TheRESCUEBRAINstudy:AFrenchmulticenterrandomizedtrialonneuroprotectionwithlowerlimb

ischaemicper-conditioningintheacutephaseofcerebralinfarction(<H6)

F Pico, B Lapergue, M Ferrigno, ML Chadenat, F Bourdain, E Meseguer, M Obadia, C Hirel , DLDuong,SDeltour,CRosso,PAegerter,JLabreuche,ACattenoy,DSmadja,HHosseini,BGuillon,VWolff,YSamson,CCordonnier,PAmarenco,onbehalftheRESCUEBRAINinvestigators

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TheuniquesourceoffundingisagrantfromtheFrenchMinistryofHealth(PHRC).Therewasnoindustryfundingorinvolvementinanyaspectofthetrial

•  Thereisaneedforneuroprotectiveagent.

•  Ischemicconditioning:transientischemiawithoutnecrosis.Endogenousmechanism

•  Ingoodqualitypreclinicalstudiesinbraininfarction(STAIRrecommendation):positiveresultsØ  RIPerCeffectivealone.AdditiveeffectwithrTPainamurinemodelofembolicstroke(Hodaetal.Stroke2012)

•  Promisingresultsincardiologyinmyocardialinfarction:Ø  Botkeretal.Lancet2010,CONDI2Largeongoingtrial(n=5400).Nosafetyissue

BACKGROUND

ToevaluateifremoteischemicPer-Conditionning(RIPerC)intheunaffected

lowerlimb,performedinthefirst6hoursofcerebralinfarctionreducesthe

growthofthebraininfarction

OBJECTIVE

•  RESCUEBrainisaninterventional,randomized,multicentertrialwithPROBEdesign

•  (ProspectiveRandomizedOpen,BlindedEnd-point)

•  Sourceoffunding:PHRCIR2014-A00104-43(MinistryofHealth)

•  ApprovedbytheInstitutionalReviewBoard(IRB)(IledeFranceXI,approvalnumber14023).

•  ClinicalTrials.govIdentifier:NCT02189928

•  DesignpublishedinIntJStroke.2016Oct;11(8):938-943.

•  RandomizationhasbeenstratifiedonthecenterandonIVthrombolysis.(Draftin2013)

•  MechanicalthrombectomywasallowedfollowingIVthrombolysis(Draftin2013)

•  Interimanalysisathalfrecruitment(n=102patients)

DESIGN

Patientsintheinterventiongroup:•  Cuffisplacedinthethigh(unaffectedside)•  TargetinflationBP=110mmHgabovesystBP•  Electronictourniquetisprogramtodeliver•  4cyclesof5mininflation•  With4cyclesofdeflationinbetween•  Totalduration=40minutes

PrimaryEndpoint:•  DWIvolume(cc)H24-Baseline(<H6)•  CentrallabforlectureofbrainMRI,

blindedtoclinicaldata,dateofMRI.

Maininclusioncriteria:•  patientswithcarotidBI•  provenbybrainMRI<H6•  NIHSSscore:5and25.

DESIGN

I:5’ D:5’ I:5’ D:5’ I:5’ D:5’ I:5’ D:5’

PatientsintheControlgroup:•  Thecuffisplacedbutnoinflation

RDWI<H6 DWIH24

(H24-H36)

•  H24NIHSS•  D7:NIHSS•  M3:Rankin

RESCUEBRAINNetwork11Frenchstrokecenters(7inParisarea)

BrainMRIDrRossoDrHirel

PrAmarenco DrMeseguer

DrPiotinDrObadia

PrSamsonDrDeltourPrHosseini

DrGuillon

PrWolff

PrCordonnier DrFerrigno

PrSmadja

PrPico DrChadenat

DrLapergue DrConsoli

DrRonzière

FLOWCHART

Baselinedemographics

andmedicalhistory

Overall

(N=188)

rIPerC

(N=93)

Control

(N=95)

Age,years,mean(SD) 67.2(15.7) 67.8(15.1) 66.7(16.4)

Men 98/188(52.1) 45/93(48.4) 53/95(55.8)

BMI,Kg/m2,mean(SD)1 26.3(5.4) 26.2(5.1) 26.5(5.8)

Medicalhistory

Hypertension 98/188(52.1) 48/93(51.6) 50/95(52.6)

Diabetes 30/188(16.0) 12/93(12.9) 18/95(19.0)

Hypercholesterolemia 72/188(38.3) 32/93(34.4) 40/95(42.1)

Currentsmoking 30/179(16.8) 14/88(15.9) 16/91(17.6)

Coronaryarterydisease 24/188(12.8) 12/93(12.9) 12/95(12.6)

PreviousstrokeorTIA 24/188(12.8) 11/93(11.8) 13/95(13.7)

Previousatrialfibrillation 32/188(17.0) 18/93(19.4) 14/95(14.7)

BASELINECHARACTERISTICS

CurrentstrokeeventOverall

(N=188)

rIPerC

(N=93)

Control

(N=95)

AdmissionNIHSSscore,median(IQR) 10(6to16) 9(6to15) 10(7to17)

OnsettobaselineMRItime,min,median(IQR) 104(82to145) 105(81to147) 103(83to142)

OcclusionatMRI

None 59/188(31.4) 30/93(32.3) 29/95(30.5)

MCA 94/188(50.0) 45/93(48.4) 49/95(51.6)

CervicalICA 6/188(3.2) 6/93(6.4) 0/95(0.0)

CarotidT 11/188(5.9) 6/93(6.4) 5/95(5.3)

Others 18/188(9.6) 6/93(6.4) 12/95(12.6)

Baselinebraininfarctvolume,cm3,median(IQR)3 11.4(3.6to35.8) 10.2(3.4to38.7) 12.2(3.7to32.3)

BASELINECHARACTERISTICS

TreatmentsofcurrentstrokeeventOverall

(N=188)

rIPerC

(N=93)

Control

(N=95)

IVthrombolysis 164/188(87.2) 82/93(88.2) 82/95(86.3)

OnsettoIVthrombolysistime,min,median(IQR) 149(111to179) 154(111to186) 145(112to175)

Endovasculartreatment 64/188(34.0) 30/93(32.3) 34/95(35.8)

Onsettogroinpuncturetime,min,median(IQR) 187(145to247) 187(130to250) 182(150to245)

OnsettorIPerCtime,min,median(IQR) - 222(176to275) -

BASELINECHARACTERISTICS

•  87%ofpatientshavebeentreatedbyI.V.thrombolysiswithamediantimeof2h30•  34%patientshavebeentreatedbyendovasculartreatmentwithamediantimeof3h10•  ConcerningrIPerCthemediantimebetweenstrokeonsetandcuffinflationwas3h40.

BrainMRIVolume rIPerC(n=93) Control(n=95) P-Value

ITTanalysis

Baseline,median(IQR) 9.3(3.4to38.3) 12.2(3.7to32.3)

24-hours,median(IQR) 13.0(3.2to54.7) 18.8(4.9to66.7)

Mean(loge)change(95%CI) 0.30(0.11to0.48)2 0.37(0.19to0.55) 0.57

PPanalysis

Baseline,median(IQR) 9.1(3.3to37.9) 12.1(3.8to32.0)

24-hours,median(IQR) 13.0(3.6to45.4) 18.5(4.8to60.0)

Mean(loge)change(95%CI) 0.30(0.12to0.49)2 0.33(0.14to0.51) 0.86

PRIMARYENDPOINT

rIPerC(n=93) Control(n=95) P-Value

%changeinBIvolumeat24-hours,median(IQR)1 36.5(-7.3to98.1) 34.1(-11.0to106.4) 0.80

ChangeNIHSSscoreat24-hours

Baseline,median(IQR) 9(6to15) 10(7to17)

24-hours,median(IQR) 5(2to9) 7(2to12)

Mean(loge)change(95%CI) -0.59(-0.75to-0.43) -0.51(-0.67to-0.35) 0.48

SuccessfulrecanalizationinIV-treatedpatients 62(75.6) 65(79.5) 0.65

90-dayBathel≥95 61(67.2) 56(61.3) 0.41

90-daymRs0-1 44(48.6) 37(40.3) 0.26

90-daymRs,median(IQR) 2(1to3) 2(1to3) 0.35

SECONDARYENDPOINT

SAFETY Withatleastonecycleof

deflation/inflation

Yes(n=94) No(n=94) P-Value

SymptomaticIntracerebralhemorrhage 4/88(4.6) 4/88(4.6) 0.97

90-dayAll-causemortality,n(%) 14(15.8) 10(10.4) 0.45

Pain(VAS)duringper-conditioningischemicprocedure

>0 41/78(52.6) - -

Median(IQR)

(DatareportedforonlyforpatientswithVAS>0)6(3to7) - -

PerCIDrelatedevent:•  Noacutelimbischemia•  Nodeepvenousthrombosis

•  PreviousRCTonrIPerCinacuteStroke(KDHougaardetal.Stroke2014)GAndersen,AarhusUniversityDenmark–  Prehospitalsetting:64and57patientsanalyzedwithpostrIPerCMRI(DWIandPWI)

–  LowNIHSS=4andsmallvolume1cc.

–  NeutralbutposthocvoxelanalysessuggestrIPerCcanbebeneficial

DISCUSSION

Name Country(PI) n Patients Intervention Intervention Outcomes

RESIST Denmark(RABlauenfeldt)

1500 AISHIC

•  PreHosp•  NonpareticArm

•  InHospH6•  D1-D7=*2/d

mRS2022

REMOTE-CAT Spain,Catalonia(FPurroyGarcia)

575 AIS •  PreHosp<H8•  NonpareticArm

•  Once mRS2022

RECAST-2 UnitedKingdom(TEngland)

120 AIS •  InHosp•  Nonpareticarm

•  D1-D4*2/d Feasibility2018

TRIPCAIS China(AJiaqi)

120 AISrTPA •  InHosp•  Nonpareticarm

•  OnceafterIVthrombolysis

2020

REPOST Netherlands(TLandman)

200 AIS •  InHosp•  Nonpareticarm

•  Twiledaily Infarctsize

•  5ongoingtrialonrIPerCinAIS:2inPrehospitaland3withmultiplecycleofperCID

CONCLUSION

RESCUEBRAINisaneutralRCTevaluating

inhospitalremoteischemicperconditioningatlowerlimb

withinthe6firsthoursofprovenischemicstroke

ontoponIVthrombolysisandmechanicalthrombectomy

Acknowledgements

Center(numberofpatientsincluded)VERSAILLESHOSPITAL(n=48)PrPICO,DrCHADENAT,DrDUONGetal.FOCHHOSPITAL(n=42)DrLAPERGUE,DrBOURDAIN,DrCONSOLI,etal.LILLEHOSPITAL(n=28)PrCORDONNIER,DrFERRIGNOetal.BICHATAP-HP(n=18) PrAMARENCO,DrMESEGUERetal.SALPETRIEREAPHP(n=15)PrSAMSON,DrROSSO,DrDELTOURetal.CHSUDFRANCILIEN(n=15) PrSMADJA,DrCHAUSSON,DrAGHASARYANetal.ROTSCHILDHOSPITAL(n=11)DrOBADIA,DrPIOTIN,DrFISSELIERetal.MONDORAPHP(n=5) PrHOSSEINI,DrMAJHAIetal.NANTESHOSPITAL(n=3)DrGUILLON,DrSEVINetal.STRASBOURGHOSPITAL(n=3)PrWOLFFetal.RENNESHOSPITAL(n=0)DrRONZIEREetal.

VERSAILLESCLINICALRESEARCHUNIT:•  MsMORISSET•  MsCATTENOY,MsROUX•  MsLEFEVRE,MrTURBE

PARISOUESTCLINICALRESEARCHUNIT•  PrAEGERTER(Methodologist)•  MsAZERAD(DataManager)•  MsNKAM(Statistician)

DSMB:•  PrALAMOWITCH(Paris)•  PrOLIVOT(Toulouse)•  MsCOZIC(Paris)

BRAINMRILecturegroup:•  DrCROSSO(BRAINANDSPINEINSTITUTE)•  DrCHIREL(VERSAILLESHOSPITAL)

Patientsandtheirfamilies

LILLEBIOSTATISTICDEPARTMENT•  PrDUHAMEL•  MrLABREUCHE(Statistician)