tempo-2 protocol v3
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Confidential TEMPO-2 Final Protocol v3.3 2017-03-24
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TitlePageTEMPO-2–ArandomizedcontrolledtrialofTNK-tPAversusstandardofcareforminorischemicstrokewithprovenocclusionLongtitle:Multicentre,prospectiverandomizedopenlabel,blinded-endpoint(PROBE)controlledtrialofthrombolysiswithlowdoseTenecteplase(TNK-tPA)versusstandardofcareinthepreventionofdisabilityat3monthsinminorischemicstrokewithprovenacutesymptomaticocclusionProtocolVersion3.3 24thMarch2017
TableofContents
TITLEPAGE 1
TABLEOFCONTENTS 1
PROTOCOLSYNOPSIS 3
TRIALORGANIZATION 6
STUDYOBJECTIVES 6
BACKGROUND 7BULLETPOINTRATIONALE 7ASSOCIATIONOFVESSELOCCLUSIONANDOUTCOMEINMINORSTROKE 8THROMBOLYSISINMINORSTROKEPATIENTS:EFFICACYANDSAFETY 8TENECTEPLASE(TNK-TPA,TNKASE™) 9TIMINGOFTREATMENT 11
STUDYDESIGN 12PRIMARYOUTCOME 12SECONDARYOUTCOMES 12
SELECTIONANDENROLMENTOFSUBJECTS 13INCLUSIONCRITERIA 13EXCLUSIONCRITERIA 13SELECTINGPATIENTS 15ENROLMENT 16
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STUDYINTERVENTIONS 16RANDOMIZATION:CONCEALMENTANDBLINDING 17STUDYDRUG 17SCHEDULEOFASSESSMENTS 18
LABORATORYEVALUATIONS 19
CLINICALEVALUATIONS 19
PROHIBITEDMEDICATIONSANDPROCEDURES 19
GUIDELINESFORCLINICALCARE 20
IMAGING 21
CLINICALMANAGEMENTOFADVERSEEXPERIENCES 21
ADVERSEEVENTREPORTINGANDREVIEW 22
DATASAFETYANDMONITORINGBOARD(DSMB) 22
EXPECTEDDRUGREACTIONS 22
CRITERIAFORINTERVENTIONDISCONTINUATION 22
STATISTICALCONSIDERATIONS 23
DATACOLLECTIONANDMANAGEMENTOVERVIEW 23HUMANSUBJECTS 23ETHICSAPPROVAL 24CONDITIONSFORTERMINATINGTHESTUDY 24CONFIDENTIALITY 24SITEMONITORING 25INVESTIGATOR'SFILES/RETENTIONOFDOCUMENTS 25SOURCEDOCUMENTSANDBACKGROUNDDATA 25AUDITSANDINSPECTIONS 26CASEREPORTFORMS 26
PUBLICATIONANDPRESENTATIONPOLICY 26
ANCILLARYSTUDIESPOLICY 26
DATA-SHARINGPLAN 27
REFERENCES 27
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Protocolsynopsis TEMPO-2trial
ObjectivesTheprimaryobjective:todemonstratetheefficacyofusingTNK-tPAtotreatminorischemicstrokewithprovenarterialocclusion.
ExperimentalDesign
APhase3,prospective,randomizedcontrolled,open-labelwithblindedoutcomeassessment(PROBE)controlledtrial.
Population
Upto1274maleandfemaleadultpatientsInclusionCriteria
1. Acuteischemicstrokeinanadultpatient(18yearsofageorolder)
2. Onset(last-seen-well)timetotreatmenttime≤12hours.3. TIAorminorstrokedefinedasabaselineNIHSS≤5atthe
timeofrandomization.Patientsdonothavetohavepersistentdemonstrableneurologicaldeficitonphysicalneurologicalexamination.
4. Anyacuteintracranialocclusionornearocclusion(TICI0or1)(MCA,ACA,PCA,VBterritories)definedbynon-invasiveacuteimaging(CTangiographyorMRangiography)thatisneurologicallyrelevanttothepresentingsymptomsandsigns.AnacuteocclusionisdefinedasTICI0orTICI1flow.1PracticallythiscanincludeasmallamountofforwardflowinthepresenceofanearocclusionAND;DelayedwashoutofcontrastwithpialvesselsonmultiphaseCTAinaregionofbrainconcordantwithclinicalsymptomsandsignsOR,AnyareaoffocalperfusionabnormalityidentifiedusingCTorMRperfusion–e.g.transitdelay(TTP,MTTorTMax),inaregionofbrainconcordantwithclinicalsymptomsandsigns.
5. Pre-strokeindependentfunctionalstatus–mRS≤2.6. Informedconsent.7. Patientscanbetreatedwithin90minutesofthefirstslice
ofCT(orMRI)ExclusionCriteria
1. HyperdensityonNCCTconsistentwithintracranialhemorrhage.
2. LargeacutestrokeASPECTS<7visibleonbaselineCTscan.
3. Coreofestablishedinfarction.Nolargearea(estimated>10cc)ofgreymatterhypodensityatasimilardensitytowhitematterorinthejudgmentoftheenrolling
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neurologistisconsistentwithasubacuteischemicstroke.4. Patienthasasevereorfatalordisablingillnessthatwill
preventimprovementorfollow-uporsuchthatthetreatmentwouldnotlikelybenefitthepatient.
5. Pregnancy.6. PlannedthrombolysiswithintravenoustPAor
endovascularacutetreatment.7. In-hospitalstrokeunlessthesepatientsareattheir
baselinepriortothestroke.8. Commonlyacceptedexclusionsformedicalthrombolytic
treatmentthatpotentiallyputthepatientatanincreasedriskofbleeding.Countryspecificproductmonographsandstrokethrombolysisguidelinesshouldbeconsulted.Thesearecommonlyrelativecontraindications(i.e.thefinaldecisionisatthediscretionofthetreatingphysician)butforthepurposesofTEMPO-2includethefollowing:
a. Significantbleedingdisordereitheratpresentorwithinthepast6months
b. Internationalnormalizedratio>1.7orknownfullanticoagulationwithuseofanystandardordirectoralanticoagulanttherapywithfullanticoagulantdosing.[DVTprophylaxisdosingshallnotprohibitenrolment].Forlowmolecularweightheparins(LMWH)morethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Fordirectoralanticoagulants;inpatientswithnormalrenalfunctionmorethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Patientsondirectoralanticoagulantswhohaveanydegreeofrenalimpairmentshouldnotbeenrolledinthetrialunlesstheyhavenottakenadoseofthedruginthelast5days.
c. Dualantiplatelettherapydoesnotprohibitenrolment.[Forpatientswhoareknownnottobetakinganticoagulanttherapyitisnotnecessarytowaitforcoagulationlabresults(e.g.PT,PTT)priortotreatment]
d. Prolongedcardiopulmonaryresuscitation(>2minutes)withinthepast2weeks
e. Acutepericarditisand/orsubacutebacterialendocarditis
f. Acutepancreatitisg. Severehepaticdysfunction,includinghepatic
failure,cirrhosis,portalhypertension(oesophagealvarices)andactivehepatitis
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h. Neoplasmwithincreasedbleedingriski. Arterialaneurysmandknownarterial/venous
malformationj. Patientswhohavebeenacutelytreatedwith
GP2b3ainhibitors.k. Arterialpunctureatanon-compressiblesiteinthe
previoussevendaysl. Clinicalstrokeorseriousheadorspinaltraumain
theprecedingthreemonthsthatwouldnormallyprecludeuseofathrombolyticagent.
m. Historyofintracranialhemorrhage,subarachnoidhemorrhageorotherbrainhemorrhagethatwouldnormallyprecludeuseofathrombolyticagent.
n. Majorsurgerywithinthelast3monthsthatthetreatingphysicianconsidersacontraindicationtothrombolytictherapy.
o. Severehypo-(<50mg/dLor2.8mmol/l)orhyperglycemia(>400or22.2mmol/l)
p. Hypertensionrefractorytoanti-hypertensivemedicationsuchthattargetbloodpressure<185/110cannotbeachievedbeforetreatment.
q. Knownplateletcountbelow100,000percubicmillimeter.[Treatmentshouldnotbedelayedtowaitforplateletcountunlessthrombocytopeniaisknownorsuspected]
r. Gastrointestinalorgenitourinarybleedingwithinthepast3monthsthatwouldnormallyprecludeuseofathrombolyticagent.
Regions NorthAmerica,Europe,Asia,Australasia
Treatments
PatientswillberandomizedtoTNK-tPAorstandardofcare.IntheinterventiongroupTNK-tPAisgivenasasingle,intravenousbolus(0.25mg/Kg)immediatelyuponrandomization.Maximumdose50mg.Thecontrolgroupwillreceiveantiplateletagent(s)asdecidedbythetreatingphysician.Antiplateletagent(s)choicewillbeatthetreatingphysician’sdiscretion.
DurationofTreatment
Onetreatmentdeliveredacutelywitha90-dayfollow-upperiod.
EvaluationCriteria
Primaryoutcome:ReturntobaselineneurologicalfunctioningasmeasuredonthemRS.Analysiswillbearesponderanalysiswherereturntobaselinelevelofneurologicalfunctioningisdefinedasfollows:Ifpre-morbidmRSis0-1thenmRS0-1at90daysisagoodoutcome.Ifpre-morbidmRSis2thenmRS0-2isagoodoutcome.Pre-morbidmRSisassessedusingthestructuredmRSpriorto
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randomization.Secondaryoutcomes:Safety,recanalization,ordinalshiftanalysisofmRS,NIHSS0atday5(ordischarge),Euroqol,everydayactivitiessub-questiononEuroqol,LawtonInstrumentalActivitiesofDailyLivingScale(IADL),allcausemortality,recurrentstrokeorprogression,mRS0-1at90days,mRS0-2at90days,meanmRSusinglinearregression,compositeofrecanalizationormRS0-1at90daysandmortality.
SampleSize
Wetestthehypothesisthatthereisa9%absoluteriskbenefitofTNK-tPAoverstandardofcareinthetreatmentofminorstroke(NIHSS0-5)with90%power.Therateofgoodoutcomeinthestandardofcaregroupisassumedtobe60%and69%intheTNK-tPAgroupandthepredictedsamplesizeis1228.Samplesizeisinflated4%to1274toaccountforlosstofollowup.
Randomization
Randomizationwillbe1:1toTNK-tPAorcontrol.Randomizationwillbecentral,computergeneratedandutilizeaminimizationalgorithmtoensurebalanceonkeyvariablesthroughoutthecourseofthetrial.
Consent Writteninformedconsentisrequired.
TrialOrganizationThetrialwillbecoordinatedandexecutedbyasteeringcommitteebasedinCalgaryandinvolveapproximately80sitesinNorthAmerica,Europe,AsiaandAustralasia.AnindependentDSMBwillprovidesafetyevaluationduringthetrial.Thetrialwillbeleadbyprincipalinvestigator:ShelaghB.Coutts.Co-investigators–MichaelD.Hill, MayankGoyal AndrewM.Demchuk BijoyK.MenonThetrialwillbeleadinEuropebyPeterKelly,attheUniversityCollegeinDublin,Ireland.
StudyObjectivesTodemonstratetheefficacyofusingTNK-tPA(tenecteplase),athrombolyticagentthatisrelativelynoveltothetreatmentischemicstrokebutwell-establishedinthetreatmentofmyocardialinfarction,totreatminorischemicstrokepatientswithprovenacutesymptomaticocclusionsorperfusionabnormalities.
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Background
BulletPointRationale(i) Atleast50%ofischemicstrokeisinitiallyminor.(ii) Minorornon-disablingischemicstrokeisfrequentlytreated
conservativelywithantiplateletagentsonly.(iii) UptoathirdofpatientswithTIAorminorstrokearedeadordisabledat
90days,implyingthattheinitialseverityofpresentingsymptomscanbemisleading.
(iv) Arterialocclusioncanbedemonstratednon-invasivelyusingCTangiographyorMRangiographyin10-15%ofpatientswithTIAorminorstroke.
(v) Arterialocclusionisstronglyassociatedwithapooroutcome(deadordisabledat3months).
(vi) Treatmenttorelievearterialocclusionisexpectedtoresultinagreaterproportionofpatientsachievinganexcellentneurologicaloutcome.
(vii) AdvantagesofTNK-tPA(tenecteplase)overtPA(alteplase)a. TNK-tPAhasgreaterfibrinspecificityandpossiblyalower
intracranialhemorrhageriskcomparedtotPA.b. LowerdoseTNK-tPAmayofferlowerriskandhigherrecanalization
ratesduetoalongerserumhalf-life.c. TNK-tPAisinfusedusingasimplebolusinjection,whichreduces
nursingneedscomparedtothe60-minutetPAinfusion.Thiswould,forexample,facilitatefurtherimaging.
(viii) Proofofefficacyandsafetyofthrombolytictherapyinthesettingofminorstrokewithprovenocclusionwouldchangeclinicalpractice.
Atleast50%ofischemicstrokeisminorandinitiallynon-disabling.2Inthe“getwiththeguidelines”registryintheUnitedStates41%werenottreatedwiththrombolysisduetomildorimprovingsymptoms.3Thesepatientspresentwithatransientischemicattack(TIA)orminorstroke.Thetreatmentofminorstrokewiththrombolysishasalwaysbeencontroversialwithmuchvariationinpractice.Mostphysiciansdonottreatallpatientswithminordeficitspresentingwithinthestandardthrombolyticwindowduetoconcernsregardingbalancingtheriskofhemorrhagecomparedtoanypotentialreductionindisability.Howeveranumberofstudieshavereportedthatthisjudgmentofriskmaybewrong.Severalgroupshavereportedthatamongpatientsconsideredtoomildforthrombolysis,thatuptoathirdaredeadordisabledatthetimeoffollowup.4-7Recentdata,involvingasmallsubsetofpatientsinanindividualpatientdatameta-analysisofrandomisedtrialsoftPAsuggeststhatthrombolysiswithIVtPAamongpatientswithminordeficitsmayimproveoutcome(OR1.48,adjustedforageandtimefromonset(95%CI:1.07−2.06).8
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AssociationofvesselocclusionandoutcomeinminorstrokeMinorstrokepatientswithdocumentedvesselocclusionareatthehighestriskofearlyneurologicaldeteriorationandpooroutcomewhenthrombolysisiswithheld.6,7,9,10ThesestudiesallusedMRItoassessarterialstatus,whichhaslimitedthenumberofpatientsassessedinthesestudies.Multi-slicehelicalCTscannerswithCTAngiography(CTA)capabilityarewidelyavailableinmanyemergencydepartments.CTAusestheadministrationofintravenouscontrastmediatoassesstheintracranialandextracranialvasculaturewithhighspatialresolution.TheadditionofCTAaddslessthan5minutestoastandardCTbrainandcanbesafelycompletedinmostpatients.11CTAisonepotentialwayofincreasingthenumberofpatientsthatcanhaveearlyvascularimagingamongpatientswithminorstroke.AlthoughweexpectthatmostsiteswilluseCTAtomeettheinclusioncriteriaforthisstudy,wewillallowMRI/MRAincentresthathaveprocessesinplacetomanagepatientsinthisway.Werecentlycompletedaprospectivecohortstudyof510TIAandminorstrokepatients(NIHSS<4)whowerenottreatedwiththrombolysis–theCATCHstudy.12AllofthesepatientshadaCTandCTAcompletedwithamediantimetoCTAof5.5hours(IQR:6.4hours)showingthefeasibilityofusingCTAtoscreenthesepatientsforlargearteryocclusion.10%(52/510)ofpatientshadanintracranialocclusion.19%(10/52)ofpatientswithintracranialocclusionhadearlyneurologicaldeteriorationversus2%(9/447)inpatientswithoutocclusion,p<0.0001.Wefoundthatstrokeprogressionoccurredinbothproximalanddistalocclusionswithsimilarfrequency.13Clinicaloutcomeswerealsoworsewithpatientshavinganintracranialocclusionhavingmoredisabilityatthetimeof90dayfollowup(31%versus13%,p=0.0016)thanpatientswithoutanintracranialocclusion.Thiswastruewhetherthepatientsclinicallydeterioratedornot.14Anothergrouphasfoundthatlargearteryocclusionpredictsdisabilityevenamongpatientswhohavecompletelysymptomaticallyresolvedatbaseline(i.e.TIApatients).15Inthesettingofintracranialocclusiontheproposedmechanismofneurologicalworseningisfailureofcollateralbloodsupply.16,17Insummary,minorstrokepatientswithadocumentedintracranialocclusionhaveahigherriskofneurologicaldeteriorationanddisabilitythanthosewithoutintracranialocclusion.
Thrombolysisinminorstrokepatients:efficacyandsafetyThebiggestreasonforphysicianstowithholdthrombolysisisalackofevidencetocountertheirconcernsregardingthepotentialrisksoftreatment.Mostofthethrombolysistrialscompletedtodatehaveincludedfewornominorstrokepatients.ThetrialwiththelargestnumberofminorstrokepatientstreatedtodateisthethirdInternationalStrokeTrial(IST-3).18InIST-3minorstrokewasdefinedasabaselineNIHSSof0-5inclusive.IST-3included612patientswithanNIHSSof0-5(304withtPA,308tocontrol).Therewasnoevidenceofatreatmentbenefitwithgoodoutcome(mRS0-1)seenin54%(164/304)oftPAtreatedpatientsvs.48%
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(147/308)ofcontrols(RR1.13,95%CI:0.97-1.32,p=0.12).19ArecentanalysisoftheVirtualInternationalStrokeTrialArchive(VISTA)databasefailedtodemonstrateabenefitofthrombolysisinaNIHSS1-4population.20Symptomaticintracranialhemorrhage(SICH)wasseenin3%oftPApatients(9/304,95%CI:1.3-5.5)inIST-3,butnotinanycontrolpatients.TherewasnoevidenceofaninteractionwithtimeforSICH(lessthan4.5hoursorgreaterthan4.5hours).InasubgroupanalysisoftheCASESstudytherewere77tPAtreatedpatientswithaNIHSSscore<6andthesepatientshada2.6%(95%CI:0.8-9%)rateofsymptomatichemorrhage.21IntheNINDStPAstudytherewasasimilarhemorrhagerateof2.3%(95%CI:0.6-12%)amongpatientswithNIHSSscore<6.22Webelievethatthesubgroupofpatientswithanintracranialocclusionarethepopulationwheretheriskbenefitswingstowardsbenefit.Thefewpatientswithminorstroke(NIHSS<6)thathavebeenincludedinthrombolysisstudieshavelowerratesofintracranialhemorrhage(ICH)thaninmoreseverestrokes,howevertheconfidenceintervalsarewidegivenhowfewpatientshavebeenenrolledinthisgroup[NINDStPA222.3%(95%CI:0.6-12%),CASES212.6%(95%CI:0.8-9%),IST-3193%(95%CI:1.3-5.5)].OverallratesofsymptomaticICHhavealsobeenfallingasexperiencewithstrokethrombolysishasgrownworldwide.23Ingeneral,symptomaticICHamongdisablingstrokepatientstreatedwithintravenoustPAhasbeenshowntobeassociatedwiththeseverityofinfarction,thevolumeofinfarctionshownonimaging,leukoaraiosis,thetimefromstrokeonset,anticoagulationuseandelevatedserumglucose.24However,thesevariablesaccountforonlyasmallproportionofthevariancesothattoalargeextent,symptomaticICHseemsarandomoccurrenceclinically.Thus,itisourexpectationthattheratesofsymptomatichemorrhagewillbenomorethan2%amongpatientstreatedinthisstudy.Wenotethatpatientwithestablishedinfarctionobservableonbrainimagingareatgreaterriskofhemorrhage.Weproposetoexcludepatientswithevidenceoflargevolumesofinfarctionorclearlysubacuteischemia.MostminorstrokepatientsarejudgedtohavesuchagoodprognosisthattheriskofsymptomaticICHisnotworthtaking.However,therateofpooroutcomeismuchhigherthanpreviouslyassumed,particularlyinpatientswithintracranialocclusion.And,withevolvingknowledgeandexperiencewithstrokethrombolysis,thesafetyprofilehasimprovedsubstantially.
Tenecteplase(TNK-tPA,TNKase™)Tenecteplase,ageneticallyengineeredmutanttissueplasminogenactivator,hasalongerhalf-life,ismorefibrinspecific,produceslesssystemicdepletionofcirculatingfibrinogen,andismoreresistanttoplasminogenactivatorinhibitor25thanalteplase.26Thesepharmacodynamicdifferencesresultinmorerapidreperfusion.Tenecteplaseisnowthefirst-lineintravenousthrombolyticdrugfor
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myocardialinfarction27,28andhasshowntocausecompletereperfusionwithreducedICHincomparisontoalteplaseinanimalstrokemodels.29,30Adoseescalationsafetystudyoftenecteplaseinpatientswithacuteischemicstrokeobservednosymptomaticintracranialhemorrhages(ICHs)among88patientstreatedwithdosesrangingfrom0.1mg/kgto0.4mg/kg.31At0.5mg/kg,thestudywasclosedearlyinthedosetierduetoanexcessofsymptomatichemorrhage.0.5mg/kg,isthecurrentlyapprovedcoronarythrombolysisdose.Asymptomatichemorrhagebegantoappearat0.1mg/kg(8%of25patients)andwashigherat0.2mg/kg(32%of25patients)and0.4mg/kg(28%of25patients),indicatingthattheremaybesomerelationshipwithdose.Thistrialwasstoppedprematurelyduetoslowenrollment.AmorerecentPhaseIIbstudycomparingthrombolysiswithtPAandlowdoseTNK(0.1mg/Kgor0.25mg/Kg)inmoderatetoseverestrokewassuggestivethatTNKhadhigherrecanalizationratesthantPA.32Thestudywasnotpoweredtolookatclinicaldifferencesbetweenthegroups,howevertherewerecleardifferencesinrecanalizationratesat24hours.Completerecanalizationat24hourswasseenin36%ofthetPAgroup,35%ofthe0.1mg/KgTNKgroupand80%ofthe0.25/kggroup(p=0.002).Partialorcompleterecanalizationwasseenin68%ofthetPAgroup,78%ofthe0.1mg/KgTNKand95%of0.25mg/KgTNKgroup(p=0.02).NotonlywasrecanalizationgreaterwithTNK,therateofsymptomaticintracranialhemorrhagewaslowerinboththeTNKtreatedgroups(12%versus4%and4%).Theinvestigatorsarecurrentlyrunningaphase3trialcomparingtPAwith0.25mg/KgTNKbasedontheseresults.33Werecentlycompletedadose-escalationsafetystudyofTNK-tPAinthetreatmentofminorstrokewithprovenocclusion–TEMPO-1study.34Weprospectivelyenrolled50patientswithminorstrokeandprovenintracranialocclusion,andtreatedthemwithTNK-tPAina12-hourwindow.Thefirsttierof25patientswastreatedatadoseof0.1mg/kg.Thesecondtierof25patientswastreatedat0.25mg/kg.TheoverallrateofsICHwas2%(1/50)CI950.5%-10.6%.Therewerenodrugrelatedseriousadverseeventsintier1.Intier2therewas1symptomaticICH(4%,95%CI:0.01-20.0).Strokeprogressionoccurredin6%ofcases.Overall,66%hadexcellentfunctionaloutcome(mRS0-1)at90-days.Recanalizationrateswerehigh;0.1mg/Kg(39%complete,17%partial),0.25mg/Kg(52%complete,9%partial).Completerecanalizationwassignificantlyrelatedtoexcellentfunctionaloutcome(mRS0-1)at90-days(RR1.65:CI951.09-2.5,p=0.026,SeeFigure1).
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Figure1:Figureshowsthebreakdownoffunctionaloutcomesat90daysbyrecanalizationstatus(complete,partialornorecanalization).Basedontheknownpharmacologicaldifferences,thehigherrecanalizationrateandanempiricdose-escalationsafetystudy(TEMPO-1)wehavechosenTNKatadoseof0.25mg/kg.
TimingoftreatmentIVtPAisinroutineuseinCanadaupto4.5hoursfromsymptomonsetfortreatmentofdisablingstroke.Patientswithintracranialocclusion,butonlymildsymptomsaredifferentthanpatientswithmoreseveresymptoms,likelyduetocollateralcirculation.17Thesepatientsalsohaveatendencytopresentlaterthanpatientswithmoremajorsymptoms.IntheCATCHstudy12mostpatientsdeterioratedatamediantimeof1day(deteriorationwasmostlyovernightthefirstnight)suggestingthattheremaybeanextendedwindowinthesepatients.Manytertiarystrokecentres,includingtheCalgaryStrokeProgramhavebeenusingthe“smallcore,largeareaofbrainatrisk”paradigmtothrombolysestrokepatientsoutsideofguideline-basedcareforanumberofyears.DifferenttechniqueshavebeenusedtoidentifythispatientparadigmincludingMRI,CTperfusion(CTP)andCTAngiography(CTA).Wehavechosenarelativelysimpleapproach,whichisintracraniallargearteryocclusion(orafocalareaofdecreasedperfusionandsmallareaofinfarctedbrain).InTEMPO-1wesafelyused12hoursasourmaximumpotentialtreatmentwindow.Weshowedthatthiswassafetreatmentparadigm.Therealityisthatmostpatients
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presentearlierratherthanlater.Thereistheoccasionalpatientwhowakesupwiththeirdeficitsandtheirlasttimeseennormaliscloseto12hours.
StudyDesignThestudywillbea,prospective,randomized,open,blindedend-point(PROBE)study.Randomizationwillbe1:1to0.25mg/KgTNK-tPA(experimental)orstandardofcare(control).
PrimaryOutcomePrimaryoutcome:ReturntobaselineneurologicalfunctioningasmeasuredbythemRS.Analysiswillbearesponderanalysiswherereturntobaselinelevelofneurologicalfunctioningisdefinedasfollows:Ifpre-morbidmRSis0-1thenmRS0-1at90daysisagoodoutcome.Ifpre-morbidmRSis2thenmRS0-2isagoodoutcome.Pre-morbidmRSisassessedusingthestructuredmRSpriortorandomization.(seeappendix1).35Outcomeswillbeassessedbyanindividualblindedtothetreatmentassignment.The90daymRSwillberatedusingthestructuredmRSquestionnaire(seeappendix1).The90daymRSwillbecompletedinpersonwherepossibleandbytelephoneotherwise.ThestructuredquestionnairehasbeenshowedtoimprovereliabilityinassessingthemRSbothinpersonandbytelephone.35
SecondaryOutcomes1) Proportionofpatientswithmajorbleeding:Thiswillincludeananalysisof
symptomaticintracranialhemorrhagealoneandthencombinedwithmajorextracranialhemorrhage.Thisisthemainsafetyoutcome. a) Symptomaticintracranialhemorrhagedefinedasnewintracranial
hemorrhage(ICH,SAH,IVH,SDH)associatedwithclinicalevidenceofneurologicalworsening,inwhich,thehemorrhageisjudgedtobethemostimportantcauseoftheneurologicalworsening.ClinicalworseningwillbeguidedbytheNIHSSscoreofaminimumof2ormorepointsdifferentfrombaseline.
b) Majorextracranialhemorrhagedefinedaslifethreatening,resultinginhemodynamiccompromiseorhypovolemicshock,requiringinotropicsupportorothermeanstomaintaincardiacoutput,requiringbloodtransfusionofmorethan2unitsofpackedredbloodcells,orassociatedwithafallinhemoglobingreaterthanorequalto5g/L.
2) Proportionofpatientswithcompleteandpartialrecanalization(TICI2b-3)posttreatment.ThiswillbeassessedonCTA4-8hoursposttreatment.Recanalizationwillbeassessedbythecentralcore-imaginglabblindedtoallclinicalinformation.
3) CategoricalshiftanalysisonthefullrangeofthemRS(0-6).
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4) AbsenceofdisabilitydefinedasmRS0-1.5) FunctionalindependencedefinedasmRS0-2.6) ComparisonofthemeanmRSusinglinearregressionusingthemRSasa
continuousvariable.7) LawtonInstrumentalActivitiesofDailyLivingScale(IADL)36,378) ProportionofpatientswithanNIHSS0atday5(ordischargefromhospitalif
dischargedbeforeday5)9) QualityoflifemeasuredonEuroQol3810) Qualityoflifeasmeasuredbythe“problemswithusualactivities”questionon
theEuroQol.11) Strokeprogressionandrecurrentstroke.12) All-causemortality
SelectionandEnrolmentofSubjects
Inclusioncriteria1. Acuteischemicstrokeinanadultpatient(18yearsofageorolder)2. Onset(last-seen-well)timetotreatmenttime≤12hours.3. TIAorminorstrokedefinedasabaselineNIHSS≤5atthetimeof
randomization.Patientsdonothavetohavepersistentdemonstrableneurologicaldeficitonphysicalneurologicalexamination.
4. Anyacuteintracranialocclusionornearocclusion(TICI0or1)(MCA,ACA,PCA,VBterritories)definedbynon-invasiveacuteimaging(CTangiographyorMRangiography)thatisneurologicallyrelevanttothepresentingsymptomsandsigns.MultiphaseCTAorCTperfusionarerequiredforthisstudy.AnacuteocclusionisdefinedasTICI0orTICI1flow.1PracticallythiscanincludeasmallamountofforwardflowinthepresenceofanearocclusionAND,DelayedwashoutofcontrastwithpialvesselsonmultiphaseCTAinaregionofbrainconcordantwithclinicalsymptomsandsignsOR,AnyareaoffocalperfusionabnormalityidentifiedusingCTorMRperfusion–e.g.transitdelay(TTP,MTTorTMax),inaregionofbrainconcordantwithclinicalsymptomsandsigns.
5. Pre-strokeindependentfunctionalstatus–structuredmRS≤2.6. Informedconsentfromthepatientorsurrogate.Surrogateconsentisonly
allowedincountries/jurisdictionswherethisisapproved.7. Patientscanbetreatedwithin90minutesofthefirstsliceofCTorMRI.Scans
canberepeatedtomeetthisrequirement;ifthereisnochangeneurologicallythenonlyaCTheadneedberepeatedforassessmentofextentanddepthofischemia.
Exclusioncriteria1. HyperdensityonNCCTconsistentwithintracranialhemorrhage.2. LargeacutestrokeASPECTS<7visibleonbaselineCTscan.
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3. Coreofestablishedinfarction.Nolargearea(estimated>10cc)ofgreymatterhypodensityatasimilardensitytowhitematterorinthejudgmentoftheenrollingneurologistisconsistentwithasubacuteischemicstroke>12hoursofage.
4. Patienthasasevereorfatalordisablingillnessthatwillpreventimprovementorfollow-uporsuchthatthetreatmentwouldnotlikelybenefitthepatient.
5. Pregnancy.Allwomenwiththepotentialofbeingpregnanti.e.havenotgonethroughmenopauseorhavenotundergonesurgicalsterilization,shouldhaveapregnancytestpriortoenrollment.
6. PlannedthrombolysiswithIVtPAorendovascularthrombolysis/thrombectomytreatment.
7. In-hospitalstrokeunlessthesepatientsareattheirbaselinepriortotheirstroke.E.g.apatientwhohadastrokeduringadiagnosticcoronaryangiogram.
8. Commonlyacceptedexclusionsformedicalthrombolytictreatmentthatpotentiallyputthepatientatanincreasedriskofbleeding.Countryspecificproductmonographsandstrokethrombolysisguidelinesshouldbeconsulted.Thesearecommonlyrelativecontraindications(i.e.thefinaldecisionisatthediscretionofthetreatingphysician)butforthepurposesofTEMPO-2includethefollowing:
a. Significantbleedingdisordereitheratpresentorwithinthepast6months
b. Internationalnormalizedratio>1.7orknownfullanticoagulationwithuseofanystandardordirectoralanticoagulanttherapywithfullanticoagulantdosing.[DVTprophylaxisdosingshallnotprohibitenrolment].Forlowmolecularweightheparins(LMWH)morethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Fordirectoralanticoagulants;inpatientswithnormalrenalfunctionmorethan48hoursoffdrugwillbeconsideredsufficienttoallowtrialenrollment.Patientsondirectoralanticoagulantswhohaveanydegreeofrenalimpairmentshouldnotbeenrolledinthetrialunlesstheyhavenottakenadoseofthedruginthelast5days.Dualantiplatelettherapydoesnotprohibitenrolment.[Forpatientswhoareknownnottobetakinganticoagulanttherapyitisnotnecessarytowaitforcoagulationlabresults(e.g.PT,PTT)priortotreatment]
c. Prolongedcardiopulmonaryresuscitation(>2minutes)withinthepast2weeks
d. Acutepericarditisand/orsubacutebacterialendocarditise. Acutepancreatitisf. Severehepaticdysfunction,includinghepaticfailure,cirrhosis,portal
hypertension(oesophagealvarices)andactivehepatitisg. Neoplasmwithincreasedbleedingriskh. Arterialaneurysmandknownarterial/venousmalformationi. PatientswhohavebeenacutelytreatedwithGP2b3ainhibitors.j. Arterialpunctureatanon-compressiblesiteinthepreviousseven
days
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k. Clinicalstrokeorseriousheadorspinaltraumaintheprecedingthreemonthsthatwouldnormallyprecludeuseofathrombolyticagent.
l. Historyofintracranialhemorrhage,subarachnoidhemorrhageorotherbrainhemorrhagethatwouldnormallyprecludeuseofathrombolyticagent.
m. Majorsurgerywithinthelast3monthsthatthetreatingphysicianconsidersacontraindicationtothrombolytictherapy.
n. Severehypo-(<50mg/dLor2.8mmol/l)orhyperglycemia(>400or22.2mmol/l)
o. Hypertensionrefractorytoanti-hypertensivemedicationsuchthattargetbloodpressure<185/110cannotbeachievedbeforetreatment.
p. Knownplateletcountbelow100,000percubicmillimeter.[Treatmentshouldnotbedelayedtowaitforplateletcountunlessthrombocytopeniaisknownorsuspected]
q. Gastrointestinalorgenitourinarybleedingwithinthepast3monthsthatwouldnormallyprecludeuseofathrombolyticagent.
SelectingPatientsTheprinciplesofpatientselectionarebaseduponthebroadcriteriaof:
a. TIAorminorstrokepresentationwithadiagnosisofanischemicstrokesyndrome
b. Imagingproofofanintracranialocclusionoraperfusionabnormalityrelevanttothepresentingsymptoms
c. Noregionofwell-definedhypodensityontheNCCTconsistentwiththepresentingsymptomsorconsistentwiththesuspectedpathophysiologyofthepresentingsymptomsthatsuggestswell-evolvedinfarction,judgedtobepotentiallypronetobleeding.
Themostchallengingoftheseprinciplesis(c)sinceitrequiresjudgmentandimaginginterpretation.WeknowfromimagingstudiesusingMRperfusionimagingthatregionsofverylowCBVarepronetohemorrhage.39Yet,usingMRdiffusionimagingitcanbeshownthatmanypatientswithminorlesionswhothenpresentwithsubsequentmajorstrokeandaretreatedwithIVtPAdonotsufferhemorrhage.40Clinically,ithasbeenamaximofstrokethrombolysisthatamongpatientswhopresentwithaTIA-likepresentationwhoneurologicallyresolveandthensubsequentlydeteriorate,theclockcanberesettothetimeofdeterioration.Yet,weknowthat50%ormoreofpatientswithTIA/minorstrokepresentationshaveMRdefinedsmallischemiclesions.41,42Empiricalclinicalexperiencesuggeststhatthrombolysisinpresenceofsmalllesionvolumesissafe.Patientwhoareatincreasedriskofhemorrhagiccomplicationsshouldnotbeenrolledinthetrial.Generally,standardthrombolyticagentcontraindicationswillbeconsideredatthediscretionofthetreatingphysicianasexclusioncriteria.Theuseoftenecteplaseorotherthrombolyticagentsinpatientswhoaretakingorhavebeenrecentlytakingdirectoralanticoagulantmedicineisuncertain.Thisis
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particularlytrueforthemedicinesthataredependentuponnormalrenalfunctionforexcretion.Thereare4currentlymarketeddirectoralanticoagulants:Dabigatran,rivaroxaban,apixaban,betrixaban.Therefore,patientswithanydegreeofrenalfailurewhohavetakenoneormoredosesofthesemedicinesintheprior5daysareexcluded.Patientswithnormalrenalfunctionareexcludediftheyhavetakenoneormoredosesofthesemedicinesintheprior48hours.
EnrolmentPatientswillbescreenedusingtheusualstroketeamprocessofcareatthesite.Candidatesforenrolmentwillbeapproachedforconsent.Sinceallsubjectsareexpectedtoberelativelymildlyaffectedclinicallyatpresentation,many/mostwillbeabletoprovideconsentthemselves.Incertaincountries/jurisdictionsanincompetentpatient,whootherwisemeetscriteria,maystillbeenrolledwiththeconsentofasurrogateorlegallyauthorizedrepresentative.Allpatientsortheirsurrogatemustprovidewritteninformedconsent.AllpatientswillbeevaluatedclinicallyandthenundergobrainimagingusingCTfollowedimmediatelybyaCTangiogram.Iftheyremaineligible,afterreviewofclinicaltesting,imagingandlaboratorytesting,theywillbeimmediatelyenrolledandtreated.Allpatientswillbetreatedwithin90minutesofthefirstsliceofthebaselineCT.InsiteswhereMRI/MRAisroutinelyusedthiscanbesubstitutedforCT/CTA.InallpartsoftheprotocolMRI/MRAcanbesubstitutedforCT/CTA.Apatientisconsideredenrolledintothetrialatthepoint(dateandtime)ofrandomization.Ifrandomizedtoactivetreatmenttheyshouldimmediatelyreceivestudydrug.Randomizationisconsideredtime0.Apatientwhoprovidesconsentbutisnotenrolledintothetrialisconsideredascreenfailure.
StudyInterventionsRandomizationwillbe1:1toTNK-tPA(experimental)orstandardofcareantiplateletagents(control).
Experimental:TNK-tPA(0.25mg/kg)givenasasingle,intravenousbolusimmediatelyuponrandomization.Experimentaltreatmentwillbeadministeredasasingleintravenousbolusover5-10secondsasperthestandardmanufacturers’instructionsforuse.PleaserefertocurrentProductMonographfordetailsonreconstitutionandinfusionofthedrug.Control:Patientswillbetreatedwithstandardofcarebasedantiplatelettreatment–choiceatthediscretionoftheinvestigator.Lowdoseaspirin(singleagent)willbethechoiceofmostphysicians,howevergiventheresultsoftheFASTERtrial43andtherecentlypublishedCHANCEtrial44somewillchosetousethecombinationofaspirinandclopidogrel.Asthisisamulti-centre,internationaltrialwherelocalpracticeswillvary,ratherthanmandatingaspecificantiplateletagent,wewillallowthelocalinvestigatortochosewhichantithromboticregimeshouldbeused.
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Standardofcaremedication(s)shouldbegivenimmediatelyuponrandomization.
PatientswillundergoastudyCTangiogramoftheintracranialcirculationbetween4-8hoursaftertreatmenttodeterminethebiologicaleffectofthedrug-whethertheoccludedarteryhasrecanalizedornot.Anypatientwhohasneurologicalworseningshouldhavestandardofcarebrainimagingcompletedtoruleoutintracranialhemorrhage.Allpatientswillhavestandardofcaremedicalmanagementonanacutestrokeunitandundergofollow-upimagingat24hourswithCTorMR.UseofMRwillbeencouraged.
Randomization:ConcealmentandBlindingRandomizationwillbecompletedbyacomputergeneratedminimizationalgorithm–minimalsufficientbalancerandomization.Thiswillensurebalancethroughoutthetrial,basedonkeyvariables.Thisalgorithmwillbedevelopedcentrallyandthedetailswillnotbeavailabletothetreatingsites.Theminimizationalgorithmpreservesbalanceonpre-specifiedprognosticvariables.Variablesthatwillbeincludedintheminimizationalgorithmareage,sex,baselineNIHSSscore,pre-morbidmRS,andtimeofrandomization(under4.5hoursversusnot).Thesearethekeyvariablesknowntoinfluenceoutcomeinminorstroke.10,14,45Randomizationwillbedynamicandgeneratedinthemomentviaaweb-basedsystem;thusarandomizationlistdoesnotexist.Theresultwillberandomallocationthatisfullyconcealed.Randomizationwillbebiasedcointhatwillvaryfromfullybalanced(50:50)tobiased(65:35)dependentonwhatcharacteristicsbeenpreviouslyenrolledhave.Thesystemwillbeenabledforsmart-phone,tablet,laptopordesktopcomputeruse.
StudyDrugThetradenamefortenecteplaseisTNKase™inNorthAmericaandMetalyse™inEuropeandAustralasia.Offtheshelftenecteplasewillbeusedinthisstudy.Staffwillbetrainedinthemixingandadministrationofthedrug.STORAGEANDSTABILITYStorelyophilizedTNKase™(orMetalyse™) tenecteplase,TNK-tPA)atcontrolledroomtemperature(2-30°C)nottoexceed30°Corunderrefrigeration(2°C-8°C).Ifstandardhospitalsuppliesarebeingusedthentemperaturemonitoringisnotrequired. Donotusebeyondtheexpirationdatestampedonthevial.UnusedreconstitutedTNKase™(inthevial)maybestoredat2°C-8°Candusedwithin8hours.Afterthattime,anyunusedportionofthereconstitutedmaterialshouldbediscarded.DOSAGEFORMS,COMPOSITIONANDPACKAGINGDosageForms:
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TherearedifferentsizedvialsofTNKase™(orMetalyse™)availableindifferentcountries.InCanadaforexample50mgvialsareavailable.Each50mgvialofTNKase™(orMetalyse™)ispackagedwithone10mlvialofSterileWaterforInjectionforreconstitution.Forothervialsizesfollowthereconstitutioninstructionsincludedwiththedrug.Reconstitutionof50mgoftenecteplasein10mlofsterilewaterresultsinasolutionconcentrationof5mg/ml.Forothersizesoftenecteplasefollowthereconstitutioninstructionsincludedwiththedrug.Thedoseis0.25mg/kgor0.05ml/kg.Composition:TNKase™isasterile,whitetooff-white,lyophilizedpowderforsingleintravenous(IV)bolusadministrationafterreconstitutionwithSterileWaterforInjection,USP.50mg(10,000units)/vialTenecteplase*52.5mgL-Arginine0.55gPhosphoricAcid0.17gPolysorbate204.3mg*Thisincludesa5%overfillsothateachvialwilldeliver50mgoftenecteplase.Packaging:Each50mgvialofTNKase™ispackagedwithone10mLvialofSterileWaterforInjection,USPforreconstitutionandoneB-D®10ccSyringewithTwinPak®DualCannulaDevice.
ScheduleofAssessments Baseline 4-8
hDay1(24±8hfromrandomization)
Day5ordischarge(±1d)
Day90(±14d)§
Informedconsent X Regainedcapacityconsent(ifneeded)
X
Historyandexamination X Weight X± X± X± X± NIHSS X X X XmRS XPre-strokemRS¶ X EuroQol XLawtonInstrumentalActivitiesofDailyLivingScale(IADL)
X
NCCTheadorMR X* X*** CTACOWorMRA X* X** Fullemergencystrokelabs X‡ Creatinine X X ECG X‡ Adverseeventassessment X X X Seriousadverseeventassessment X X X X§Priormedications X‡ Concomitantmedications§ X X X X *MRI/MRAcanbesubstitutedforbaselineCT/CTAatthediscretionofthelocalsite.**4-8hoursCTACircleofWillis(COW).AtthediscretionofthelocalinvestigatorthefollowupCTAcanbenotcompletediftheeGFRis<40ml/minuteortherewasanallergicreactiontothebaselinescan.
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***Day+1NCCTheadmaybesupplantedbyanMRheadincludingdiffusionweightedimaging(DWI)andgradientecho(GRE)atthediscretionofthelocalsite.¶Thepre-strokemRSisanestimateofthepre-strokescoreandisbasedonthehistorygivenbythepatient/family.‡Thesetestsarerequiredatbaseline.Bloodshouldbedrawnatbaseline,butresultsarenotrequiredpriortorandomization.Incertaincountriesasrecommendedbynationalguidelines;bloodworkforgroupandhold(typeandscreen)shouldbecollected.ECGshouldbedonewithin6hoursofhospitaladmission,butisnotrequiredpriortorandomization.Priormedicationsshouldbecollectedbutarenotrequiredpriortorandomization.§ConcomitantmedicationsarecollectedouttoDay5orinconjunctionwithanySAE.Collectconcomitantmedicationsat90daysonlyaspartoftheSAEnarrativeonlyonpatientswithSAEs.All90evaluationsshouldbeperformedbyanevaluatorblindedtotheacuteintervention.Weareencouragingthatthisvisitbecompletedinperson,butifthisisnotpossibleatelephonefollowupcanbesubstituted.d=days;h=hours±ActualweightmustbeperformedoncebyDay5orDischargeandrecorded,notnecessarytobedoneatalltimepoints.
LaboratoryEvaluationsRoutinebloodworkwillbetakenintheemergencydepartment.ThiswillincludePT/PTT,CBC,electrolytes,glucoseandcreatinine.Thecoagulationstatusmustbeknownpriortotreatmentamongpatientswhoareknowntobeonanyformanticoagulationtherapy.ECGshouldbecompletedatbaselineeitherpriortotreatmentorwithin6hoursoftreatment.IftheestimatedGFRissubsequentlyfoundtobe<40ml/minuteortherewasanallergicreactiontothebaselineCTAthentherepeatCTAshouldnotbecompleted.Thisisnotaprotocoldeviation.
ClinicalevaluationsAllpatientswillhaveastrokehistoryandphysicalbeforetreatmentiscommenced.AllinvestigatorswillbetrainedinboththeNIHSSandmRS.Patientswillbeassessedat24hoursoratthetimeofanydeteriorationusingtheNIHSS.At5days(oratdischargefromhospitalifsooner)patientswillhaveanNIHSScompleted.At90daystheNIHSS,Euroqol,LawtonInstrumentalActivitiesofDailyLivingScale(IADL)andmRSwillbecompletedbyablindedinvestigator.ThemRSwillberatedusingthestructuredmRSquestionnaire.35Theinvestigatorcompletingthe90doutcomeassessmentshouldbeablindedsitetrialinvestigator,sub-investigatororcoordinatordefinedasabsenceofinvolvementinthefirst48hoursoftreatmentofthepatient.Ifnotfeasibletocompleteinpersonthisinterviewcanbecompletedbytelephone.
ProhibitedmedicationsandproceduresIntheexperimentaltreatmentgroup:noantiplateletagent,otherantithromboticmedicinesshouldbegivenwithinthefirst24hours(+/-8h)ofthetreatment.Thesecanbestarted,ifclinicallyindicated,oncethe24-hour(+/-8h)follow-upCThasbeencompletedandshowsnoclinicallysignificantintracranialhemorrhage.Inpractice,thismeansthatifthereisnohemorrhageonfollow-upbrainimaging,antithromboticorantiplateletmedicinesmaybegivenwithoutrestriction.Ifthereishemorrhage,ajudgmentmustbemadeabouttherelativesafetyofantiplateletorantithromboticmedicine.Forexample,itismedicallyappropriateifthe
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hemorrhageislimitedorsmallorsimplypetechial(hemorrhagicinfarctiontype)andthebenefitisjudgedtooutweightherisk.Itisexpectedthatamajorityofthecontrolgroupwillbetreatedwithsingle(ordual)antiplatelettherapy.Giventhepresenceofalargearteryocclusionwewouldrecommendnotimmediatelyusingheparinoroneofthedirectoralanticoagulantseveninthepresenceofatrialfibrillation.Wewouldrecommendthattheuseofanticoagulantsisdelayedforatleast24hoursinbothgroupsofpatients.Howeverthefinaldecisionislefttothejudgmentofthetreatingphysician.Patientsshouldnotundergoendovascularthrombectomyorthrombolysisoutsideofthetrialprotocol.Thisisconsideredaprotocolviolation.However,intheeventofaclinicaldeteriorationandthistypeofprotocolviolation,thepatientswillbeconsideredtohavesufferedanearlyrecurrentstroke(whichisapre-specifiedsecondaryoutcome),eveniftheyarecuredbyendovasculartherapy.Adverseeventsthatoccurrelatedtosuchtreatmentwillberecordedandadjudicatedaccordingly.
GuidelinesforClinicalCareItisexpectedthatsubjectswillreceivethebestusualstandardofstrokeunitcare.Allsubjectsareexpectedtobeadmittedtohospitalaspartofroutinestandardofcare.Mostsubjectswillhavemildsymptomsandrecoverin1-2daysandlikelywillbesubsequentlydischargedhome.
Itisexpectedthatallsubjectswillundergoaroutinework-upforthemechanismoftheirstrokeandbetreatedappropriatelyanddefinitively.Thisiscriticallyimportantbecausesubjectswithmildstrokesecondarytolargearterydiseaseareatthehighestriskofearlyrecurrentstroke.46Wewishtopreventrecurrentstrokefromconfoundingthe90-dayclinicaloutcomesuchthatpatientswhoarewellatdischargeremainthatwayforthedurationofthe90-dayfollow-upperiod.
Weexpectthatmostpatientswithatrialfibrillationwillbeanti-coagulated.Patientswithsymptomaticcarotidarterystenosisshouldundergocarotidrevascularizationearlyanddefinitelywithin2weeksofstrokeonset.47Riskfactors,includinghypertension,elevatedcholesterol,diabetesmellitus,tobaccosmoking,shouldbetreatedappropriatelyandaggressivelyaccordingtocurrentstandardsofcare.
Weexpectpatientstoreceiveadequatehydrationtopreventrenalcomplicationsoftheuseofradio-contrastmediafordiagnosticimaging.Whilethismedicationisgenerallyextremelysafe,simplehydrationcanpreventrenalcomplications,particularlyamongpatientswithbaselineborderlinerenalfunctionandamongthosewithdiabetesmellitus.Further,patientswithischemicstrokearegenerallyslightlyhypovolemicatbaseline.Werecommenduseofintravenousnormalsaline(0.9%saline)infusionat1.5–2.0cc/kg/huntilthepatientiseatinganddrinking
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safelyandwell.Therefore,forthetypicalpatientthiswillmeanIVNSat75-150cc/hovernightonly.WedonotrecommendtheuseofbicarbonatesolutionsorN-acetyl-cysteinesolutions.Forpatientsthataredisabledfromtheirstrokeandrequirealongerin-patientstayand/orrehabilitation,itisexpectedthattheywillreceivestandardstrokeunitcaretopreventcomplications.Theseinclude:
• DVTprophylaxisforpatientswhoarebed-boundorprimarilybed-bound• Swallowingassessmentsandpreventionofaspirationpneumonia• Earlymobilizationandphysiotherapytopreventskinbreakdown,
pneumonia,DVT/PE• Earlydiagnosisandtreatmentoffever
ImagingAllimagingcompletedofthebrain,CT,CTA,andMRIinthefirst48hwillberenderedanonymousandsenttoCalgaryforcentraladjudication.Minimallythebaseline,4-8hCTAandthe24-hourimagingshouldbeincluded.
ClinicalManagementofAdverseExperiencesAnadverseeventisanyuntowardmedicaloccurrenceassociatedwiththeuseofadruginhumans,whetherornotconsidereddrugrelated.Adverseeventscanbeanyunfavorableandunintendedsign(e.g.,anabnormallaboratoryfinding),symptom,ordiseasetemporarilyassociatedwiththeuseofadrug,withoutanyjudgmentaboutcausality.Adverseeventsoccurafterenrolmentandaredefinedasnotbeingpresentpriortoenrolment.Forexample,apatientwithknownepisodicgoutyarthritisofthegreattoe,whodevelopsanattackofgout,isnotconsideredtohavesufferedanadverseevent;theeventwasknownpriortoenrolment.Apatientwhodevelopsanewdiagnosisofgoutduringthestudyperiodisjudgedhavesufferedanadverseevent.Thisisreportableasanadverseeventeventhoughitismostlikelyentirelyunrelatedcausallytothestudydrug,butisinsteadonlyassociatedwithstudydrugusetemporally.Adverseeventsshouldbemanagedaccordingtothebestcurrentstandardofcare.
Seriousadverseevents(SAEs)arethoseadverseeventsthatarelifethreatening,requireasurgicalormedicalproceduretopreventdisabilityordeath,resultinadmissiontohospital,prolongationofhospitalizationortransfertoanICU,orresultindeath.ASAEcanalsobeanimportantmedicaleventthatmaynotresultindeath,belife-threatening,orrequirehospitalization,butmayjeopardizethesubjectandmayrequiremedicalorsurgicalinterventiontopreventoneoftheoutcomeslistedinthisdefinition.Anynewdiagnosisofcancer(madeafterstudyenrollment)isconsideredanimportantmedicalevent.ASAEisalsoaneventthatresultsinacongenitalanomalyorbirthdefect,butthisisanunlikelyconsiderationforthistrialsinceallornearlyallparticipantswillnotbeofreproductivepotential.Seriousadverseeventsshouldbemanagedaccordingtothebest
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currentstandardofcare.
AdverseEventReportingandReviewAdverseeventswillonlybecollectedthroughthefirst5daysoftrialparticipation.AdverseeventsshouldbereportedastheyoccurontheeCRF.Therearenotimelinesforreportingsimpleadverseevents.Documentationmustbesupportedbyanentryinthesubject’sfile.Eacheventshouldbedescribedindetailalongwithstartandstopdates,severity,relationshiptoinvestigationalproductasjudgedbytheInvestigator,actiontakenandoutcome. Seriousadverseevents(SAEs)willbecollectedforthefull90-daytrialperiod.SAEsmustbereportedimmediatelybytheinvestigatorwithinaveryshortperiodoftimeandundernocircumstancesshouldthisexceed24hoursfollowingknowledgeoftheSAE.SAEswillbereviewedbythetrialmedicalmonitor.SAEswillbereportedtotheappropriateregulatoryauthorityinaccordancetotherelevantregulationsandlegislationinthatregionandstate/country.BecausetheadverseeventprofileofTNK-tPAiswellknownduetotheexperienceofitsuseforcoronarythrombolysis,wedonotpredictthattherewillbeunexpectedadverseevents.
PregnanciesoccurringinstudysubjectswillbetreatedprocedurallyasSAEs.PregnanciesoccurringinstudysubjectsaftersigninginformedconsentshouldbereportedseparatelyonPregnancyReportForm.
DataSafetyandMonitoringBoard(DSMB)MembersoftheDSMBwillbeacknowledgedpublicallybutwillnotbeconsideredauthorsforanymanuscriptsthatarisefromthistrial.
ExpectedDrugReactionsForexpectedadversedrugreactions(ie.withrelationshiptoMetalyseorTNKase)investigatorsaredirectedtotheproductmonograph.
CriteriaforInterventionDiscontinuationBecausethestudydrugisadeliveredbyasingleintravenousbolusinjection,itwillnotbepossibletodiscontinuetheintervention.
Intheeventthatasubjectwithdrawsconsentforfollow-upinthestudy,thatsubjectwillbediscontinuedfromthetrialonthedateoftheirwithdrawalofconsent.Datacollectedpriortothisdatewillbeincludedinthefinalstudyreport.
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StatisticalConsiderationsAsampleof1228patientsallowsustodemonstratea9%absoluteriskdifference(60%à69%primaryoutcome)with90%powerbetweeninterventionandcontrolgroups.Therecentpooledthrombolysisshowedaneffectsizeof10%inthesubsetofminorstrokepatientstreatedwiththrombolysis.8Enrollmentinthetrialsincludedinthemeta-analysisdidnotrequirepatientstohaveanintracranialocclusion,thusitislikelythatthemajorityofthesepatientsdidnothaveanintracranialocclusion.Thusalthoughweexpectthattheeffectsizeishigherinapopulationthatonlyincludespatientswithintracranialocclusionwewillconservativelyestimateanoverall9%effectsizewithachangeinproportionwithexcellentneurologicaloutcomefrom60%to69%.Thesamplesizeforeachgroupis614(1228total).Adding4%losstofollowupgivesasamplesizeestimateof1274patients(637ineachtreatmentgroup).Therewillbeongoingmonitoringforsafetyandfulldetailswillbeavailableinaformalsafetyplan.Asingleinterimanalysisforfutilityandefficacywillbeconductedatapproximatelytwo-thirdspatientenrolment(n=840).StandardO’BrienFlemingboundarieswillbeusedtoestablishthealphaspendingfunction.FulldetailswillbeavailableintheDSMBcharter.Itispossiblethataftercentralimagingreviewsomepatientswillbeenrolledinviolationoftheprotocolorthetreatmentprotocolmaybebreechedduetothedynamicnatureofacutestroke.Thismayoccurentirelyinthebestinterestsofpatientcare.Intheprimaryanalysis,allrandomizedpatientswillbeincludedinthefinalanalysisforsafetyandclinicaloutcome(ITTanalysis).Thesafetypopulationwillbedefinedasallpatientswhoreceiveanydoseofstudydrug.Theper-protocolpopulationwillbedefinedasallpatientswhoreceivedanydoseofstudydrugandmetalltheinclusionandexclusioncriteria.Secondaryanalyseswillincludeanalysisofthepre-statedsecondaryoutcomesandmultivariableanalysesofboththeprimaryoutcomesandpre-statedsecondaryoutcomes.AformalStatisticalAnalysisPlanwillbedocumentedpriortobreakingoftheblind.
DataCollectionandManagementOverviewDatawillbehousedandmanagedinacustomdatabaseattheHotchkissBrainInstituteClinicalResearchUnitinCalgary,AB,Canadausingregulatorycompliantdatasystems.
HumanSubjectsLocalRegulations/DeclarationofHelsinkiTheSponsor-Investigator(andanyParticipatingSiteInvestigators)willensurethatthisstudyisconductedinfullconformancewiththeprinciplesofthe“Declarationof
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Helsinki”orwiththelawsandregulationsofthecountryinwhichtheresearchisconducted,whicheveraffordsthegreaterprotectiontotheindividual.Thestudymustfullyadheretotheprinciplesoutlinedin“GuidelineforGoodClinicalPractice”ICHTripartiteGuidelineorwithlocallawifitaffordsgreaterprotectiontothepatient.
EthicsapprovalThisprotocolandtheinformedconsentdocumentandanysubsequentmodificationsarereviewedandapprovedbythelocalethicscommitteeresponsibleforoversightofthestudy.Approvalfromthecommitteemustbeobtainedbeforestartingthestudy,andshouldbedocumentedinalettertotheSponsor-Investigator(andanyParticipatingSiteInvestigators)specifyingthedateonwhichthecommitteemetandgrantedtheapproval.Asignedconsentformmustbeobtainedfromthesubject.Incertaincountries/jurisdictionswherepermitted,forsubjectswhocannotprovideconsentthemselves,alegallyauthorizedrepresentative,orpersonwithpowerofattorney,maysigntheconsentform.Theconsentformdescribesthepurposeofthestudy,theprocedurestobefollowed,andtherisksandbenefitsofparticipation.Acopyoftheconsentformmustbegiventothesubject,thelegallyauthorizedrepresentative,orthepersonwithpowerofattorney;andthisfactmustbedocumentedinthesubject’srecord.Ifnewsafetyinformationresultsinsignificantchangesintherisk/benefitassessment,theconsentformshouldbereviewedandupdatedifnecessary.Allpatients(includingthosealreadybeingtreated)shouldbeinformedofthenewinformation,givenacopyoftherevisedform,andgivetheirconsenttocontinueinthestudy.
ConditionsforTerminatingtheStudyTheSponsor-Investigatorreservestherighttoterminatethestudyatanytime.Shouldthisbenecessary,theSponsor-InvestigatorwillworkwithanyParticipatingSiteInvestigatorstoarrangetheproceduresonanindividualstudybasisafterreviewandconsultation.Interminatingthestudy,theSponsor-Investigator(andanyParticipatingSiteInvestigators)willassurethatadequateconsiderationisgiventotheprotectionofthepatients’interests.
ConfidentialityAllimaging,evaluationforms,reports,andotherrecordsthatleavethesiteareidentifiedonlybythesiteandsubjectnumbertomaintainsubjectconfidentiality.Allrecordsarekeptinalockedfilecabinet.Clinicalinformationisnotreleasedwithoutwrittenpermissionofthesubject,exceptasnecessaryformonitoringbyethicscommittees,regulatorybodies,thesponsor,orthesponsor’sdesignee.Allstudyinvestigatorsattheclinicalsitesmustensurethattheconfidentialityofpersonalidentityandallpersonalmedicalinformationofstudyparticipantsismaintainedatalltimes.Countryspecificprivacyregulationswhereapplicable,mustbefollowed.OntheCRFsandotherstudydocumentsorimagematerialssubmittedtotheCRU,thesubjectsareidentifiedonlybystudyidentificationcodes.
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PersonalmedicalinformationmaybereviewedforthepurposeofverifyingdatarecordedintheCRFbythesitemonitors.Otherproperlyauthorizedpersons,suchastheregulatoryauthorities,mayalsohaveaccesstotheserecords.Personalmedicalinformationisalwaystreatedasconfidential.
SiteMonitoringAllsiteswillhaveremotedatamonitoringconductedbythecentraltrialsstaff.Datawillbecheckedforcompleteness,logic,andvalidity.Querieswillbesenttositestoverifydataasrequired.Foron-sitemonitoringavarietyofrisk-basedmonitoringmodelswillbeused.Thismayincludebothtrainedemployeesandindustryexperiencedindependentcontractorclinicalresearchmonitors.Detailsofmonitoringwillbeinaseparatesitemonitoringplan.
StudyDocumentation,CRFsandRecordKeeping
Investigator'sFiles/RetentionofDocumentsTheSponsor-Investigator(andanyParticipatingSiteInvestigators)mustmaintainadequateandaccuraterecordstoenabletheconductofthestudytobefullydocumentedandthestudydatatobesubsequentlyverified.Thesedocumentsshouldbeclassifiedintotwodifferentseparatecategories:(1)Investigator'sStudyFile;and(2)patientclinicalsourcedocuments.
TheInvestigator'sStudyFilewillcontaintheprotocol/amendments,CaseReportandQueryForms,ethicscorrespondenceandgovernmentalapprovalwithcorrespondence,sampleinformedconsent,drugrecords,staffcurriculumvitaeandauthorizationformsandotherappropriatedocuments/correspondence,etc.Someorallofthesefilesmaybestoredelectronically.
Patientclinicalsourcedocuments(usuallydefinedbytheprojectinadvancetorecordkeyefficacy/safetyparametersindependentoftheCRFs)wouldincludepatienthospital/clinicrecords,physician'sandnurse'snotes,appointmentbook,originallaboratoryreports,ECG,diagnosticimaging,pathologyandspecialassessmentreports,signedICFs,consultantletters,andpatientscreeningandenrollmentlogs.TheSponsor-Investigator(andanyParticipatingSiteInvestigators)mustkeepthesetwocategoriesofdocumentsonfilefor25yearsaftercompletionordiscontinuationofthestudy.Afterthatperiodoftimethedocumentsmaybedestroyed,subjecttolocalregulations.
SourceDocumentsandBackgroundDataAnyParticipatingSiteInvestigatorsshallsupplytheSponsor-Investigatoronrequestwithanyrequiredbackgrounddatafromthestudydocumentationorclinicrecords.ThisisparticularlyimportantwhenCRFsareillegibleorwhenerrorsindatatranscriptionaresuspected.Incaseofspecialproblemsand/orgovernmental
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queriesorrequestsforauditinspections,itisalsonecessarytohaveaccesstothecompletestudyrecords,providedthatpatientconfidentialityisprotected.
AuditsandInspectionsTheSponsor-InvestigatorandanyParticipatingSiteInvestigatorsshouldunderstandthatsourcedocumentsforthistrialshouldbemadeavailabletoappropriatelyqualifiedpersonnelfromtheSponsor-Investigatorordesigneeortohealthauthorityinspectorsafterappropriatenotification.TheverificationoftheCRFdatamustbebydirectinspectionofsourcedocuments.
CaseReportFormsForeachpatientenrolled,aCRFmustbecompletedandsignedbytheSponsor-Investigator(andanyParticipatingSiteInvestigator)orauthorizeddelegatefromthestudystaff.Thisalsoappliestorecordsforthosepatientswhofailtocompletethestudy.Ifapatientwithdrawsfromthestudy,thereasonmustbenotedontheCRF.
Allformsshouldbefilledoutclearlyandlegibly.Errorsshouldbecrossedoutbutnotobliterated,thecorrectioninserted,andthechangeinitialedanddatedbytheSponsor-Investigator(andanyParticipatingSiteInvestigators)orhis/herauthorizeddelegate.TheSponsor-Investigator(andanyParticipatingSiteInvestigators)shouldensuretheaccuracy,completeness,legibility,andtimelinessofthedatareportedtotheSponsor-InvestigatorintheCRFsandinallrequiredreports.
PublicationandPresentationPolicyThetrialexecutivecommitteewillbeco-authorsonallpublicationsandpresentations.Theprimaryauthorlistfortheprimarypublicationwillconsistoftheexecutivecommitteeandthesiteprincipalinvestigatorateachofthesites.Theresultsofthisstudymaybepublishedorpresentedatscientificmeetings.
AncillaryStudiesPolicyAncillaryorsub-studiesmaybeconsideredbythetrialexecutivecommittee.Importantprinciplesthatguidetheadditionofancillarystudiesare:
(1) nopatientshallbeenrolledinaconcurrentinvestigationaldrug/devicetrialduringthestudyperiod.
(2) concurrentenrollmentofaTEMPO-2studypatientinasitespecificobservationalcohortstudyisallowable,wherethefollowingconditionsaremet:
a. theexecutivecommitteeisnotifiedb. theconcurrentstudydoesnotinterferewithanystudyfollow-up
proceduresorpotentiallyconfoundtheoutcomeoftheTEMPO-2trial
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c. thesitePIoftheconcurrentstudyexplicitlyacknowledgesthatthetreatmentgivenintheTEMPO-2trialmayconfoundtheoutcomeofthesite-specificconcurrentstudy
d. thepatientmaynotbeincludedinanypublicationorreportuntiltheTEMPO-2studyhasbeenconcludedandpublished.
(3) Ancillaryorsub-studiesshallbevettedandapprovedbythetrialexecutivecommittee.
Data-sharingplanTheExecutiveCommitteewillfollowthespiritoftheNIHpolicyondata-sharing[http://grants2.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm].Inaddition,theExecutiveCommitteewillfollowtheCIHRguidelinesonpublicaccesstotrialresultsandmaketheresultsavailableasfree-accessusingPubMed.UponcompletionoftheTEMPO-2Trial,apublicusedatabasewillbepreparedbystrippinganyandallpersonalidentifiers.Thepublicusedatabase,consistingofseveraldatafiles,shouldcontain:(1)baselineanddemographiccharacteristics;(2)outcomesassessments;(3)CT/MRIdata;(4)concomitantmedicationsandprocedures;and(5)adverseevents.EachdatafileismadeavailableasaformattedSASdatasetorotherelectronicformat.Thedatafilesaredistributedalongwiththedatadictionaryandabriefinstruction(“Readme”)file.Thesedatafileswillbemadeavailabletothepubliconlyafterallmajormanuscripts(includingsecondaryanalysispapers)oftheTrialareacceptedforpublicationinpeer-reviewedjournals.
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Appendix1:StructuredmRS-TakenfromBrunoetal.35