JOVIN Banff DAWN February2106.pptx.pdf

THE DAWN TRIAL AND THE STATUS OF ENDOVASCULAR TREATMENT FOR ACUTE STROKE

BEYOND 6 HOURS

Tudor G. Jovin, M.D.

Associate Professor of Neurology and NeurosurgeryDirector, UPMC Stroke Institute

Director UPMC Center for Neuroendovascular TherapyUniversity of Pittsburgh Medical Center

SHOULDTHEREBEATIMEWINDOWFORACUTESTROKEINTERVENTIONS???

DISCLOSURES

Consultant/AdvisoryBoard:OwnershipInterest:SilkRoadMedical–modest

Consultant/AdvisoryBoard:Covidien/Medtronic:unpaid

Consultant:StrykerNeurovascularunpaid

PI:REVASCAT(FundacioIctusMalalGaVascular),unpaid

PI:DAWN(StrykerNeurovascular),unpaid

Consultant:CodmanNeurovascular(DSMBmember–modest)

Infarct volume (both treatment groups) strongly correlates with clinical outcome

(p<0.0001) P<0.0001

SWIFTPRIME,AlbersG.,etal,Stroke2015 IMS3,JovinT.,etal,ISC2015

DarbyDGetal.Stroke.1999;30(10):2043

0 6 12 18 24

%

Time(hr)A=erStrokeOnset

PenumbralCore

00

25

50

75

100

Ischemic Penumbra

CORE

SERIALMRI’S(CORONALSECTIONS)ATTHREELEVELSINTHEBRAINDEPICTINGTHEAPPARENTDIFFUSIONCOEFFICIENTOFWATER(ADC)(MARKEDBYTHEBLUECOLOUR)DEMONSTRATINGTHETIME-DEPENDENTGROWTHOFTHEISCHEMICCORE.

PROGRESSIVE GROWTH OF CORE IN MCA OCCLUSION

Hossmanetal.,CellMolNeurobiol,2006

DEFUSE2

-20

30

80

130

180

230

0 2 4 6 8 10 12

Baselin

eDW

IVolum

e(m

l)

TimebetweenSymptomOnsetandBaselineMRI(hrs)

Initial Growth Rate: Known Onset & M1 Occlusion

WheelerHM,etal.IntJStroke.2015

DEFUSE2

-20

30

80

130

180

230

0 2 4 6 8 10 12

Baselin

eDW

IVolum

e(m

l)

TimebetweenSymptomOnsetandBaselineMRI(hrs)

Initial Growth Rate: Known Onset & M1 Occlusion

WheelerHM,etal.IntJStroke.2015

COLLATERALS

Baseline MRI DEFUSE protocol

65YEAROLDMANPRESENTSWITHNIHSSOF15,9HOURSPOSTSX’SONSET.CTA-LICAOCCLUSION

Khatri,LancetNeurology,2014

INTHEEARLYTIMEWINDOWIT’SALLABOUTTHETIMETOREPERFUSION

Every30minutedelayinreperfusionisassociatedwitha10%rela<vereduc<oninprobabilityof

goodclinicaloutcome(mRS0-2).

N=183MedianASPECTS:8

Every30minutedelayinreperfusionisassociatedwitha5%rela<vereduc<oninprobabilityofgoodclinicaloutcome(mRS0-2).

Fransenetal.,JAMANeurol2016

RELATIONSHIPBETWEENTIMEFROMONSETTOREPERFUSIONANDGOODOUTCOMESINMRCLEAN

N=115MedianASPECTS=9

KHATRICURVEREVISITED

RELATIONSHIPBETWEENONSETTOREPERFUSIONANDLIKELIHOODOFGOODOUTCOMEINESCAPE

CourtesyofDr.BMenon

N=113MedianASPECTS=9

Every30minutedelayinreperfusionisassociatedwitha0.5%rela<vereduc<oninprobabilityof

goodclinicaloutcome(mRS0-2).

KHATRICURVEREVISITED

RELATIONSHIP BETWEEN TIME FROM ONSET TO REPERFUSION AND GOOD OUTCOMES IN REVASCAT

ProbabilityofmRS0-2-5%every30’ N=67

MedianASPECTS:7

RiboM,etal.,ESOC2015

Every30minutedelayinreperfusionisassociatedwitha5%rela<vereduc<oninprobabilityofgoodclinicaloutcome(mRS0-2).

KHATRICURVEREVISITED

Only OR values with 95% CI < 1 are shown

-26% for each 30´ -28% for each 30´

-44% for each 30´ -50% for each 30´

LIKELIHOOD OF GOOD OUTCOME ACCORDING TO TIME INTERVALS FROM SX’S ONSET TO REPERFUSION AND

ASPECTS

Ribo et. al., Stroke, in press

RELATIONSHIP BETWEEN TIME FROM ONSET TO REPERFUSION AND GOOD OUTCOMES IN DEFUSE 2

N=46Medianbaselineinfarctvolume=16cc

LansbergM.etal.,Neurology2015

DEFUSE 2: Response to reperfusion is not time-dependent

in patients with salvageable tissue (mismatch)

16 LansbergandCereda,etal.Neurology;Aug2015

Treatment<6hoursTreatment>6hours

WAKEUPSTROKEVSWITTNESEDONSETBEYOND8HRS-ISTHEREADIFFERFENCEINOUTCOMESWITHIAT?

AghaebrahimA.etal.,JNIS2015

SHOULD WE TREAT PATIENTS WITH LVO AND MISMATCH BEYOND 6 HOURS WITH NO TIME LIMIT ???

88 year old woman with L M1 occlusion, TLSW 22 hours, NIHSS 21, no intervenVon mRS at 3 weeks: 3

BaselineMRI/MRA–NIHSS21

4dayMRI/MRA–NIHSS11

MCAocclusion

MCAparGallyrecanalized

88 year old woman with R M1 occlusion, TLSW 20 hours, NIHSS 17, no intervenVon mRS at 30 days 1

BaselineMRI/MRA

Follow-upMRI/MRAat24hours(NIHSS17)–noinfarctgrowthandparGalrecanalizaGon

61 year old man with R M1 occlusion, TLSW 14 hours, NIHSS 21, no intervenVon 3 months mRS 4

BaselineMRI/MRA/CTP

MRI/MRAat24hours,NIHSS20

MRIatday5,NIHSS18

OverviewTitle DWIorCTPAssessmentwithClinicalMismatchintheTriageof

WakeUpandLatePresenGngStrokesUndergoingNeurointervenGon(DAWN)

Sponsor StrykerNeyrovascularInc.

PIs TudorG.Jovin,MDandRaulG.Nogueira,MD

Funding StrykerNeurovascularInc.

Studydevice Trevo®ProVue™andTrevo®XPProVue™Retrievers

ControlintervenGon(IV-tPAyes/no?)

Bestmedicaltherapyincludingivt-PAineligiblepaGents(whichwillbeesGmatedtomakeupmaximium20%oftotal)

StudypopulaGon AcutestrokepaGentswithnoupperagelimitpresenGnginthe6-24hourGmewindowwithproximalanteriorcirculaGonocclusions(M1,ICAT)andsubstanGalclinical/coremismatch

ObjecGve ToevaluatethehypothesisthatTrevothrombectomyplusmedicalmanagementleadstosuperiorclinicaloutcomesat90daysascomparedtomedicalmanagementaloneinappropriatelyselectedsubjectsexperiencinganacuteischemicstrokewhentreatmentisiniGatedwithin6-24hoursamerlastseenwell.

DAWN Trial: Why Do We Need to Do It?

“PaGentseligibleforintravenousrtPAshouldreceiveintravenousrtPAevenifintra-arterialtreatmentsarebeingconsidered.”

ClassI LevelofEvidenceA UnchangedGuideline

EndovascularProtocolandPa`entSelec`on

PaGentsshouldreceiveendovasculartherapywithastentretrieveriftheymeetallthefollowingcriteria

a)  prestrokemRSscore0to1,b)  acuteischemicstrokereceivingintravenousr-tPAwithin4.5hoursofonset

accordingtoguidelinesfromprofessionalmedicalsocieGes,c)  causaGveocclusionoftheinternalcaroGdarteryorproximalMCA(M1),d)  age≥18years,e)  NIHSSscoreof≥6,f)  ASPECTSof≥6,andg)  treatmentcanbeiniGated(groinpuncture)within6hoursofsymptomonset

NewRecommenda`onClassI LevelofEvidenceA

WilliamJ.Powers,ColinP.Derdeyn,JoséBiller,ChristopherS.Coffey,BrianL.Hoh,EdwardC.Jauch,KarenC.Johnston,S.ClaiborneJohnston,AlexanderA.Khalessi,ChelseaS.Kidwell,JamesF.Meschia,BruceOvbiagele,andDileepR.Yavagal.“2015AHA/ASAFocusedUpdateofthe2013GuidelinesfortheEarlyManagementofPaGentsWithAcuteIschemicStrokeRegardingEndovascularTreatment:AGuidelineforHealthcareProfessionalsFromtheAmericanHeartAssociaGon/AmericanStrokeAssociaGon.”AmericanHeartAssociaGonStrokeCouncil.StrokePublishedonlineJune29th2015.

Raul Nogueira, MD

ForEvery10RandomizedPaGents

NNT=5

1:1RandomizaGon

5EndovascularArm 5ControlArm

DAWN

OpenRx

AssumingtheDAWNTreatmentParadigmisbeneficialandhasaverystrong

treatmenteffect(NNT=5)wewouldbemissingtheopportunitytohelponly1forevery10paGentsinthetrial

WhatistheWorstPriceWeCouldPay?

Counterpoints Supporting Equipoise: Why DAWN Can Fail?

Longer Time from Stroke Onset to Treatment = ? Increased Risk of Hemorrhagic Transformation Longer Time from Stroke Onset to Treatment = ? Worse Reperfusion Rates Longer Time from Stroke Onset to Treatment = Better Collaterals = ? Better Natural History RCTs of Delayed IV Thrombolysis (including Mismatch-Based) Have Failed to Show a Benefit

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DAWN™ Trial

PrimaryObjecGveDWIorCTPAssessmentwithClinicalMismatchintheTriageofWake-UpandLatePresenGngStrokesUndergoingNeurointervenGon

ToevaluatethehypothesisthatTrevothrombectomyplusmedicalmanagementleadstosuperiorclinicaloutcomesat90daysascomparedwithmedicalmanagementaloneinappropriatelyselectedsubjectsexperiencinganacuteischemicstrokewhentreatmentisiniGatedwithin6-24hrsamerlastseenwell.

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Trevo® Retriever Thrombectomy Procedure

PhotographsandillustraGonsprovidedbyStrykerNeurovascular.

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• ProspecGve,randomized(1:1),mulG-center,PhaseII/III(feasibility/pivotal),adapGve,populaGonenrichment,blindedendpoint,controlledtrial

• Upto50sites(worldwide)•  150subjects(feasibility)upto500(pivotal)max• Primaryendpoint:

•  DifferencebetweentheaverageweightedmRSat90daysbetweentreatmentandcontrolgroups

DAWN™ Trial Design

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DAWN™ Trial Unique Design Elements

PrimaryEndpoint:WeightedmRS

•  DesignedtocapturehealthstatetransiGonsacrosstheenGrespectrum•  EndpointthatisacombinaGonofbothefficacyandsafety•  DifferenGatesoutcomes•  PaGent-centeredoutcomesanalysis

Enrichment

•  DesignedtofinetunethepaGentpopulaGonbasedoncoreinfarctsize•  IdenGfysubgroupsexperiencingclinicalbenefit

mRS 0 1 2 3 4 5 6

Weight 10 9.1 7.6 6.5 3.3 0 0

Designedtomeasure

effecGveness&safetyinsingle

endpoint

0-50ccà0-45ccà0-40ccà0-35ccà0-30cc

hwp://dawntrial.trainingcampus.net

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UTILITY WEIGHTED MRS VS OTHER MODALITIES

Chasnainunkul,Saveretal.,Stroke2015

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DAWN™ Trial Unique Design Elements

ClinicalImagingMismatch

•  Standardizesclinicalimagingtoselectsubjects

•  LiteraturesupportscoreinfarctsizebeingpredicGveofoutcomes

• NIHSSassessment(clinicaldeficit)representsGssueatriskinrealGme,canbeeasilyadministered(andrepeated)mulGpleGmes,andisvalidatedinclinicalpracGce

CLINICAL EXAM (NIHSS): A GOOD ESTIMATION OF THE AT RISK TERRITORY ??

Davalosetal.,Neurology2004

DAWN™ Clinical Trial

RandomizaGonBalancedre:CIMsubgroup,GmeandocclusionlocaGon

StandardizedRAPIDsomware

ProximalOcclusion:

ICA-Tand/orMCA-M1Occlusion

ClinicalMismatch:

NIHSS>10

+SmallInfarct

Goal: To idenVfy the Target Mismatch PaVent in the 6-24h Window (including Wake-Up Strokes)

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ClinicalImagingMismatch(CIM)definedasoneofthefollowingonRAPIDMR-DWIorCTP-rCBFmaps:

a.  0-20cccoreinfarct&NIHSS≥10(&≥80yrsold)b.  0-30cccoreinfarct&NIHSS≥10(&<80yrsold)c.  31to≤50cccoreinfarct&NIHSS≥20(&<80yrsold)

WriwenConsentfromsubjectorLAR(ifnotobtainedpriortoRAPID)

Age≥18NIHSS≥10

Pre-strokemRS0-1<1/3MCAterritoryinvolved,asevidencedbyCTorMRI

OcclusionoftheintracranialICAand/orMCA-M1,byMRAorCTASubjectcanberandomizedwithin6-24hfromTLSW

DAWN Flow Chart – Screening and Enrollment

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RAPIDSo=warestandardizesmeasurementofcoreinfarctsize•  SupportsobjecGvityinarandomizedclinicaltrial•  Especiallyimportantfor6+hourpaGentpopulaGonwithunknowntreatmenteffect

• ONLYtheRAPIDcoreinfarctsizemaybeusedtodetermineeligibilityandstraGficaGon

• MRI-DWIorCTP-rCBF•  510(k)clearedhoweverDAWNTrialversioncanONLYbeusedforstudysubjectevaluaGon

• BaselineNIHSSmustbeobtainedwithin1houroftheRAPIDprocessedimagesusedforqualificaGon

DAWN™ Trial uses RAPID Socware

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Safety Outcomes

•  Incidenceofstroke-relatedmortalityat90days•  IncidenceofsICH,byECASSIIIdefiniGon,within24(-6/+24)hrspostrandomizaGon(Gmezero)

•  IncidenceofneurologicaldeterioraGonfrombaselineNIHSSscorethroughDay5-7/Discharge(whicheverisearlier)postrandomizaGon(Gmezero).NeurologicaldeterioraGonisdefinedas≥4pointincreaseintheNIHSSscorefromthebaselinescore.

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Site Status Maximum Number of Sites 31 Contracts Executed 21 Sites Qualified 31 Initiation Training Complete 26 IRB/EC Approvals 28 Subjects Enrolled 74

DAWN Trial Update (as of 18-Feb-2016)

Actual / Projected Enrollment

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Enrollment by Authorized Site (as of 18-Feb-2016)

0

0

0

0

0

0

0

1

1

1

2

2

2

4

5

6

7

17

26

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Baptist Jacksonville (Dr. Hanel, ATE 01/21/16)

Christiana (Dr. Satti, ATE 01/21/16)

Kaiser LA (Dr. Feng, ATE 11/19/15)

Royal Melbourne (Dr. Mitchell, ATE 11/12/15)

KUMC (Dr. Abraham, ATE 02/01/16)

Florida Hospital (Dr. Hellinger, ATE 11/09/15)

Rush (Dr. Chen, ATE 05/07/15)

Buffalo (Dr. Levy, ATE 12/01/15)

CPMC (Dr. English, ATE 05/05/15)

Capital (Dr. Vez, ATE 07/01/14)

Erlanger (Dr. Devlin, ATE 06/05/15)

Hopital Purpan Toulouse (Dr. Cognard, ATE 01/28/16)

Abington (Dr. Shah, ATE 10/29/15)

Valley Baptist (Dr. Hassan, ATE 03/31/15)

UH Cleveland (Dr. Sila, ATE 05/04/15)

Riverside (Dr. Budzik, ATE 08/28/14)

Texas Stroke Institute (Dr. Bhuva, ATE 04/10/15)

Grady (Dr. Nogueira, ATE 11/25/14)

UPMC (Dr. Jadhav, ATE 10/31/14)

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DAWN Time Points

61

111

133

78

27

0

20

40

60

80

100

120

140

Door to

Imaging

Door to

Randomization

Door to

Puncture

Imaging to

Puncture

Randomization to

Puncture

DAWN Trial Median Time Points (Minutes)

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CURRENT ENROLLMENT STATUS

•  Stroke/Interven`onalNeurology•  TudorJovin,MD

•  AshuJadhav,MDPhD

•  LawrenceWechsler,MD

•  MaximHammer,MD

•  VivekReddy,MD

•  MawStarr,MD

•  ViktoriaTotoraiGs,MD

•  NimaAghaebrahim,mD

•  DanVictorGiurgiuGu,MD

•  VascularEndovascularNeurosurgery•  BrianJankowitz,MD

•  AndrewDucruet,MD

•  RobertFriedlander,MD

•  PaulGardner,MD

•  DanWecht,MD

•  StrokeIns`tuteNursingStaff•  LoriMassaro–CRNP

•  SusanKim-CRNP

•  MariaAbraham–PA

•  ChrisGnaBonaccorsi–PA

•  KathySeiler,RN

•  CherieAdamsRN

•  JonyaBrooks,RN

•  KenCoval,RN

•  Pa{Williams,RN

•  Neurocri`calCare•  BradMolyneaux,MD

•  LoriShuwer,MD

•  SherryChou,MD

•  RuchiJha,MD

•  KeesPolderman,MD

•  Neuroanesthesia•  ColeenMoran,MD

•  FrankGyulai,MD

•  TheresaGelzinis,MD

•  EmergencyMedicine•  CharissaPacella,MD

•  FrankGuyewe,MD

•  ChrisGill-MarGn,MD

•  CliffCallaway,MD

•  DonYealy,MD

•  MikeTurturro,MD

•  MariaGuyewe,MD

•  Neuroradiology•  BillDelfyew,MD

•  CharBranstewer,MD

•  EmanuelKanal,MD

•  StrokeIns`tuteResearchStaff•  LisaBaxendell–Researchcoord

•  CarlynnGraves–Researchcoord

•  PatriciaPorter–Researchcoord

•  KaraArmbruster–Researchcoord

•  YvonneCannon–Researchcoord

•  HollyKromer-DataManagement

•  NeuroIRRadiologyTechs&NursingStaff•  KiwyO’Toole,RTVI

•  CaseyFoster,RTVI

•  JenniferHamil,RTVI

•  JimBozak,RTVI

•  JasonPaul,RTVI

•  CandaceAcklin,RN

•  JosieStashko,RN

•  Neurorahabil`a`on•  JenniferShen

•  CaraCamiolo

•  MikeBonimnger

•  NeuroscienceNursing•  MelanieSmith,RN

•  BenMorrow,RN

•  KateSpiering,RN

•  ThereseDawson,RN

UPMCACUTEENDOVASCULARSTORKETEAM