Clinical Trial Protocol · 2019. 4. 26. · DSMB Data safety and monitoring board ... HCMC Hennepin...

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ClinicalTrialProtocol

StudyTitle: BougieuseinEmergencyAirwayManagement(BEAM)Investigators: BrianDriver,MD;LaurenKlein,MD;JonCole,MD;Matt

Prekker,MD,JohannaMoore,MD;RobertReardon,MD;JamesMiner,MD

Phase: IVContact: HennepinCountyMedicalCenter DepartmentofEmergencyMedicine 701ParkAve,MailstopR2 Minneapolis,MN55415 612.293.8286Institutional MinneapolisMedicalResearchFoundationReviewBoard 701ParkAve,SuitePP7.700 Minneapolis,MN55415 612.873.5300

DateProtocolversion1.0: 15December2015

Protocolversion1.1: 18May2016

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TableofContentsTableofContents.......................................................................................................................................2LISTOFABBREVIATIONSANDDEFINITIONSOFTERMS.......................................................41 INTRODUCTION................................................................................................................................51.1 Previouspublishedliterature...........................................................................................51.2 Rationaleforfurtherinvestigation.................................................................................71.3 Knownrisksoftheinterventions....................................................................................71.3.1 Knownrisksoforotrachealintubationwithoutabougie................................81.3.2 Knownrisksoforotrachealintubationwithabougie.......................................8

1.4 ProposedStudyPopulation................................................................................................82 STUDYOBJECTIVES.........................................................................................................................82.1 Primaryoutcome....................................................................................................................82.2 Secondaryoutcomes.............................................................................................................9

3 MEASUREMENTOFSTUDYOUTCOMES.............................................................................103.1 Measurementofprimaryoutcome..............................................................................103.2 Measurementofsecondaryoutcomes........................................................................10

4 INVESTIGATIONALPLAN..........................................................................................................114.1 OverallStudyDesignandPlan.......................................................................................114.1.1 StudyPopulationandRandomization...................................................................114.1.2 StudyTreatmentandBlinding.................................................................................11

4.2 Assessments...........................................................................................................................114.2.1 OutcomeAssessments..................................................................................................114.2.2SafetyAssessments...........................................................................................................11

4.3 StudyDuration......................................................................................................................125 STUDYPOPULATIONSELECTION..........................................................................................135.1 StudyPopulation..................................................................................................................135.2 InclusionCriteria.................................................................................................................135.3 ExclusionCriteria................................................................................................................135.4 SubjectWithdrawalCriteria...........................................................................................13

6 STUDYCONSENT...........................................................................................................................146.1 Researchinvolvesnomorethanminimalrisktothesubjects........................146.2 Thewaiveroralterationwillnotadverselyaffecttherightsandwelfareofthesubjects...........................................................................................................................................156.3 Theresearchcouldnotpracticablybecarriedoutwithoutthewaiveroralteration...............................................................................................................................................156.3.1 Patientobjection.............................................................................................................166.3.2 LARorFamilymemberobjection...........................................................................16

6.4 Notificationafterenrollment..........................................................................................167 STUDYPROCEDURES..................................................................................................................177.1 StudyEntranceCriteria.....................................................................................................177.2 Enrollment..............................................................................................................................177.3 BaselineandEDDataCollection...................................................................................177.4 AdverseEventAssessments...........................................................................................17

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7.4.1 AdverseEventMonitoringandPeriodofObservation..................................187.4.2 ReportingSeriousAdverseEvents.........................................................................18

7.5 Safety-RelatedStoppingRules.......................................................................................188 PLANNEDSTATISTICALMETHODS......................................................................................198.1 GeneralConsiderations.....................................................................................................198.2 Samplesizecalculation.....................................................................................................198.3 MethodofAssigningStudyPatientstoTreatmentGroups...............................198.4 PopulationDescription.....................................................................................................198.4.1 AnalysisPopulations.....................................................................................................208.4.2 TreatmentCompliance................................................................................................20

8.5 OutcomeAnalysis................................................................................................................208.6 Statistical/AnalyticIssues...............................................................................................208.6.1 HandlingofMissingData............................................................................................208.6.2 InterimAnalysisandDataMonitoring..................................................................21

9 ADMINISTRATIVECONSIDERATIONS.................................................................................229.1 InstitutionalReviewBoardApproval.........................................................................229.2 Datamonitoringcommittee............................................................................................229.3 ProtocolViolations/Deviations.....................................................................................229.4 PrematureClosureoftheStudy....................................................................................22

10 LISTOFREFERENCES............................................................................................................23

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LISTOFABBREVIATIONSANDDEFINITIONSOFTERMSAbbreviation DefinitionAE AdverseeventDSMB DatasafetyandmonitoringboardED EmergencyDepartmentETT EndotrachealtubeGEB Gum-elasticbougieHCMC HennepinCountyMedicalCenterIRB InstitutionalreviewboardITT Intention-to-treatLAR Legally-authorizedrepresentativeSAE SeriousAdverseEvent

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1 INTRODUCTIONRapidanddefinitiveairwaymanagementisanessentialskillforallemergencyphysicians.Orotrachealintubationisthemostcommonmeanstoobtainadefinitiveairway,andisclassicallyperformedusinganendotrachealtubewithanintubatingsyletinsertedintothetubeforrigidity.Thetubeandstyletarepassedunderdirectvision.Usingthesemethods,themajorityofpatientsintheemergencydepartmentcanbesuccessfullyintubated,andthereforesuccessfullyoxygenatedandventilated.Theconceptoffirst-passsuccess,thatis,passingtheendotrachealtubesuccessfullyonthefirstintubationattempt,isparamountinemergencyairwaymanagement.Ithasbeenshownthatforeveryattemptafterthefirst,complicationsincreasedramatically.1Whileemergencymedicinehasbeenimprovingairwaymanagementandfirstpasssuccessoverthepastseveralyears,alargecross-sectionalsampledemonstratedthatfirstpasssuccessremainsapproximately85%.2Firstpasssuccessislikelylowerinthehandsoflessexperiencedoperators,suchasemergencymedicineresidentsintraining.Therefore,thereissubstantialroomforimprovement.Asimpleadjuncttoendotrachealintubation,thegumelasticbougie(GEB),mayincreasefirstpasssuccessanddecreaseratesofintubation-associatedhypoxemia.TheGEBisa60or70-centimeterstyletwithanapproximately30-degreeangleatitstip.Whenusedduringanintubationattempt,theGEBispassedbetweenthevocalcords;thentheendotrachealtubeispassedovertheGEBintothetrachea.TheGEBessentiallyservesasaflexibleguideintothetrachea.Itcanenablesuccessfulintubationindifficultairwaysduetoitsflexiblematerial,allowingtheintubatingprovidertobeabletodirectitstipanteriorlythroughthevocalcords.ProperplacementoftheGEBcanbeperformedbydirectvisualization,videoassistedvisualization,andalsoboththefeelingof“clicks”astheGEBpassesovertrachealringsanda“hardstop”whentheGEBcomesintocontactwithamainstembronchusatthelevelofthecarina.3,41.1 PreviouspublishedliteratureThefirstreportofadjunctiveGEBuseindifficultendotrachealintubationwasin1949,describedbyMacintosh.5Althoughitdidnotreceivemuchattentionintheliteratureformanyyearsthereafter,thelate1980’sandearly1990’ssawmultiplecasereportsandcaseseriesdescribingtheeffectivenessoftheGEBintheseclinicalscenarios.3,6-8AstheGEBbecamemorepopular,severallargerserieswerepublishedsupportingitsuse.Oneseriesof2000anesthesiologyincidentreportsofdifficultintubationsconcludedthatthemostsuccessfulairwayadjunctwasthe

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GEB.9Anotherretrospectivetrialfounda99%successratewhenusingtheGEBduring301difficultintubationsoveran8-yearperiod.10SeveralprospectivestudieshavealsobeenpublisheddescribingtheuseoftheGEBindifficultairways.Oneprospectivetrialfoundthat199outof200attemptsatplacingtheGEBinthetracheaweresuccessful.11Inthisstudy,theproviderselectedtousetheGEBduetoapoorlaryngealvieworfailedattemptsatconventionalsyletintubation.Anotherprospectiveobservationalcross-overstudydescribedtheuseoftheGEBincadavericairways.12ThecadaversweremanipulatedtohaveeitheraCormack-LehaneGrade1orGrade3view,andemergencymedicineresidentsintubatedthemwitheitherastyletoraGEB.TheauthorsfoundatrendtowardincreasedsuccessintheGEBgroupintheGrade3viewcadaversbutthisresultdidnotachievestatisticalsignificance.ThefirstrandomizedstudytoassesstheefficacyoftheGEBwasconductedin1993.13Thisstudysimulatedcervicalspineinjuriestocreateadifficultairway.Thepatientsinthisstudyhadmanualin-linestabilizationmaintainedduringintubation,whichsignificantlydecreasedtheviewofthelarynx.PatientswererandomizedtodirectvisualizationversusintubationusingaGEB.Theauthorsfoundthatallpatientswhohadfailedintubationinthedirectvisualizationgroupweresuccessfullyintubatedwithin45secondsusingtheGEB.AnotherrandomizedtrialdescribingGEBusewaspublishedin1996.14TheauthorsofthisstudyrandomizedpatientstoaGEBversusastandardstyletduringdirectlaryngoscopy.TheauthorscreateddifficultintubationscenariobysimulatingaCormack-LehaneGrade3viewwithlaryngoscopeplacement.Eachgrouphadtwoattemptsatintubationwiththeirrandomizedequipmentbeforetheycouldcrossover.TheyfoundthattheGEBgroupwassuccessful96%ofthetimewhilethestyletgroupwassuccessful66%ofthetimeafterthefirsttwoattempts,demonstratingcompellingevidencefortheuseoftheGEBindifficultairways. CertaintypesofdifficultairwaysmaybemoreamenabletoGEB-facilitatedintubation.Onescenariothathasbeenwelldescribedisthedifficulttraumaairway,particularlythosewithfacialandnecktrauma.13,15,16Thetraumaairwayprovidesauniquesetofcomplicationstoairwaycontrolincludingactivehemorrhage,distortedanatomy,andcervicalimmobilityduetocervicalcollaruse.AnotherscenarioinwhichtheuseGEBiscommonlydescribedisinthesettingofpre-hospitaldifficultairways.17-20Basedonitsobservedsuccess,onegroupreportedthattheGEBbecamepartofapre-hospitalinstitutionalalgorithmfordifficultairwaymanagement.17MostoftheevidencedescribingtheuseoftheGEBhasstemmedfromtheanesthesiologyliterature,withrelativelylittlereferencetoitsuseintheemergencydepartments.FewstudiesdescribeemergencyprovidersutilizingtheGEBonairwaytask-trainers,21manikins,22,23andcadavers,12butallarelimitedbyartificialairwaysimulations.

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Therearetwoobservationaltrialsinhumanspublishedin2011bythesamegroupofauthors.24,25ThesetrialsreportdataontheuseoftheGEBasarescuedeviceafterfailedintubation.Thesuccessratesdescribedinthesetrialswere20outof26(76.9%)and70outof88(79.6%)attempts,respectively.Thesesuccessratesarelowerthatwhatistypicallycited,buttheauthorsidentifiedlimitationsincludingthefactthattheparticipantsintheirstudywereresidentsusingtheGEBforthefirsttime,suggestingtheneedforeducationonitsusepriortoutilizationintheemergencydepartment.1.2 RationaleforfurtherinvestigationBasedonthisreviewoftheliterature,thereisevidencesupportingGEBuseasanadjunctfordifficultairways.However,becauseitisnotalwayspossibletoanticipateadifficultairway,orevensemi-difficultairway,beforeanintubationattemptbegins,thebougiemayimprovetheoverallsuccessofroutineintubationsaswell,especiallyforpatientswithanydifficultairwaycharacteristics.However,whiletheGEBhassignificantfacevalidityinitsabilitytoimproveintubationsuccess,alargemulti-centerstudydemonstratedthatonly3.5%offirstattemptsusetheGEB.2ThisspeakstothepossibilitythatincreasingtheuseoftheGEB,asimple,low-costintervention,mayimprovefirstpasssuccessanddecreaseintubation-associatedcomplications.ThepracticeintheEmergencyDepartmentatHennepinCountyMedicalCenter(HCMC),however,variesfromnationwidepracticeinthattheGEBisavailableforeveryfirstintubationattempt.Basedonthetreatingphysicianspreference,theGEBmayormaynotbeusedonthefirstattempt.Thus,itisstandardofcareatHCMCtouseandnotusetheGEBonthefirstattempt.Wehaveexperiencedfacultymembers,manyofwhomareairwayexperts,whofeelstronglyonbothsides,withsomestatingthatitshouldbeuseduniformly,andotherssayingthatitshouldbereservedforintubationsthatarenotsuccessfulonthefirstattempt.Thus,thereisaclinicalequipoiseonwhethertouseornotuseaGEBonthefirstattempt.Toourknowledgetherearenorandomizedcontroltrialsstudyingfirstpasssuccessandperi-intubationhypoxemiawithandwithouttheuseofaGEB.ThisproposedresearchstudywillattempttoanswerthequestionofwhethertheuseoftheGEBissuperiortonon-useoftheGEBinemergencydepartmentairwaymanagement.1.3 KnownrisksoftheinterventionsWhiletheprocedureofendotrachealintubationhasmanyinherentrisks,therearenosignificantdifferencesinriskbetweenorotrachealintubationwithandwithoutabougie.

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1.3.1KnownrisksoforotrachealintubationwithoutabougieRisksoforotrachealintubationwithoutabougieinclude:inabilitytopasstheETTandstyletpastthehypopharnxthroughthevocalcords,andinabilitytoslidetheendotrachealtubeoverthestylet.Therearerarecasereportsofbreakageofthemetaltipofthestylet.Patientsintubatedwithanendotrachealtubewithoutabougieareatriskforairwayperforation,oropharyngealtrauma,laryngealtrauma,tracheobronchialtrauma,andesophagealintubation.1.3.2KnownrisksoforotrachealintubationwithabougieRisksoforotrachealintubationwithabougieincludes:inabilitytopasstheGEBpastthehypopharynxthroughthevocalcords,andinabilitytopasstheendotrachealtubeoverthebougie25.ThereareraremechanicalcomplicationsthathavebeenreportedwiththeGEB,includingbreakageoftheGEBtip,26andfractureofthematerial.27MajormedicalcomplicationsofGEBusearerare..ThereportedcomplicationsofGEBuseincludehemopneumothorax28,pharyngealwallperforation,29traumaticbleedingwithintheairway,30,31andtrachealinjury.32Severalofthesecasereportsdescribepatientswithpost-surgicalandcomplexairwayanatomy,andGEBuseasthesoleincitingmechanismforthetraumaisdebatable..1.4 ProposedStudyPopulationAdultpatientsundergoingorotrachealintubationintheEDwithaMacintoshblade(usingeithervideoordirectlaryngoscopy)foranyindicationwillberandomizedtouseoftheGEBduringthefirstintubationattempt.Allothercarewillbeatthediscretionofthetreatingemergencyphysician.2 STUDYOBJECTIVES2.1 PrimaryoutcomeTheprimaryoutcomeofthisstudywillbefirstpasssuccess.

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Firstpasssuccessisdefinedasplacementoftheendotrachealtube(ETT)intothetracheaonthefirstattempt.Anattemptbeginswhenthelaryngoscopeentersthemouth,andendsifeitherofthefollowingoccur:

1. thelaryngoscopeleavesthemouth,regardlessofwhetheranattemptwasmadetopasstheendotrachealtubeorbougie.

2. iftheoperatorcannotintubatethetracheawiththefirsttubedevice(ETTorbougie),andswitchestoanyothertubedevice,evenifthelaryngoscopebladeremainsinthemouth.

Apatientwillbeconsideredtoachievetheprimaryoutcomeiftheyareintubatedsuccessfullyonthefirstattempt.TrachealpositionoftheETTisconfirmedimmediatelyusingastandardprotocolinvolvingmultiplemodalities(physicalexam,capnography,andchestx-ray,amongothers).2.2 Secondaryoutcomes1) Firstpasssuccesswithouthypoxemia.Hypoxemiaisdefinedasapulse

oximetryvalue(SpO2)lessthan90%atanypointduringintubation,oradropofmorethan10%frombaselineifstartingbelow90%.TheoutcomeofhypoxemiawillberecordedbeginningwhenthefirstattemptbeginsandendingoneminuteafterinflationoftheETTcuff.

Apatientwillbeconsideredtoachievethisoutcomeif1)theyareintubatedsuccessfullyonthefirstattempt,and2)donotexperiencehypoxemiaonthefirstattempt.

2) Timetointubation(firstattemptonly).Timetointubationwillbedefinedas

thetimeelapsedbetweenthebeginningoftheintubationattempttoinflationoftheETTcuffwhenthetubeisinthetrachea.

3) Esophagealintubation:definedaspassageoftheETTintotheesophagus,

withsubsequentventilation,andthenremoval.Clinically,esophagealintubationisidentifiedbytheabsenceofend-tidalcarbondioxide,abnormalphysicalexam,andhypoxia.ThisdoesnotcountpassageoftheETTintotheesophagusduringtheattemptiftheETTisremovedduringtheattempt.

4) Hypoxemia,asdefinedabove.

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3 MEASUREMENTOFSTUDYOUTCOMES3.1 MeasurementofprimaryoutcomeAtrainedresearchassistantwillbepresentintheroomforallstudysubjects.Thistrainedassistantwillobservetheintubationandrecordthenumberofattempts.Theintubatingphysicianwillalsobeaskedthenumberofattemptsattheendofthecase.Incaseswherethereisadiscrepancybetweentheresearchassistantandtheintubatingphysician,thevideoforthestabilizationcasewillbereviewedtodeterminetheactualnumberofattempts.3.2 MeasurementofsecondaryoutcomesForsecondaryoutcome1):Firstpasssuccesswillbemeasuredasdescribedabove.Forhypoxemia,aresearchassistantwillrecordtheSpO2atthebeginningoftheattemptandevery20secondsthereafter,until1minuteafterinflationoftheETTcuff.ThelowestSpO2willalsoberecorded,evenifthisdoesnotfallata20-secondinterval.Forsecondaryoutcome2):Theresearchassistantwillhaveastopwatchandrecordthetimetointubation,asdefinedin2.2.Forsecondaryoutcome3):Theintubatingphysicianwillfilloutadatacollectionsheetaftertheintubation.Thisformwillincludewhethertherewasanesophagealintubation,asdefinedin2.2.Forsecondaryoutcome4):.Hypoxemiawillbemeasured,asdescribedaboveinsecondaryoutcome1).

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4 INVESTIGATIONALPLAN4.1 OverallStudyDesignandPlanThisPhaseIVstudyisdesignedasarandomized,unblinded,two-armstudythatwillbeconductedatasinglecenter.Theprimaryaimistodetermineiffirstpasssuccessdiffersbymorethan9%(absolutedifference)inpatientswhouseaGEBduringthefirstintubationattemptcomparedtothosethatdonot.4.1.1StudyPopulationandRandomizationAdultpatientsundergoingorotrachealintubationintheEDwithaMacintoshblade(usingeithervideoordirectlaryngoscopy)foranyindicationwillbeenrolledintothestudy.Ifthepatientmeetsalloftheeligibilitycriteria,he/shewillbeenrolledandrandomizedata1:1ratiotoundergointubationwithorwithoutaGEBforthefirstattempt.Therandomizationwillbepermuted-blockwithrandomblocksizesof2,4,6,8,and10.Therandomizationwillbestratifiedintotwogroups:1)thosewithanyofthefollowing:cervicalcollar,obesity(gestalt),andapparentfacialornecktrauma;and2)thosewithnoneofthosecharacteristics.Atrainedresearchcoordinatorwhowillnotbeperforminganydatacollectionorchartreviewduringthestudywillgeneratethetreatmentassignments.Thestudyallocationswillbesealedinsequentiallynumberedopaqueenvelopesandstoredinthecriticalcarearea.Whenaneligiblepatientisenrolled,thenextsequentialenvelopewillbeopenedtorevealthetreatmentassignment.Skippingastudynumberisnotallowed.4.1.2StudyTreatmentandBlindingThestudywillbeunblindedbecauseitisnotpossibletoblindphysicianstothisstudy,andnoshaminterventionispossible.4.2 Assessments4.2.1OutcomeAssessmentsDescribedinsection34.2.2SafetyAssessmentsAnyadverseeventsrelatedtotheuseornon-useoftheGEBshouldbeobservedimmediatelyintheEDduringtheintubationprocess.Ifeitherdevicefailsto

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intubatethepatient,asecondattemptwillbeperformed.Thesecondattemptcanproceedwithanydeviceorstrategythattheintubatingphysicianfeelsisbestforthepatient.Directtraumatothemouth,upperairway,andairwayarepossibleinbothgroups.Fullassessmentofthemouth,upperairway,andairwayisnotpossiblewithoutexposingthepatienttofurtherharmfromrepeatedlaryngoscopyandbronchoscopy.Therefore,toassessanydirecttrauma,theintubatingphysicianwillbeaskediftherewasanydirecttraumatothemouth,upperairway,orairway,andiftherewasanyexcessivebleedingduringorafterintubationwhileintheED.4.3 StudyDurationApatient’sparticipationinthistrialwillbeginatenrollment,andend1-minuteaftersuccessfulintubation.Nofurtherdatawillbecollectedfromthepatientorelectronicmedicalrecord.

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5 STUDYPOPULATIONSELECTION5.1 StudyPopulationAdultpatientsundergoingorotrachealintubationintheEDwithaMacintoshblade(usingeithervideoordirectlaryngoscopy)foranyindicationwillbeenrolledintothestudy.Tobeeligibleforenrollment,thepatientmustmeetalloftheinclusioncriteriaandnoneoftheexclusioncriteria.Thesubgroupofpatientswithanyofthefollowingdifficultairwaycharacteristicswillbetheprimaryanalysispopulation,thoughallenrolledpatientswillbeincludedinasecondaryanalysis.Difficultairwaycharacteristicsinclude:cervicalimmobility,obesity,largetongue,shortneck,smallmandible,facialornecktrauma,airwayedema,bloodintheairway,orvomitintheairway.5.2 InclusionCriteriaPatientsmustmeetallofthefollowingcriteriatobeeligibletoparticipateinthestudy:

1. ThepatientmustbeundergoingorotrachealintubationintheEDwith

aMacintoshblade(usingeithervideoordirectlaryngoscopy)2. Thepatientmustbepresumedtobe18yearsofageorolderatthe

timeofenrollment.

5.3 ExclusionCriteriaPatientswhomeetanyofthefollowingcriteriaarenoteligibletoparticipateinthisstudy:

1. Knownanatomicdistortionoftheupperairwayorperilaryngealstructures.

2. Prisonerorunderarrest3. Knownorsuspectedtobepregnant,basedontheopinionofthe

treatingphysician.

5.4 SubjectWithdrawalCriteriaAsthestudydurationisveryshort,therewillnotbetimeforsubjectwithdrawal.

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6 STUDYCONSENTThisinvestigationwillbeconductedunder45CFR46.116WaiverofInformedConsent,asbothdevicesarestandardofcare.45CFR46.116(d)iscopiedbelow:

(d)AnIRBmayapproveaconsentprocedurewhichdoesnotinclude,orwhichalters,someoralloftheelementsofinformedconsentsetforthinthissection,orwaivetherequirementstoobtaininformedconsentprovidedtheIRBfindsanddocumentsthat:

(1)Theresearchinvolvesnomorethanminimalrisktothesubjects;(2)Thewaiveroralterationwillnotadverselyaffecttherightsandwelfareofthesubjects;(3)Theresearchcouldnotpracticablybecarriedoutwithoutthewaiveroralteration;and(4)Wheneverappropriate,thesubjectswillbeprovidedwithadditionalpertinentinformationafterparticipation.(e)Theinformedconsentrequirementsinthispolicyarenotintendedtopreemptanyapplicablefederal,state,orlocallawswhichrequireadditionalinformationtobedisclosedinorderforinformedconsenttobelegallyeffective.(f)Nothinginthispolicyisintendedtolimittheauthorityofaphysiciantoprovideemergencymedicalcare,totheextentthephysicianispermittedtodosounderapplicablefederal,state,orlocallaw.

6.1 Researchinvolvesnomorethanminimalrisktothe

subjectsTheuseornon-useoftheGEBbotharethecurrentstandardofcareintheEmergencyDepartment.ThedecisionwhethertouseaGEBdependsontheintubatingphysician’spreferencesandbiases.Theresidentphysicians(whoperformapproximately98%oftheendotrachealintubations)receiveextensivetraininginintubatingwithandwithoutaGEB,androutinelyperformendotrachealintubationwithandwithoutaGEB.Thoughpatientsrequiringintubationarecriticallyillbydefinition,andhavesignificantriskofmorbidityandmortalitythroughoutthehospitalstay,thisriskisimpartedbytheunderlyingillnessorinjury,andshouldnotbealteredmorethan

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minimallybytheuseornon-useofaGEBforintubation.Becausebothmethodsareacceptableasstandardofcareforthefirstintubationattempt,thereiscurrentlynoreasontothinkthatonehasanyhigherriskthantheother;thatis,thereisminimaladdedrisktothepatientbeyondtheriskcausedbytheirsevereillnessorinjury.6.2 Thewaiveroralterationwillnotadverselyaffectthe

rightsandwelfareofthesubjectsThereisnoreasonthiswaiverofconsentcouldadverselyaffecttherightsnorwelfareofthesubjects.AllsubjectswillreceivethehighestlevelofcareprovidedbytheHCMCEmergencyPhysicians.Allothercareisatthediscretionofthetreatingphysicians.6.3 Theresearchcouldnotpracticablybecarriedout

withoutthewaiveroralterationPatientswhorequireemergentendotrachealintubationintheEDarecriticallyillbydefinition.Manyareobtundedorcomatose;othersaredyspneicandunabletotalk;stillothershavemyriadsevereillnessesthatprecludeaninvolveddiscussionregardingthestudyalongwithitsrisksandbenefits.Forthesereasons,itisnotpracticaltoobtaininformedconsentforthisinvestigationforthevastmajorityofcriticallyillpatients.Apatientwhorequiresemergentendotrachealintubationhasapressingneedformedicalinterventionthatcannotbedelayedforanyreason.Orotrachealintubationmustbecompletedonanemergentbasis,andcannotwaitfortheconsentofalegallyauthorizedrepresentative(LAR),unlesstheLARisatthebedsideofthepatient.Patientswhoarecriticallyilloftenbecomecriticallyillunexpectedly.Thereareamultitudeofacuteillnessesthatoccurwithoutwarning:majortrauma,headtrauma,stroke,spontaneousintracranialhemorrhage,sepsis,drugoverdose,acutecoronarysyndrome,andmanyothers.Thereisnoreasonablemethodtoprospectivelyidentifyindividualpatientslikelytobecomeeligibleforparticipationinthisclinicaltrial.Ifonlycriticallyillpatientswhowereabletoprovideinformedconsentwereincludedinthisstudy,theresultswouldnotbegeneralizabletocriticallyillwhocouldnotprovideinformedconsent,asthisisamoreillcohort.Previousrandomizedtrialsexaminingemergencyintubationhavebeencompletedunderawaiverofinformedconsent.33,34

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6.3.1PatientobjectionBecausethistrialinvolvesnomorethanminimalrisktothepatient,andbecauseendotrachealintubationmustbecompletedemergently,thepatientwillnotbeapproachedforconsent.Intheunlikelyeventthepatientisabletohaveareasonedconversationpriortointubation,thepatientwillbeaskedifhe/shewouldliketodeclinebeinginaresearchstudy.Ifthepatientdeclines,he/shewillnotbeenrolled.6.3.2LARorFamilymemberobjectionIfaLARorfamilymemberisatthebedsidepriortoendotrachealintubation,theywillbeaskediftheyobjecttothepatientbeingenrolledinanemergencyairwayinvestigation.Iftheyobject,thepatientwillnotbeenrolled6.4 NotificationafterenrollmentAsthesoonestfeasibleopportunityafterstudyenrollment,thepatientorthepatient’sLARwillbenotifiedofthestudyenrollment.Detailsoftheinvestigationwillbeprovidedonaninformationsheetwiththecontactinformationoftheinvestigatorsandresearchoffice.Becausethestudywillhavebeencompleted1minuteaftersuccessfulintubation,itwillnotbepossibletowithdrawfromthestudy.

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7 STUDYPROCEDURESDetaileddescriptionsofpatientevaluationsrequiredforthisprotocolaredescribedinthissection.Theseevaluationswillbeperformedduringtheindicatedtimesofthestudyasdetailed.7.1 StudyEntranceCriteriaAtbaseline,eachpatientwillbereviewedforeligibilityagainstthestudyentrancecriteria.Patientswhodonotmeetthestudyentrancecriteriawillnotbeallowedtoparticipateinthestudy.Patienteligibilityaccordingtothestudyinclusionandexclusioncriteriawillbeconfirmedatbaseline.7.2 EnrollmentIfthepatientiseligibleforenrollmentandneitherthepatientnoraLARorfamilymemberobjecttoenrollment,thepatientwillbeenrolledintothestudy.Uponenrollment,thestudyallocationwillberevealedanddisclosedtothetreatingphysicians.7.3 BaselineandEDDataCollectionBaselinevitalsignswillbecollectedimmediatelyafterrandomization.Iftimepermits,theintubatingphysicianwillbeaskedtodeterminewhich,ifany,difficultairwaycharacteristicsthepatienthas.Thisdatawillberecordedonastructureddatacollectionform.Attemptsatendotrachealintubationwillbecollectedinrealtime.Furtherbaselineinformation,andinformationregardingdifficultairwaycharacteristics(ifnotalreadygathered),willbeobtainedafterthepatienthasleftthecriticalcarearea.AlldatagatheredislistedinAppendix1.7.4 AdverseEventAssessmentsAnyadverseevents(AE)relatedtotheuseornon-useoftheGEBshouldbeobservedimmediatelyintheEDduringtheintubationprocess.Ifeitherdevicefailstointubatethepatient,asecondattemptwillbeperformed.Thesecondattemptcanproceedwithanydeviceorstrategythattheintubatingphysicianfeelsisbestforthepatient.Directtraumatothemouth,upperairway,andairwayarepossibleinbothgroups.Fullassessmentofthemouth,upperairway,andairwayisnotpossiblewithoutexposingthepatienttofurtherharmfromrepeatedlaryngoscopyandbronchoscopy.Therefore,toassessanydirecttrauma,theintubatingphysicianwillbeaskediftherewasanydirecttraumatothemouth,upperairway,orairway,andiftherewasanyexcessivebleedingduringorafterintubationwhileintheED.

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7.4.1AdverseEventMonitoringandPeriodofObservationAEswillbemonitoredcontinuouslywhilethepatientisintheED,duringwhichanyAErelatedtothestudywouldbeevident..7.4.2ReportingSeriousAdverseEventsThelocalIRBwillbenotifiedofanyrelatedsevereandunexpected,life-threatening,orfatalSAEassoonaspossible,generallywithin24hoursdependingonthedayofweek.Thedatasafetyandmonitoringboardwillalsobenotifiedassoonaspossible.7.5 Safety-RelatedStoppingRulesAnindependentdatasafetyandmonitoringboard(DSMB)willbeestablishedtoprovideanongoing,independentreviewandassessmentofthesafetydata,andtosafeguardtheinterestsandsafetyoftheparticipatingpatientsinthestudy.Onanongoingbasis,theDSMBwillreviewSAEsthatarejudgetobeatleastpossiblyrelatedtothestudy.TheDSMBwillbenotifiedimmediatelyoftheSAEandrequestedtomakeanassessmentwithinfiveworkingdays.BasedontheDSMB’sassessmentoftheevent,aswellasevaluationoftheoverallaccumulatingsafetydatafromthetrial,theDSMBwillmakearecommendationastowhetherthestudyshouldbehaltedifthereisasafetyconcernorshouldcontinueasplanned.Seesection8.7.2forpossiblestoppingaftertheplannedinterimanalysis.

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8 PLANNEDSTATISTICALMETHODS8.1 GeneralConsiderationsAllstatisticalanalyseswillbeperformedwithSTATAVersion12.1(StataCorp.2011.CollegeStation,TX).

Unlessotherwisespecified,summarytabulationswillbepresentedbytreatmentgroup.Forcategoricalvariables,thenumberandpercentageofpatientswithineachcategory(withacategoryformissingdataasneeded)oftheparameterwillbepresented.Forcontinuousvariables,thenumberofpatients,mean,median,standarddeviation,minimum,andmaximumvalueswillbepresented.Time-to-eventdatawillbesummarizedusingKaplan-Meierestimatesofthe25th,50th,and75thpercentileswithassociatedtwo-sided95%CI,aswellaspercentageofcensoredobservations.

Formalstatisticalhypothesistestingwillbeperformedontheprimaryandkeysecondaryoutcomes,withalltestsconductedatthe2-sided,0.05levelofsignificance.

8.2 Samplesizecalculation

AssumingafirstpasssuccessrateintheGEBgroupof95%,todetectanabsolutedifferenceof9%(86%withoutuseofGEB)with80%powerbetweengroups,374patients(187pergroup)withadifficultairwaycharacteristicwillneedtobeenrolled.Approximately1,500patientsareintubatedannuallyinourEmergencyDepartment.Becauseoflogisticconsiderations,wepredictthatonly1,000patientswillbeabletobeenrolled,30-40%ofwhomwillhaveadifficultairwaycharacteristic.Therefore,weplantoenrollfor1calendaryear,oruntilweenroll1,000patients,whicheveroccursfirst.Ifwehavenotenrolled374patientswithadifficultairwaycharacteristicatthattime,wewilldiscusswiththeIRBaboutextendingthetimeframeoftheinvestigation.

ThissamplesizecalculationwasperformedinSTATAversion12.1withthefollowingcommand:sampsi0.950.86,p(0.8).

8.3 MethodofAssigningStudyPatientstoTreatmentGroups

Seesection4.1.1.

8.4 PopulationDescription

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8.4.1AnalysisPopulations

Theintent-to-treat(ITT)populationwillbetheprimaryoutcomeanalysispopulation.Thisgroupwillincludeallpatientswhoareendotracheallyintubatedafterrandomization,excludingthoseintubatedwithadeviceotherthanaMacintoshBlade,becausethisgroupcouldnotpossiblyuseabougieorendotrachealtube.PatientswhohavenointubationattemptperformedwillnotbeapartoftheITTpopulationandwillbeconsideredscreeningfailures.Thiswillsometimesoccurbecauseemergentendotrachealintubationisplanned,butthepatient’sconditionsometimesrapidlyimproves,obviatingtheneedforintubation.Becausethisisapatientgroupthatisvastlydifferentthanpatientswhoareintubated,andbecausetheyreceivednoairwayprocedure,theywillnotbeincludedintheITTanalysis.

TheprimaryoutcomewillbeanalyzedforthesubsetofpatientsintheITTpopulationwhohaveanydifficultairwaycharacteristic.Thiswillbethemainoutcomeoftheinvestigation.Thedatafromallenrolledpatientswillalsobepresentedinthefinalanalysis,asitisplausiblethattheGEBimprovesfirstpasssuccesssignificantlyinevenroutineintubations.

8.4.2TreatmentCompliance

Itisanticipatedtherewillnopatientcomplianceissues.Theactualdeviceusedforthefirstintubationattemptwillberecorded,andthenumberoftimesthisdeviatesfromprotocolwillberecorded.TheIRBwillbenotifiedofallprotocoldeviations.

8.5 OutcomeAnalysisThechisquaretestwillbeusedtocomparetheprimaryoutcomebetweenthetwotreatmentgroups,withtheprimaryanalysisincludingonlythosewithanydifficultairwaycharacteristic,andasecondaryanalysisofallenrolledpatients.Secondaryoutcomeswithcategoricalandcontinuousvariableswillbeanalyzedastheappropriateconfidenceintervalofthedifferencebetweenthetwogroups,againstratifiedbythepresenceofanydifficultairwaycharacteristic.Otherdatawillbepresenteddescriptively.8.6 Statistical/AnalyticIssues8.6.1HandlingofMissingDataFortheprimaryoutcome,ifboththeresearchassistantdatacollectionformandthetreatingphysicianpost-intubationcollectionformaremissing,thestabilizationcase

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videowillbereviewedtodetermineiffirstpasssuccesswithouthypoxemiawasachieved.Ifthevideoisnotavailable,thepatientwillbeexcludedfromtheanalysis.Secondaryoutcomes:ifdatafortheseoutcomesismissing,thestabilizationcasevideowillbereviewedtoascertainthetruevalue(s).Ifthevideoismissing,thepatientwillbeexcludedfromanalysisoftherelevantoutcomes.8.6.2 InterimAnalysisandDataMonitoringAninterimanalysiswillbeperformedafter500patientsareenrolled.Thedatawillbeanalyzedfortheprimaryoutcomeonly.

Thetrialwillbestoppedearlyonlyforfutility.Afterthedatafromthefirst500patientsisanalyzed,asensitivityanalysiswillbeperformed.Ananalysiswillbeperformedwithasamplesizeof1000patients(equalallocationinbotharms)withthefollowingassumptions:

• Firstpasssuccessratewithnon-usetheGEBremainsthesameinthesecondhalfofthetrial

• FirstpasssuccessratewithuseoftheGEBis15%higher(absolutedifference,uptoasuccessrateof100%)thanobservedinthefirsthalfofthestudy

Ifnodifferenceisfoundinfirstpasssuccesswiththisanalysis,thenthetrialwillbestoppedearlyforfutility.

Asdetailedinsection9.2,anindependentDSMBwillbeestablishedtoprovideanongoing,independentreviewandassessmentofthesafetydata,andtosafeguardtheinterestsandsafetyoftheparticipatingpatientsinthestudy.AnyadditionalanalysesforDSMBreviewmaybescheduledatthediscretionoftheDSMB.

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9 ADMINISTRATIVECONSIDERATIONS9.1 InstitutionalReviewBoardApprovalThestudywillnotbeinitiateduntilwrittenIRBapprovalhasbeenobtainedforthisinvestigation.

9.2 DatamonitoringcommitteeAnindependentDSMBwillbeestablishedtoprovideanongoing,independentreviewandassessmentofthesafetydata,andtosafeguardtheinterestsandsafetyoftheparticipatingpatientsinthestudy.TheDSMBwillincludeMichelleBiros,MD.***

Onanongoingbasis,theDSMBwillreviewSAEsthatarejudgedtobeatleastpossiblyrelatedtostudydrug.TheDSMBmayalsobeaskedtoreviewonanongoingbasisotherSAEsofconcern.TheDSMBwillbenotifiedimmediatelyoftheSAEandrequestedtomakeanassessmentwithinfiveworkingdays.BasedontheDSMB’sassessmentoftheevent,aswellasevaluationoftheoverallaccumulatingsafetydatafromthetrial,theDSMBwillmakearecommendationastowhetherthestudyshouldbehaltedifthereisasafetyconcernorshouldcontinueasplanned.9.3 ProtocolViolations/DeviationsTheinvestigatorwillconductthestudyincompliancewiththeprotocol.TheprotocolwillnotbeinitiateduntiltheIRBandtheappropriateregulatoryauthoritieshavegivenapproval.ChangestotheprotocolwillrequirewrittenIRBapprovalopinionpriortoimplementation,exceptwhenthemodificationisneededtoeliminateanimmediatehazard(s)topatients.TheIRBmayprovideexpeditedreviewandapprovalforminorchange(s)inongoingstudiesthathavetheapprovaloftheIRB.

Anydeparturesfromtheprotocolwillbefullydocumentedasaprotocoldeviation.ProtocoldeviationswillberequiredtobesubmittedtotheIRB.

9.4 PrematureClosureoftheStudyIftheinvestigator,DSMB,orregulatoryauthoritiesdiscoverconditionsarisingduringthestudythatindicatethattheclinicalinvestigationshouldbehaltedduetoanunacceptablepatientrisk,thestudymaybeterminated.

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