Post on 29-May-2020
Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
Study Protocol
NCT02586415
April 20, 2017
Gregory W. Albers, MD, Principal Investigator Stanford University
Stanford, California 94305
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
PROTOCOLTITLE
DEFUSE3:EndovascularTherapyFollowingImagingEvaluationforIschemicStroke3
ProtocolVersion/VersionDate
Version2.4
April20,2017
ProtocolDirectors
GregoryAlbers,MDMichaelMarks,MD
MaartenLansberg,MD,PhD
StanfordUniversityStanfordStrokeCenter
780WelchRd.SuiteCJ350Stanford,CA94304
Supportedby
TheNationalInstituteofNeurologicalDisordersandStroke(NINDS)
U01NS092076
IDENumber
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
DEFUSE3
AGREEMENTONTHEPROTOCOL
BysigningbelowIconfirmthat:
1) IhavereadthisprotocolanditcontainsallnecessarydetailsforconductingthisstudyAND
2) Iagreetoconductthetrialincompliancewiththisprotocolandtoadheretoallregulationsthatgoverntheconductofthestudy.
________________________________________________________ _______________________PrincipalInvestigator’sSignature Date________________________________________________________PrincipalInvestigator’sName
_________________________________________________________SiteName:
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
1
TABLEOFCONTENTS
TableofContents…………………………………………………………………………………………… P.1
1. SummaryofTrial……….…………………………………………………………… P.2
2.ScientificBackground…………………………………………………………………………. P.2
2.1StateoftheScienceonEndovascularStrokeTherapyforstroke…….. P.2
2.2PriorStudiesandrationalefordevelopment…………………………………. P.3
3. InvestigationalPlan………………………….……………………………………………….. P.6
3.1Purpose………………………………………………………………………….. P.6
3.2ProtocolDesign………………………………………………………………. P.6
3.3EnrollmentCriteria………………………………………………………….. P.7
3.3.1ClinicalInclusionCriteria…………………………………. P.7
3.3.2ClinicalExclusionCriteria………………………………… P.7
3.3.3NeuroimagingInclusionCriteria………………………. P.8
3.3.4NeuroimagingExclusionCriteria……………………… P.8
3.4EnrollmentandRandomization……………………………………….. P.9
3.4.1Enrollment………………………………………………………. P.9
3.4.2Randomization………………………………………………… P.10
3.5AcuteTreatment……………………………………………………………… P.10
3.5.1EndovascularTherapy……………………………………… P.10
3.5.2MedicalTherapy………………………………………………. P.11
3.6ClinicalandImagingEvaluations……………………………………… P.11
3.6.1Studyassessmentsandfollow‐upvisits…………….. P.12
3.7SiteApprovalandMonitoringPlan……………………………………. P.12
3.8Samplesize,AdaptiveDesignandStatisticalAnalysis………… P.14
3.9RiskAnalysis……………………………………………...……………………. P.18
3.10DeviceDescription………………………………………………………… P.21
3.11MonitoringProceduresandAdverseEventReporting.……. P.22
4.Investigator’sAgreement&CurrentInvestigators……..……………………..….. P.25
5.ExecutiveCommittee/Keyinvestigators…………………………………………...... P.27
6.InstitutionalReviewBoard………………………………………………………………….. P.27
7.Costs…………………………………………………………………………………………………… P.27
8.References…………………………………………………………………………………………... P.28
9.Appendix:PatientInformedConsentForm...…………………………………………. P.32
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
2
1. SUMMARYOFTRIALDEFUSE3isaprospective,randomized,multi‐center,PhaseIII,adaptive,blindedendpoint,controlledtrial.Amaximumof476patientswillberandomizedandtreatedbetween6and16hoursofsymptomonset.Subjectswillberandomized1:1toendovasculartherapyplusmedicalmanagementormedicalmanagementalone.OnlythedeviceslistedinthisprotocolareapprovedforuseinDEFUSE3.Thechoiceofdeviceordevicesemployedisatthediscretionoftheclinicalinvestigator.
2. SCIENTIFICBACKGROUNDAlthoughstrokeisthenumberonecauseofadultdisabilityintheUnitedStates1,treatmentoptionsforstrokearelimited.TheonlyFDAapprovedtreatmentforstrokeisadministrationofintravenous(iv)tissueplasminogenactivator(tPA)within3hoursaftersymptomonset.Nationwide,onlyabout4percentofstrokepatientsreceivethistherapy.2Themainreasonforthislowtreatmentrateisthatmostpatientspresenttothehospitaloutsidethetime‐windowfortPA.3,4Evenwhenadministered,tPAisoftennoteffectivebecauseiteitherfailstorecanalizetheoccludedartery5‐7orbecausethebrainisalreadyirreversiblyinjured.8Asaresult,itisestimatedthatonly12‐25%oftreatedpatientsbenefitfromtPA.9Thus,inordertoimproveoutcomesfromstroke,weneedbettertreatmentsthatareavailabletoagreaterproportionofstrokepatients.
2.1StateofthescienceonendovascularstroketherapyforacutestrokeEndovascularstroketherapy,theremovalofbloodclotswithmechanicaldevicesorthrombolyticdrugsadministeredintra‐arterially,isthemostpromisingnewtreatmentforpatientswho“fail”treatmentwithivtPAorarenoteligibleforivtPA.Themainadvantageofendovasculartherapyisthatithasahighrateofrecanalization.10,11Bloodflowcanberestoredwithasuccessrateofupto82%withmodernthrombectomydevicesand66%forintra‐arterialthrombolysis.10,12,13ThisisapproximatelytwiceaseffectiveasivtPAwhichhasarecanalizationrateof10‐50%dependingonthelocationofthebloodclot.6,7Despitehigherratesofrecanalizationwithendovasculartherapy,tworecentrandomizedcontrolledtrialsofendovasculartherapy,IMSIIIandMRRESCUE,havefailedtodemonstrateaclinicalbenefit.Patientandtreatmentrelatedfactorslikelybothcontributedtotheneutralresultsofthesetrials(seebelowfordetails).
Patient‐relatedfactors:Acentralconsiderationintheoptimizationofpatientselectionforacutestroketherapiesistheconceptoftheischemicpenumbra.Ischemicpenumbraisdefinedasischemictissuethatispotentiallysalvageableandisdistinguishedfromtheischemiccorethathasalreadysustainedirreversibleinjury.Clearly,thetargetofacutestroketherapiesissalvageoftheischemicpenumbra,preventinginfarctgrowthand,mostimportantly,improvedfunctionaloutcome.Acutestroketrialsshouldthereforeideallybelimitedtopatientswithanischemicpenumbra.MRI‐basedstudies,suchasDEFUSE1and2,indicatethatMRIcanbeusedtoidentifythesepatients.8,14,1516,17
Treatment‐relatedfactors:Recentstudieshaveemphasizedtheimportanceofrecanalizationrates,demonstratingtheinfluenceonpatientoutcomeofhighlyeffectiveendovascularproceduresthatleadtocompleteornear‐completereperfusion.18,19Currently,themostcommonmetricforratingthequalityofreperfusionisthemodifiedThrombolysis
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
3
InCerebralInfarction(mTICI)scale,andaclearrelationshipexistsbetweenthedegreeofreperfusiononthemTICIscaleandpatientoutcome.20‐22Patientswith>50%reperfusion(mTICI2B‐3)aremuchmorelikelytohaveagoodoutcomethanpatientswith<50%reperfusion.
IMSIII,thelargestendovasculartrialtodate,didnotuseadvancedimagingcriteriatoselectpatients.23Insteaditusedrelativelystricttime‐criteria,anticipatingthatthiswouldyieldahighproportionofpatientswithasubstantialpenumbra.However,severalcategoriesofpatientswholikelydidnothavesubstantialpenumbrawereenrolled.Nearlyonethirdofthepatientsdidnothaveavesselocclusionatangiographyand23%haddistalMCAocclusions;bothofthesesubgroupsareunlikelytohavesubstantialpenumbraltissue.Inaddition,42%ofpatientshadsomeevidenceofirreversibletissueinjury(ASPECTS<8)ontheirbaselineCTand14%hadevidenceofextensiveirreversibleinjury(ASPECTS<5).24Finally,theendovasculardevicesthatwereavailableduringIMSIIIhadrelativelylowratesofearlyreperfusion;mTICI2B‐3wasonly40%inIMSIII.MRRESCUE,astroketrialthataimedtodemonstratebenefitofendovasculartherapyinpatientswithapenumbrabasedonMRI,hadneutralresults.25Severalfactorslikelycontributedtothis.First,therateofendovascularreperfusionwasextremelylow.Only8patients(24%)intheMRRESCUEpenumbralgroupachievedTICI2B‐3reperfusionduringendovasculartherapy.Second,patientsinthepenumbralgroupinMRRESCUEhadlargerbaselineinfarctcorelesions(medianvolume36ml;IQR24–51ml)thantheTargetMismatchpatientsinDEFUSE2(medianvolume13ml;IQR5–26ml).Thecombinationoflowratesofendovascularreperfusionandrelativelylargecorelesions,bothstrongpredictorsofpoorclinicaloutcome,likelyexplainsthelackofatreatmenteffectin“penumbralpatients”inMRRESCUE.Moreover,withonly8endovascularpatientsinthepenumbralcohortachievingTICI2B‐3reperfusion,MRRESCUEwassubstantiallyunderpowered.NewGenerationTrials:Recently,aseriesofpositiverandomizedstudiesofendovasculartherapywithtreatmentinitiatedwithin6hoursofstrokeonsetinthevastmajorityofpatientswerereported.Thishaspromptednewguidelinesendorsingendovasculartherapyupto6hoursaftersymptomonset.TheAmericanHeartAssociationisnowcallingforlatewindowstudiesusingadvancedimagingforpatientselection:“"Furtherrandomized,controlledtrialsshouldbedonetodeterminewhetheradvancedimagingparadigmsusingCTperfusionandMRIperfusion,CTA,anddiffusionimaging,includingmeasuresofinfarctcore,collateralflowstatus,andpenumbra,arebeneficialforselectingpatientsforacutereperfusiontherapywhoarebeyond6hoursfromsymptomonset.(Newrecommendation,2015AHAGuidelines).DEFUSE3willaddressthisnewmandate.Enrollmentislimitedtopatientswithsalvageabletissue(TargetMismatchpatients)whoarelikelytorespondfavorablytoendovascularreperfusioninthe6‐16hourwindow.Useofthelatestgenerationthrombectomydevices,coupledwithstrictqualificationandoversightcriteriafortheneuro‐interventionalists,willresultinhighratesofreperfusion.BasedonthecompellingpreliminarydatafromDEFUSE2,thetrialisadequatelypoweredtodemonstrateacleartreatmenteffect.
2.2.Priorstudiesandrationalefordevelopment
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
4
Thisprotocolaimstoshifttheselectionofpatientsforreperfusiontherapyfromarelativelyarbitrarydecisionbasedonpoorlyvalidatedclinicalcharacteristicstoanobjectivedecisionbasedonscientificevidence.Manyfactorsaffecttheevolutionoftheischemicpenumbraintotheischemiccore,andtherateofprogressionofirreversibleinjuryishighlyvariablebetweenindividuals.Thisvariabilityislikelymediatedbytheadequacyofcollateralbloodflowaswellasthemetabolicmilieuofindividualstrokepatients.Theindividualityofpenumbralevolutionamongstrokepatientsimpliesthatidentifyingtheextentoftheischemiccoreandpenumbraisusefulformakingtreatmentdecisions.Currentlydiffusion‐weightedimaging(DWI)/perfusion‐weightedimaging(PWI)magneticresonanceimaging(MRI)affordsthebestopportunityforapproximatingtheischemiccoreandpenumbrainrealtimeclinicalpractice.27
TheDWIlesionprovidesadependableestimationoftheischemiccoreandonlyveryrarelyshowspermanentreversalfollowingearlyreperfusion.28,29PWIidentifieshypoperfusedischemictissue.RegionsdefinedasabnormalonPWIthatdonotdemonstrateaDWIabnormality,oftenreferredtoastheDWI/PWImismatch,canestimatetheischemicpenumbra.30ItiscriticalthatPWIutilizesanappropriatelyvalidatedthresholdparameterthatexcludesischemictissuewithmodestbloodflowreduction(i.e.benignoligemia),becausethistissueisunlikelytoinfarctevenifreperfusiondoesnotoccur.WhichPWIparameterisoptimal,aswellaswhatthresholdtousetodefinecriticalhypoperfusion,hasbeenthefocusofmultipleresearchefforts.31PriorworkfromourgroupandotherssupportstheuseofTmax,thresholdedat>6seconds,astheoptimalPWIparametertoidentifyischemictissuedestinedtobecomeinfarctediftimelyreperfusiondoesnotoccur.32ThisTmaxthresholdcorrelateswellwiththepenumbralrangeofcerebralbloodflowdeclineasdeterminedbybothpositronemissiontomographyandXenonCT.33,34
UsingadifferencebetweenthevolumeofthebaselinePWITmaxlesionandtheDWIvolumetoidentifymismatch,theDEFUSEandEPITHETstudiesfoundthatmostpatientswithaPWI/DWImismatchrespondedfavorablyifreperfusionoccurredfollowingivtPAtreatmentinthe3‐to6‐hourtimewindow.However,despitehavingamismatch,patientswithverylargebaselineDWIlesions(largecoreinfarctvolumes)hadhighlyunfavorableoutcomesfollowingreperfusion.PatientswiththisMRIpattern,referredtoastheMalignantprofile,hadasignificantlyhigherrateofbothparenchymalhemorrhageandseveredisability/deathifreperfusionoccurred.35MismatchpatientswhodonothavetheMalignantprofilehavebeendesignatedashavingaTargetMismatch,andthesepatentsrespondextremelyfavorablytoreperfusionfollowingivtPAtherapy.InapooledanalysisofDEFUSEandEPITHET,TargetMismatchprofilepatientswhoexperiencedreperfusionhada5‐foldincreaseinfavorableclinicalresponseat90daysandsignificantlylessinfarctgrowthwhencomparedtothosewhodidnotreperfuse.36Noassociationbetweenreperfusionandfavorableoutcomes,orareductionininfarctgrowth,wasapparentforpatientswithoutthemismatchprofile.
TheDEFUSE2studyutilizedanautomatedmismatchanalysisprogram(RAPID)toprospectivelyestablishMRIprofilesinaconsecutivecohortofpatientswhothenunderwentendovasculartherapy.DEFUSE2confirmedtheconceptsdemonstratedinDEFUSEandEPITHET;TargetMismatchpatientswhoachieveearlyreperfusiontherapyhavelessinfarctgrowthandmorefavorableclinicaloutcomes(8·8,95%CI2·7–29·0).37Noassociationbetweenreperfusionandfavorableoutcomesorinfarctgrowthwaspresentinpatients
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
5
withoutTargetMismatch.Furthermore,thepositiveassociationbetweenreperfusion,favorableclinicalresponse,andattenuationofinfarctgrowthdidnotdiminishinDEFUSE2patientswithTargetMismatchwhoweretreatedrelativelylate(6‐12hoursaftersymptomonset,seeFigure1).
Figure1:Theeffectoftimeontheassociationbetweenreperfusionandgoodfunctionaloutcome(graphontheleft)andtheeffectoftimetotreatmentontheprobabilityofgoodfunctionaloutcomepatientswithreperfusion(graphontheright)inTargetmismatchpatients.95%CIsareindicatedbydashedlines.Estimatesarebasedonmultivariatelogisticregression,adjustedforageandbaselineDWIvolume.Thereisnosignificanteffectoftimeineithermodel.38
Thisfindingcontrastssharplywithpriorstudiesthatdidnotusepenumbralimagingtoselectpatientsandsuggeststhatimagingfindingsmaybeofequal,orpotentiallyevengreater,importancethantimefromsymptomonsetforidentificationofoptimalpatientswhomightbenefitfromreperfusiontherapy.
HowcouldTargetMismatchpatientswhoaretreatedlatehaveoutcomesthatareasfavorableasthoseofearliertreatedpatients?Atlatertimepoints,theTargetMismatchprofileidentifiespatientsinwhomtheinfarctisevolvingatarelativelyslowrate;aDWIlesionthatisstillconsiderablysmallerthanthePWIlesionreflectsgoodcollateralcirculation.Thesecollateralstypicallyallowprolonged,butnotpermanent,survivalofthehypoperfusedmismatchregion.Evidencethatthemismatchregionisstillatconsiderableriskforinfarctexpansion,evenatlatertimepoints,wasprovidedbytheDEFUSE2findingthatTargetMismatchpatientsimagedbetween6and12hoursfromsymptomonsetconsistentlydemonstratedsubstantialinfarctgrowthifreperfusionwasnotachieved.38Patientswithslowlyevolvinginfarctcoresareidealcandidatesforlatertimewindowreperfusiontherapy,particularlyendovasculartherapies.Oneofthedrawbacksoftheendovascularapproachisthatthetimebetweenhospitalarrivalandachievementofendovascularreperfusionistypicallyatleast90to120minutes.Forpatientswithrapidlygrowinginfarctcores(suchaspatientswiththeMalignantprofile),substantialgrowthoftheinfarctcorehasbeenreporteddespiteendovascularreperfusion.Therefore,removingthispopulation,whichrepresentsabout20%ofeligiblepatients,fromarandomizedendovasculartrial,hasimportantadvantages.
DEFUSE2confirmedthatearlyDWIlesionsareanexcellentsurrogatefortheischemiccore.Despiteendovasculartherapy,only2patientshadafinalinfarctthatwassmallerthanthebaselineDWIlesionandthesizeandlocationoftheearlyDWIlesionwasareliablepredictorofthefinalinfarctvolumeinpatientswithcompletereperfusion.39,40InDEFUSE2,youngerageandsmallerDWIvolumeweresignificantindependentpredictorsoffavorableoutcome.SubgroupanalysisofEPITHETidentifiedDWIlesionsize≤25mlasastrongpredictorofa
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
6
favorableresponsetoreperfusion.37,41Thesefindingssuggestthatcertainsubgroups,inparticularindividualswithTargetmismatchandsmallDWIlesionsaremostlikelytobenefitfromreperfusion.TheadaptivedesignofDEFUSE3(seebelow)hasthepotentialtofocuspatientenrollmentonasubgroupofpatients(e.g.thosewithsmallerDWIlesionvolumesand/orshortertimesfromsymptomonsettorandomization)whorespondmostfavorablytoendovasculartherapy.Thiswillallowthestudytoidentifythelargestpopulationthathasastatisticallyreliablebenefitofendovasculartherapy.
Newdata(presentedattheInternationalStrokeConference,February2015)suggestthatCTPerfusionstudies,processedwiththesamesoftware(RAPID)usedinthestudiesdescribedabove,canidentifytheischemiccorewithaccuracysimilartoMRI(Cereda,etalISC2015)andselectpatientswhorespondtoendovascularreperfusiontherapyinearlytimewindows(Campbell,etalNEJM2015,EXTEND‐IAstudy,Saver,etalNEJM2015,SWIFTPRIMEstudy).Therefore,DEFUSE3willallowpatientselectionwithbothMRIandCTPerfusion.
3. INVESTIGATIONALPLAN3.1.Purpose
DEFUSE3isaprospectiverandomizedPhaseIIImulticentercontrolledtrialofpatientswithacuteischemicanteriorcirculationstrokesduetolargearteryocclusiontreatedbetween6‐16hoursofstrokeonsetwithendovascularthrombectomytherapyvs.control.Theprimaryendpoint,themodifiedRankinScale,willbeassessedat3months.Thepatients’participationinthestudyconcludesatthattime(3monthsfromstrokeonset).Thestudywillrandomizeupto476patientsover4years.ThepurposeofDEFUSE3istoassessthesafetyandefficacyofthrombectomyincarefullyselectedpatientsinanextendedtimewindow.Onlythedeviceslistedinthisprotocolwillbeused.Selectionofthespecificdevice(ordevices)isdeterminedbytheindividualendovasculartherapist.
3.2.ProtocolDesignDEFUSE3isaprospectiverandomizedPhaseIIImulticentercontrolledtrialofpatientswithacuteischemicanteriorcirculationstrokesduetolargearteryocclusiontreatedbetween6‐16hoursofstrokeonset.PatientswhomeettheinclusioncriteriawillundergoeitherCTPerfusion/CTAorMRDWI/PWI/MRAstudiespriortorandomization.PatientswhohaveevidenceofanICAorMCAM1occlusionandaTargetMismatchProfilewillberandomizedina1:1ratiototreatmentwithendovasculartherapy(usingoneormoreDEFUSE3approvedthrombectomydevices)plusstandardmedicaltherapyversusstandardmedicaltherapyalone.Patientswhoareconsented,butnotrandomized,willreceivestandardtherapyaccordingtolocalguidelines.Baselinedata,andinformationaboutearlystroketherapies,willbecapturedforthisgroupofpatients.Randomizationofamaximumof476patientsisplanned.Atthefirstinterimanalysiswhen200subjectscompletefollow‐up,iftheoverallanalysiscrossesthefutilityboundary,anoveladaptivedesignwillidentify,ifitexists,asubgroupwiththebestprospectforshowingbenefitfromendovasculartreatment,basedonbaselineischemiccorelesionvolumesandthetimetotreatment.Thesecondinterimanalyseswillbeconductedat340patientsatwhichtimethestudymaystopforefficacy/futility,ortheinclusioncriteriamaybeadjustedinthecaseoffutility.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
7
Approximately45siteswillbechosen.Individualsiteselectionwillbebasedonanumberoffactorsincludingendovascularvolume,MRIand/orCTperfusionaccess,numberofcompetingtrials,clinicaltrialexperience,andthediversityoftheirpatientpopulation.Ifasitedoesnotconsentapatientwithin4monthsofactivation,itwillbeplacedonprobation.Ifnopatientconsentoccursinthenext2months,thesitewillbereplacedwitha“back‐up”site.
3.3.EnrollmentCriteria3.3.1.ClinicalInclusionCriteria:1. Signsandsymptomsconsistentwiththediagnosisofanacuteanteriorcirculation ischemicstroke2. Age18‐90years3. BaselineNIHSSSis≥6andremains≥6immediatelypriortorandomization4. Endovasculartreatmentcanbeinitiated(femoralpuncture)between6and16 hoursofstrokeonset.Strokeonsetisdefinedasthetimethepatientwaslastknownto beattheirneurologicbaseline(wake‐upstrokesareeligibleiftheymeettheabovetime limits).5. modifiedRankinScalelessthanorequalto2priortoqualifyingstroke(functionally independentforallADLs)6. Patient/LegallyAuthorizedRepresentativehassignedtheInformedConsentform.3.3.2.ClinicalExclusionCriteria:1. Otherserious,advanced,orterminalillness(investigatorjudgment)orlifeexpectancy islessthan6months.2. Pre‐existingmedical,neurologicalorpsychiatricdiseasethatwouldconfoundthe neurologicalorfunctionalevaluations3. Pregnant4. UnabletoundergoacontrastbrainperfusionscanwitheitherMRIorCT5. Knownallergytoiodinethatprecludesanendovascularprocedure6. TreatedwithtPA>4.5hoursaftertimelastknownwell7. TreatedwithtPA3‐4.5hoursafterlastknownwellANDanyofthefollowing:age >80,currentanticoagulantuse,historyofdiabetesANDpriorstroke,NIHSS>258. Knownhereditaryoracquiredhemorrhagicdiathesis,coagulationfactordeficiency; recentoralanticoagulanttherapywithINR>3(recentuseofoneoftheneworal anticoagulantsisnotanexclusionifestimatedGFR>30ml/min).9. SeizuresatstrokeonsetifitprecludesobtaininganaccuratebaselineNIHSS10. Baselinebloodglucoseof<50mg/dL(2.78mmol)or>400mg/dL(22.20mmol)11. Baselineplateletcount<50,000/uL12. Severe,sustainedhypertension(SystolicBloodPressure>185mmHgorDiastolic BloodPressure>110mmHg)13. Currentparticipationinanotherinvestigationaldrugordevicestudy14. Presumedsepticembolus;suspicionofbacterialendocarditis15. Clotretrievalattemptedusinganeurothrombectomydevicepriorto6hoursfrom
symptomonset16. Anyotherconditionthat,intheopinionoftheinvestigator,precludesanendovascular procedureorposesasignificanthazardtothesubjectifanendovascularprocedurewas performed.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
8
3.3.3.NeuroimagingInclusionCriteria:1. ICAorMCA‐M1occlusion(carotidocclusionscanbecervicalorintracranial;withor
withouttandemMCAlesions)byMRAorCTAAND
2. TargetMismatchProfileonCTperfusionorMRI(ischemiccorevolumeis<70ml,mismatchratiois>1.8andmismatchvolume*is>15ml)Notes: The mismatch volume is determined by the RAPID software in real time based on the difference between the ischemic core lesion volume and the Tmax>6s lesion volume. If both a CT perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is assessed to determine eligibility. Only an intracranial MRA is required for patients screened with MRA; cervical MRA is not required. Cervical and intracranial CTA are typically obtained simultaneously in patients screened with CTA, but only the intracranial CTA is required for enrollment.
Alternativeneuroimaginginclusioncriteria(ifperfusionimagingorCTA/MRAistechnicallyinadequate):A)IfCTA(orMRA)istechnicallyinadequate:
Tmax>6sperfusiondeficitconsistentwithanICAorMCA‐M1occlusionAND
TargetMismatchProfile(ischemiccorevolumeis<70ml,mismatchratiois>1.8andmismatchvolumeis>15mlasdeterminedbyRAPIDsoftware)
B)IfMRPistechnicallyinadequate:
ICAorMCA‐M1occlusion(carotidocclusionscanbecervicalorintracranial;withorwithouttandemMCAlesions)byMRA(orCTA,ifMRAistechnicallyinadequateandaCTAwasperformedwithin60minutespriortotheMRI)
ANDDWIlesionvolume<25ml
C)IfCTPistechnicallyinadequate:
PatientcanbescreenedwithMRIandrandomizedifneuroimagingcriteriaaremet.
3.3.4.NeuroimagingExclusionCriteria:1. ASPECTscore<6onnon‐contrastCT(ifpatientisenrolledbasedonCTperfusion
criteria)2. Evidenceofintracranialtumor(exceptsmallmeningioma)acuteintracranial
hemorrhage,neoplasm,orarteriovenousmalformation3. Significantmasseffectwithmidlineshift4. Evidenceofinternalcarotidarterydissectionthatisflowlimitingoraorticdissection5. Intracranialstentimplantedinthesamevascularterritorythatprecludesthesafe
deployment/removaloftheneurothrombectomydevice6. Acutesymptomaticarterialocclusionsinmorethanonevascularterritoryconfirmedon
CTA/MRA(e.g.,bilateralMCAocclusions,oranMCAandabasilararteryocclusion).
3.4.EnrollmentandRandomization
3.4.1Enrollment:Allpatientswhomeettheclinicalcriterialistedaboveareeligiblefor
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
9
enrollment.Thisincludesbothpatientswhoaredirectlyadmittedtothestudysiteandpatientswhoaretransferredfromanoutsidehospital.Thetimeofenrollmentisthetimewhentheinformedconsentissigned.AfterobtainingconsenttheRAPIDoutputfromaCTperfusionormultimodalMRIscanwillbeassessed.Ifthepatientisconfirmedtomeettheneuroimagingeligibilitycriterialistedaboveandnothaveanyoftheneuroimagingexclusioncriteria,thenthepatientwillberandomized.Ingeneral,patientswillbeconsentedpriortoobtainingtheRAPIDoutputmaps.InsomesituationstheCTperfusion/multimodalMRImayhavebeenperformedaspartofstandardcarepriortothepatientbeingassessedforstudyeligibility.Patientswhoareconsentedbutdonotmeettheimagingcriteriawillnotberandomized.
DeterminationofTargetMismatchandLargeArteryOcclusion:AttheconclusionoftheMRIorCTPerfusionscan,thetechnologistsendsthesequencesfromtheconsoletoRAPIDwithasinglemouseclickforautomatedprocessing.TheRAPIDsoftwarewasdevelopedbasedondatafromDEFUSE1andwasprospectivelyvalidatedinDEFUSE2.Thesystemprovidesfullyautomatedprocessingofbrainimages.TheRAPIDoutputmaps,whichidentifythevolumeandlocationofischemiccoreandperfusionlesions,areemailedtoinvestigators(protectedhealthinformationisautomaticallyremoved)andauto‐senttoPACSaswellastoasecureemailsystemforviewingwithin5minutesofcompletionofthescan.Immediatelyaftertheimagesareavailable,theinvestigatorwillreviewtheresultsoftheRAPIDmismatchmap(Figure2)andtheMRA/CTAtodetermineifthepatientmeetstheimagingcriteria(listedabove).Ifapatienthasundergonemultipleimagingevaluations(bothMRIandCTormultipleCTsorMRIs),themostrecentimagingstudywillbeusedtodetermineifthepatientmeetstheimagingcriteria.Theaccuracyofthesoftwareforidentifyingthesizeandlocationofperfusionanddiffusionlesionshasbeenestablishedbyextensivevalidationandtestingonbloodflowphantoms;thesoftwarereceivedFDA510Kclearanceforclinicalusein2013.TheagreementbetweenlocalinvestigatorsandtheImagingCoreLabforidentificationofthemismatchprofileinDEFUSE2was97%,κ0·92;95%CI0·83–1·
Baselinedatawillbecapturedforallconsentedpatients,includingforpatientswhodonotmeettheimagingcriteria.Patientswhodonotmeettheimagingeligibilitycriteriawillreceivestandardcareperlocalhospitalpractice.3.4.2RandomizationusingaDynamicStratificationAlgorithm:OnceaconsentedpatientisdeterminedtomeetallNeuroimagingcriteria,thepatientwillimmediatelybe
Figure2.TheRAPIDmismatchsummaryallowsinvestigatorstoquickly,accuratelyandeasilydetermineifthepatientmeetstheimagingcriteriaforenrollment.ThepatientabovemeetstheTargetMismatchcriteria:corevolumeis<70ml,mismatchratiois>1.8andmismatchvolumeis>15ml.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
10
randomizedontheWebDCUTMwebsite.Adynamicstratificationsystemwillensurewell‐balancedsubgroups.Therandomizationalgorithm,whichwillbeprogrammedintothedatacapturesystem,willemploybiased‐coinminimizationandthevariancemethodwithstratificationweights.44Thestrategyistobalancetreatmentassignmentalongthemarginaldistributionofeachstratificationfactor.Thestratificationfactorsusedwillbe:1)age,2)corelesionvolume,3)timefromsymptomonsettoenrollment,4)baselineNIHSS,and5)studysite.Whenanewpatientisenrolled,thesitewillenterthestratificationfactorvaluesintotheeCRF(electroniccasereportform)onWebDCUTM.Thedynamicrandomizationalgorithmwilldetermineanimbalancemeasureforeachtreatmentgroup.Thetreatmentgroupassociatedwiththesmallestimbalancemeasurewillreceivethelargestprobabilityofassignmentinthebiased‐coinrandomization.Thebiased‐coinacceptanceregionandstratificationweightsarespecifiedintheRandomizationPlan.Thesuperiorbalancingcharacteristicsofdynamicrandomizationoverblockedrandomizationhavebeenwellestablished.
Patientswillbeassignedtoeitherendovasculartherapyplusmedicaltherapyortomedicaltherapyalone(1:1randomization).Crossoverfrommedicaltoendovasculartherapyisstrictlyprohibited;endovasculartomedicaltherapycrossoverisdefinedasapatientwhoisassignedtoendovasculartherapybutdoesnothaveaconventionalangiogramperformed.Endovasculartomedicaltherapycrossoverisonlyallowedifanendovascularcontraindicationarisesafterrandomization.Siteswillbecloselymonitoredforcrossovers(seesitemonitoringplanbelow).
3.5 AcuteTreatment
3.5.1EndovascularTherapy:Inpatientsrandomizedtoendovasculartherapy,thegoalforfemoralarterypuncturewillbewithin45minutesofrandomization;femoralarterypuncturemustoccurwithin90minutesofthecompletionofthequalifyingimaging.Patientswillbetreatedwiththrombectomydevices(stent‐retrievers)and/orsuctionthrombectomysystemscurrentlyclearedbytheFDAforthrombusremovalinpatientsexperiencinganacutestrokewithin8hoursofsymptomonsetfollowingthepublishedinstructionsforuseforthesedevices.Thesedeviceswillbeusedupto16hoursfollowingsymptomonsetinDEFUSE3basedonanFDAIDE.ThedeviceswhichwillbeusedaretheTrevoRetriever,theSolitaireRevascularizationDevice,CovidienMindFrameCaptureRevascularizationDeviceandthePenumbrathrombectomysystem.
Standardmedicaltherapy,basedoncurrentAHAguidelines,willalsobeprovidedforallpatients.IndividualinvestigatorsmayuseanyofthesedevicesoranycombinationofthesedevicestoremovethrombusfromtheICA,MCAM1segmentor,ifneeded,fromM2segmentsoftheintracranialcirculation.Theseareallapprovedanatomiclocationsforthesedevices.Theuseofthrombectomydevicesshouldbeperformedinaccordancewiththeindicationsforuse.Ifthereisaseverestenosisofthecommoncarotidarteryortheproximalinternalcarotidartery,investigatorsmayalsouseotherFDAdevicesapprovedforangioplastyorFDAdevicesapprovedforstentingofthecarotidarteryasdeemedappropriate.Theuseofadjuvantintra‐arterial(IA)thrombolyticmedicationisnotcurrentlyapprovedbytheFDAforstroketreatmentandcannotbeusedinDEFUSE3.
Siteswilluselocalprotocolsforfemoralaccess,sedation,heparininfusion,monitoring,etc.Siteswillperformacervicalinjectionoftheinvolvedcarotidcirculationasabaseline
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
11
angiogram.Attheconclusionoftheprocedure,apost‐treatmentangiogramasacervicalinjectionoftheinvolvedcarotidcirculationwillalsobeobtained.ImagingwillcoverthefullregionofthenormalcirculationinAPandlateralprojectionsat2‐3filmspersecondthroughtheentirevenousphase.Allbrainimagingfromstrokeonsetthroughhospitaldischarge,includingthebaselineMRIandCT,aswellasangiographicimagesobtainedforthediagnosticandtherapeuticportionsoftheprocedure,willbetransmittedtothecorelab.
3.5.2MedicalTherapy:PatientsrandomizedtomedicaltherapywillreceivestandardmedicaltherapybasedoncurrentAHAguidelines.BasedonthetimewindowforDEFUSE3,itisanticipatedthatveryfewofthepatientsenrolledinDEFUSE3willhavereceivedivtPApriortorandomization(“tPAfailures”).Forthesepatients,thesites’post‐tPAprotocolwillbefollowed.Non‐tPAtreatedpatientsrandomizedtomedicaltherapywillbetreatedwithaspirin,325mgonDay1,and81‐325mg/day(investigator’spreference)onday2‐5,unlessanindicationforearlyanticoagulationispresent(asdeterminedbythepatient’sattendingphysician).AllpatientswillreceivestandardDVTpreventiontherapy.Intravenousanticoagulantsareprohibited(unlessaclearindicationforearlyanticoagulationisdocumented);dualantiplatelettherapyisprohibitedunlesscarotidstentingwasperformedduringtheendovascularprocedureoraclearindicationfordualantiplatelettherapyisdocumented.Subsequentantithrombotictherapywillbedeterminedbythepatient’sattendingphysician.
3.6ClinicalandImagingEvaluations
Follow‐up(imagingandclinical):Randomizedpatientswillbefollowedclinicallyfor90daysandwillhaveanMRI/MRA/MRperfusionat24hours(range18‐30hours)toassessinfarctvolume,recanalization,hemorrhageandreperfusion(Table1below).
Table1ScheduleofEvents
Screening Enrollment Baseline /
Randomization
EndovascularProcedure
24 hours (+/‐6 hrs)
Hospital Discharge
Day 30 (+/‐ 7 days)
Day 90 (+/‐ 14 days)
Screen Failure Log X
Informed Consent X
Subject Enrollment X
Inclusion and Exclusion Criteria X
MRI or CTP X X++
Randomization X
Medical History X
Vital Signs X
NIH Stroke Scale X X X X X
Modified Rankin Scale X+ X X X
Baseline ASPECTS Score X
Baseline Labs* X
EndovascularTherapy X
24 Hour Labs X
Hospital Discharge X
Adverse Event Assessment X X X X X
NeuroQOL X
*LaboratoryEvaluationincludesCBCwithPlatelets,Creatinine,Glucose,INR,activatedPTT,andPregnancytest(ifapplicable).At24hourfollow‐uponlycreatinineisrequired.+HistoricalmRSatbaseline,mRS/NIHSStobeperformedbyanNIHSS/mRScertifiedmemberoftheresearchteamwhoisblindedtotreatmentallocationat30and90days.++PatientswillpreferablyundergoanMRIwithMRAANDMRPerfusionat24hours;ifanMRcannotbeperformed,aCTwithCTAANDCTPcanbesubstituted.Forpatientswhoareconsentedbutnotrandomized,thescheduleofeventsislimitedtoasummaryofstroketherapiesreceivedwithin24‐hrsofstrokeonset.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
12
3.6.1Assessmentsandfollow‐upvisits
Baselinevisit:AllitemsinTable1abovelistedunder“baseline”aretobeperformedpriortorandomization.TheMRIorCTscanshouldbeperformedwiththeDEFUSE3(baseline)protocol,whichwillbeinstalledatallstudysites.Inaddition,theinclusion/exclusionpageofthecasereportformmustbecompletedtodetermineifthepatientmeetstheeligibilityrequirementsforthestudy.Ifthepatientiseligibleandtheconsentformissignedbythepatientorauthorizedrepresentative,thentherandomizationprocedureshouldoccurimmediately.
24hourvisit(+/‐6hours):TheitemslistedforthisvisitinTable1shouldbeperformedbetween18and30hoursfromthetimeofrandomization.Theonlylaboratoryvaluerequiredatthe24hourvisitisaserumcreatinine.Ifpossible,the24hourfollow‐upimagingstudyshouldbeperformedwithmultimodalMRI,ratherthanCTperfusion.TheMRIorCTscanperformedatthistimeshouldbeperformedwiththeDEFUSE3protocol.
Dischargevisit:TheitemslistedforthisvisitinTable1shouldbeperformedonthedayofhospitaldischarge
30and90dayvisits:TheitemslistedforthisvisitinTable1shouldbeperformedonDay30(+/‐7)daysandDay90(+/‐14)days.ThemRSscoremustbeperformedbyanmRScertifiedinvestigatorwhoisblindedtotreatmentallocationatboththe30and90dayvisits.Ifaninpersonvisitisnotpossible,thenthemRSshouldbeperformedbyphonebyanmRScertifiedinvestigatorwhoisblindedtotreatmentallocation.Ifaninpersonvisitisnotpossible,thentheNIHSSscorewillbemarked“notavailable”inthecasereportform.
Neurologicalworsening:Ifclinicalworsening(definedasa>4pointincreaseontheNIHSSscore)occurspriortodischarge,aCTscanorMRIshouldbeobtainedassoonaspossible.Neurologicalworseningisareportableadverseevent.3.6.2SourcesofMaterialsInformationontheclinicalstatusofpatientswillbeobtainedfromthepatient’smedicalrecord.StudycoordinatorsatthesitewillcompletetheDEFUSE3casereportformstocollectbasicdemographicandmedicalinformationaboutthepatients.DatawillsubsequentlybeenteredintotheStrokeNet’sWebDCUelectronicdatacapturesystem.ImagingdatawillbeelectronicallytransmittedtothecoordinatingcenteratStanfordviaRAPID(allpatientidentifiersareremovedbythesoftwarepriortoexportingthedataoutsideofthesite’sfirewall).Allstudysiteswillcompleteastrokescreeninglogthatdocumentsallpatientstreatedinthecathlabbeyond6hoursattheircenter,andreasonforexclusionofpatientsnotenrolled,intheStrokeNet’sWebDCUelectronicdatacapturesystem.Seriousadverseevents(SAEs)willbereportedwithin24hoursoftheeventintheStrokeNet’sWebDCUelectronicdatacapturesystem.Thedatacollectionprocesswillincludepatientdemographics,medicalhistory,vitalsigns,laboratoryassessments,NIHSSandmRSscores,andresultsofdiagnosticstudiesperformedtoclarifystrokeetiology.
3.7.SiteApprovalandMonitoringPlanSiteapproval:Individualsitesapprovedforparticipationinthestudywillbehigh‐volumesites.SelectedsiteswillhaveaccesstoemergentCTperfusionand/orMRimaging24/7.Priortoactivatingasite,wewillverifythatRAPIDisfunctionalatthesite.Togetherwiththe
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
13
site’sCTand/orMRtechnologists,wewillinstalltheDEFUSE3scanprotocolonthelocalscannersandperformadummy‐runtoassessimagequalityandtrainthetechnologistsinsoftwarehandlinganddatasending.AsitewillbeactivatedforenrollmentaftertestcasesprocessedwithRAPIDhaveensuredgoodqualitymaps.
Monitoringforimagingquality:TheImagingCoreLabwillmonitorimagequalitythroughoutthestudy.Ifsignificantinadequaciesorprotocolerrorsarenotedatasite,enrollmentwillbehalted.Enrollmentwillresumeafterallimagingproblemshavebeenresolvedandrepeatdummyrunshavebeenobtainedthatdemonstrateadequateimagequality.Table 2. Example Imaging Sequences for DEFUSE 3 scans
Sequence Scan Parameters (3T) Time
MRI 6 min
Localizer 128X256; 28 FOV;5/5mm, GRE 24 sec
Calibration 5 sec DWI 128x128, 24 FOV, 5/0mm, 30 slices, 1 NEX, R=2; b=0 and 1000 s/mm2
over 3 axes, TE/TR=min/7000ms. 25 sec
GRE 256x192; 24 FOV; 5/0 mm, 30 slices, TE/TR= 25/800ms, flip 20, interleaved EPI, 16 shots
27 sec
MRA intracranial
256x192, 1 mm; 4 slabs, 26 phase-encodes; 6 overlap, 22 FOV, 0.8 rFOV, fractional echo, ZIPx2, ZIPx512, minTE, flowcomp, TR=18ms, flip=18, inferior->superior ramppulse, R=2; 19 MIPS
143 sec
PWI 128x128; 24 FOV; 5/0 mm, 17 slices, TE/TR=35ms/1800ms, R=2 using 0.1mmol/kg Gadolinium @ 4ml/sec.
108 sec
CT (example below for GE VCT; comparable protocols will be used for other scanner models)
5-6 min
Non-con head 2.5 – 5mm, 40 slices, 120-140kV, 265-290mA 120-180 sec
CTA 0.625mm, 0.984:1/39.37cm, 120kV, 550mA , inject and observe for 15 sec until contrast concentration in ascending aorta reaches 80HU (smart prep) then the CT gantry moves along with the bolus of the contrast material from the aortic arch up to the apex of the brain in 5sec.
90 sec
CTP 22 FOV, 40mm, 8x5mm, 1.8sec time interval, 45 cycles, 80kV, 125mA; 2 runs
90 sec
Monitoringforbias:Adetailedsite‐monitoringplanhasbeendevelopedtodetectbias.Thisplanwillprotectthestudyfromenrollment,randomization,andtreatmentbias.Thefirstcomponentinvolvesmonitoringthepercentageofeachsite’sendovascularvolume(within6‐16hrs)thatisenrolledinDEFUSE3.Siteswillreporttheirvolumeofendovascularstrokeprocedures(within6‐16hrs)eachmonthonascreeninglog.IfaDEFUSE3eligiblepatientistreatedwithendovasculartherapyoutsidetheDEFUSE3study,anexplanationwillberequireddetailingwhythepatientwasnotenrolled.Thesecondcomponentoftheplaninvolvestrackingofpatientswhoareconsentedbutnotrandomized.ThesepatientswillrequireanentryintheWebDCUwithanexplanationwhythepatientwasnotrandomizedaswellasdocumentationwhetherendovasculartherapywasperformedoutsideofthestudy.Athirdcomponentinvolvesmonitoringofcrossoverafterrandomization.TheExecutiveCommitteewillreviewthedatadescribedaboveforeachsiteevery6months.Ifevidenceofenrollmentbiasissuspected,itwillbeinvestigated.Ifconfirmed,thesitewillbeplacedonprobation.Ifadditionalincidentsof
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
14
suspectedbiasareconfirmed,thesitewillbewithdrawn.RoutinemonitoringoftheclinicalsitesforsourcetodatabaseverificationwillbeperformedbytheStrokeNetDataManagementCenter.
3.8.SampleSize,AdaptiveDesignandStatisticalAnalysisDEFUSE3willfeatureanoveladaptivetrialdesignthatwillallowthestudytofocusonasubpopulationifinterimorfinalanalysesindicatefutilityintheoverallpopulation.59TheadaptivedesignwasdevelopedspecificallyforDEFUSE3.ItisbasedonclosedtestingtheoryandthegroupsequentialmethodsfortheGeneralizedLikelihoodRatio(GLR)statisticdevelopedbyLaiandShih.60Theadaptivedesignwaschosenbecausethereisstrongpreliminarydatathatsuggeststhattheeffectofendovasculartreatmentismodifiedbytwobaselinevariables:corelesionsizeandtime‐to‐treatment.Thewaytheadaptivedesigntakesadvantageofthesebiologicalassumptions(whentheyaretrue)isbyreallocationoffutureaccrualtothesubgroupwiththebestprospectsforshowingefficacy.Specifically,ifasubgroupischosenataninterimanalysis,subsequentenrollmentislimitedtopatientsinthatsubgroup.Asaresult,thissubgroupwillbecomelargerthanitwouldhavebeenintheabsenceoftheadaptivedesign.Thecriterionfordecidingwhichsubgrouphasthebestchanceofshowingabenefitfromendovasculartherapycombinesboththeestimatedsizeoftheeffectinthesubgroupandthesamplesizeofthesubgroup.TheGLRstatistic(Kullback‐Leiblercriterion)isusedtoidentifythissubgroupbecauseitoptimallybalancesthosetwocriteria.Itselectsthesubgroupthathasthebestchanceofshowinganeffectbecauseithasanapparentlylargeeffectandisalsoofsubstantialsize(notethereare5subgroupsofincreasinglylargersize,figure3).Theadaptivedesignemploystwobiologically‐basedassumptionstolimittheinflationofsamplesize;amonotonicity/contiguityassumptionandanapriorassumptionthattheeffectislargestinthepatientswiththesmallestDWIlesionsandtheshortesttimetorandomization(cellC11infigure3).Theboundariesofthecategories(cells)willbedeterminedjustpriortothe1stinterimanalysisbasedonthedistributionofpatientsacrossthesetwodimensions(lesionvolumeandtime‐to‐treatment).
Primaryanalysis:TheprimaryendpointisthedistributionofscoresonthemodifiedRankinScale(mRS)atday90.WewilltestthenullhypothesisattheinterimandfinalanalysisusinganormalapproximationoftheWilcoxon‐Mann‐Whitneytest(thegeneralizedlikelihoodratio[GLR]test).Theprimaryanalysiswillbeintentiontotreat,adjustedfordesignandnotadjustedforcovariates.
Foreachanalysis,anefficacyboundwillbesettocontroltheoverall(one‐sided)TypeIerrorrateat2.5%.Ateachinterimanalysisafutilityboundwillbesettodecideifthestudyshouldcontinuerecruitmentintheoverallgroup,shiftaccrualandtestingtoasubgroup,orstopinitsentirety.Thefutilityboundaryadaptswhenasubgroupisselectedtothefactthatthemaximumanalyzedsamplesizeisarandomvariablethatisnolargerthanthefixedmaximumnumberofpatientsrandomized(n=476).Becausesubgroupselectionreducesthe
Figure 3. The cohort is stratified according to core lesion volume and time to randomization. Exact boundaries of the stratification will be determined based on the distribution of patients just prior to the first interim analysis. Depending on the results of the 1st interim analysis, subsequent enrollment will continue in all 6 cells or will be limited to one of 5 sub-groups (C11, C11+21, C11+21+12, C11+21+12+22, or C11+21+12+22+13).
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
15
maximumnumberofpatientsavailableforanalysisatcompletionofthestudy,thismethodeffectivelyallowsaneasierfutilitystopaftersubgroupselection.Thissetupreplacesconditionalpoweranalyseswithanautomaticandmorepowerfuladjustmentofboundaries.
Firstinterimanalysis(n=200randomizedandcompleted90dayfollow‐up):Thenullhypothesisistestedintheentirepatientpopulation:1. Ifneitherefficacynorfutilityboundiscrossed,thetrialcontinuesenrollmenttothe2nd
interimanalysis.2. Iftheefficacyboundiscrossed,thetrialstopsandefficacyisdeclaredintheoverall
population.3. Ifthefutilityboundiscrossed,theoptimalsubgroupisselectedbasedontheKullback‐
Leiblercriterionandthenullistestedinthatsubgroup.Thefutilityboundisrelaxedasdescribedabove,basedontheexpectedmaximumnumberofpatientsinthetrialatcompletion(ie476minusthenumberofpatientsalreadyenrolledincellsthatwillnolongerbeopenforenrollment).3.1. Ifneitherboundiscrossed,thetrialwillcontinuewithenrollmentlimitedtothe
selectedsubgroup3.2. Iftheefficacyboundiscrossed,thetrialstopsandefficacyisdeclaredintheselected
subgroup3.3. Ifthefutilityboundiscrossed,thetrialstopsforfutility.
Secondinterimanalysis(n=340randomizedandcompleted90dayfollow‐up):If,afterthefirstinterimanalysis,thestudyproceedswithenrollmentintheoverallpopulation(option1above),thetestingatthe2ndinterimanalysisisidenticaltothefirstinterim.Ifenrollmentislimitedtoaselectedsubgroup(option3.1),thenullistestedinthatsubgroup:1. Ifneitherboundiscrossed,thetrialcontinuestothefinalanalysiswithenrollmentof136
additionalpatientslimitedtotheselectedsubgroup2. Iftheefficacyboundiscrossed,thetrialstopsandefficacyisdeclaredintheselected
subgroup3. Ifthefutilityboundiscrossed,thetrialstopsforfutility.
Finalanalysis(n=476randomizedandcompleted90dayfollow‐up):If,afterthesecondinterimanalysis,thestudyproceedswithenrollmentintheoverallpopulation,thenullistestedintheoverallpopulation:1. Iftheefficacyboundiscrossed,endovasculartherapyisdeclaredefficaciousintheoverall
population.2. Iftheefficacyboundisnotcrossed,theoptimalsubgroupisselectedandthenullistestedin
thatgroup:2.1. Iftheefficacyboundiscrossed,endovasculartherapyisdeclaredefficaciousinthat
subgroup2.2. Iftheefficacyboundisnotcrossed,endovasculartherapywillbedeclaredofnobenefit.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
16
Ifenrollmentafteroneoftheinterimanalysesislimitedtoaselectedsubgroup,thenullwillbetestedinthatsubgrouponlyandefficacyorlackthereofwillbedeclaredasperoptions2.1and2.2above.
Powerandsamplesizeconsiderations:Theprojectedoveralleffectofendovasculartherapyisbasedon1)theobserved90‐daymodifiedRankinScaleoutcomesinDEFUSE2oftargetmismatchpatientstreated>6hrsaftersymptomonsetand2)theassumptionthatearlyreperfusionwillbeachievedin75%oftheendovasculararmvs.20%ofthemedicaltherapyarm.20,21,61Usingthesedata,weprojectedthedistributionsonthemRSat90daysintheendovascularandcontrolarmsofDEFUSE3:
mRS at day 90
0 1 2 3 4 5 6 Total
Endovascular group 18.0% 11.5% 19.6% 11.5% 16.4% 11.5% 11.5% 100%
Medical group 9.7% 7.9% 15.0% 17.7% 14.4% 17.7% 17.7% 100%
Thisdistributioncorrespondstoastandardizedeffectof0.36fortheprimaryanalysis.Basedonthesedata,thefixedsamplesizeforanon‐adaptivedesignrequiresatotalof376patients(188/arm)tohave90%poweratanalphaof5%(Wilcoxon‐Mann‐Whitneytest);100additionalpatientsareaddedfortheadaptivedesigntoreachamaximumsamplesizeof476forDEFUSE3.
Weransimulations(n=5000)tocomparetheperformanceofatraditionalfixedsample‐sizedesign(fixedn=476)totheadaptivedesign(maxn=476)undervariousscenarios(seeTable3,below).Forthesimulationstheeffectsizeisexpressedasastandardizedeffect,whereastandardizedeffectof0.3correspondstoaconservativeprojectedeffectofendovasculartherapy(anticipatedeffect0.36;seeabove).
Imagingoutcomes:Wehypothesizethatendovasculartreatmentimprovesradiologicaloutcomesinstrokepatientswithfavorableclinicalandimagingcharacteristics.DEFUSE2demonstratedasubstantialreductionininfarctgrowthamongTargetmismatchpatientstreatedinthe6‐12hourtime‐windowwhoachievedearlyreperfusion:mediangrowth0.5ml(IQR:‐2–10)withreperfusion(n=23)vs.39ml(IQR:18‐121)withoutreperfusion(n=13),p<0.001.ThesedatahavebeenextrapolatedtoDEFUSE3usingthesameassumptionsdescribedabove;anticipatedanearlyreperfusionrateof75%intheendovasculararmvs.20%inthemedicalarm.Thisyieldsasamplesizeof42pergroupfor90%power.Therefore,DEFUSE3ishighlypoweredtodemonstratedifferencesinlesiongrowth.Infarctvolumes,ischemiclesiongrowth,andreperfusionratesat24hourswillbecomparedbetweengroupswiththeMann‐WhitneyUtest.The24hourendpointisbasedondatademonstratingthatassessmentofinfarctvolumeat24hourscapturestheeffectofreperfusiontherapiesoninfarctgrowthandpredictsoutcomessimilarlytoday90infarctvolumes.29,62RAPID‐assessedischemiccorevolumeatbaselinewillbecorrelatedwith24hinfarctvolume(DWIvolume)insubjectswhoachievereperfusionwithoutPH1orPH2intracranialhemorrhage.Pearson’scorrelationcoefficientwillbecalculatedandthemedianabsoluteerror(ml)willbereported.Similarly,correlationofthebaselineTmax>6volumeandthe24hinfarctvolumeinpatientswithoutPH1orPH2intracranialhemorrhagewhohave<10%reperfusionwillbeperformed.CorrelationofRAPIDpredictedinfarctvolume(coregisteredbaselineischemiccoreand24hTmax>6volume)withtheactual24hinfarctvolumewillalsobeperformed.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
17
Scenario Standardized effect in cells
C11, C12, C21, C22, C31, C32
Average standard. effect
Adaptive Design Fixed Design
Average No. randomized
Power Number randomized
Power
#0 0 0 0 0 0 0 0 361 2.2% 476 2.5%
#1 0.3 0.3 0.3 0.3 0.3 0.3 0.3 354 80% 476 89%
#2 0.5 0.4 0.3 0 0 0 0.2 400 86% 476 55%
#3 0.5 0.5 0 0 0 0 0.17 403 87% 476 41%
Table 3. Under the null (Scenario #0), the adaptive design controls the total Type 1 error below 2.5%, stops early for futility 63% of the time, and the average number of randomizations is 361. If the effect is uniform across cells (scenario #1), the fixed-sample design is optimal, but the adaptive design results in only a small loss of power (from 89 to 80%). The adaptive design performs much better (higher power and smaller expected sample size) than the fixed sample, conventional trial when the effect size distribution across the subgroups is in accord with the biological assumptions (scenarios #2 and 3). If the effect is concentrated in two cells with small core volumes (scenario #3), the adaptive design maintains power (87%) while the conventional design collapses (41% power). The adaptive design also performs well compared to a non-adaptive, fixed sample that includes efficient multiple comparisons-adjusted testing for effect in subgroups at the end of the study. (see Lai et al59)
Secondaryanalysis:OursecondaryendpointistheproportionofpatientswithmRS0‐2atday90(indicatingfunctionalindependence).ThedifferenceintheproportionsofpatientswithmRS0‐2betweentreatmentarmswillbeassessedusinglogisticregression.
Subgroupanalyses:Subgroupanalysesoftheeffectofendovasculartherapyontheprimaryandsecondaryendpointswillbeperformed.Subgroupswillbedefinedbasedonthestratificationvariables,keydemographicfactors(suchasraceandethnicity),tPAvs.notPA,CTPvs.MRIselection,andwitnessedvs.unwitnessedsymptomonset,wake‐upvsnon‐wake‐upstroke,andTICI0‐2avs.TICI2b/3resultsincathlab.
Missingdata/losttofollow‐up(LTFU):
Alleffortisputforthtoensurenearcompletefollow‐up,inparticularwiththeassessmentoftheprimaryoutcome(mRSat90days),death(mRS=6),andstrokerecurrence.Iftheprimaryoutcome(mRSat90days)cannotbeassessedintheclinic,itwillinsteadbeobtainedbyphoneusingastructuredinterview.Ifthesubject’smRScannotbeobtainedinclinicorbyphonewithinthewindowof60to120daysfromrandomization,thenforprimaryanalysestheday30mRSscorewillbeusedastheprimaryoutcome(ieday30mRScarriedforward).Ifneitherthe30‐daynorthe90‐daymRSisavailable,thenthemRSwillbeimputed.WedonotexpectthistoalterthemainstudyresultsgivenourestimatedverylowLTFUrate(<2%).
DEFUSE3Timetable
Year1 Year2 Year3 Year4 Year5 InstallRAPIDatallsites
Beginenrollment(anticipatedtobeginmid‐year)
Ptenrollmentcontinuesforatotalof4yrs
1stinterimanalysisPotentialmodificationofenrollmentcriteriabasedonadaptivedesign
2ndinterimanalysisPotentialmodificationofenrollmentcriteriabasedonadaptivedesign
Finishenrollment
DataAnalyses Publicationofresults
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
18
3.9.RiskanalysisDescriptionandanalysisofallincreasedriskstotheresearchsubjects:PotentialcomplicationsofMRIscanincludelocalizedtwitchingsensationduetothemagneticfieldchangesduringthescan,anxietyduetoclaustrophobiaandallergicreactiontothecontrastagent.Theallergicreactionmayincludeheadache,nausea,rash,hives,nasalcongestion,sneezing,itchingorswelling.Ifaseverereactionoccurs,swellingofthethroat,chesttightness,oramarkeddropinbloodpressuremayoccur.Inaddition,pain,bleeding,bruising,coldnessorinflammationattheinjectionsitemayoccur.Precautionswillbetakenforearlydetectionandrapidtreatmentifsuchreactionsoccur.PotentialcomplicationsofCTscanincluderadiationexposureandallergicreactiontoCTcontrastagents.Radiationdoses:Combinedscanningwithcomprehensivestrokeimaging,whichincludesanoncontrastheadCTscan,perfusionimaging,andCTangiographyofthecervicocranialvesselsstartingattheaorticarchresultsinadoseofapproximately7‐10mSv.(AJNR201031:1003‐1009).AccordingtotheNationalCouncilonRadiationProtectionandMeasurement,theaverageannualradiationdoseperpersonintheU.S.is620millirem(6.2milliSieverts).Reactionstocontrastagents:
MildNausea,Vomiting,Headache,Cough,Nasalstuffiness,Alteredtaste,Flushing,Itching,Rash,Hives,Sweats,Swellingofeyesorface
ModerateMildhypotension,TachycardiaorBradycardia,Bronchospasm,Wheezing,Dyspnea,Laryngealedema,Generalizedordiffuseerythema
SevereCardiopulmonaryarrest,Clinicallymanifestedarrhythmias,Profoundhypotension,Convulsions,Unresponsiveness,Respiratoryfailure,LaryngealedemaTherateofmajorreactions(e.g.,anaphylaxis,death)isverylow,estimatedatonein170,000administrations.
Potentialcomplicationsofendovasculartherapyincludestroke;newclotinanartery;totalblockageofanartery;infectionandpainintheregionofinsertionsite;lackofbloodflowtothebrain;ruptureorpunctureofanartery;significanttearingofthevesselwall;bleedingrequiringbloodtransfusion;allergicreactiontocontrastdye;abnormallowbloodpressurerequiringtreatment;temporaryclosingoftheartery(vesselspasm);formationofordislodgmentsofclotswhichblockthearteries(embolism).Inrarecircumstances,theprocedurecouldresultindeath.Atthepuncturesiteinthegroin,abloodclotorotherbloodvesselinjurymayoccurandrequirebloodtransfusionorsurgicalrepair.Infectionmayoccuratthepuncturesite;thiscouldcausepainandrequireadditionalmedications.Thereissomechanceofanallergicreactiontothex‐raycontrast(dye)usedduringtheangiogramprocedure.Minorallergicreactionsmayincludearashorhives.Thereisalsothepossibilityofaseriousallergicreactionthatcouldincludeshortnessofbreathandswelling,dropin
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
19
bloodpressure,andevendeath.Patientswillbecloselymonitoredforthesereactionsandreceiveprompttreatmenttoreverseanyallergicreactions.Safetyofendovasculartherapybeyond8hoursMechanicalthrombectomydeviceshavebeenusedbeyond8hoursofstokeonsetinanumberofclinicaltrialsandregistries.Nosafetyconcernshavebeenassociatedwithlatewindowtherapy.InDEFUSE237,patientsweretreatedupto12hoursaftersymptomonset,andnosafetyconcernswereidentifiedinanytimewindow.Basedonbothfavorablesafetydataandencouragingefficacydata,StrykerNeurovascularhasinitiatedtheDAWNStudywitha24hourtreatmentwindow.NosafelyissueshavebeenidentifiedtodateinDAWN.TheDAWNstudyisbeingrununderanFDAIDE.MethodstomitigateriskstosubjectsinthetrialMethodstomitigateriskstosubjectsinthetrialincludeexclusionofsubjectswithbleedingdisordersandselectionofsubjectsvianeuroimaging(infarctcorelesionslessthan70ml)tominimizetheriskofsymptomaticintracranialhemorrhage.ComputedTomography(CT)scanswillbeperformedforneurologicaldeterioration(≥4pointincreaseinNationalInstitutesofHealthStrokeScale(NIHSS)score)toidentifynewstrokes,hemorrhage,oredema.Hospitalswillfollowtheirlocalstandardofcaresafetyproceduresinordertoreducetheriskofkidneydysfunctioncausedbycontrastagents.Onlyinvestigatorswhoaretrainedandexperiencedwithuseofthedevicesallowedwithinthetrialareeligibletoparticipate(seeSiteApprovalandMonitoringPlan)above.Theadaptivedesignwilleliminatesubgroupswithanunfavorabletherapeuticresponse.PatientswillbecarefullyscreenedforCT,MRIandendovasculartreatmentcontraindicationsaccordingtotheinclusion/exclusioncriteriaandexcludedfromenrollmentifanyarepresent.Radiationexposure:Radiationexposureduringalltestswillbeminimizedbyoptimizingtheimagingprotocolsandbylimitingfluoroscopy‐timeduringtheendovascularprocedure.AllCTsequences,includingtheCTPsequence,meetallFDAguidelinesforradiationexposure.StoppingrulesorsafetytriggersforthestudySymptomaticICHordeathratesthatexceedpre‐specifiedthresholdswilltriggerameetingoftheDSMBtodiscusstheeventsandmakeadeterminationonthecontinuationofthetrial.Belowarethepre‐specifiedtriggers:TheDEFUSE3hasestablishedthefollowingautomaticstoppingrules,basedonidentifyingwith95%probability:1) therateofsymptomaticICH(NIHSSworseningof4ormorepointsassociatedwithICH)in
theendovasculargroupisexceeding10%2) therateof90daymortalityintheendovasculargroupisexceeding20%.Ifeitherthresholdiscrossed,thestudywillbeautomaticallyplacedonholduntiltheinvestigatorsandtheDSMBcanconductareviewofevents.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
20
Adverseevents(AEs)willbecollected,recorded,andanalyzedinaccordancewithSection3.11below.SafetyoversightforthisstudywillbeprovidedbyboththeDSMBandanindependentMedicalSafetyMonitor.PleaseseeSection3.11fordetails.PatientPopulation:Fourhundredandseventysixacutestrokepatientsmeetingthepre‐definedinclusioncriteriawillbeenrolledinthetrial.Themeanageisanticipatedtobe69yearsofage.Ourtargetedplannedenrollmentbreakdownisasfollows:
RacialCategories
EthnicCategories
TotalNothispanicorLatino HispanicorLatino
Female Male Female Male
American Indian/Alaska Native 2 2 1 1 6
Asian 13 13 1 1 28
Native Hawaiian or Other Pacific Islander 2 3 0 0 5
Black or African American 32 32 1 1 66
White 175 174 11 11 371
Racial Categories: Total of All Subjects 224 224 14 14 476
Imagingcorelab:TheStanfordimagingcorelabhas15yearsofexperiencewithMRimagestorageandprocessing.Itwillperformtheorganization,archivingandblindedanalysisofallimagingdatacollectedinDEFUSE3.TheywillberesponsibleforMRIandCTPerfusionimageprocessingandartifactremovalandwillgeneratefinallesionvolumesforallMRIscansperformedinthestudy.
DSAAngiogramssenttothecorelabwillincludeabaseline(pre‐treatment)andafinalangiogramfortheterritoryoftreatment.Inaddition,angiographicimagesfromMRAorCTAwillbesenttothecorelab.TheMRAorCTAwillbeusedtoassignaprimaryarteriallesion(AOL)fromnon‐invasiveimaging.ThebaselineDSAangiogramwillalsobeusedtoassignaprimaryarterialocclusivelesion(AOL)andapre‐treatmentmTICIscore.Thefinalangiogramwillhaveapost‐treatmentmTICIscoreassigned.22,52ThisscoringsystemdefinesTICI2Aaspartialperfusionof<50%ofthevasculardistributionoftheoccludedarteryand2Baspartialperfusionof>50%ofthevasculardistribution.Thescoringsystemwillusethesepreviouslydescribeddefinitions22:
Grade0Noperfusion
Grade1Antegradereperfusionpasttheinitialocclusion,butlimiteddistalbranchfillingwithlittleorslowdistalreperfusion
Grade2aAntegradereperfusionoflessthanhalfoftheoccludedtargetarterypreviouslyischemicterritory(eg,in1majordivisionoftheMCAanditsterritory)
Grade2bAntegradereperfusionofmorethanhalfofthepreviouslyoccludedtargetarteryischemicterritory(eg,in2majordivisionsoftheMCAandtheirterritories)
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
21
Grade3Completeantegradereperfusionofthepreviouslyoccludedtargetarteryischemicterritory,withabsenceofvisualizedocclusioninalldistalbranches
Twoseniorneurointerventionalistswillperformtheangiographicanalysis,blindedtotheclinicaldata,MRimagingandCTPerfusionresults,andtheanalysisoftheothercorelabreader.AnydisagreementsintheAOLinterpretationorthemTICIscoreswillbeadjudicatedbycommonreviewofthosecasesandaconsensusreadingwillbeapplied.
NationalDataManagementCenter:DatamanagementandsitemonitoringwillbeperformedbytheStrokeNetNationalDataManagementCenter(NDMC)atMedicalUniversityofSouthCarolina(Director, ,PhD,seeletterofsupport).TheNDMCwillcreatethedatabaseandsetuptheinterfaceonthewebsite(WebDCU™)whereclinicalsitepersonnelwillenterthedataintotheelectronicCRF.Dataqualityassuranceprocessesinclude:(1)logicandrulechecksbuiltintothedatabase;(2)monitoringbytheDataManagerattheNDMC;(3)centralmonitoringbythestatisticalprogrammerattheNDMC;and(4)risk‐basedsourceverificationmonitoringbytheClinicalResearchAssociates.DEFUSE3data,includingneuroimaging,willbesharedinaccordancewiththeStrokeNetdatasharingpolicies.AnonymizedneuroimagingwillbestoredonsecureserversattheStanfordStrokeCenterwithnightlyback‐up.NINDSCommonDataElementswillbeusedforbothclinicalandimagingdata.
3.10.DescriptionofdevicesThefollowingFDAapprovedthrombectomydeviceswillbeincluded:
1) TrevoRetriever2) Solitaire™RevascularizationDevice3) CovidienMindFrameCaptureRevascularizationDevice4) Penumbrathrombectomysystemincludingthefollowingdevicesandpumps:
Penumbra Aspiration Pump (1115V) Penumbra System [026, 032, 041]
Penumbra System 054 Penumbra System Separator Flex [026, 032, 041, 054]
Penumbra System MAX Penumbra Pump MAX
Penumbra System 110 Aspiration Tubing Penumbra System Reperfusion Catheter ACE64 & ACE68
3.11.Monitoringprocedures
ThecoordinationoftheDEFUSE3Trialoperationswillbecentralizedthroughthefollowing:NIHStrokeNetNationalCoordinatingCenter(NCC)/PI: ,MDUniversityofCincinnati
Cincinnati,Ohio LeadingtheNCCteamwillbetheProjectManager,whowillbeassignedtocoordinatethefollowingstudyoversight:trialcommunicationrequiredtrainingactivities,siteassessmentand/orinitiationvisits,collectionoftrialrelatedregulatorydocuments,recruitmentperformancetracking,sitemonitoring,andperformanceanalysis.StudyoversightwillbehandledaccordingtotheDataMonitoringStandardOperatingProcedure(SOPNumberADM19).
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
22
DEFUSE3willhaveanindependentDataandSafetyMonitoringBoard(DSMB)appointedbytheNIHtooverseestudysafety.Patientsinbothstudyarmswillbeassessedfortheincidenceofstroke‐relatedmortalityat90days,theincidenceofsymptomaticintracranialhemorrhageat36hoursfromsymptomonset(definedasa≥4pointworseningofimmediatepre‐deteriorationNIHSSneurologicalstatusvs.postdeteriorationandassociatedwithbrainhemorrhage),andtheincidenceofsignificantneurologicdeteriorationpriortodischarge(definedas≥4pointworseningoftheimmediatepre‐deteriorationNIHSSneurologicalstatusvs.postdeteriorationandnotattributedtosedation).Intheendovasculararmpatientswillbeassessedforintra‐proceduralcomplicationsincluding:intra‐proceduralmortality,vesselperforation,arterialdissection,accesssitecomplicationrequiringsurgicalrepairorbloodtransfusion,embolizationanddevicefailure.SAEswillbereportedwithin24hoursofawarenessoftheevent.TheDSMBwillmeetinpersonorbyteleconference,onasemi‐annualbasis,tomonitorthecumulativesafetydataduringparticipantfollow‐up.Innoinstancewillmorethan12monthselapsebetweenDSMBreviewsofcumulativesafetydataafterthefirstparticipanthasbeenrandomized.TheDSMBwillmonitorthestudyaccordingtotheguidelinesspecifiedinthestudyprotocolandtheoperatingproceduresestablishedattheinitialmeeting,unlesstheDSMBdeterminesduringthecourseofthetrialthatmodificationoftheguidelinesisinthebestinterestofthestudyanditsparticipants.IndependentMedicalSafetyMonitor:InadditiontotheDSMB,Dr. hasbeenappointedastheindependentMedicalSafetyMonitor(MSM)forDEFUSE3.Dr. isnotinvolvedinthestudyandhasnoconflictofinterest.HewillberesponsibleforongoingmonitoringofreportsofSAEssubmittedbytheclinicalcentersinrealtimetoensuregoodclinicalpracticeandtoidentifysafetyconcernsquickly.Dr. maysuggestprotocolmodificationstopreventtheoccurrenceofparticularAEs,e.g.,modifyingtheprotocoltorequirefrequentmeasurementoflaboratoryvaluespredictiveoftheeventortoimproveexpeditiousidentificationofSAEs.IntheeventofunexpectedSAEsoranundulyhighrateofSAEs,Dr. willpromptlycontacttheDSMBLiaisonwhowillnotifytheDSMBChair.Intheeventthatheisunavailableforanextendedperiodoftime(i.e.,extendedvacation,sabbatical,illness,etc.),aback‐upMSMwillbenominatedbythestudyPIandapprovedbytheDSMB.AdverseEventReportingConsiderationofadverseeventswillhereafterconsistofadverseevents,seriousadverseevents,andadversedeviceeffects,includinganticipatedadversedeviceeffectsandunanticipatedadversedeviceeffects.
• Adverse event (AE)is definedas anyuntoward/undesirableclinicaloccurrence inaclinicalinvestigationofasubjectwhichdoesnotnecessarilyhaveacausalrelationshipwiththetreatmentunderinvestigation.AnAdverseEventcanthereforebeanyunfavorableand/orunintendedsign, symptom, or disease temporally associatedwith the use of a device product, whether or notconsideredrelated to thedeviceproduct.Onlyabnormal laboratoryvalues thataredeemedclinicallysignificantbytheinvestigatorwillbeclassifiedasadverseevents.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
23
• Seriousadverseevent(SAE)isdefinedasanyuntoward/undesirableadverseexperiencethatresultsinanyof the followingoutcomes:1)death;2)a life‐threateningadverseexperience;3) inpatienthospitalization or prolongation ofexisting hospitalization; 4) a permanent/persistent or significantdisability/incapacityora congenitalanomaly/birthdefect;5) importantmedicalevents thatmaynotresultindeath,belife‐threatening,orrequirehospitalizationmaybeconsideredaseriousadverseeventwhen, based upon appropriatemedicaljudgment, theymay jeopardize the subject andmay requiremedicalorsurgicalinterventiontopreventoneoftheoutcomeslistedinthisdefinition.Thiscategoryincludestheuseofintra‐arterialthrombolyticsand/orintracranialstents.
• Anticipated adverse device effect (AADE) is defined asany adverse effectrelated to
the device orprocedure,whichisidentifiedintheprotocolortheIFUforthedevice.
• UnanticipatedAdverseDevice Effects (UADEs) is defined as any serious adverseeffect onhealthorsafetyorany life‐threateningproblemordeathcausedby,orassociatedwithadevice, if that effect,problem, ordeathwasnotpreviouslyidentifiedinnature,severity, ordegreeof incidenceintheinvestigationalplanorapplication,oranyotherunanticipatedseriousproblemassociatedwithadevicethatrelatesto therights,safety,orwelfareofsubjects.
ReportsofUADEswillbemadetotheFDAwithin10daysofreceivingnotificationoftheUADE(asrequiredin21CFR81218p(b)(1)).SafetyMonitoring
TheMSMwillmonitorallAEreportstoidentifyandtrendalleventsthatwouldrequiretemporarydiscontinuationofstudyenrollment,tofullycharacterizedevicesafety,tomodifythestudyprotocol,ortoterminatethestudy.
ReportingProceduresforAllAdverseEventsAll Adverse Events,whetherornotattributedtothestudyand/orthedevices,observedbytheinvestigatororreportedbythesubject, will be recordedfromthetimeofrandomizationthroughDay5ordischarge,whicheverisearlier.AllSAEswillberecordedthroughDay90.
The following attributes w i l l beassignedbythereportinginvestigator:
1. Descriptionofevent2. Dateofonset3. Dateofresolution(ifapplicable)4. Seriousness5. Relationshiptothestudydeviceand/orprocedure(s)6. Severity7. Action(s)taken8. Outcome(s)
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
24
Severityisdefinedasameasureoftheintensityofareaction,effectorexperience.Themeasurement(s)aredescribedasmild,moderate,severe,lifethreateningordeath.Theeventitself,however,maybeofrelativeminormedicalsignificance.TheseverityofAdverseEventsisassessedaccordingtothefollowingindexscale:
Mildasymptomaticormildsymptoms;clinicalordiagnosticobservationsonly;interventionnotindicated
Moderateminimal,localornoninvasiveinterventionindicated;limitingage‐appropriateinstrumentalActivitiesofDailyLiving.
Severemedicallysignificantbutnotimmediatelylife‐threatening;hospitalizationorprolongationofhospitalizationindicated;disabling;limitingselfcareActivitiesofDailyLiving.
Life‐threateningconsequences;urgentinterventionindicated
DeathrelatedtoAE
TherelationshipofanAEtothestudydeviceorprocedurewillbegradedasfollows: Unrelated Unlikely Reasonablepossibility Definitely
SeriousAdverseEventsAllSeriousAdverseEventsincludingdeathswillbereportedtotheMSM, theCentra l InstitutionalReviewBoard (IRB)andtheFDA,as required.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
25
4. INVESTIGATOR’SAGREEMENT
AsthisstudywillbecarriedoutbytheNIHStrokeNet,thenamesofthespecificsitesandinvestigatorsarenotyetavailable.Investigator’sagreementsforkeyinvestigatorsatthecoordinatingsiteareincluded.Allinvestigatorswillberequiredtosignthefollowingagreement: INVESTIGATOR AGREEMENT FOR THE CLINICAL INVESTIGATION OF THE DEFUSE 3 TRIAL I___________________________________________________ agree to participate as an Investigator on the DEFUSE 3 trial. I have been provided a copy of the following Food and Drug Administration (FDA) regulations: 21 CFR Part 812, Investigational Device Exemptions; 21 CFR Part 50, Protection of Human Subjects; and 21 CFR Part 54, Financial Disclosure by Clinical Investigators. I agree and/or certify that:
1. I will conduct the clinical investigation in accordance with this agreement, all requirements of the investigational plan, IDE regulations, other applicable regulations of the FDA, and any conditions of approval imposed by my reviewing Institutional Review Board (IRB) or FDA. I agree to abide by all of the responsibilities of Investigators addressed under 21 CFR Part 812, Subpart E and Subpart G, including but not limited to the following:
2. I will obtain written approval from the authorized IRB for the institution at which this
investigation will be conducted.
3. I will ensure that Informed Consent is obtained from each subject participating in this clinical investigation in accordance with the informed consent regulation found in 21 CFR Part 50, and that a signed copy of the informed consent is available to the sponsor (sponsor-investigator) and the sponsor’s (sponsor- investigator’s) designated monitor.
4. I will ensure the accurate completion of protocol case report forms and, if I am not also the
sponsor- investigator of the corresponding IDE application, I will submit completed protocol case report forms to the sponsor (sponsor-investigator) at the time frames specified in the Protocol and/or FDA regulations.
5. I have the appropriate, relevant qualification to conduct and to oversee the conduct of the
clinical investigation as documented by the following: (initial applicable statement) ____ My relevant qualifications, including dates, location, extent and type of experience are listed in my most recent curriculum vitae (CV), which is attached to the Agreement and which will be maintained by the sponsor (sponsor-investigator) of the corresponding IDE application. ____ My curriculum vitae (CV) does not reflect my relevant qualifications, therefore attached to this Agreement is a statement of my relevant experience (including dates,
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
26
location(s), extent and type of experience) which will be maintained by the sponsor (sponsor-investigator) of the corresponding IDE application.
6. There are no reasons to question my ability to oversee the appropriate conduct of this
clinical investigation. (Initial applicable statement) ____ I have never participated in an investigation or other research activity which was terminated (disqualified) by the FDA, IRB (or equivalent), or sponsor of a study due to non-compliance issue. ____ I have participated in an investigation or other research activity which was terminated (disqualified) by the FDA, IRB (or equivalent), or sponsor of a study due to non-compliance issue. The specific circumstances leading to this termination and my role in the respective problems or issues and the resolution of these problems or issues are summarized in an attachment to this Agreement.
I further certify that I have not been debarred under the Generic Drug Enforcement Act of 1992, 21 USC §§ 335a and 335b. In the event that I become debarred or receive notice of an action or threat of action with respect to my debarment during the term of this Agreement, I agree to immediately notify the sponsor (sponsor-investigator) and the authorized IRB for my study site. If I am the sponsor-investigator of the corresponding IDE application I will notify the authorized IRB and the FDA. As required by 21 CFR Part 54, Financial Disclosure by Clinical Investigator, I will disclose sufficient and accurate financial information to the sponsor (sponsor-investigator) by completing the Certification of Financial Interest Form (attached) and if applicable, the Disclosure of Financial Interest Form (attached). I will also notify the sponsor (sponsor-investigator) if my disclosed financial information changes at any time during the clinical investigation or up to one year following the closure of the study. Site Name and Address: __________________________________________ __________________________________________ __________________________________________ ________________________________________ __________ Investigator Signature Date
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
27
5. EXECUTIVECOMMITTEE/KEYPARTICIPATINGINVESTIGATORS
TheExecutivecommittee,composedofexpertsinvascularneurology,endovasculartherapyandneuroimaging,willprovidetheoverallscientificguidanceforthestudy.Thecommitteewilltypicallymeetmonthlybyphone(1hour/month)forthefulldurationofthestudy.Responsibilitiesincludeoversightoftheoverallconductofthestudywithregardtoprotocolcomplianceandmodifications/amendments,studyprogress,andproblem‐solving.Dr.Alberswillchairtheexecutivecommittee.KeyParticipatingInvestigatorsatCoordinatingSiteGregoryW.Albers,MDPrincipalInvestigatorStanfordStrokeCenter780WelchRd.Suite350PaloAlto,CA94305650‐723‐4448galbers@stanfordmed.org
MichaelMarks,MDCo‐PrincipalInvestigatorStanfordUniversityMedicalCenter300PasteurDr.Stanford,CA94305‐5105650‐723‐6767mmarks@stanford.edu
MaartenLansberg,MD,PhDProtocolDirectorStanfordStrokeCenter780WelchRd.Suite350PaloAlto,CA94305650‐723‐4448lansberg@stanford.edu
6. INSTITUTIONALREVIEWBOARDTheUniversityofCincinnatiInstitutionalReviewBoardwillserveastheNationalCentralInstitutionalReviewBoardforallparticipatingsites.TheCentralInstitutionalReviewBoard(CIRB)formulticenterprotocolsisthesingleIRBofrecord.IthasregulatoryresponsibilityforassuringtheprotectionoftherightsandwelfareofresearchparticipantsinaccordancewithStandardOperatingProcedureADM12;CentralInstitutionalReviewBoardReporting.TheNationalInstituteofNeurologicalDisordersandStroke(NINDS)selectedtheUniversityofCincinnatiInstitutionalReviewBoard(IRB)toserveastheCIRBfortheNIHStrokeNet(StrokeNet).UniversityofCincinnatiIRBRegistration#00000180FWA#:00003152ExpirationDate:6/27/2016
,PhD,CIPChairmanCIRB
7. COSTS
Alloftheeligibledevicesthatwillbeusedinthisstudyarecurrentlyonthemarket.Therewillbenochargesbeyondthetypicalstandardofcareforuseoftheseapproveddevices.Thesedeviceswillbeusedandbilledaccordingtothestandardofcareforeachinstitution.
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
28
8. REFERENCES1. LopezAD,MathersCD,EzzatiM,JamisonDT,MurrayCJL.Globalandregionalburdenof
diseaseandriskfactors,2001:Systematicanalysisofpopulationhealthdata.TheLancet.2006;367:1747‐1757
2. KleindorferD,LindsellCJ,BrassL,KoroshetzW,BroderickJP.Nationalusestimatesofrecombinanttissueplasminogenactivatoruse:Icd‐9codessubstantiallyunderestimate.Stroke.2008;39:924‐928
3. KatzanIL,HammerMD,HixsonED,FurlanAJ,Abou‐CheblA,NadzamDM.Utilizationofintravenoustissueplasminogenactivatorforacuteischemicstroke.ArchNeurol.2004;61:346‐350
4. QureshiAI,KirmaniJF,SayedMA,SafdarA,AhmedS,FergusonR,etal.Timetohospitalarrival,useofthrombolytics,andin‐hospitaloutcomesinischemicstroke.Neurology.2005;64:2115‐2120
5. SaqqurM,UchinoK,DemchukAM,MolinaCA,GaramiZ,CallejaS,etal.Siteofarterialocclusionidentifiedbytranscranialdopplerpredictstheresponsetointravenousthrombolysisforstroke.Stroke.2007;38:948‐954
6. MoriE,YonedaY,TabuchiM,YoshidaT,OhkawaS,OhsumiY,etal.Intravenousrecombinanttissueplasminogenactivatorinacutecarotidarteryterritorystroke.Neurology.1992;42:976‐982
7. delZoppoGJ,PoeckK,PessinMS,WolpertSM,FurlanAJ,FerbertA,etal.Recombinanttissueplasminogenactivatorinacutethromboticandembolicstroke.AnnNeurol.1992;32:78‐86
8. AlbersGW,ThijsVN,WechslerL,KempS,SchlaugG,SkalabrinE,etal.Magneticresonanceimagingprofilespredictclinicalresponsetoearlyreperfusion:Thediffusionandperfusionimagingevaluationforunderstandingstrokeevolution(defuse)study.AnnalsofNeurology.2006;60:508‐517
9. LansbergMG,SchrootenM,BluhmkiE,ThijsVN,SaverJL.Treatmenttime‐specificnumberneededtotreatestimatesfortissueplasminogenactivatortherapyinacutestrokebasedonshiftsovertheentirerangeofthemodifiedrankinscale.Stroke.2009;40:2079‐2084
10. FieldsJD,LindsayK,LiuKennethC,NesbitGM,LutsepHL.Mechanicalthrombectomyforthetreatmentofacuteischemicstroke.ExpertReviewofCardiovascularTherapy.2010;8:581‐592
11. LeeM,HongK‐S,SaverJL.Efficacyofintra‐arterialfibrinolysisforacuteischemicstroke:Meta‐analysisofrandomizedcontrolledtrials.Stroke.2010;41:932‐937
12. SmithWS,SungG,SaverJ,BudzikR,DuckwilerG,LiebeskindDS,etal.Mechanicalthrombectomyforacuteischemicstroke:Finalresultsofthemultimercitrial.Stroke.2008;39:1205‐1212
13. FurlanA,HigashidaR,WechslerL,GentM,RowleyH,KaseC,etal.Intra‐arterialprourokinaseforacuteischemicstroke.Theproactiistudy:Arandomizedcontrolledtrial.Prolyseinacutecerebralthromboembolism.Jama.1999;282:2003‐2011
14. ThomallaG,SchwarkC,SobeskyJ,BluhmkiE,FiebachJB,FiehlerJ,etal.Outcomeandsymptomaticbleedingcomplicationsofintravenousthrombolysiswithin6hoursinmri‐selectedstrokepatients:Comparisonofagermanmulticenterstudywiththepooleddataofatlantis,ecass,andnindstpatrials.Stroke.2006;37:852‐858
15. HsiaA,KidwellC.Developmentsinneuroimagingforacuteischemicstroke:Diagnosticandclinicaltrialapplications.CurrentAtherosclerosisReports.2008;10:339‐346
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
29
16. KakudaW,LansbergMG,ThijsVN,KempSM,BammerR,WechslerLR,etal.Optimaldefinitionforpwi/dwimismatchinacuteischemicstrokepatients.JCerebBloodFlowMetab.2008;28:887‐891
17. LansbergMG,ThijsV,BammerR,KakudaW,HamiltonS,WechslerL,etal.Clinicalandmri‐basedriskfactorsforsymptomaticintracerebralhemorrhagefollowingtreatmentwithtissueplasminogenactivator.Stroke.2006;37:654
18. SaverJL,JahanR,LevyEI,JovinTG,BaxterB,NogueiraRG,etal.Solitaireflowrestorationdeviceversusthemerciretrieverinpatientswithacuteischaemicstroke(swift):Arandomised,parallel‐group,non‐inferioritytrial.Lancet.2012;380:1241‐1249
19. NogueiraRG,LutsepHL,GuptaR,JovinTG,AlbersGW,WalkerGA,etal.Trevoversusmerciretrieversforthrombectomyrevascularisationoflargevesselocclusionsinacuteischaemicstroke(trevo2):Arandomisedtrial.Lancet.2012;380:1231‐1240
20. MarksMP,LansbergMG,MlynashM,KempS,McTaggartRA,ZaharchukG,etal.Angiographicoutcomeofendovascularstroketherapycorrelatedwithmrfindings,infarctgrowth,andclinicaloutcomeinthedefuse2trial.IntJStroke.2014
21. YooAJ,SimonsenCZ,PrabhakaranS,ChaudhryZA,IssaMA,FugateJE,etal.Refiningangiographicbiomarkersofrevascularization:Improvingoutcomepredictionafterintra‐arterialtherapy.Stroke.2013;44:2509‐2512
22. ZaidatOO,YooAJ,KhatriP,TomsickTA,vonKummerR,SaverJL,etal.Recommendationsonangiographicrevascularizationgradingstandardsforacuteischemicstroke:Aconsensusstatement.Stroke.2013;44:2650‐2663
23. BroderickJP,PaleschYY,DemchukAM,YeattsSD,KhatriP,HillMD,etal.Endovasculartherapyafterintravenoust‐paversust‐paaloneforstroke.NEnglJMed.2013;368:893‐903
24. HillMD,DemchukAM,GoyalM,JovinTG,FosterLD,TomsickTA,etal.Albertastrokeprogramearlycomputedtomographyscoretoselectpatientsforendovasculartreatment:Interventionalmanagementofstroke(ims)‐iiitrial.Stroke.2014;45:444‐449
25. KidwellCS,JahanR,GornbeinJ,AlgerJR,NenovV,AjaniZ,etal.Atrialofimagingselectionandendovasculartreatmentforischemicstroke.NEnglJMed.2013;368:914‐923
26. O.A.Berkhemer,P.S.S.Fransen,D.Beumer,etal.ARandomizedTrialofIntraarterialTreatmentforAcuteIschemicStroke.NEnglJMed2015;372:11‐20.
27. MuirKW,BuchanA,vonKummerR,RotherJ,BaronJ‐C.Imagingofacutestroke.TheLancetNeurology.2006;5:755‐768
28. CampbellB,PurushothamA,ChristensenS,DesmondP,NagakaneY,ParsonsM,etal.Theinfarctcoreiswellrepresentedbytheacutediffusionlesion:Sustainedreversalisinfrequent.Journalofcerebralbloodflowandmetabolism:officialjournaloftheInternationalSocietyofCerebralBloodFlowandMetabolism.2012;32:50‐56
29. ChemmanamT,CampbellBC,ChristensenS,NagakaneY,DesmondPM,BladinCF,etal.Ischemicdiffusionlesionreversalisuncommonandrarelyaltersperfusion‐diffusionmismatch.Neurology.2010;75:1040‐1047
30. BairdAE,WarachS.Magneticresonanceimagingofacutestroke.JCerebBloodFlowMetab.1998;18:583‐609
31. DaniKA,ThomasRG,ChappellFM,ShulerK,MacLeodMJ,MuirKW,etal.Computedtomographyandmagneticresonanceperfusionimaginginischemicstroke:Definitionsandthresholds.AnnNeurol.2011;70:384‐401
32. OlivotJM,MlynashM,ThijsVN,KempS,LansbergMG,WechslerL,etal.Optimaltmaxthresholdforpredictingpenumbraltissueinacutestroke.Stroke.2009;40:469‐475
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
30
33. Zaro‐WeberO,Moeller‐HartmannW,HeissWD,SobeskyJ.Mapsoftimetomaximumandtimetopeakformismatchdefinitioninclinicalstrokestudiesvalidatedwithpositronemissiontomography.Stroke.2010;41:2817‐2821
34. OlivotJM,MlynashM,ZaharchukG,StrakaM,BammerR,SchwartzN,etal.Perfusionmri(tmaxandmtt)correlationwithxenonctcerebralbloodflowinstrokepatients.Neurology.2009;72:1140‐1145
35. MlynashM,LansbergMG,DeSilvaDA,LeeJ,ChristensenS,StrakaM,etal.Refiningthedefinitionofthemalignantprofile:Insightsfromthedefuse‐epithetpooleddataset.Stroke;ajournalofcerebralcirculation.2011;42:1270‐1275
36. LansbergMG,LeeJ,ChristensenS,StrakaM,DeSilvaDA,MlynashM,etal.Rapidautomatedpatientselectionforreperfusiontherapy:Apooledanalysisoftheechoplanarimagingthrombolyticevaluationtrial(epithet)andthediffusionandperfusionimagingevaluationforunderstandingstrokeevolution(defuse)study.Stroke.2011;42:1608‐1614
37. LansbergMG,StrakaM,KempS,MlynashM,WechslerLR,JovinTG,etal.Mriprofileandresponsetoendovascularreperfusionafterstroke(defuse2):Aprospectivecohortstudy.LancetNeurology.2012;11:860‐867
38. LansbergMG,CeredaCW,MlynashM,MishraNK,InoueM,KempS,etal.Responsetoreperfusionnottime‐dependentinpatientswithsalvageabletissue.Neurology,inpress2015
39. InoueM,MlynashM,ChristensenS,WheelerHM,StrakaM,TipirneniA,etal.Earlydiffusion‐weightedimagingreversalafterendovascularreperfusionistypicallytransientinpatientsimaged3to6hoursafteronset.Stroke.2014;45:1024‐1028
40. WheelerHM,MlynashM,InoueM,TipirneniA,LigginsJ,ZaharchukG,etal.Earlydiffusion‐weightedimagingandperfusion‐weightedimaginglesionvolumesforecastfinalinfarctsizeindefuse2.Stroke.2013;44:681‐685
41. ParsonsMW,ChristensenS,McElduffP,LeviCR,ButcherKS,DeSilvaDA,etal.Pretreatmentdiffusion‐andperfusion‐mrlesionvolumeshaveacrucialinfluenceonclinicalresponsetostrokethrombolysis.JCerebBloodFlowMetab.2010;30:1214‐1225
42. MarksMP,OlivotJM,KempS,LansbergMG,BammerR,WechslerLR,etal.Patientswithacutestroketreatedwithintravenoustpa3‐6hoursafterstrokeonset:Correlationsbetweenmrangiographyfindingsandperfusion‐anddiffusion‐weightedimaginginthedefusestudy.Radiology.2008;249:614‐623
43. WeisstannerC,GratzPP,SchrothG,VermaRK,KochlA,JungS,etal.Thrombusimaginginacutestroke:Correlationofthrombuslengthonsusceptibility‐weightedimagingwithendovascularreperfusionsuccess.EurRadiol.2014
44. PocockSJ,SimonR.Sequentialtreatmentassignmentwithbalancingforprognosticfactorsinthecontrolledclinicaltrial.Biometrics.1975;31:103‐115
45. ChimowitzMI,LynnMJ,TuranTN,FiorellaD,LaneBF,JanisS,etal.Designofthestentingandaggressivemedicalmanagementforpreventingrecurrentstrokeinintracranialstenosistrial.JStrokeCerebrovascDis.2011;20:357‐368
46. PereiraVM,GrallaJ,DavalosA,BonafeA,CastanoC,ChapotR,etal.Prospective,multicenter,single‐armstudyofmechanicalthrombectomyusingsolitaireflowrestorationinacuteischemicstroke.Stroke.2013;44:2802‐2807
47. MolinaCA,MontanerJ,AbilleiraS,IbarraB,RomeroF,ArenillasJF,etal.Timingofspontaneousrecanalizationandriskofhemorrhagictransformationinacutecardioembolicstroke.Stroke.2001;32:1079‐1084
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
31
48. WolpertSM,BruckmannH,GreenleeR,WechslerL,PessinMS,delZoppoGJ.Neuroradiologicevaluationofpatientswithacutestroketreatedwithrecombinanttissueplasminogenactivator.Thert‐paacutestrokestudygroup.AJNRAmJNeuroradiol.1993;14:3‐13
49. AlexandrovAV,MolinaCA,GrottaJC,GaramiZ,FordSR,Alvarez‐SabinJ,etal.Ultrasound‐enhancedsystemicthrombolysisforacuteischemicstroke.NEnglJMed.2004;351:2170‐2178
50. RubinD.Multipleimputationfornonresponseinsurveys.Wiley&Sons;1987.51. CampbellBC,TuHT,ChristensenS,DesmondPM,LeviCR,BladinCF,etal.Assessing
responsetostrokethrombolysis:Validationof24‐hourmultimodalmagneticresonanceimaging.ArchNeurol.2012;69:46‐50
52. TomsickT,BroderickJ,CarrozellaJ,KhatriP,HillM,PaleschY,etal.Revascularizationresultsintheinterventionalmanagementofstrokeiitrial.AJNRAmJNeuroradiol.2008;29:582‐587
53. ChristouI,AlexandrovAV,BurginWS,WojnerAW,FelbergRA,MalkoffM,etal.Timingofrecanalizationaftertissueplasminogenactivatortherapydeterminedbytranscranialdopplercorrelateswithclinicalrecoveryfromischemicstroke.Stroke.2000;31:1812‐1816
54. NguyenTN,MalischT,CastonguayAC,GuptaR,SunCH,MartinCO,etal.Balloonguidecatheterimprovesrevascularizationandclinicaloutcomeswiththesolitairedevice:Analysisofthenorthamericansolitaireacutestrokeregistry.Stroke.2014;45:141‐145
55. SanRomanL,ObachV,BlascoJ,MachoJ,LopezA,UrraX,etal.Single‐centerexperienceofcerebralarterythrombectomyusingthetrevodevicein60patientswithacuteischemicstroke.Stroke.2012;43:1657‐1659
56. TurkAS,FreiD,FiorellaD,MoccoJ,BaxterB,SiddiquiA,etal.Adaptfaststudy:Adirectaspirationfirstpasstechniqueforacutestrokethrombectomy.JNeurointervSurg.2014;6:260‐264
57. BangOY,SaverJL,LeeKH,KimGM,ChungCS,KimSJ,etal.Characteristicsofpatientswithtargetmagneticresonancemismatchprofile:Datafromtwogeographicallyandraciallydistinctpopulations.CerebrovascDis.2010;29:87‐94
58. HackeW,FurlanAJ,Al‐RawiY,DavalosA,FiebachJB,GruberF,etal.Intravenousdesmoteplaseinpatientswithacuteischaemicstrokeselectedbymriperfusion‐diffusionweightedimagingorperfusionct(dias‐2):Aprospective,randomised,double‐blind,placebo‐controlledstudy.Lancet.Neurology.2009;8:141‐150
59. LansbergMG,ThijsVN,BammerR,OlivotJM,MarksMP,WechslerLR,etal.Themra‐dwimismatchidentifiespatientswithstrokewhoarelikelytobenefitfromreperfusion.Stroke.2008;39:2491‐2496
60. MishraNK,AlbersGW,ChristensenS,MarksM,HamiltonS,StrakaM,etal.Comparisonofmagneticresonanceimagingmismatchcriteriatoselectpatientsforendovascularstroketherapy.Stroke.2014;45:1369‐1374
DEFUSE 3 clinical protocol Version 2.4; 20 APR 2017
32
APPENDIX
I. DEFUSE3PatientInformedConsentForm