TEMPO-2 protocol v3

Confidential TEMPO-2 Final Protocol v3.3 2017-03-24

1

TitlePageTEMPO-2–ArandomizedcontrolledtrialofTNK-tPAversusstandardofcareforminorischemicstrokewithprovenocclusionLongtitle:Multicentre,prospectiverandomizedopenlabel,blinded-endpoint(PROBE)controlledtrialofthrombolysiswithlowdoseTenecteplase(TNK-tPA)versusstandardofcareinthepreventionofdisabilityat3monthsinminorischemicstrokewithprovenacutesymptomaticocclusionProtocolVersion3.3 24thMarch2017

TableofContents

TITLEPAGE 1

TABLEOFCONTENTS 1

PROTOCOLSYNOPSIS 3

TRIALORGANIZATION 6

STUDYOBJECTIVES 6

BACKGROUND 7BULLETPOINTRATIONALE 7ASSOCIATIONOFVESSELOCCLUSIONANDOUTCOMEINMINORSTROKE 8THROMBOLYSISINMINORSTROKEPATIENTS:EFFICACYANDSAFETY 8TENECTEPLASE(TNK-TPA,TNKASE™) 9TIMINGOFTREATMENT 11

STUDYDESIGN 12PRIMARYOUTCOME 12SECONDARYOUTCOMES 12

SELECTIONANDENROLMENTOFSUBJECTS 13INCLUSIONCRITERIA 13EXCLUSIONCRITERIA 13SELECTINGPATIENTS 15ENROLMENT 16


2

STUDYINTERVENTIONS 16RANDOMIZATION:CONCEALMENTANDBLINDING 17STUDYDRUG 17SCHEDULEOFASSESSMENTS 18

LABORATORYEVALUATIONS 19

CLINICALEVALUATIONS 19

PROHIBITEDMEDICATIONSANDPROCEDURES 19

GUIDELINESFORCLINICALCARE 20

IMAGING 21

CLINICALMANAGEMENTOFADVERSEEXPERIENCES 21

ADVERSEEVENTREPORTINGANDREVIEW 22

DATASAFETYANDMONITORINGBOARD(DSMB) 22

EXPECTEDDRUGREACTIONS 22

CRITERIAFORINTERVENTIONDISCONTINUATION 22

STATISTICALCONSIDERATIONS 23

DATACOLLECTIONANDMANAGEMENTOVERVIEW 23HUMANSUBJECTS 23ETHICSAPPROVAL 24CONDITIONSFORTERMINATINGTHESTUDY 24CONFIDENTIALITY 24SITEMONITORING 25INVESTIGATOR'SFILES/RETENTIONOFDOCUMENTS 25SOURCEDOCUMENTSANDBACKGROUNDDATA 25AUDITSANDINSPECTIONS 26CASEREPORTFORMS 26

PUBLICATIONANDPRESENTATIONPOLICY 26

ANCILLARYSTUDIESPOLICY 26

DATA-SHARINGPLAN 27

REFERENCES 27


3

Protocolsynopsis TEMPO-2trial

ObjectivesTheprimaryobjective:todemonstratetheefficacyofusingTNK-tPAtotreatminorischemicstrokewithprovenarterialocclusion.

ExperimentalDesign

APhase3,prospective,randomizedcontrolled,open-labelwithblindedoutcomeassessment(PROBE)controlledtrial.

Population

Upto1274maleandfemaleadultpatientsInclusionCriteria

1. Acuteischemicstrokeinanadultpatient(18yearsofageorolder)

2. Onset(last-seen-well)timetotreatmenttime≤12hours.3. TIAorminorstrokedefinedasabaselineNIHSS≤5atthe

timeofrandomization.Patientsdonothavetohavepersistentdemonstrableneurologicaldeficitonphysicalneurologicalexamination.

4. Anyacuteintracranialocclusionornearocclusion(TICI0or1)(MCA,ACA,PCA,VBterritories)definedbynon-invasiveacuteimaging(CTangiographyorMRangiography)thatisneurologicallyrelevanttothepresentingsymptomsandsigns.AnacuteocclusionisdefinedasTICI0orTICI1flow.1PracticallythiscanincludeasmallamountofforwardflowinthepresenceofanearocclusionAND;DelayedwashoutofcontrastwithpialvesselsonmultiphaseCTAinaregionofbrainconcordantwithclinicalsymptomsandsignsOR,AnyareaoffocalperfusionabnormalityidentifiedusingCTorMRperfusion–e.g.transitdelay(TTP,MTTorTMax),inaregionofbrainconcordantwithclinicalsymptomsandsigns.

5. Pre-strokeindependentfunctionalstatus–mRS≤2.6. Informedconsent.7. Patientscanbetreatedwithin90minutesofthefirstslice

ofCT(orMRI)ExclusionCriteria

1. HyperdensityonNCCTconsistentwithintracranialhemorrhage.

2. LargeacutestrokeASPECTS<7visibleonbaselineCTscan.

3. Coreofestablishedinfarction.Nolargearea(estimated>10cc)ofgreymatterhypodensityatasimilardensitytowhitematterorinthejudgmentoftheenrolling


4

neurologistisconsistentwithasubacuteischemicstroke.4. Patienthasasevereorfatalordisablingillnessthatwill

preventimprovementorfollow-uporsuchthatthetreatmentwouldnotlikelybenefitthepatient.

5. Pregnancy.6. PlannedthrombolysiswithintravenoustPAor

endovascularacutetreatment.7. In-hospitalstrokeunlessthesepatientsareattheir

baselinepriortothestroke.8. Commonlyacceptedexclusionsformedicalthrombolytic

treatmentthatpotentiallyputthepatientatanincreasedriskofbleeding.Countryspecificproductmonographsandstrokethrombolysisguidelinesshouldbeconsulted.Thesearecommonlyrelativecontraindications(i.e.thefinaldecisionisatthediscretionofthetreatingphysician)butforthepurposesofTEMPO-2includethefollowing:

a. Significantbleedingdisordereitheratpresentorwithinthepast6months

b. Internationalnormalizedratio>1.7orknownfullanticoagulationwithuseofanystandardordirectoralanticoagulanttherapywithfullanticoagulantdosing.[DVTprophylaxisdosingshallnotprohibitenrolment].Forlowmolecularweightheparins(LMWH)morethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Fordirectoralanticoagulants;inpatientswithnormalrenalfunctionmorethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Patientsondirectoralanticoagulantswhohaveanydegreeofrenalimpairmentshouldnotbeenrolledinthetrialunlesstheyhavenottakenadoseofthedruginthelast5days.

c. Dualantiplatelettherapydoesnotprohibitenrolment.[Forpatientswhoareknownnottobetakinganticoagulanttherapyitisnotnecessarytowaitforcoagulationlabresults(e.g.PT,PTT)priortotreatment]

d. Prolongedcardiopulmonaryresuscitation(>2minutes)withinthepast2weeks

e. Acutepericarditisand/orsubacutebacterialendocarditis

f. Acutepancreatitisg. Severehepaticdysfunction,includinghepatic

failure,cirrhosis,portalhypertension(oesophagealvarices)andactivehepatitis


5

h. Neoplasmwithincreasedbleedingriski. Arterialaneurysmandknownarterial/venous

malformationj. Patientswhohavebeenacutelytreatedwith

GP2b3ainhibitors.k. Arterialpunctureatanon-compressiblesiteinthe

previoussevendaysl. Clinicalstrokeorseriousheadorspinaltraumain

theprecedingthreemonthsthatwouldnormallyprecludeuseofathrombolyticagent.

m. Historyofintracranialhemorrhage,subarachnoidhemorrhageorotherbrainhemorrhagethatwouldnormallyprecludeuseofathrombolyticagent.

n. Majorsurgerywithinthelast3monthsthatthetreatingphysicianconsidersacontraindicationtothrombolytictherapy.

o. Severehypo-(<50mg/dLor2.8mmol/l)orhyperglycemia(>400or22.2mmol/l)

p. Hypertensionrefractorytoanti-hypertensivemedicationsuchthattargetbloodpressure<185/110cannotbeachievedbeforetreatment.

q. Knownplateletcountbelow100,000percubicmillimeter.[Treatmentshouldnotbedelayedtowaitforplateletcountunlessthrombocytopeniaisknownorsuspected]

r. Gastrointestinalorgenitourinarybleedingwithinthepast3monthsthatwouldnormallyprecludeuseofathrombolyticagent.

Regions NorthAmerica,Europe,Asia,Australasia

Treatments

PatientswillberandomizedtoTNK-tPAorstandardofcare.IntheinterventiongroupTNK-tPAisgivenasasingle,intravenousbolus(0.25mg/Kg)immediatelyuponrandomization.Maximumdose50mg.Thecontrolgroupwillreceiveantiplateletagent(s)asdecidedbythetreatingphysician.Antiplateletagent(s)choicewillbeatthetreatingphysician’sdiscretion.

DurationofTreatment

Onetreatmentdeliveredacutelywitha90-dayfollow-upperiod.

EvaluationCriteria

Primaryoutcome:ReturntobaselineneurologicalfunctioningasmeasuredonthemRS.Analysiswillbearesponderanalysiswherereturntobaselinelevelofneurologicalfunctioningisdefinedasfollows:Ifpre-morbidmRSis0-1thenmRS0-1at90daysisagoodoutcome.Ifpre-morbidmRSis2thenmRS0-2isagoodoutcome.Pre-morbidmRSisassessedusingthestructuredmRSpriorto


6

randomization.Secondaryoutcomes:Safety,recanalization,ordinalshiftanalysisofmRS,NIHSS0atday5(ordischarge),Euroqol,everydayactivitiessub-questiononEuroqol,LawtonInstrumentalActivitiesofDailyLivingScale(IADL),allcausemortality,recurrentstrokeorprogression,mRS0-1at90days,mRS0-2at90days,meanmRSusinglinearregression,compositeofrecanalizationormRS0-1at90daysandmortality.

SampleSize

Wetestthehypothesisthatthereisa9%absoluteriskbenefitofTNK-tPAoverstandardofcareinthetreatmentofminorstroke(NIHSS0-5)with90%power.Therateofgoodoutcomeinthestandardofcaregroupisassumedtobe60%and69%intheTNK-tPAgroupandthepredictedsamplesizeis1228.Samplesizeisinflated4%to1274toaccountforlosstofollowup.

Randomization

Randomizationwillbe1:1toTNK-tPAorcontrol.Randomizationwillbecentral,computergeneratedandutilizeaminimizationalgorithmtoensurebalanceonkeyvariablesthroughoutthecourseofthetrial.

Consent Writteninformedconsentisrequired.

TrialOrganizationThetrialwillbecoordinatedandexecutedbyasteeringcommitteebasedinCalgaryandinvolveapproximately80sitesinNorthAmerica,Europe,AsiaandAustralasia.AnindependentDSMBwillprovidesafetyevaluationduringthetrial.Thetrialwillbeleadbyprincipalinvestigator:ShelaghB.Coutts.Co-investigators–MichaelD.Hill, MayankGoyal AndrewM.Demchuk BijoyK.MenonThetrialwillbeleadinEuropebyPeterKelly,attheUniversityCollegeinDublin,Ireland.

StudyObjectivesTodemonstratetheefficacyofusingTNK-tPA(tenecteplase),athrombolyticagentthatisrelativelynoveltothetreatmentischemicstrokebutwell-establishedinthetreatmentofmyocardialinfarction,totreatminorischemicstrokepatientswithprovenacutesymptomaticocclusionsorperfusionabnormalities.


7

Background

BulletPointRationale(i) Atleast50%ofischemicstrokeisinitiallyminor.(ii) Minorornon-disablingischemicstrokeisfrequentlytreated

conservativelywithantiplateletagentsonly.(iii) UptoathirdofpatientswithTIAorminorstrokearedeadordisabledat

90days,implyingthattheinitialseverityofpresentingsymptomscanbemisleading.

(iv) Arterialocclusioncanbedemonstratednon-invasivelyusingCTangiographyorMRangiographyin10-15%ofpatientswithTIAorminorstroke.

(v) Arterialocclusionisstronglyassociatedwithapooroutcome(deadordisabledat3months).

(vi) Treatmenttorelievearterialocclusionisexpectedtoresultinagreaterproportionofpatientsachievinganexcellentneurologicaloutcome.

(vii) AdvantagesofTNK-tPA(tenecteplase)overtPA(alteplase)a. TNK-tPAhasgreaterfibrinspecificityandpossiblyalower

intracranialhemorrhageriskcomparedtotPA.b. LowerdoseTNK-tPAmayofferlowerriskandhigherrecanalization

ratesduetoalongerserumhalf-life.c. TNK-tPAisinfusedusingasimplebolusinjection,whichreduces

nursingneedscomparedtothe60-minutetPAinfusion.Thiswould,forexample,facilitatefurtherimaging.

(viii) Proofofefficacyandsafetyofthrombolytictherapyinthesettingofminorstrokewithprovenocclusionwouldchangeclinicalpractice.

Atleast50%ofischemicstrokeisminorandinitiallynon-disabling.2Inthe“getwiththeguidelines”registryintheUnitedStates41%werenottreatedwiththrombolysisduetomildorimprovingsymptoms.3Thesepatientspresentwithatransientischemicattack(TIA)orminorstroke.Thetreatmentofminorstrokewiththrombolysishasalwaysbeencontroversialwithmuchvariationinpractice.Mostphysiciansdonottreatallpatientswithminordeficitspresentingwithinthestandardthrombolyticwindowduetoconcernsregardingbalancingtheriskofhemorrhagecomparedtoanypotentialreductionindisability.Howeveranumberofstudieshavereportedthatthisjudgmentofriskmaybewrong.Severalgroupshavereportedthatamongpatientsconsideredtoomildforthrombolysis,thatuptoathirdaredeadordisabledatthetimeoffollowup.4-7Recentdata,involvingasmallsubsetofpatientsinanindividualpatientdatameta-analysisofrandomisedtrialsoftPAsuggeststhatthrombolysiswithIVtPAamongpatientswithminordeficitsmayimproveoutcome(OR1.48,adjustedforageandtimefromonset(95%CI:1.07−2.06).8


8

AssociationofvesselocclusionandoutcomeinminorstrokeMinorstrokepatientswithdocumentedvesselocclusionareatthehighestriskofearlyneurologicaldeteriorationandpooroutcomewhenthrombolysisiswithheld.6,7,9,10ThesestudiesallusedMRItoassessarterialstatus,whichhaslimitedthenumberofpatientsassessedinthesestudies.Multi-slicehelicalCTscannerswithCTAngiography(CTA)capabilityarewidelyavailableinmanyemergencydepartments.CTAusestheadministrationofintravenouscontrastmediatoassesstheintracranialandextracranialvasculaturewithhighspatialresolution.TheadditionofCTAaddslessthan5minutestoastandardCTbrainandcanbesafelycompletedinmostpatients.11CTAisonepotentialwayofincreasingthenumberofpatientsthatcanhaveearlyvascularimagingamongpatientswithminorstroke.AlthoughweexpectthatmostsiteswilluseCTAtomeettheinclusioncriteriaforthisstudy,wewillallowMRI/MRAincentresthathaveprocessesinplacetomanagepatientsinthisway.Werecentlycompletedaprospectivecohortstudyof510TIAandminorstrokepatients(NIHSS<4)whowerenottreatedwiththrombolysis–theCATCHstudy.12AllofthesepatientshadaCTandCTAcompletedwithamediantimetoCTAof5.5hours(IQR:6.4hours)showingthefeasibilityofusingCTAtoscreenthesepatientsforlargearteryocclusion.10%(52/510)ofpatientshadanintracranialocclusion.19%(10/52)ofpatientswithintracranialocclusionhadearlyneurologicaldeteriorationversus2%(9/447)inpatientswithoutocclusion,p<0.0001.Wefoundthatstrokeprogressionoccurredinbothproximalanddistalocclusionswithsimilarfrequency.13Clinicaloutcomeswerealsoworsewithpatientshavinganintracranialocclusionhavingmoredisabilityatthetimeof90dayfollowup(31%versus13%,p=0.0016)thanpatientswithoutanintracranialocclusion.Thiswastruewhetherthepatientsclinicallydeterioratedornot.14Anothergrouphasfoundthatlargearteryocclusionpredictsdisabilityevenamongpatientswhohavecompletelysymptomaticallyresolvedatbaseline(i.e.TIApatients).15Inthesettingofintracranialocclusiontheproposedmechanismofneurologicalworseningisfailureofcollateralbloodsupply.16,17Insummary,minorstrokepatientswithadocumentedintracranialocclusionhaveahigherriskofneurologicaldeteriorationanddisabilitythanthosewithoutintracranialocclusion.

Thrombolysisinminorstrokepatients:efficacyandsafetyThebiggestreasonforphysicianstowithholdthrombolysisisalackofevidencetocountertheirconcernsregardingthepotentialrisksoftreatment.Mostofthethrombolysistrialscompletedtodatehaveincludedfewornominorstrokepatients.ThetrialwiththelargestnumberofminorstrokepatientstreatedtodateisthethirdInternationalStrokeTrial(IST-3).18InIST-3minorstrokewasdefinedasabaselineNIHSSof0-5inclusive.IST-3included612patientswithanNIHSSof0-5(304withtPA,308tocontrol).Therewasnoevidenceofatreatmentbenefitwithgoodoutcome(mRS0-1)seenin54%(164/304)oftPAtreatedpatientsvs.48%


9

(147/308)ofcontrols(RR1.13,95%CI:0.97-1.32,p=0.12).19ArecentanalysisoftheVirtualInternationalStrokeTrialArchive(VISTA)databasefailedtodemonstrateabenefitofthrombolysisinaNIHSS1-4population.20Symptomaticintracranialhemorrhage(SICH)wasseenin3%oftPApatients(9/304,95%CI:1.3-5.5)inIST-3,butnotinanycontrolpatients.TherewasnoevidenceofaninteractionwithtimeforSICH(lessthan4.5hoursorgreaterthan4.5hours).InasubgroupanalysisoftheCASESstudytherewere77tPAtreatedpatientswithaNIHSSscore<6andthesepatientshada2.6%(95%CI:0.8-9%)rateofsymptomatichemorrhage.21IntheNINDStPAstudytherewasasimilarhemorrhagerateof2.3%(95%CI:0.6-12%)amongpatientswithNIHSSscore<6.22Webelievethatthesubgroupofpatientswithanintracranialocclusionarethepopulationwheretheriskbenefitswingstowardsbenefit.Thefewpatientswithminorstroke(NIHSS<6)thathavebeenincludedinthrombolysisstudieshavelowerratesofintracranialhemorrhage(ICH)thaninmoreseverestrokes,howevertheconfidenceintervalsarewidegivenhowfewpatientshavebeenenrolledinthisgroup[NINDStPA222.3%(95%CI:0.6-12%),CASES212.6%(95%CI:0.8-9%),IST-3193%(95%CI:1.3-5.5)].OverallratesofsymptomaticICHhavealsobeenfallingasexperiencewithstrokethrombolysishasgrownworldwide.23Ingeneral,symptomaticICHamongdisablingstrokepatientstreatedwithintravenoustPAhasbeenshowntobeassociatedwiththeseverityofinfarction,thevolumeofinfarctionshownonimaging,leukoaraiosis,thetimefromstrokeonset,anticoagulationuseandelevatedserumglucose.24However,thesevariablesaccountforonlyasmallproportionofthevariancesothattoalargeextent,symptomaticICHseemsarandomoccurrenceclinically.Thus,itisourexpectationthattheratesofsymptomatichemorrhagewillbenomorethan2%amongpatientstreatedinthisstudy.Wenotethatpatientwithestablishedinfarctionobservableonbrainimagingareatgreaterriskofhemorrhage.Weproposetoexcludepatientswithevidenceoflargevolumesofinfarctionorclearlysubacuteischemia.MostminorstrokepatientsarejudgedtohavesuchagoodprognosisthattheriskofsymptomaticICHisnotworthtaking.However,therateofpooroutcomeismuchhigherthanpreviouslyassumed,particularlyinpatientswithintracranialocclusion.And,withevolvingknowledgeandexperiencewithstrokethrombolysis,thesafetyprofilehasimprovedsubstantially.

Tenecteplase(TNK-tPA,TNKase™)Tenecteplase,ageneticallyengineeredmutanttissueplasminogenactivator,hasalongerhalf-life,ismorefibrinspecific,produceslesssystemicdepletionofcirculatingfibrinogen,andismoreresistanttoplasminogenactivatorinhibitor25thanalteplase.26Thesepharmacodynamicdifferencesresultinmorerapidreperfusion.Tenecteplaseisnowthefirst-lineintravenousthrombolyticdrugfor


10

myocardialinfarction27,28andhasshowntocausecompletereperfusionwithreducedICHincomparisontoalteplaseinanimalstrokemodels.29,30Adoseescalationsafetystudyoftenecteplaseinpatientswithacuteischemicstrokeobservednosymptomaticintracranialhemorrhages(ICHs)among88patientstreatedwithdosesrangingfrom0.1mg/kgto0.4mg/kg.31At0.5mg/kg,thestudywasclosedearlyinthedosetierduetoanexcessofsymptomatichemorrhage.0.5mg/kg,isthecurrentlyapprovedcoronarythrombolysisdose.Asymptomatichemorrhagebegantoappearat0.1mg/kg(8%of25patients)andwashigherat0.2mg/kg(32%of25patients)and0.4mg/kg(28%of25patients),indicatingthattheremaybesomerelationshipwithdose.Thistrialwasstoppedprematurelyduetoslowenrollment.AmorerecentPhaseIIbstudycomparingthrombolysiswithtPAandlowdoseTNK(0.1mg/Kgor0.25mg/Kg)inmoderatetoseverestrokewassuggestivethatTNKhadhigherrecanalizationratesthantPA.32Thestudywasnotpoweredtolookatclinicaldifferencesbetweenthegroups,howevertherewerecleardifferencesinrecanalizationratesat24hours.Completerecanalizationat24hourswasseenin36%ofthetPAgroup,35%ofthe0.1mg/KgTNKgroupand80%ofthe0.25/kggroup(p=0.002).Partialorcompleterecanalizationwasseenin68%ofthetPAgroup,78%ofthe0.1mg/KgTNKand95%of0.25mg/KgTNKgroup(p=0.02).NotonlywasrecanalizationgreaterwithTNK,therateofsymptomaticintracranialhemorrhagewaslowerinboththeTNKtreatedgroups(12%versus4%and4%).Theinvestigatorsarecurrentlyrunningaphase3trialcomparingtPAwith0.25mg/KgTNKbasedontheseresults.33Werecentlycompletedadose-escalationsafetystudyofTNK-tPAinthetreatmentofminorstrokewithprovenocclusion–TEMPO-1study.34Weprospectivelyenrolled50patientswithminorstrokeandprovenintracranialocclusion,andtreatedthemwithTNK-tPAina12-hourwindow.Thefirsttierof25patientswastreatedatadoseof0.1mg/kg.Thesecondtierof25patientswastreatedat0.25mg/kg.TheoverallrateofsICHwas2%(1/50)CI950.5%-10.6%.Therewerenodrugrelatedseriousadverseeventsintier1.Intier2therewas1symptomaticICH(4%,95%CI:0.01-20.0).Strokeprogressionoccurredin6%ofcases.Overall,66%hadexcellentfunctionaloutcome(mRS0-1)at90-days.Recanalizationrateswerehigh;0.1mg/Kg(39%complete,17%partial),0.25mg/Kg(52%complete,9%partial).Completerecanalizationwassignificantlyrelatedtoexcellentfunctionaloutcome(mRS0-1)at90-days(RR1.65:CI951.09-2.5,p=0.026,SeeFigure1).


11

Figure1:Figureshowsthebreakdownoffunctionaloutcomesat90daysbyrecanalizationstatus(complete,partialornorecanalization).Basedontheknownpharmacologicaldifferences,thehigherrecanalizationrateandanempiricdose-escalationsafetystudy(TEMPO-1)wehavechosenTNKatadoseof0.25mg/kg.

TimingoftreatmentIVtPAisinroutineuseinCanadaupto4.5hoursfromsymptomonsetfortreatmentofdisablingstroke.Patientswithintracranialocclusion,butonlymildsymptomsaredifferentthanpatientswithmoreseveresymptoms,likelyduetocollateralcirculation.17Thesepatientsalsohaveatendencytopresentlaterthanpatientswithmoremajorsymptoms.IntheCATCHstudy12mostpatientsdeterioratedatamediantimeof1day(deteriorationwasmostlyovernightthefirstnight)suggestingthattheremaybeanextendedwindowinthesepatients.Manytertiarystrokecentres,includingtheCalgaryStrokeProgramhavebeenusingthe“smallcore,largeareaofbrainatrisk”paradigmtothrombolysestrokepatientsoutsideofguideline-basedcareforanumberofyears.DifferenttechniqueshavebeenusedtoidentifythispatientparadigmincludingMRI,CTperfusion(CTP)andCTAngiography(CTA).Wehavechosenarelativelysimpleapproach,whichisintracraniallargearteryocclusion(orafocalareaofdecreasedperfusionandsmallareaofinfarctedbrain).InTEMPO-1wesafelyused12hoursasourmaximumpotentialtreatmentwindow.Weshowedthatthiswassafetreatmentparadigm.Therealityisthatmostpatients


12

presentearlierratherthanlater.Thereistheoccasionalpatientwhowakesupwiththeirdeficitsandtheirlasttimeseennormaliscloseto12hours.

StudyDesignThestudywillbea,prospective,randomized,open,blindedend-point(PROBE)study.Randomizationwillbe1:1to0.25mg/KgTNK-tPA(experimental)orstandardofcare(control).

PrimaryOutcomePrimaryoutcome:ReturntobaselineneurologicalfunctioningasmeasuredbythemRS.Analysiswillbearesponderanalysiswherereturntobaselinelevelofneurologicalfunctioningisdefinedasfollows:Ifpre-morbidmRSis0-1thenmRS0-1at90daysisagoodoutcome.Ifpre-morbidmRSis2thenmRS0-2isagoodoutcome.Pre-morbidmRSisassessedusingthestructuredmRSpriortorandomization.(seeappendix1).35Outcomeswillbeassessedbyanindividualblindedtothetreatmentassignment.The90daymRSwillberatedusingthestructuredmRSquestionnaire(seeappendix1).The90daymRSwillbecompletedinpersonwherepossibleandbytelephoneotherwise.ThestructuredquestionnairehasbeenshowedtoimprovereliabilityinassessingthemRSbothinpersonandbytelephone.35

SecondaryOutcomes1) Proportionofpatientswithmajorbleeding:Thiswillincludeananalysisof

symptomaticintracranialhemorrhagealoneandthencombinedwithmajorextracranialhemorrhage.Thisisthemainsafetyoutcome. a) Symptomaticintracranialhemorrhagedefinedasnewintracranial

hemorrhage(ICH,SAH,IVH,SDH)associatedwithclinicalevidenceofneurologicalworsening,inwhich,thehemorrhageisjudgedtobethemostimportantcauseoftheneurologicalworsening.ClinicalworseningwillbeguidedbytheNIHSSscoreofaminimumof2ormorepointsdifferentfrombaseline.

b) Majorextracranialhemorrhagedefinedaslifethreatening,resultinginhemodynamiccompromiseorhypovolemicshock,requiringinotropicsupportorothermeanstomaintaincardiacoutput,requiringbloodtransfusionofmorethan2unitsofpackedredbloodcells,orassociatedwithafallinhemoglobingreaterthanorequalto5g/L.

2) Proportionofpatientswithcompleteandpartialrecanalization(TICI2b-3)posttreatment.ThiswillbeassessedonCTA4-8hoursposttreatment.Recanalizationwillbeassessedbythecentralcore-imaginglabblindedtoallclinicalinformation.

3) CategoricalshiftanalysisonthefullrangeofthemRS(0-6).


13

4) AbsenceofdisabilitydefinedasmRS0-1.5) FunctionalindependencedefinedasmRS0-2.6) ComparisonofthemeanmRSusinglinearregressionusingthemRSasa

continuousvariable.7) LawtonInstrumentalActivitiesofDailyLivingScale(IADL)36,378) ProportionofpatientswithanNIHSS0atday5(ordischargefromhospitalif

dischargedbeforeday5)9) QualityoflifemeasuredonEuroQol3810) Qualityoflifeasmeasuredbythe“problemswithusualactivities”questionon

theEuroQol.11) Strokeprogressionandrecurrentstroke.12) All-causemortality

SelectionandEnrolmentofSubjects

Inclusioncriteria1. Acuteischemicstrokeinanadultpatient(18yearsofageorolder)2. Onset(last-seen-well)timetotreatmenttime≤12hours.3. TIAorminorstrokedefinedasabaselineNIHSS≤5atthetimeof

randomization.Patientsdonothavetohavepersistentdemonstrableneurologicaldeficitonphysicalneurologicalexamination.

4. Anyacuteintracranialocclusionornearocclusion(TICI0or1)(MCA,ACA,PCA,VBterritories)definedbynon-invasiveacuteimaging(CTangiographyorMRangiography)thatisneurologicallyrelevanttothepresentingsymptomsandsigns.MultiphaseCTAorCTperfusionarerequiredforthisstudy.AnacuteocclusionisdefinedasTICI0orTICI1flow.1PracticallythiscanincludeasmallamountofforwardflowinthepresenceofanearocclusionAND,DelayedwashoutofcontrastwithpialvesselsonmultiphaseCTAinaregionofbrainconcordantwithclinicalsymptomsandsignsOR,AnyareaoffocalperfusionabnormalityidentifiedusingCTorMRperfusion–e.g.transitdelay(TTP,MTTorTMax),inaregionofbrainconcordantwithclinicalsymptomsandsigns.

5. Pre-strokeindependentfunctionalstatus–structuredmRS≤2.6. Informedconsentfromthepatientorsurrogate.Surrogateconsentisonly

allowedincountries/jurisdictionswherethisisapproved.7. Patientscanbetreatedwithin90minutesofthefirstsliceofCTorMRI.Scans

canberepeatedtomeetthisrequirement;ifthereisnochangeneurologicallythenonlyaCTheadneedberepeatedforassessmentofextentanddepthofischemia.

Exclusioncriteria1. HyperdensityonNCCTconsistentwithintracranialhemorrhage.2. LargeacutestrokeASPECTS<7visibleonbaselineCTscan.


14

3. Coreofestablishedinfarction.Nolargearea(estimated>10cc)ofgreymatterhypodensityatasimilardensitytowhitematterorinthejudgmentoftheenrollingneurologistisconsistentwithasubacuteischemicstroke>12hoursofage.

4. Patienthasasevereorfatalordisablingillnessthatwillpreventimprovementorfollow-uporsuchthatthetreatmentwouldnotlikelybenefitthepatient.

5. Pregnancy.Allwomenwiththepotentialofbeingpregnanti.e.havenotgonethroughmenopauseorhavenotundergonesurgicalsterilization,shouldhaveapregnancytestpriortoenrollment.

6. PlannedthrombolysiswithIVtPAorendovascularthrombolysis/thrombectomytreatment.

7. In-hospitalstrokeunlessthesepatientsareattheirbaselinepriortotheirstroke.E.g.apatientwhohadastrokeduringadiagnosticcoronaryangiogram.

8. Commonlyacceptedexclusionsformedicalthrombolytictreatmentthatpotentiallyputthepatientatanincreasedriskofbleeding.Countryspecificproductmonographsandstrokethrombolysisguidelinesshouldbeconsulted.Thesearecommonlyrelativecontraindications(i.e.thefinaldecisionisatthediscretionofthetreatingphysician)butforthepurposesofTEMPO-2includethefollowing:

a. Significantbleedingdisordereitheratpresentorwithinthepast6months

b. Internationalnormalizedratio>1.7orknownfullanticoagulationwithuseofanystandardordirectoralanticoagulanttherapywithfullanticoagulantdosing.[DVTprophylaxisdosingshallnotprohibitenrolment].Forlowmolecularweightheparins(LMWH)morethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Fordirectoralanticoagulants;inpatientswithnormalrenalfunctionmorethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Patientsondirectoralanticoagulantswhohaveanydegreeofrenalimpairmentshouldnotbeenrolledinthetrialunlesstheyhavenottakenadoseofthedruginthelast5days.Dualantiplatelettherapydoesnotprohibitenrolment.[Forpatientswhoareknownnottobetakinganticoagulanttherapyitisnotnecessarytowaitforcoagulationlabresults(e.g.PT,PTT)priortotreatment]

c. Prolongedcardiopulmonaryresuscitation(>2minutes)withinthepast2weeks

d. Acutepericarditisand/orsubacutebacterialendocarditise. Acutepancreatitisf. Severehepaticdysfunction,includinghepaticfailure,cirrhosis,portal

hypertension(oesophagealvarices)andactivehepatitisg. Neoplasmwithincreasedbleedingriskh. Arterialaneurysmandknownarterial/venousmalformationi. PatientswhohavebeenacutelytreatedwithGP2b3ainhibitors.j. Arterialpunctureatanon-compressiblesiteinthepreviousseven

days


15

k. Clinicalstrokeorseriousheadorspinaltraumaintheprecedingthreemonthsthatwouldnormallyprecludeuseofathrombolyticagent.

l. Historyofintracranialhemorrhage,subarachnoidhemorrhageorotherbrainhemorrhagethatwouldnormallyprecludeuseofathrombolyticagent.

m. Majorsurgerywithinthelast3monthsthatthetreatingphysicianconsidersacontraindicationtothrombolytictherapy.

n. Severehypo-(<50mg/dLor2.8mmol/l)orhyperglycemia(>400or22.2mmol/l)

o. Hypertensionrefractorytoanti-hypertensivemedicationsuchthattargetbloodpressure<185/110cannotbeachievedbeforetreatment.

p. Knownplateletcountbelow100,000percubicmillimeter.[Treatmentshouldnotbedelayedtowaitforplateletcountunlessthrombocytopeniaisknownorsuspected]

q. Gastrointestinalorgenitourinarybleedingwithinthepast3monthsthatwouldnormallyprecludeuseofathrombolyticagent.

SelectingPatientsTheprinciplesofpatientselectionarebaseduponthebroadcriteriaof:

a. TIAorminorstrokepresentationwithadiagnosisofanischemicstrokesyndrome

b. Imagingproofofanintracranialocclusionoraperfusionabnormalityrelevanttothepresentingsymptoms

c. Noregionofwell-definedhypodensityontheNCCTconsistentwiththepresentingsymptomsorconsistentwiththesuspectedpathophysiologyofthepresentingsymptomsthatsuggestswell-evolvedinfarction,judgedtobepotentiallypronetobleeding.

Themostchallengingoftheseprinciplesis(c)sinceitrequiresjudgmentandimaginginterpretation.WeknowfromimagingstudiesusingMRperfusionimagingthatregionsofverylowCBVarepronetohemorrhage.39Yet,usingMRdiffusionimagingitcanbeshownthatmanypatientswithminorlesionswhothenpresentwithsubsequentmajorstrokeandaretreatedwithIVtPAdonotsufferhemorrhage.40Clinically,ithasbeenamaximofstrokethrombolysisthatamongpatientswhopresentwithaTIA-likepresentationwhoneurologicallyresolveandthensubsequentlydeteriorate,theclockcanberesettothetimeofdeterioration.Yet,weknowthat50%ormoreofpatientswithTIA/minorstrokepresentationshaveMRdefinedsmallischemiclesions.41,42Empiricalclinicalexperiencesuggeststhatthrombolysisinpresenceofsmalllesionvolumesissafe.Patientwhoareatincreasedriskofhemorrhagiccomplicationsshouldnotbeenrolledinthetrial.Generally,standardthrombolyticagentcontraindicationswillbeconsideredatthediscretionofthetreatingphysicianasexclusioncriteria.Theuseoftenecteplaseorotherthrombolyticagentsinpatientswhoaretakingorhavebeenrecentlytakingdirectoralanticoagulantmedicineisuncertain.Thisis


16

particularlytrueforthemedicinesthataredependentuponnormalrenalfunctionforexcretion.Thereare4currentlymarketeddirectoralanticoagulants:Dabigatran,rivaroxaban,apixaban,betrixaban.Therefore,patientswithanydegreeofrenalfailurewhohavetakenoneormoredosesofthesemedicinesintheprior5daysareexcluded.Patientswithnormalrenalfunctionareexcludediftheyhavetakenoneormoredosesofthesemedicinesintheprior48hours.

EnrolmentPatientswillbescreenedusingtheusualstroketeamprocessofcareatthesite.Candidatesforenrolmentwillbeapproachedforconsent.Sinceallsubjectsareexpectedtoberelativelymildlyaffectedclinicallyatpresentation,many/mostwillbeabletoprovideconsentthemselves.Incertaincountries/jurisdictionsanincompetentpatient,whootherwisemeetscriteria,maystillbeenrolledwiththeconsentofasurrogateorlegallyauthorizedrepresentative.Allpatientsortheirsurrogatemustprovidewritteninformedconsent.AllpatientswillbeevaluatedclinicallyandthenundergobrainimagingusingCTfollowedimmediatelybyaCTangiogram.Iftheyremaineligible,afterreviewofclinicaltesting,imagingandlaboratorytesting,theywillbeimmediatelyenrolledandtreated.Allpatientswillbetreatedwithin90minutesofthefirstsliceofthebaselineCT.InsiteswhereMRI/MRAisroutinelyusedthiscanbesubstitutedforCT/CTA.InallpartsoftheprotocolMRI/MRAcanbesubstitutedforCT/CTA.Apatientisconsideredenrolledintothetrialatthepoint(dateandtime)ofrandomization.Ifrandomizedtoactivetreatmenttheyshouldimmediatelyreceivestudydrug.Randomizationisconsideredtime0.Apatientwhoprovidesconsentbutisnotenrolledintothetrialisconsideredascreenfailure.

StudyInterventionsRandomizationwillbe1:1toTNK-tPA(experimental)orstandardofcareantiplateletagents(control).

Experimental:TNK-tPA(0.25mg/kg)givenasasingle,intravenousbolusimmediatelyuponrandomization.Experimentaltreatmentwillbeadministeredasasingleintravenousbolusover5-10secondsasperthestandardmanufacturers’instructionsforuse.PleaserefertocurrentProductMonographfordetailsonreconstitutionandinfusionofthedrug.Control:Patientswillbetreatedwithstandardofcarebasedantiplatelettreatment–choiceatthediscretionoftheinvestigator.Lowdoseaspirin(singleagent)willbethechoiceofmostphysicians,howevergiventheresultsoftheFASTERtrial43andtherecentlypublishedCHANCEtrial44somewillchosetousethecombinationofaspirinandclopidogrel.Asthisisamulti-centre,internationaltrialwherelocalpracticeswillvary,ratherthanmandatingaspecificantiplateletagent,wewillallowthelocalinvestigatortochosewhichantithromboticregimeshouldbeused.


17

Standardofcaremedication(s)shouldbegivenimmediatelyuponrandomization.

PatientswillundergoastudyCTangiogramoftheintracranialcirculationbetween4-8hoursaftertreatmenttodeterminethebiologicaleffectofthedrug-whethertheoccludedarteryhasrecanalizedornot.Anypatientwhohasneurologicalworseningshouldhavestandardofcarebrainimagingcompletedtoruleoutintracranialhemorrhage.Allpatientswillhavestandardofcaremedicalmanagementonanacutestrokeunitandundergofollow-upimagingat24hourswithCTorMR.UseofMRwillbeencouraged.

Randomization:ConcealmentandBlindingRandomizationwillbecompletedbyacomputergeneratedminimizationalgorithm–minimalsufficientbalancerandomization.Thiswillensurebalancethroughoutthetrial,basedonkeyvariables.Thisalgorithmwillbedevelopedcentrallyandthedetailswillnotbeavailabletothetreatingsites.Theminimizationalgorithmpreservesbalanceonpre-specifiedprognosticvariables.Variablesthatwillbeincludedintheminimizationalgorithmareage,sex,baselineNIHSSscore,pre-morbidmRS,andtimeofrandomization(under4.5hoursversusnot).Thesearethekeyvariablesknowntoinfluenceoutcomeinminorstroke.10,14,45Randomizationwillbedynamicandgeneratedinthemomentviaaweb-basedsystem;thusarandomizationlistdoesnotexist.Theresultwillberandomallocationthatisfullyconcealed.Randomizationwillbebiasedcointhatwillvaryfromfullybalanced(50:50)tobiased(65:35)dependentonwhatcharacteristicsbeenpreviouslyenrolledhave.Thesystemwillbeenabledforsmart-phone,tablet,laptopordesktopcomputeruse.

StudyDrugThetradenamefortenecteplaseisTNKase™inNorthAmericaandMetalyse™inEuropeandAustralasia.Offtheshelftenecteplasewillbeusedinthisstudy.Staffwillbetrainedinthemixingandadministrationofthedrug.STORAGEANDSTABILITYStorelyophilizedTNKase™(orMetalyse™) tenecteplase,TNK-tPA)atcontrolledroomtemperature(2-30°C)nottoexceed30°Corunderrefrigeration(2°C-8°C).Ifstandardhospitalsuppliesarebeingusedthentemperaturemonitoringisnotrequired. Donotusebeyondtheexpirationdatestampedonthevial.UnusedreconstitutedTNKase™(inthevial)maybestoredat2°C-8°Candusedwithin8hours.Afterthattime,anyunusedportionofthereconstitutedmaterialshouldbediscarded.DOSAGEFORMS,COMPOSITIONANDPACKAGINGDosageForms:


18

TherearedifferentsizedvialsofTNKase™(orMetalyse™)availableindifferentcountries.InCanadaforexample50mgvialsareavailable.Each50mgvialofTNKase™(orMetalyse™)ispackagedwithone10mlvialofSterileWaterforInjectionforreconstitution.Forothervialsizesfollowthereconstitutioninstructionsincludedwiththedrug.Reconstitutionof50mgoftenecteplasein10mlofsterilewaterresultsinasolutionconcentrationof5mg/ml.Forothersizesoftenecteplasefollowthereconstitutioninstructionsincludedwiththedrug.Thedoseis0.25mg/kgor0.05ml/kg.Composition:TNKase™isasterile,whitetooff-white,lyophilizedpowderforsingleintravenous(IV)bolusadministrationafterreconstitutionwithSterileWaterforInjection,USP.50mg(10,000units)/vialTenecteplase*52.5mgL-Arginine0.55gPhosphoricAcid0.17gPolysorbate204.3mg*Thisincludesa5%overfillsothateachvialwilldeliver50mgoftenecteplase.Packaging:Each50mgvialofTNKase™ispackagedwithone10mLvialofSterileWaterforInjection,USPforreconstitutionandoneB-D®10ccSyringewithTwinPak®DualCannulaDevice.

ScheduleofAssessments Baseline 4-8

hDay1(24±8hfromrandomization)

Day5ordischarge(±1d)

Day90(±14d)§

Informedconsent X Regainedcapacityconsent(ifneeded)

X

Historyandexamination X Weight X± X± X± X± NIHSS X X X XmRS XPre-strokemRS¶ X EuroQol XLawtonInstrumentalActivitiesofDailyLivingScale(IADL)

X

NCCTheadorMR X* X*** CTACOWorMRA X* X** Fullemergencystrokelabs X‡ Creatinine X X ECG X‡ Adverseeventassessment X X X Seriousadverseeventassessment X X X X§Priormedications X‡ Concomitantmedications§ X X X X *MRI/MRAcanbesubstitutedforbaselineCT/CTAatthediscretionofthelocalsite.**4-8hoursCTACircleofWillis(COW).AtthediscretionofthelocalinvestigatorthefollowupCTAcanbenotcompletediftheeGFRis<40ml/minuteortherewasanallergicreactiontothebaselinescan.


19

***Day+1NCCTheadmaybesupplantedbyanMRheadincludingdiffusionweightedimaging(DWI)andgradientecho(GRE)atthediscretionofthelocalsite.¶Thepre-strokemRSisanestimateofthepre-strokescoreandisbasedonthehistorygivenbythepatient/family.‡Thesetestsarerequiredatbaseline.Bloodshouldbedrawnatbaseline,butresultsarenotrequiredpriortorandomization.Incertaincountriesasrecommendedbynationalguidelines;bloodworkforgroupandhold(typeandscreen)shouldbecollected.ECGshouldbedonewithin6hoursofhospitaladmission,butisnotrequiredpriortorandomization.Priormedicationsshouldbecollectedbutarenotrequiredpriortorandomization.§ConcomitantmedicationsarecollectedouttoDay5orinconjunctionwithanySAE.Collectconcomitantmedicationsat90daysonlyaspartoftheSAEnarrativeonlyonpatientswithSAEs.All90evaluationsshouldbeperformedbyanevaluatorblindedtotheacuteintervention.Weareencouragingthatthisvisitbecompletedinperson,butifthisisnotpossibleatelephonefollowupcanbesubstituted.d=days;h=hours±ActualweightmustbeperformedoncebyDay5orDischargeandrecorded,notnecessarytobedoneatalltimepoints.

LaboratoryEvaluationsRoutinebloodworkwillbetakenintheemergencydepartment.ThiswillincludePT/PTT,CBC,electrolytes,glucoseandcreatinine.Thecoagulationstatusmustbeknownpriortotreatmentamongpatientswhoareknowntobeonanyformanticoagulationtherapy.ECGshouldbecompletedatbaselineeitherpriortotreatmentorwithin6hoursoftreatment.IftheestimatedGFRissubsequentlyfoundtobe<40ml/minuteortherewasanallergicreactiontothebaselineCTAthentherepeatCTAshouldnotbecompleted.Thisisnotaprotocoldeviation.

ClinicalevaluationsAllpatientswillhaveastrokehistoryandphysicalbeforetreatmentiscommenced.AllinvestigatorswillbetrainedinboththeNIHSSandmRS.Patientswillbeassessedat24hoursoratthetimeofanydeteriorationusingtheNIHSS.At5days(oratdischargefromhospitalifsooner)patientswillhaveanNIHSScompleted.At90daystheNIHSS,Euroqol,LawtonInstrumentalActivitiesofDailyLivingScale(IADL)andmRSwillbecompletedbyablindedinvestigator.ThemRSwillberatedusingthestructuredmRSquestionnaire.35Theinvestigatorcompletingthe90doutcomeassessmentshouldbeablindedsitetrialinvestigator,sub-investigatororcoordinatordefinedasabsenceofinvolvementinthefirst48hoursoftreatmentofthepatient.Ifnotfeasibletocompleteinpersonthisinterviewcanbecompletedbytelephone.

ProhibitedmedicationsandproceduresIntheexperimentaltreatmentgroup:noantiplateletagent,otherantithromboticmedicinesshouldbegivenwithinthefirst24hours(+/-8h)ofthetreatment.Thesecanbestarted,ifclinicallyindicated,oncethe24-hour(+/-8h)follow-upCThasbeencompletedandshowsnoclinicallysignificantintracranialhemorrhage.Inpractice,thismeansthatifthereisnohemorrhageonfollow-upbrainimaging,antithromboticorantiplateletmedicinesmaybegivenwithoutrestriction.Ifthereishemorrhage,ajudgmentmustbemadeabouttherelativesafetyofantiplateletorantithromboticmedicine.Forexample,itismedicallyappropriateifthe


20

hemorrhageislimitedorsmallorsimplypetechial(hemorrhagicinfarctiontype)andthebenefitisjudgedtooutweightherisk.Itisexpectedthatamajorityofthecontrolgroupwillbetreatedwithsingle(ordual)antiplatelettherapy.Giventhepresenceofalargearteryocclusionwewouldrecommendnotimmediatelyusingheparinoroneofthedirectoralanticoagulantseveninthepresenceofatrialfibrillation.Wewouldrecommendthattheuseofanticoagulantsisdelayedforatleast24hoursinbothgroupsofpatients.Howeverthefinaldecisionislefttothejudgmentofthetreatingphysician.Patientsshouldnotundergoendovascularthrombectomyorthrombolysisoutsideofthetrialprotocol.Thisisconsideredaprotocolviolation.However,intheeventofaclinicaldeteriorationandthistypeofprotocolviolation,thepatientswillbeconsideredtohavesufferedanearlyrecurrentstroke(whichisapre-specifiedsecondaryoutcome),eveniftheyarecuredbyendovasculartherapy.Adverseeventsthatoccurrelatedtosuchtreatmentwillberecordedandadjudicatedaccordingly.

GuidelinesforClinicalCareItisexpectedthatsubjectswillreceivethebestusualstandardofstrokeunitcare.Allsubjectsareexpectedtobeadmittedtohospitalaspartofroutinestandardofcare.Mostsubjectswillhavemildsymptomsandrecoverin1-2daysandlikelywillbesubsequentlydischargedhome.

Itisexpectedthatallsubjectswillundergoaroutinework-upforthemechanismoftheirstrokeandbetreatedappropriatelyanddefinitively.Thisiscriticallyimportantbecausesubjectswithmildstrokesecondarytolargearterydiseaseareatthehighestriskofearlyrecurrentstroke.46Wewishtopreventrecurrentstrokefromconfoundingthe90-dayclinicaloutcomesuchthatpatientswhoarewellatdischargeremainthatwayforthedurationofthe90-dayfollow-upperiod.

Weexpectthatmostpatientswithatrialfibrillationwillbeanti-coagulated.Patientswithsymptomaticcarotidarterystenosisshouldundergocarotidrevascularizationearlyanddefinitelywithin2weeksofstrokeonset.47Riskfactors,includinghypertension,elevatedcholesterol,diabetesmellitus,tobaccosmoking,shouldbetreatedappropriatelyandaggressivelyaccordingtocurrentstandardsofcare.

Weexpectpatientstoreceiveadequatehydrationtopreventrenalcomplicationsoftheuseofradio-contrastmediafordiagnosticimaging.Whilethismedicationisgenerallyextremelysafe,simplehydrationcanpreventrenalcomplications,particularlyamongpatientswithbaselineborderlinerenalfunctionandamongthosewithdiabetesmellitus.Further,patientswithischemicstrokearegenerallyslightlyhypovolemicatbaseline.Werecommenduseofintravenousnormalsaline(0.9%saline)infusionat1.5–2.0cc/kg/huntilthepatientiseatinganddrinking


21

safelyandwell.Therefore,forthetypicalpatientthiswillmeanIVNSat75-150cc/hovernightonly.WedonotrecommendtheuseofbicarbonatesolutionsorN-acetyl-cysteinesolutions.Forpatientsthataredisabledfromtheirstrokeandrequirealongerin-patientstayand/orrehabilitation,itisexpectedthattheywillreceivestandardstrokeunitcaretopreventcomplications.Theseinclude:

• DVTprophylaxisforpatientswhoarebed-boundorprimarilybed-bound• Swallowingassessmentsandpreventionofaspirationpneumonia• Earlymobilizationandphysiotherapytopreventskinbreakdown,

pneumonia,DVT/PE• Earlydiagnosisandtreatmentoffever

ImagingAllimagingcompletedofthebrain,CT,CTA,andMRIinthefirst48hwillberenderedanonymousandsenttoCalgaryforcentraladjudication.Minimallythebaseline,4-8hCTAandthe24-hourimagingshouldbeincluded.

ClinicalManagementofAdverseExperiencesAnadverseeventisanyuntowardmedicaloccurrenceassociatedwiththeuseofadruginhumans,whetherornotconsidereddrugrelated.Adverseeventscanbeanyunfavorableandunintendedsign(e.g.,anabnormallaboratoryfinding),symptom,ordiseasetemporarilyassociatedwiththeuseofadrug,withoutanyjudgmentaboutcausality.Adverseeventsoccurafterenrolmentandaredefinedasnotbeingpresentpriortoenrolment.Forexample,apatientwithknownepisodicgoutyarthritisofthegreattoe,whodevelopsanattackofgout,isnotconsideredtohavesufferedanadverseevent;theeventwasknownpriortoenrolment.Apatientwhodevelopsanewdiagnosisofgoutduringthestudyperiodisjudgedhavesufferedanadverseevent.Thisisreportableasanadverseeventeventhoughitismostlikelyentirelyunrelatedcausallytothestudydrug,butisinsteadonlyassociatedwithstudydrugusetemporally.Adverseeventsshouldbemanagedaccordingtothebestcurrentstandardofcare.

Seriousadverseevents(SAEs)arethoseadverseeventsthatarelifethreatening,requireasurgicalormedicalproceduretopreventdisabilityordeath,resultinadmissiontohospital,prolongationofhospitalizationortransfertoanICU,orresultindeath.ASAEcanalsobeanimportantmedicaleventthatmaynotresultindeath,belife-threatening,orrequirehospitalization,butmayjeopardizethesubjectandmayrequiremedicalorsurgicalinterventiontopreventoneoftheoutcomeslistedinthisdefinition.Anynewdiagnosisofcancer(madeafterstudyenrollment)isconsideredanimportantmedicalevent.ASAEisalsoaneventthatresultsinacongenitalanomalyorbirthdefect,butthisisanunlikelyconsiderationforthistrialsinceallornearlyallparticipantswillnotbeofreproductivepotential.Seriousadverseeventsshouldbemanagedaccordingtothebest


22

currentstandardofcare.

AdverseEventReportingandReviewAdverseeventswillonlybecollectedthroughthefirst5daysoftrialparticipation.AdverseeventsshouldbereportedastheyoccurontheeCRF.Therearenotimelinesforreportingsimpleadverseevents.Documentationmustbesupportedbyanentryinthesubject’sfile.Eacheventshouldbedescribedindetailalongwithstartandstopdates,severity,relationshiptoinvestigationalproductasjudgedbytheInvestigator,actiontakenandoutcome. Seriousadverseevents(SAEs)willbecollectedforthefull90-daytrialperiod.SAEsmustbereportedimmediatelybytheinvestigatorwithinaveryshortperiodoftimeandundernocircumstancesshouldthisexceed24hoursfollowingknowledgeoftheSAE.SAEswillbereviewedbythetrialmedicalmonitor.SAEswillbereportedtotheappropriateregulatoryauthorityinaccordancetotherelevantregulationsandlegislationinthatregionandstate/country.BecausetheadverseeventprofileofTNK-tPAiswellknownduetotheexperienceofitsuseforcoronarythrombolysis,wedonotpredictthattherewillbeunexpectedadverseevents.

PregnanciesoccurringinstudysubjectswillbetreatedprocedurallyasSAEs.PregnanciesoccurringinstudysubjectsaftersigninginformedconsentshouldbereportedseparatelyonPregnancyReportForm.

DataSafetyandMonitoringBoard(DSMB)MembersoftheDSMBwillbeacknowledgedpublicallybutwillnotbeconsideredauthorsforanymanuscriptsthatarisefromthistrial.

ExpectedDrugReactionsForexpectedadversedrugreactions(ie.withrelationshiptoMetalyseorTNKase)investigatorsaredirectedtotheproductmonograph.

CriteriaforInterventionDiscontinuationBecausethestudydrugisadeliveredbyasingleintravenousbolusinjection,itwillnotbepossibletodiscontinuetheintervention.

Intheeventthatasubjectwithdrawsconsentforfollow-upinthestudy,thatsubjectwillbediscontinuedfromthetrialonthedateoftheirwithdrawalofconsent.Datacollectedpriortothisdatewillbeincludedinthefinalstudyreport.


23

StatisticalConsiderationsAsampleof1228patientsallowsustodemonstratea9%absoluteriskdifference(60%à69%primaryoutcome)with90%powerbetweeninterventionandcontrolgroups.Therecentpooledthrombolysisshowedaneffectsizeof10%inthesubsetofminorstrokepatientstreatedwiththrombolysis.8Enrollmentinthetrialsincludedinthemeta-analysisdidnotrequirepatientstohaveanintracranialocclusion,thusitislikelythatthemajorityofthesepatientsdidnothaveanintracranialocclusion.Thusalthoughweexpectthattheeffectsizeishigherinapopulationthatonlyincludespatientswithintracranialocclusionwewillconservativelyestimateanoverall9%effectsizewithachangeinproportionwithexcellentneurologicaloutcomefrom60%to69%.Thesamplesizeforeachgroupis614(1228total).Adding4%losstofollowupgivesasamplesizeestimateof1274patients(637ineachtreatmentgroup).Therewillbeongoingmonitoringforsafetyandfulldetailswillbeavailableinaformalsafetyplan.Asingleinterimanalysisforfutilityandefficacywillbeconductedatapproximatelytwo-thirdspatientenrolment(n=840).StandardO’BrienFlemingboundarieswillbeusedtoestablishthealphaspendingfunction.FulldetailswillbeavailableintheDSMBcharter.Itispossiblethataftercentralimagingreviewsomepatientswillbeenrolledinviolationoftheprotocolorthetreatmentprotocolmaybebreechedduetothedynamicnatureofacutestroke.Thismayoccurentirelyinthebestinterestsofpatientcare.Intheprimaryanalysis,allrandomizedpatientswillbeincludedinthefinalanalysisforsafetyandclinicaloutcome(ITTanalysis).Thesafetypopulationwillbedefinedasallpatientswhoreceiveanydoseofstudydrug.Theper-protocolpopulationwillbedefinedasallpatientswhoreceivedanydoseofstudydrugandmetalltheinclusionandexclusioncriteria.Secondaryanalyseswillincludeanalysisofthepre-statedsecondaryoutcomesandmultivariableanalysesofboththeprimaryoutcomesandpre-statedsecondaryoutcomes.AformalStatisticalAnalysisPlanwillbedocumentedpriortobreakingoftheblind.

DataCollectionandManagementOverviewDatawillbehousedandmanagedinacustomdatabaseattheHotchkissBrainInstituteClinicalResearchUnitinCalgary,AB,Canadausingregulatorycompliantdatasystems.

HumanSubjectsLocalRegulations/DeclarationofHelsinkiTheSponsor-Investigator(andanyParticipatingSiteInvestigators)willensurethatthisstudyisconductedinfullconformancewiththeprinciplesofthe“Declarationof


24

Helsinki”orwiththelawsandregulationsofthecountryinwhichtheresearchisconducted,whicheveraffordsthegreaterprotectiontotheindividual.Thestudymustfullyadheretotheprinciplesoutlinedin“GuidelineforGoodClinicalPractice”ICHTripartiteGuidelineorwithlocallawifitaffordsgreaterprotectiontothepatient.

EthicsapprovalThisprotocolandtheinformedconsentdocumentandanysubsequentmodificationsarereviewedandapprovedbythelocalethicscommitteeresponsibleforoversightofthestudy.Approvalfromthecommitteemustbeobtainedbeforestartingthestudy,andshouldbedocumentedinalettertotheSponsor-Investigator(andanyParticipatingSiteInvestigators)specifyingthedateonwhichthecommitteemetandgrantedtheapproval.Asignedconsentformmustbeobtainedfromthesubject.Incertaincountries/jurisdictionswherepermitted,forsubjectswhocannotprovideconsentthemselves,alegallyauthorizedrepresentative,orpersonwithpowerofattorney,maysigntheconsentform.Theconsentformdescribesthepurposeofthestudy,theprocedurestobefollowed,andtherisksandbenefitsofparticipation.Acopyoftheconsentformmustbegiventothesubject,thelegallyauthorizedrepresentative,orthepersonwithpowerofattorney;andthisfactmustbedocumentedinthesubject’srecord.Ifnewsafetyinformationresultsinsignificantchangesintherisk/benefitassessment,theconsentformshouldbereviewedandupdatedifnecessary.Allpatients(includingthosealreadybeingtreated)shouldbeinformedofthenewinformation,givenacopyoftherevisedform,andgivetheirconsenttocontinueinthestudy.

ConditionsforTerminatingtheStudyTheSponsor-Investigatorreservestherighttoterminatethestudyatanytime.Shouldthisbenecessary,theSponsor-InvestigatorwillworkwithanyParticipatingSiteInvestigatorstoarrangetheproceduresonanindividualstudybasisafterreviewandconsultation.Interminatingthestudy,theSponsor-Investigator(andanyParticipatingSiteInvestigators)willassurethatadequateconsiderationisgiventotheprotectionofthepatients’interests.

ConfidentialityAllimaging,evaluationforms,reports,andotherrecordsthatleavethesiteareidentifiedonlybythesiteandsubjectnumbertomaintainsubjectconfidentiality.Allrecordsarekeptinalockedfilecabinet.Clinicalinformationisnotreleasedwithoutwrittenpermissionofthesubject,exceptasnecessaryformonitoringbyethicscommittees,regulatorybodies,thesponsor,orthesponsor’sdesignee.Allstudyinvestigatorsattheclinicalsitesmustensurethattheconfidentialityofpersonalidentityandallpersonalmedicalinformationofstudyparticipantsismaintainedatalltimes.Countryspecificprivacyregulationswhereapplicable,mustbefollowed.OntheCRFsandotherstudydocumentsorimagematerialssubmittedtotheCRU,thesubjectsareidentifiedonlybystudyidentificationcodes.


25

PersonalmedicalinformationmaybereviewedforthepurposeofverifyingdatarecordedintheCRFbythesitemonitors.Otherproperlyauthorizedpersons,suchastheregulatoryauthorities,mayalsohaveaccesstotheserecords.Personalmedicalinformationisalwaystreatedasconfidential.

SiteMonitoringAllsiteswillhaveremotedatamonitoringconductedbythecentraltrialsstaff.Datawillbecheckedforcompleteness,logic,andvalidity.Querieswillbesenttositestoverifydataasrequired.Foron-sitemonitoringavarietyofrisk-basedmonitoringmodelswillbeused.Thismayincludebothtrainedemployeesandindustryexperiencedindependentcontractorclinicalresearchmonitors.Detailsofmonitoringwillbeinaseparatesitemonitoringplan.

StudyDocumentation,CRFsandRecordKeeping

Investigator'sFiles/RetentionofDocumentsTheSponsor-Investigator(andanyParticipatingSiteInvestigators)mustmaintainadequateandaccuraterecordstoenabletheconductofthestudytobefullydocumentedandthestudydatatobesubsequentlyverified.Thesedocumentsshouldbeclassifiedintotwodifferentseparatecategories:(1)Investigator'sStudyFile;and(2)patientclinicalsourcedocuments.

TheInvestigator'sStudyFilewillcontaintheprotocol/amendments,CaseReportandQueryForms,ethicscorrespondenceandgovernmentalapprovalwithcorrespondence,sampleinformedconsent,drugrecords,staffcurriculumvitaeandauthorizationformsandotherappropriatedocuments/correspondence,etc.Someorallofthesefilesmaybestoredelectronically.

Patientclinicalsourcedocuments(usuallydefinedbytheprojectinadvancetorecordkeyefficacy/safetyparametersindependentoftheCRFs)wouldincludepatienthospital/clinicrecords,physician'sandnurse'snotes,appointmentbook,originallaboratoryreports,ECG,diagnosticimaging,pathologyandspecialassessmentreports,signedICFs,consultantletters,andpatientscreeningandenrollmentlogs.TheSponsor-Investigator(andanyParticipatingSiteInvestigators)mustkeepthesetwocategoriesofdocumentsonfilefor25yearsaftercompletionordiscontinuationofthestudy.Afterthatperiodoftimethedocumentsmaybedestroyed,subjecttolocalregulations.

SourceDocumentsandBackgroundDataAnyParticipatingSiteInvestigatorsshallsupplytheSponsor-Investigatoronrequestwithanyrequiredbackgrounddatafromthestudydocumentationorclinicrecords.ThisisparticularlyimportantwhenCRFsareillegibleorwhenerrorsindatatranscriptionaresuspected.Incaseofspecialproblemsand/orgovernmental


26

queriesorrequestsforauditinspections,itisalsonecessarytohaveaccesstothecompletestudyrecords,providedthatpatientconfidentialityisprotected.

AuditsandInspectionsTheSponsor-InvestigatorandanyParticipatingSiteInvestigatorsshouldunderstandthatsourcedocumentsforthistrialshouldbemadeavailabletoappropriatelyqualifiedpersonnelfromtheSponsor-Investigatorordesigneeortohealthauthorityinspectorsafterappropriatenotification.TheverificationoftheCRFdatamustbebydirectinspectionofsourcedocuments.

CaseReportFormsForeachpatientenrolled,aCRFmustbecompletedandsignedbytheSponsor-Investigator(andanyParticipatingSiteInvestigator)orauthorizeddelegatefromthestudystaff.Thisalsoappliestorecordsforthosepatientswhofailtocompletethestudy.Ifapatientwithdrawsfromthestudy,thereasonmustbenotedontheCRF.

Allformsshouldbefilledoutclearlyandlegibly.Errorsshouldbecrossedoutbutnotobliterated,thecorrectioninserted,andthechangeinitialedanddatedbytheSponsor-Investigator(andanyParticipatingSiteInvestigators)orhis/herauthorizeddelegate.TheSponsor-Investigator(andanyParticipatingSiteInvestigators)shouldensuretheaccuracy,completeness,legibility,andtimelinessofthedatareportedtotheSponsor-InvestigatorintheCRFsandinallrequiredreports.

PublicationandPresentationPolicyThetrialexecutivecommitteewillbeco-authorsonallpublicationsandpresentations.Theprimaryauthorlistfortheprimarypublicationwillconsistoftheexecutivecommitteeandthesiteprincipalinvestigatorateachofthesites.Theresultsofthisstudymaybepublishedorpresentedatscientificmeetings.

AncillaryStudiesPolicyAncillaryorsub-studiesmaybeconsideredbythetrialexecutivecommittee.Importantprinciplesthatguidetheadditionofancillarystudiesare:

(1) nopatientshallbeenrolledinaconcurrentinvestigationaldrug/devicetrialduringthestudyperiod.

(2) concurrentenrollmentofaTEMPO-2studypatientinasitespecificobservationalcohortstudyisallowable,wherethefollowingconditionsaremet:

a. theexecutivecommitteeisnotifiedb. theconcurrentstudydoesnotinterferewithanystudyfollow-up

proceduresorpotentiallyconfoundtheoutcomeoftheTEMPO-2trial


27

c. thesitePIoftheconcurrentstudyexplicitlyacknowledgesthatthetreatmentgivenintheTEMPO-2trialmayconfoundtheoutcomeofthesite-specificconcurrentstudy

d. thepatientmaynotbeincludedinanypublicationorreportuntiltheTEMPO-2studyhasbeenconcludedandpublished.

(3) Ancillaryorsub-studiesshallbevettedandapprovedbythetrialexecutivecommittee.

Data-sharingplanTheExecutiveCommitteewillfollowthespiritoftheNIHpolicyondata-sharing[http://grants2.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm].Inaddition,theExecutiveCommitteewillfollowtheCIHRguidelinesonpublicaccesstotrialresultsandmaketheresultsavailableasfree-accessusingPubMed.UponcompletionoftheTEMPO-2Trial,apublicusedatabasewillbepreparedbystrippinganyandallpersonalidentifiers.Thepublicusedatabase,consistingofseveraldatafiles,shouldcontain:(1)baselineanddemographiccharacteristics;(2)outcomesassessments;(3)CT/MRIdata;(4)concomitantmedicationsandprocedures;and(5)adverseevents.EachdatafileismadeavailableasaformattedSASdatasetorotherelectronicformat.Thedatafilesaredistributedalongwiththedatadictionaryandabriefinstruction(“Readme”)file.Thesedatafileswillbemadeavailabletothepubliconlyafterallmajormanuscripts(includingsecondaryanalysispapers)oftheTrialareacceptedforpublicationinpeer-reviewedjournals.

References1. TomsickT,BroderickJ,CarrozellaJ,etal.RevascularizationresultsintheInterventionalManagementofStrokeIItrial.AJNRAmericanjournalofneuroradiology2008;29(3):582-7.2. ReevesM,KhouryJ,AlwellK,etal.DistributionofNationalInstitutesofHealthStrokeScaleintheCincinnati/NorthernKentuckyStrokeStudy.Stroke2013.3. SmithEE,FonarowGC,ReevesMJ,etal.Outcomesinmildorrapidlyimprovingstrokenottreatedwithintravenousrecombinanttissue-typeplasminogenactivator:findingsfromgetwiththeguidelines-stroke.Stroke2011;42(11):3110-5.4. SmithEE,FonarowGC,ReevesMJ,etal.OutcomesinMildorRapidlyImprovingStrokeNotTreatedWithIntravenousRecombinantTissue-TypePlasminogenActivator:FindingsFromGetWithTheGuidelines-Stroke.Stroke2011.5. BarberPA,ZhangJ,DemchukAM,HillMD,BuchanAM.WhyarestrokepatientsexcludedfromTPAtherapy?Ananalysisofpatienteligibility.Neurology2001;56(8):1015-20.6. NedeltchevK,SchweglerB,HaefeliT,etal.Outcomeofstrokewithmildorrapidlyimprovingsymptoms.Stroke2007;38(9):2531-5.7. SmithEE,AbdullahAR,PetkovskaI,RosenthalE,KoroshetzWJ,SchwammLH.Pooroutcomesinpatientswhodonotreceiveintravenoustissueplasminogen


28

activatorbecauseofmildorimprovingischemicstroke.Stroke2005;36(11):2497-9.8. EmbersonJ,LeesKR,LydenP,etal.Effectoftreatmentdelay,age,andstrokeseverityontheeffectsofintravenousthrombolysiswithalteplaseforacuteischaemicstroke:ameta-analysisofindividualpatientdatafromrandomisedtrials.LancetAugust6th2014.9. RajajeeV,KidwellC,StarkmanS,etal.EarlyMRIandoutcomesofuntreatedpatientswithmildorimprovingischemicstroke.Neurology2006;67(6):980-4.10. KimJT,ParkMS,ChangJ,LeeJS,ChoiKH,ChoKH.ProximalarterialocclusioninacuteischemicstrokewithlowNIHSSscoresshouldnotbeconsideredasmildstroke.PloSone2013;8(8):e70996.11. KrolAL,DzialowskiI,RoyJ,etal.Incidenceofradiocontrastnephropathyinpatientsundergoingacutestrokecomputedtomographyangiography.Stroke2007;38(8):2364-6.12. CouttsSB,PatelSK,ModiJ,DemchukAM,GoyalM,MDH.EarlyCT/CTApredictsrecurrenteventsinminorstroke/TIApatients:MainresultsoftheCTAndMRIintheTriageofTIAandminorCerebrovasculareventstoidentifyHighriskpatients(CATCH)study.SubmittedtoStroke2011.13. DebucV.,ModiJ.,GoyalM.,HillMD,S.B.C.IntracranialOcclusioninProximalandDistalVesselsareatHighRiskofSymptomProgressioninTransientIschemicAttackandMinorStrokePatientsResultsoftheProspectiveCATCHStudy.CerebrovasculardiseasesInpress2014.14. CouttsSB,ModiJ,PatelSK,etal.Whatcausesdisabilityaftertransientischemicattackandminorstroke?:ResultsfromtheCTandMRIintheTriageofTIAandminorCerebrovascularEventstoIdentifyHighRiskPatients(CATCH)Study.Stroke2012;43(11):3018-22.15. PoissonSN,Nguyen-HuynhMN,JohnstonSC,FurieKL,LevMH,SmithWS.Intracraniallargevesselocclusionasapredictorofdeclineinfunctionalstatusaftertransientischemicattack.Stroke2011;42(1):44-7.16. CouttsSB,HillMD,CamposCR,etal.Recurrenteventsintransientischemicattackandminorstroke:whateventsarehappeningandtowhichpatients?Stroke2008;39(9):2461-6.17. MaasMB,LevMH,AyH,etal.CollateralvesselsonCTangiographypredictoutcomeinacuteischemicstroke.Stroke2009;40(9):3001-5.18. groupISTc,SandercockP,WardlawJM,etal.Thebenefitsandharmsofintravenousthrombolysiswithrecombinanttissueplasminogenactivatorwithin6hofacuteischaemicstroke(thethirdinternationalstroketrial[IST-3]):arandomisedcontrolledtrial.Lancet2012;379(9834):2352-63.19. CouttsSB,LindleyRI,HillMD,etal.Effectofthrombolysisinaminorstrokepopulation.AnalysisofminorstrokepatientstreatedintheIST-3study.Cerebrovasculardiseases2014;37(Suppl1):156.20. MishraNK,LydenP,GrottaJC,LeesKR,CollaboratorsV.Thrombolysisisassociatedwithconsistentfunctionalimprovementacrossbaselinestrokeseverity:acomparisonofoutcomesinpatientsfromtheVirtualInternationalStrokeTrialsArchive(VISTA).Stroke2010;41(11):2612-7.


29

21. SteffenhagenN,HillMD,PoppeAY,BuchanAM,CouttsSB.ShouldyouthrombolysealloranystrokepatientswithbaselineNationalInstitutesofHealthstrokescalescores<or=5?CerebrovascDis2009;28(2):201-2.22. Tissueplasminogenactivatorforacuteischemicstroke.TheNationalInstituteofNeurologicalDisordersandStrokert-PAStrokeStudyGroup.NEnglJMed1995;333(24):1581-7.23. WahlgrenN,AhmedN,DavalosA,etal.ThrombolysiswithalteplaseforacuteischaemicstrokeintheSafeImplementationofThrombolysisinStroke-MonitoringStudy(SITS-MOST):anobservationalstudy.Lancet2007;369(9558):275-82.24. WhiteleyWN,SlotKB,FernandesP,SandercockP,WardlawJ.Riskfactorsforintracranialhemorrhageinacuteischemicstrokepatientstreatedwithrecombinanttissueplasminogenactivator:asystematicreviewandmeta-analysisof55studies.Stroke2012;43(11):2904-9.25. VanDeWerfF,AdgeyJ,ArdissinoD,etal.Single-bolustenecteplasecomparedwithfront-loadedalteplaseinacutemyocardialinfarction:theASSENT-2double-blindrandomisedtrial.Lancet1999;354(9180):716-22.26. TanswellP,ModiN,CombsD,DanaysT.Pharmacokineticsandpharmacodynamicsoftenecteplaseinfibrinolytictherapyofacutemyocardialinfarction.ClinPharmacokinet2002;41(15):1229-45.27. BinbrekAS,RaoNS,NeimaneD,HatouE,AbdulaliS,SobelBE.Comparisonofrapidityofcoronaryrecanalizationinmenwithtenecteplaseversusalteplaseinacutemyocardialinfarction.AmJCardiol2004;93(12):1465-8.28. Al-ShwafiKA,deMeesterA,PirenneB,ColJJ.Comparativefibrinolyticactivityoffront-loadedalteplaseandthesingle-bolusmutantstenecteplaseandlanoteplaseduringtreatmentofacutemyocardialinfarction.AmHeartJ2003;145(2):217-25.29. BenedictCR,RefinoCJ,KeytBA,etal.Newvariantofhumantissueplasminogenactivator(TPA)withenhancedefficacyandlowerincidenceofbleedingcomparedwithrecombinanthumanTPA.Circulation1995;92(10):3032-40.30. ThomasGR,ThibodeauxH,ErrettCJ,etal.Along-half-lifeandfibrin-specificformoftissueplasminogenactivatorinrabbitmodelsofembolicstrokeandperipheralbleeding.Stroke1994;25(10):2072-8;discussion8-9.31. HaleyEC,Jr.,LydenPD,JohnstonKC,HemmenTM.Apilotdose-escalationsafetystudyoftenecteplaseinacuteischemicstroke.Stroke2005;36(3):607-12.32. ParsonsM,SprattN,BivardA,etal.Arandomizedtrialoftenecteplaseversusalteplaseforacuteischemicstroke.NEnglJMed2012;366(12):1099-107.33. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363714.34. CouttsSB,DubucV,MandziaJ,etal.ThrombolysisforminorischemicstrokewithprovenacutesymptomaticocclusionusingTNK-tPA(TEMPO-1).Stroke2015;Inpress.35. BrunoA,AkinwuntanAE,LinC,etal.Simplifiedmodifiedrankinscalequestionnaire:reproducibilityoverthetelephoneandvalidationwithqualityoflife.Stroke2011;42(8):2276-9.


30

36. GrafC.TheLawtoninstrumentalactivitiesofdailylivingscale.TheAmericanjournalofnursing2008;108(4):52-62;quiz-3.37. LawtonMP,BrodyEM.Assessmentofolderpeople:Self-maintainingandinstrumentalactivitiesofdailyliving.TheGerontologist,;9(3):179-86.38. DormanPJ,WaddellF,SlatteryJ,DennisM,SandercockP.IstheEuroQolavalidmeasureofhealth-relatedqualityoflifeafterstroke?Stroke1997;28(10):1876-82.39. CampbellBC,ChristensenS,ButcherKS,etal.Regionalverylowcerebralbloodvolumepredictshemorrhagictransformationbetterthandiffusion-weightedimagingvolumeandthresholdedapparentdiffusioncoefficientinacuteischemicstroke.Stroke2010;41(1):82-8.40. TisserandM,LeGuennecL,TouzeE,etal.PrevalenceofMRI-definedrecentsilentischemiaandassociatedbleedingriskwiththrombolysis.Neurology2011;76(15):1288-95.41. AyH,ArsavaEM,JohnstonSC,etal.Clinical-andimaging-basedpredictionofstrokeriskaftertransientischemicattack:theCIPmodel.Stroke2009;40(1):181-6.42. CouttsSB,SimonJE,EliasziwM,etal.Triagingtransientischemicattackandminorstrokepatientsusingacutemagneticresonanceimaging.AnnNeurol2005;57(6):848-54.43. KennedyJ,HillMD,RyckborstKJ,EliasziwM,DemchukAM,BuchanAM.Fastassessmentofstrokeandtransientischaemicattacktopreventearlyrecurrence(FASTER):arandomisedcontrolledpilottrial.LancetNeurol2007;6(11):961-9.44. WangY,WangY,ZhaoX,etal.Clopidogrelwithaspirininacuteminorstrokeortransientischemicattack.NEnglJMed2013;369(1):11-9.45. SatoS,UeharaT,OharaT,etal.Factorsassociatedwithunfavorableoutcomeinminorischemicstroke.Neurology2014.46. LovettJK,CoullAJ,RothwellPM.Earlyriskofrecurrencebysubtypeofischemicstrokeinpopulation-basedincidencestudies.Neurology2004;62(4):569-73.47. RothwellPM,EliasziwM,GutnikovSA,WarlowCP,BarnettHJ.Endarterectomyforsymptomaticcarotidstenosisinrelationtoclinicalsubgroupsandtimingofsurgery.Lancet2004;363(9413):915-24.


31

Appendix1:StructuredmRS-TakenfromBrunoetal.35