20. AppendixN.BrochuretoExplainStudyProcedurestoParticipants
OPTIMIZINGMIGRAINEPROPHYLAXISINPEDIATRICS(OMPPTrial)
1.Whatisthisstudyabout?Thisstudyistryingtodetermineiflevetiracetamandtopiramateareeffectiveinpreventing
migrainesinkids.2.Whatwillhappeninthisstudy?Ifyouagreetoparticipateinthisstudy,youwillberandomlyassignedtoreceiveeither
topiramate,levetiracetamorplacebofor24weeks.Throughoutthestudy,youwillbeaskedtocompleteaheadachediaryeveryday.Thefirst4
weekswillbeabaselineperiod,whereyoufilloutthediarysothatwecanseehowmanymigrainesyouarehaving.If,afterthe4weeks,youarestillhavingenoughmigrainesandstillwanttoparticipate,thenyouwillbeassignedtooneofthestudymedications.Afterthis,the24weeksoftreatmentwillstart.Youwillthenbeslowlytakenoffthemedicationforaperiodof4weeks,andfollowedforanother4weeks.Duringthestudy,youwillbemonitoredwithstudyvisitsandtelephonefollow-ups.
3.HowmanystudyvisitswillIhave?Everymonth,youwillcomeintothehospitaltohaveavisitwiththestudydoctor.Duringthese
visits,youwillhaveyourweighttaken,aphysicalexamifneeded,andthestudydoctorwillgooverhowthingsaregoingwithyourheadachesandthemedication.Itisveryimportantthatyoufilloutyourheadachediaryeverydayandbringittoyourvisits,becausethisishowthestudydoctorwillknowifyourmigrainesaregettingbetterornot.
4.Howmanytelephonefollow-upswillIhave?Everymonth,thestudycoordinatorwillcallyoutocheckin.Thestudycoordinatorwillgoover
howthingsarewithyourheadachesandwhetheryouareexperiencinganysideeffectsfromthemedication.Itisveryimportantthatyoufillouryourheadachediaryeveryday,becauseitwillhelpyoutogivethestudycoordinatoraccurateinformationanditwillhelpyoutokeeptrackofhowyouaredoing.
5.WhatelsewillIhavetodoforthisstudy?Asisdescribedabove,youwillhavetofilloutaheadachediaryeveryday.Thisdiarywillonly
takeacoupleofminutestofillout.Thediaryiseasytofillout:ithasafewquestionsthatrequireonlycheckboxanswers,andonequestionwhereyourecordhowmanyrescuemedicationsyoutookforyourheadache(s)thatdaywithanumber.Wewillalsogiveyouaquestionnairetoseehowyourmigrainesareaffectingyourlife.Youwilltakethissurveythreetimes:onceatbaseline,onceattheendoftreatmentandonceattheendoffollow-up.Thissurveyonlytakesafewminutestocomplete.
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Asisdescribedabove,youwillbeaskedtoattendmonthlyhospitalvisitswiththestudydoctorandtotakemonthlytelephonecallsfromthestudycoordinator.
6.Whenwillmyinvolvementinthestudybeover?Afterthestudyfollow-upperiodisover,youwillnolongerbeinvolvedwiththisstudy.Your
studydoctorwillensurethatyouhavefollow-upforyourmigraineswitheitherachildneurologistatthehospitaloryourfamilydoctor.
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21. AppendixO.PASSReport1–SuperiorityHypothesisSampleSizeCalculation
2/3/2016 1:08:35 PM 1
Group Sequential - Means Numeric Results for Two-Sided Hypothesis Test of Means Target Actual Power Power N1 N2 N Mean1 Mean2 S1 S2 Alpha 0.80 0.80197 71 71 142 2.60 1.41 2.5 2.5 0.050 References Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel Dekker. New York. Lan, K.K.G. and DeMets, D.L. 1983. 'Discrete sequential boundaries for clinical trials.' Biometrika, 70, pages 659-663. O'Brien, P.C. and Fleming, T.R. 1979. 'A multiple testing procedure for clinical trials.' Biometrics, 35, pages 549-556. Pocock, S.J. 1977. 'Group sequential methods in the design and analysis of clinical trials.' Biometrika, 64, pages 191-199. Reboussin, D.M., DeMets, D.L., Kim, K, and Lan, K.K.G. 1992. 'Programs for computing group sequential boundaries using the Lan-DeMets Method.' Technical Report 60, Department of Biostatistics, University of Wisconsin-Madison. Report Definitions Target Power is the desired power value (or values) entered in the procedure. Power is the probability of rejecting a false null hypothesis. Actual Power is the power obtained in this scenario. Because N1 and N2 are discrete, this value is often (slightly) larger than the target power. N1 and N2 are the number of items sampled from each population. N is the total sample size, N1 + N2. Mean1 is the mean of populations 1 and 2 under the null hypothesis of equality. Mean2 is the mean of population 2 under the alternative hypothesis. S1 and S2 are the population standard deviations of groups 1 and 2. Alpha is the probability of rejecting a true null hypothesis. Summary Statements Sample sizes of 71 and 71 achieve 80% power to detect a difference of 1.19 between the group means with standard deviations of 2.5 and 2.5 at a significance level (alpha) of 0.050 using a two-sided z-test. These results assume that 4 sequential tests are made using the O'Brien-Fleming spending function to determine the test boundaries. Details when Spending = O'Brien-Fleming, N1 = 71, N2 =71, S1 = 2.5, S2 = 2.5, Diff = 1.19 Lower Upper Nominal Inc Total Inc Total Look Time Bndry Bndry Alpha Alpha Alpha Power Power 1 0.50 -4.33263 4.33263 0.000 0.000 0.000 0.00178 0.002 2 1.00 -2.96311 2.96311 0.003 0.003 0.003 0.16739 0.169 3 1.50 -2.35902 2.35902 0.018 0.016 0.019 0.37325 0.542 4 2.00 -2.01406 2.01406 0.044 0.031 0.050 0.25955 0.802 Drift 2.83610
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Group Sequential - Means Chart Section
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22. AppendixP.PASSReport2–Non-InferiorityHypothesisSampleSizeCalculation
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Scenario 1 Numeric Results for Group Sequential Test of Non-Inferiority Higher Means are Better Hypotheses: H0: Mean1 - Mean2 = NIM; H1: Mean1 - Mean2 < NIM Test Statistic: T-Test Alpha-Spending Function: O'Brien-Fleming Analog Beta-Spending Function: None Futility Boundary Type: None Number of Looks: 4 Simulations: 2000 Pool Size: 10000 Numeric Summary for Scenario 1 ------------------ Power ------------------- -------------------------- Alpha ---------------------------- Value 95% LCL 95% UCL Target Actual 95% LCL 95% UCL Beta 0.811 0.794 0.828 0.050 0.050 0.040 0.060 0.189 ----- Average Sample Size ---- -- Given H0 -- -- Given H1 -- Non-Inf. Std N1 N2 Grp1 Grp2 Grp1 Grp2 Margin Mean1 Mean2 Dev 79 79 78 78 62 62 1.0000 2.6000 2.6000 2.5000 References Jennison, C.; Turnbull, B.W. 2000. Group Sequential Methods with Applications to Clinical Trials. Chapman & Hall. Boca Raton, FL. Devroye, Luc. 1986. Non-Uniform Random Variate Generation. Springer-Verlag. New York. Matsumoto, M. and Nishimura,T. 1998. 'Mersenne twister: A 623-dimensionally equidistributed uniform pseudorandom number generator.' ACM Trans. On Modeling and Computer Simulations. Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood Cliffs, New Jersey.
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Power 95% LCL and UCL are the lower and upper confidence limits for the power estimate. The width of the interval is based on the number of simulations. Target Alpha is the user-specified probability of rejecting a true null hypothesis. It is the total alpha spent. Actual Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. Alpha 95% LCL and UCL are the lower and upper confidence limits for the actual alpha estimate. The width of the interval is based on the number of simulations. Beta is the probability of accepting a false null hypothesis. It is the total proportion of alternative hypothesis simulations that do not cross the significance boundaries. N1 and N2 are the sample sizes of each group if the study reaches the final look. Average Sample Size Given H0 Grp1 and Grp2 are the average or expected sample sizes of each group if H0 is true. These are based on the proportion of null hypothesis simulations that cross the significance or futility boundaries at each look. Average Sample Size Given H1 Grp1 and Grp2 are the average or expected sample sizes of each group if H1 is true. These are based on the proportion of alternative hypothesis simulations that cross the significance or futility boundaries at each look. Non-inferiority margin is the distance from the control mean that is still considered non-inferior. Mean1, Mean2, and Std Dev are the parameters that were set by the user to define the null and alternative simulation distributions. Summary Statements Group sequential trials with group sample sizes of 79 and 79 at the final look achieve 81% power to detect a difference of 1.0000 at the 0.050 significance level (alpha) using a one-sided T-Test. Accumulated Information Details for Scenario 1 Accumulated Information -------- Accumulated Sample Size -------- Look Percent Group 1 Group 2 Total 1 25.0 20 20 40 2 50.0 40 40 80 3 75.0 60 60 120 4 100.0 79 79 158 Accumulated Information Details Definitions Look is the number of the look. Accumulated Information Percent is the percent of the sample size accumulated up to the corresponding look. Accumulated Sample Size Group 1 is total number of individuals in group 1 at the corresponding look.
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Accumulated Sample Size Group 2 is total number of individuals in group 2 at the corresponding look. Accumulated Sample Size Total is total number of individuals in the study (group 1 + group 2) at the corresponding look.
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Boundaries for Scenario 1 -- Significance Boundary -- T-Value P-Value Look Scale Scale 1 -3.26419 0.00116 2 -2.61944 0.00529 3 -1.97462 0.02532 4 -1.69088 0.04643 Boundaries Definitions Look is the number of the look. Significance Boundary T-Value Scale is the value such that statistics outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. They are sometimes called efficacy boundaries. Significance Boundary P-Value Scale is the value such that P-Values outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. This P-Value corresponds to the T-Value Boundary and is sometimes called the nominal alpha.
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Boundary Plot
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Boundary Plot - P-Value
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Significance Boundaries with 95% Simulation Confidence Intervals for Scenario 1 --------- T-Value Boundary --------- --------- P-Value Boundary --------- Look Value 95% LCL 95% UCL Value 95% LCL 95% UCL 1 -3.26419 0.00116 2 -2.61944 -2.88807 -2.42370 0.00529 0.00251 0.00884 3 -1.97462 -2.07622 -1.86435 0.02532 0.02002 0.03238 4 -1.69088 -1.82038 -1.62086 0.04643 0.03531 0.05353 Significance Boundary Confidence Limit Definitions Look is the number of the look. T-Value Boundary Value is the value such that statistics outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. They are sometimes called efficacy boundaries. P-Value Boundary Value is the value such that P-Values outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. This P-Value corresponds to the T-Value Boundary and is sometimes called the nominal alpha. 95% LCL and UCL are the lower and upper confidence limits for the boundary at the given look. The width of the interval is based on the number of simulations.
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Alpha-Spending and Null Hypothesis Simulation Details for Scenario 1 --------- Target --------- --------- Actual ---------- Proportion Cum. Cum. H1 Sims H1 Sims --- Signif. Boundary--- Spending Spending Cum. Outside Outside T-Value P-Value Function Function Alpha Alpha Signif. Signif. Look Scale Scale Alpha Alpha Spent Spent Boundary Boundary 1 -3.26419 0.00116 0.000 0.000 0.000 0.000 0.036 0.036 2 -2.61944 0.00529 0.005 0.006 0.006 0.006 0.191 0.226 3 -1.97462 0.02532 0.018 0.024 0.018 0.024 0.382 0.608 4 -1.69088 0.04643 0.026 0.050 0.027 0.050 0.204 0.811 Alpha-Spending Details Definitions Look is the number of the look. Significance Boundary T-Value Scale is the value such that statistics outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. They are sometimes called efficacy boundaries. Significance Boundary P-Value Scale is the value such that P-Values outside this boundary at the corresponding look indicate termination of the study and rejection of the null hypothesis. This P-Value corresponds to the Significance T-Value Boundary and is sometimes called the nominal alpha. Spending Function Alpha is the intended portion of alpha allocated to the particular look based on the alpha-spending function. Cumulative Spending Function Alpha is the intended accumulated alpha allocated to the particular look. It is the sum of the Spending Function Alpha up to the corresponding look. Alpha Spent is the proportion of the null hypothesis simulations resulting in statistics outside the Significance Boundary at this look. Cumulative Alpha Spent is the proportion of the null hypothesis simulations resulting in Significance Boundary termination up to and including this look. It is the sum of the Alpha Spent up to the corresponding look. Proportion H1 Sims Outside Significance Boundary is the proportion of the alternative hypothesis simulations resulting in statistics outside the Significance Boundary at this look. It may be thought of as the incremental power. Cumulative H1 Sims Outside Significance Boundary is the proportion of the alternative hypothesis simulations resulting in Significance Boundary termination up to and including this look. It is the sum of the Proportion H1 Sims Outside Significance Boundary up to the corresponding look.
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Scenario 1 Numeric Results for Group Sequential Test of Non-Inferiority Higher Means are Better Hypotheses: H0: Mean1 - Mean2 = NIM; H1: Mean1 - Mean2 < NIM Test Statistic: T-Test Alpha-Spending Function: O'Brien-Fleming Analog Beta-Spending Function: None Futility Boundary Type: None Number of Looks: 4 Simulations: 2000 Pool Size: 10000 Numeric Summary of Scenarios Non-Inf. Std Scenario Power N1 N2 Alpha Margin Mean1 Mean2 Dev 1 0.811 79 79 0.050 1.0000 2.6000 2.6000 2.5000 References Jennison, C.; Turnbull, B.W. 2000. Group Sequential Methods with Applications to Clinical Trials. Chapman & Hall. Boca Raton, FL. Devroye, Luc. 1986. Non-Uniform Random Variate Generation. Springer-Verlag. New York. Matsumoto, M. and Nishimura,T. 1998. 'Mersenne twister: A 623-dimensionally equidistributed uniform pseudorandom number generator.' ACM Trans. On Modeling and Computer Simulations. Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood Cliffs, New Jersey. Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. N1 and N2 are the sample sizes of each group if the study reaches the final look. Non-inferiority margin is the distance from the control mean that is still considered non-inferior. Mean1, Mean2, and Std Dev are the parameters that were set by the user to define the null and alternative simulation distributions. Power and Alpha Summary ------------------ Power ------------------- -------------------------- Alpha ---------------------------- Scenario Value 95% LCL 95% UCL Target Actual 95% LCL 95% UCL Beta 1 0.811 0.794 0.828 0.050 0.050 0.040 0.060 0.189
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Group Sequential Two Means Non-Inferiority Power Analysis using Simulation Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Power 95% LCL and UCL are the lower and upper confidence limits for the power estimate. The width of the interval is based on the number of simulations. Target Alpha is the user-specified probability of rejecting a true null hypothesis. It is the total alpha spent. Alpha or Actual Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. Alpha 95% LCL and UCL are the lower and upper confidence limits for the actual alpha estimate. The width of the interval is based on the number of simulations. Beta is the probability of accepting a false null hypothesis. It is the total proportion of alternative hypothesis simulations that do not cross the significance boundaries. Sample Size Summary ------- Average Sample Size ------- --- Given H0 --- --- Given H1 --- Scenario Power Alpha N1 N2 Grp1 Grp2 Grp1 Grp2 1 0.811 0.050 79 79 78 78 62 62 Report Definitions Power is the probability of rejecting a false null hypothesis at one of the looks. It is the total proportion of alternative hypothesis simulations that are outside the significance boundaries. Alpha is the alpha level that was actually achieved by the experiment. It is the total proportion of the null hypothesis simulations that are outside the significance boundaries. N1 and N2 are the sample sizes of each group if the study reaches the final look. Average Sample Size Given H0 Grp1 and Grp2 are the average or expected sample sizes of each group if H0 is true. These are based on the proportion of null hypothesis simulations that cross the significance or futility boundaries at each look. Average Sample Size Given H1 Grp1 and Grp2 are the average or expected sample sizes of each group if H1 is true. These are based on the proportion of alternative hypothesis simulations that cross the significance or futility boundaries at each look. Run Time: 23.15 seconds.
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