mild and rapidly improving stroke study agreements/mariss... · version 2.0 (r) march 30th 2016 4...

MildandRapidlyImprovingStrokeStudy

Studyprotocol

Version 2.0 (R) March 30th 2016 2

TABLEOFCONTENTS 1.AbbreviationsandGlossary…………………………………………………………………….2.StudySummary………………………………………………………………………………………3.Goals,HypothesisandSpecificAims………………………………………………………….4.BackgroundandRationale……………………………………………………………………….5.DesignandMethods……………………………………………………………………………....... 5.1.ResearchPlan…………………………………………………………………………… 5.2.StatisticalConsiderations…………………………………………………………… A)AnalysisPlan……………………………………………………………………. B)SampleSizeCalculations…………………………………………………… 5.3.StudyOrganization…………………………………………………………………….. A)StaffRoster………………………………………………………………………. B)MaRISSSteeringCommittee……………………………………………… C)MaRISSCoreCenters……………………………………………………....... D)Participatingsites…………………………………………………………......

1.Participatingsitecharacteristics……………………………… 2.Participatingsitesselection……………………………………...

3.Participatingsiteresponsibilities……………………………..4.Communicationwithsites……………………………………......

5.4Participatingsitetrainingandcertification……………………………………5.5Studyprocedures…………………………………………………………….…………. A)Summary……………………………………………………………..... B)Eligibilitycriteria…………………………………………………… C)Screening………………………………………………………………. D)Recruitment…………………………………………………………… E)Retention……………………………………………………………...... F)InformedConsentProcessandHIPAAForm……………

6.SpecificMeasurementsandOutcomes……………………………………………………… 6.1DefiningMildStroke…………………………………………………………………… 6.2DefiningRapidlyImprovingStroke……………………………………………… 6.3CodingPre‐HospitalFluctuations………………………………………………… 6.4CodingIn‐HospitalFluctuations………………………………………………....... 6.5AssessingtheNIHSS…………………………………………………………………… 6.6ObtainingtheTOASTclassification……………………………………………… 6.7PrimaryOutcomeMeasure:themodifiedRankinScale………………… 6.8SecondaryOutcomeMeasures:theBarthelIndex,theStroke……….

ImpactScale16andtheEuropeanQualityofLifeEQ‐5Dassessments.

7.EvaluationsandDataCollection………………………………………………………………..7.1Flowchartandstudyvisits…………………………………………………………..

7.2MaRISSGWTG‐SRequiredelements……………………………………………GWTGresearchelements……………………………………………………….

7.3Studyvisits………………………………………………………………………………….. Visit1.Baseline………………………………………………………………………. Visit2.At24hours………………………………………………………………….

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TABLEOFCONTENTS (cont)

Visit 3. Day 3 (or at discharge if prior to Day 3) …………………… Visit 4. Day 30 Telephone call ………………………………………

Visit 5. Day 90 Telephone call ……………………………………… 8. Adverse Event Reporting ………………………………………………………… 9. Monitoring, Compliance, Forms …………………………………………………. 9.1 Monitoring Responsibilities …………………………………………….. 9.2 Compliance with study protocol ………………………………………… 9.3 Data collection and study forms ………………………………………… 9.4 Data management ……………………………………………………….. 9.5 Quality control ………………………………………………………... ... 10. Study completion and closeout …………………………………………………. 11. References …………………………………………………………………… …. 12. Relevant Websites ………………………………………………………………. 13. Attachments Attachment 1 MaRISS modified Rankin Scale Data Collection Form ……. Attachment 2 MaRISS Barthel Index Data Collection Form ……………… Attachment 3 MaRISS EuroQoL EQ-5D Data Collection Form ………..... Attachment 4 MaRISS Stroke Impact Scale-16 Data Collection Form …… Attachment 5 MaRISS NIH Stroke Scale Data Collection Form ………..... Attachment 6 MaRISS TOAST Classification Data Collection Form …...... Attachment 7 MaRISS Criteria for coding RIS Data Collection Form …….

Attachment 8 MaRISS Pre-hospital Arrival Neurologic Fluctuations ……. Data Collection Form

Attachment 9 MaRISS In-hospital Neurologic Fluctuations Data ………… Collection Form

Attachment 10 MaRISS Clinical Research Form (CRF) ……………………. Attachment 11 MaRISS Adverse Event Reporting Form ……………………

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1.ABBREVIATIONSANDGLOSSARYBI BarthelIndexCRF CaseReportFormEuroQOL,EQ‐5D EuropeanQualityofLifescaleGWTG,GWTG‐S GetWithTheGuidelines‐StrokeRegistryIVrtPA Intravenousrecombinanttissueplasminogenactivator(Alteplase)LAR LegallyauthorizedrepresentativeMaRISS MildandRapidlyImprovingStrokeStudymRS ModifiedRankinScaleNIHSS NationalInstitutesofHealthStrokeScalePRO PatientreportedoutcomeRIS RapidlyimprovingstrokeRISS RapidlyimprovingstrokesymptomsTOAST TrialofOrg10172inAcuteStrokeTreatmentstrokeclassification,

aclassificationofischemicstrokemechanism


2.STUDYSUMMARYTitle:MildandRapidlyImprovingStrokeStudyObjective: To elucidate long‐term outcomes of patients with mild and rapidly improvingstrokeandexaminetheassociationwithtPAtreatment.Design:Investigator‐initiatedprospectiveobservationalstudy.PrimaryOutcomeMeasure:ProportionofpatientswithamRS=or>2at90daysSecondaryOutcomeMeasures:Barthel Index (BI), Stroke Impact Scale‐16 (SIS), EuroQOL, at 90 days, mRS at 30 days,mortalityat30and90days.InthosewhoreceivedIVrtPA,also:symptomatichemorrhagictransformation,endovascularacutestrokerescuetherapywithin24hours.ExploratoryOutcomeMeasure:Inasubgroupof100patientswithinternetaccess,testthereliabilityofaweb‐basedpatientreportedoutcomeinstrumentcomparedtoastructuredtelephoneinterview.Eligibility:mild ischemic stroke (NIHSS = or < 5) or rapidly improving stroke symptomswithin4.5hoursfromonset;provideinformedconsent;speakEnglishorSpanish.SampleSize:2650.Sites:100preselectedhospitalscurrentlyparticipatinginGWTG‐S.Studyduration:2yearsSitesubcontractingandIRBapproval:4monthsPatientrecruitment:18monthsCompletionoffollow‐up:3monthsNarrative: To understand the long‐term outcomes of patients with mild and rapidlyimprovingstrokesymptoms, thisprospectiveobservationalstudywill leverage thecurrentinformation in theGetWithTheGuidelines‐Strokeregistryandcollect90‐dayoutcomes.Atotalof2650patientswithmildand/orrapidlyimprovingstrokesymptomswillbeenrolledin100hospitalsparticipatinginGWTG‐S.TheprimaryoutcomeistheproportionofpatientswithamodifiedRankinScale>2assessedthroughastructuredtelephoneinterviewofstrokeoutcomes.Thefeasibilityofusinganautomatedweb‐basedpatientreportedoutcomewillbetestedinagroupof100patients.Predictivemodelsandriskscoresofpooroutcomeswillbecreated.Theefficacyandsafetyoutcomesofpatientswithmildandimprovingstrokestreatedwiththrombolyticswillbeexplored.


3.GOAL,HYPOTHESISANDSPECIFICAIMSTheoverallgoalofthisstudyistoelucidatelong‐termoutcomesofpatientswithmildandrapidly improving stroke and examine the association with tPA treatment. In order toaccomplishthisgoal,wewillpursuethefollowingspecificaims:SpecificAim1.Determinethe90‐dayoutcomesforpatientswithmildstrokesymptomsorrapidly improvingstrokesymptoms.Wehypothesize thatasubgroupofpatientswithmildstrokesymptomsdefinedbytheNIHSS,orwithrapidlyimprovingsymptoms,willhavepooroutcomes.Thepopulationtobestudiedisaprospectivecohortof2650patientsat100GWTG‐Spreselectedhospitalswithmildischemicstroke(NIHSS=or<5)orrapidlyimprovingstrokesymptomswithin4.5hours fromonset,whichprovide informedconsent,andspeakEnglishorSpanish.Outcomeswillbeobtainedthroughastructuredtelephoneinterviewwiththepatientorproxy. Theprimaryoutcome is theproportionofpatientswith amodifiedRankinScore (mRS)=or>2at90days.Secondaryoutcomes include:Barthel Index (BI),StrokeImpactScale(SIS),EuroQOL,at90days,mRSat30days,mortalityat30and90days.SpecificAim1b.Determinethereliabilityofanautomatedpatientreportedoutcome(PRO).WehypothesizethatanautomatedPROisfeasibleandreliable.Asubsetof100patientswithinternetaccesswillbeinvitedtocompleteaweb‐basedPROthatincludesthemRS,BI,SIS‐16,andEuroQOL,whichwillbecomparedtothetelephoneinterview.SpecificAim2.Determinethepredictorsforworse90‐dayoutcomesinpatientswithmild stroke symptoms or rapidly improving stroke symptoms. We hypothesize thatcertain variables can predict poor outcomes. Prediction models will use current GWTG‐Sdemographic, risk factor, and clinicalpresentationvariables, aswell asnewly collected in‐hospitalvariables(individualcomponentsofthebaselineNIHSS,serialin‐hospitalNIHSS,andstrokemechanism.Specific Aim 3. Among patients withmild or rapidly improving stroke symptoms,compare the safetyandefficacyoutcomesof intravenous thrombolysiscompared tonon‐thrombolyzedpatientsafteradjusting for treatmentpredictors. Thehypothesis isthatanalysisoftheinteractionbetweenpredictorsofpooroutcomeandIVrtPAtreatmentcanidentifyasubgroupofpatientswithmildandrapidly improvingstrokesymptomsthatcanpotentiallybenefitfromthrombolytictherapy.Weanticipatethatabout10%ofthepopulationstudiedwillbetreatedwithIVrtPA.Theprimaryefficacyoutcome:mRS0‐1at90‐days.Theprimarysafetyoutcomeissymptomatichemorrhagictransformation.Secondaryoutcomesinclude:90‐dayBI,EuroQOL,andSIS‐16,endovascularacutestrokerescuetreatmentwithin24hours.


4.BACKGROUNDANDRATIONALEStrokeisthe5thcauseofdeathintheUSand3rdcauseofdeathworldwide,aswellasaleadingcauseofdisability(1).PopulationbasedstudiesrevealthatabouthalfofallstrokeshavelowNIHSSonpresentation(2,3).Mildandrapidlyimprovingstrokesareacommonreasontonotadminister thrombolytics, although up to one third of patients with mild and rapidlyimprovingstrokesareunabletoreturnhome.Nonetheless,detailed long‐termoutcomesinthosewithmildandorrapidly improvingstrokeare lacking.This isessential todeterminewhethermoreaggressivetreatmentisreasonableforsomethesepatients.Howaremildandrapidlyimprovingsymptomsdefined?Traditionally,theNIHSShasbeenusedtodescribeaseverityofastroke.Mostrecentclinicalstudiesofinterventionforacuteischemicstroke have excluded those with an NIHSS <5 or <6. However, in clinical practice, thedeterminationofmildstrokeasareasonnottoadministerIVrtPAisleftuptotheclinician.Amongst10,295GWTG‐Spatientsnot treatedwithIVrtPAsolelybecauseofamildstroke,94%hadaNIHSSof5orless(4).However,itisclearthatanisolatedaphasicsyndrome,eventhoughitwouldaccruealowNIHSS,wouldbequitedisablingandwouldnotbeconsideredmild.The situation of rapidly improving symptoms is more complicated. Different studies andreportshavedefinedimprovementbytheabsolutechangeinNIHSSpointsfrombaseline,thefinal NIHSS score, or the percent improvement in the NIHSS (5‐10). A recent consensusstatementrecommendeddefiningrapidlyimprovingstrokesymptomsasthosethatimprovetoanNIHSS<5andarenon‐disabling(11).However,alargeproportionoftheimprovementmayoccurpriortohospitalarrival.AlthoughanumberofEMSscalesofseverityareavailable,theyhavenotbeencarefullyanalyzedtoincludepre‐hospitalfluctuationsinthedefinitionofrapidly improvingstroke.Therefore, inpractice, thephysicianascertains ifsymptomshaverapidlyimprovedornot.InGWTG‐S,amongstthosenottreatedduetoonlyrapidlyimprovingsymptoms,26%hadanNIHSS>5suggestingpersistentdisablingsymptomatology(4).Aremildstrokeandrapidlyimprovingstrokesimilar?Althoughtheremaybeoverlapbetweenmildandrapidlyimprovingstroke,withasmanyas1in4patientsrapidlyimprovingtoamildlevel, these conditions have clearly different causes, presentations and outcomes. Rapidimprovementwould suggest rapid recanalizationand reperfusionof ischemic tissue,whilemildstrokesareprobablycausedbypersistentocclusionofavessel.Inaretrospectiveanalysisof GWTG‐S, rapidly improving stroke patients tended to be older, havemore cardiac andcarotiddisease,andhaveahigherNIHSSatbaseline.Afteradjustmentformultiplevariables,rapidly improving strokes that improve to mild had the best outcomes. Therefore, eachcategory(mild,rapidlyimproving,andrapidlyimprovingtomild)hasdistinctcharacteristics.Howcommonaremildandrapidlyimprovingstrokesymptoms?About31‐46%ofpatientsthatpresenttotheEmergencyDepartmentwithin3hoursofonsetwithanacuteischemicstrokehavemildorrapidlyimprovingstrokesymptoms(12‐15).ThelargestavailableseriesincludethelargeGWTG‐Sregistrywhere31.2%of93,517patientsthatarrivedwithin2hoursofonsetwere not treated with intravenous thrombolytics (IV rtPA) because of mild or improvingstroke(14),andthe4‐statePaulCoverdellregistry,inwhichmildorrapidlyimprovingstroke


symptomswerethemaincauses(46.6%)forbeingconsideredineligibleforIVrtPAinthosearrivingwithin2hoursfromsymptomonset(15).What are the outcomes ofmild and rapidly improving stroke symptoms that donot receivethrombolytictherapy?Mostdatacomesfromregistriesorretrospectiveanalysisthatvaryinthedefinitionofmildandrapidlyimprovingstroke.InGWTG‐S,amongst29,200patientswithmildandrapidlyimprovingstrokenottreatedwithIVrtPA,27%wereunabletoreturnhome,and29%couldnotambulateindependentlyatdischarge.Smallserieshaveshownthatat3months,amRSof2‐6waspresentin15%(16)to32%(17).Therefore,asmanyasonethirdhavesuboptimaloutcomes.However,detailedlongtermoutcomesarelackingforthiscohortofpatients.HowmanymildandrapidlyimprovingstrokepatientsreceiveIVrtPA?Alteplaselabelingandprior strokeguidelines (18) recommendagainst IV rtPAadministrationwhenneurologicalsigns are clearing spontaneously and when neurological signs are minor and isolated.However,newerguidelinesrecognizethatsomeofthesepatientsmayhavepooroutcomesandthereforerecommendtreatmentofmildbutdisablingstrokewithin3hoursofsymptomonset(19).Thiscoincidedwitharevisionofthealteplaseprescribinginformationin2015thatdoesnotincludetheseexclusions.Althoughtreatmentatacademicorhighvolumescentersreportthatasmanyas21%ofmildstrokesreceiveIVrtPAtreatment(4,20),nationalregistriesshowmoremodestratesof10%to12%(21,22).DothosethatreceiveIVrtPAdobetterthanthosethatareuntreated?Thisisanopenquestionand the subject of ongoing research. It is difficult to compare outcomes outside of arandomizedcontrolledtrialasthereisthepotentialforbias(confoundingbyindication);thatis,specifichigherseveritymarkersmayguidethecliniciantoadministerIVrtPAtoonepatientbut not to another. The largest report suggests that although the risk of symptomatichemorrhageis<2%,outcomesatdischargewerepoor,with29%notdischargedhomeand31% unable to ambulate independently at discharge (4). Delayed 3‐month outcomes areavailableonlyfromsmallseriesshowingmRS2‐6in17%(23)to42%(24).Whatunderliespooroutcomesinmildandrapidlyimprovingstroke?PooroutcomesmaybeduetoanisolatedbutdisablingsymptomsuchasaphasiathatmaynottranslateintoahighNIHSSscore(25).Also,earlyprogressionofmildsymptomsisnotuncommon.Asinglecenterstudyreportedthat8.3%of229patientswithamildstrokeorTIA(NIHSS<5)hadprogressionofsymptomswithin72hours,similartothosewithmoreseverestrokes(26).Similarly, inanMRIbasedstudy,10%of thoseexcluded fromthrombolytic therapy formildor improvingsymptoms had early neurologic deterioration and infarct expansion and 20% had poordischargeoutcome(27).Rapidlyimprovingsymptomsmaysubsequentlydeteriorate.Smithandcolleagues(28)reportedthat11/41patientswithmild/improvingsymptomsnottreatedwith tPA were not discharged home; 6 of them had early worsening. Early worsening isthought to be due to hemodynamic failure, or re‐occlusion of a spontaneously reanalyzedvessel, whichmay occur in 12% of all tPA‐treated patients and 27% of thosewith initialrecanalization(29).AnORof4.1 forsubsequentdeteriorationwasdescribedinthosewithrapidlyimprovingsymptomscomparedtothosewithoutrapidimprovement(28).


IsthemodifiedRankinScaleagoodmeasureofoutcomeinmildandrapidlyimprovingstroke?ThemRSmeasuresfunctionaldisabilityinstrokeandisthemostcommonlyemployedstrokefunctionaloutcomescaleinstrokestudies.Althoughithasgoodvalidityandreliability(30),itisunidimensionalwithimportantceilingeffectsandpoorassessmentofhealth‐relatedqualityof life (31). More detailed outcomemeasures are needed to better understand functionaloutcomesaftermildandrapidlyimprovingstroke.OthermeasuresalsoemployedinMaRISSassecondaryoutcomesincludetheBarthel Index(BI), theStrokeImpactScale‐16(SIS‐16),andEuroQOL(EQ‐5D).TheBImeasuresactivitiesofdailyliving;ascoreof>85correspondstoindependencewithminimalassistance,whileascore>95tominimalornodisability(32‐34). The SIS‐16 concentrates on the physical domains rather than cognitive or emotionaldomains (31,35,26). The EQ‐5D measures health outcomes and explores non‐physicaldomains(37,38).Canpooroutcomesbepredictedatbaselineevaluation?Wehaveassessedpredictorsofpooroutcome inmildandrapidly improvingstroke inGWTG‐S,andfoundthatolderage,AfricaAmericans, the greater burden of stroke risk factors such as hypertension, diabetes, priorstroke, atrial fibrillation, heart failure and peripheral vascular disease, as well as delayedarrivalandhigherNIHSSareassociatedwithworsedischargeoutcomes,whilethebaselineuseofantiplatelet,antihypertensiveandantilipidemicmedicationwasassociatedwithbetteroutcomes.Othershavefoundthatlargevesselocclusionanddistalhypoperfusionpredictedstrokeprogression(27,39).However,theinfluenceofstrokemechanismandearlyin‐hospitalfluctuationsonoutcomesisnotcurrentlyknown.SummaryofbackgroundforMaRISS.Mildandrapidlyimprovingstrokesymptomsarecommonpresentationsofacute ischemicstroke.Thegreatmajorityofpatientsarenot treatedwiththrombolytics.Theoutcomesofmildandrapidlyimprovingstrokearesuboptimalwithalmost1 in 3 unable to return home or ambulate independently at discharge. Nevertheless,continuousimprovementmayoccurinthefirst3monthsafterdischarge(40),but3‐monthoutcomesareavailable fromonlysmall series, includeonly themRS,andvaryextensively.Therefore,thelong‐termoutcomesandpredictorsofpooroutcomearenotwellcharacterized.MaRISSwilldescribethelong‐termoutcomeswithabatteryofsensitiveoutcomemeasures,and will elucidate predictors of poor outcome by carefully analyzing stroke baselinecharacteristicsandearlyfluctuations.


5.STUDYDESIGNANDMETHODSSTUDYDESCRIPTIONMaRISSisaprospectiveobservationalstudythatwillenroll2650patientsfrom100GWTG‐Shospital in order to define the 90‐day outcomes of patients with mild and/or rapidlyimprovingstrokebyatelephone‐basedassessmentofstrokeoutcomesbasedonestablishedandvalidatedmeasuresincludingthemRS,BI,SIS‐16andEuroQOL.Inaddition,wewilltestthefeasibilityofusinganautomatedweb‐basedpatientreportedoutcome.Basedondetailedbaseline and early hospitalization demographic and clinical data, assessment of earlyfluctuationsbyserialNIHSSexaminations,andevaluationofandstrokemechanismsthroughtheTOASTclassification,wewillcreatepredictivemodelsofpooroutcomes.Theefficacyandsafetyoutcomesofpatientswithmildandimprovingstrokestreatedwiththrombolyticswillbeexploredbycomparingthemtothosetreatedconservativelywithoutthrombolytics.5.1RESEARCHPLANAim 1.Determine the 90‐day outcomes for patientswithmild stroke symptoms orrapidly improvingstrokesymptoms.Basedon theavailabledata,wehypothesize thatasubgroup of patients with mild stroke symptoms defined by the NIHSS, or with rapidlyimprovingsymptoms,willhavepooroutcomes.Inordertotestthishypothesis,aprospectivecohortofpatientswithmildorrapidlyimprovingstrokeevaluatedwithin4.5hoursfromonsetwill be followed after discharge from hospital to determine the 90‐day independence anddisability.TheprimaryoutcomeforthisaimistheproportionofpatientswithamRS>2at90days;secondaryoutcomesincludetheBI,SIS‐16,andEuroQOLat90days,mRS>2at30days,andmortalityat30and90days.ThisaimwillbeattainedbycollectingoutcomevariablesthatarenotcurrentlyincludedintheGWTGdatabase,including30and90‐daymRS,and90‐dayBI,SIS‐16andEuroQOL,obtainedthroughatelephoneinterviewwiththepatientortheproxy.The30‐daymRSwillbeusedonlywhena90‐dayoutcomeisnotavailable.Atotalof2650patientswillbeenrolledacrossthe100sitesover2years.InstitutionalReviewBoardwillbeobtainedateachsite,andpatientswillsigninformedconsentafterthedecisiontotreatornotiscompleted.ThecurrentGWTGdatapointswillcontinuetobeobtained,inadditiontospecificoutcomemeasures.Eligibleindividualsincludethosewithamildorrapidlyimprovingischemicstroke,definedclinically,admittedwithin4.5hoursfromonset(41,42),thatprovideinformedconsent,andspeakEnglishorSpanish(outcomemeasuresvalidatedforthesetwolanguages).ThosewithapremorbidmRS>1willbeexcluded.Ischemicstrokeisassessedclinicallybythestroketeamattheeligiblehospitalbythepresenceoffocalneurologicalsymptomsofsuddenonsetintheabsenceofhypoglycemia<50mg/dlorbrainCTevidenceofintracerebralhemorrhage.Otherclinicalandimaginginformationmaybe used by the investigator to determine an ischemic etiology for the focal neurological


symptoms.MildstrokeisdefinedasanNIHSSof5orless,basedoncommonlyacceptedcriteria(43).Rapidlyimprovingstrokeisdefinedbythesiteneurologistorstroketeammember.Thereiscurrently no standard definition for RIS. A variety of definitions have been employed,including:a)NIHSSimprovement4pointsfrombaseline(5);b)NIHSS0or1onfollow‐uporimprovementof8pointsfrombaseline(majorneurologicalimprovement)(6);c)NIHSS3onfollow‐uporimprovementof10pointsfrombaseline(dramaticneurologicalimprovement)(7,8);d)improvementby20%(9);ande)improvementby40%frombaselineNIHSSscore(10).In thisobservational study,wewillnotmandate interventionor treatment,andwillenrollpatientsafterthedecisionhasbeenmadetotreatornottreatwithintravenousrtPA.WewillrecordthechangeinNIHSSfromarrivaltoEDtodecisiontotreat(usuallywithin1hour)andthen,post‐hoc,analyzethedriversofthedecisiontointervenebasedonthechangeinclinicalstatus. The criteria employed by the treating physician to determine a rapidly improvingstrokewillalsoberecorded.Inanattempttoincorporatepre‐hospitalimprovement,therewillbeanestimationofthechangeinclinicalstatusfromonsettohospitalarrivalbasedonEMS,familyorpatient’sreport.ThemodifiedRankinScalemeasuresdisabilityordependence in strokepatientsandhasbecomethemostcommonlyemployedstrokefunctionaloutcomemeasure,withgoodvalidityandreliability(30,44).A30‐daymRSwillbeusedonlywhena90‐daymRSisunavailable(i.e.losttofollow‐up).InordertostandardizethecollectionofthemRS,MaRISSwillemploythemRS‐9Qsurvey(45):thisvalidatedmethodconsistsof9questionswithayes/noanswer;theanswers are entered into an online calculator that screens for inconsistent answers andproducesaconsistentscorethatexcludesexaminervariability.Theanalysiswilladjustforpre‐morbidhistoricalmRS(0or1).TherearesomeshortcomingswiththemRS: itmaynotbesensitive todisablingsymptomsthat impactqualityof life,as it capturesdisabilitybutnothealth‐relatedqualityof life.Forthatreason,wewillemployassecondaryoutcomesothermeasuresofindependenceandqualityoflife:TheBarthelIndexisthemostcommonlyusedscaletomeasureactivitiesofdailyliving.Ithasgood inter‐rater reliability; a score of >85 corresponds to independence with minimalassistance,whileascore>95tominimalornodisability(32‐34).Forstatisticalpurposes,theBIwillbedichotomizedwithascoreof95‐100consideredfavorable.OneoftheshortcomingsoftheBIisthatitsuffersfromaceilingeffect.TheStroke Impact Scale‐16 has less ceiling and floor effects than generic health‐relatedqualityoflifeinstrumentssuchastheSF‐36andisabletodiscriminateacrosslowmRSlevels(31,35).TheSIS‐16concentratesonthephysicaldomainsratherthancognitiveoremotional,andisfeasibletoadministerbytelephoneinterview(36).ForstatisticalpurposestheSIS‐16willbetreatedasacontinuousmeasure,andthedistribution,mean,standarddeviation,range,median,andinterquartilerangewillbecalculated.


TheEQ‐5D/EuroQOLisastandardizedinstrumentthatmeasureshealthoutcomes,itisabriefand simple test, with good inter‐rater reliability, and is comparable to the SF‐36; it alsoexploresnon‐physicaldomains,comparedtotheSIS‐16(37,38).ForstatisticalpurposestheEuroQOL will be treated as a continuous measure, and the distribution, mean, standarddeviation,range,median,andinterquartilerangewillbecalculated.TheseoutcomemeasureinstrumentsareavailableinEnglishandSpanish.Sitecoordinatorswillperformtheoutcomemeasuresthroughatelephoneinterview.Theywillbecertifiedinthe performance of the outcome measures through an online training program. Theseoutcomesarealignedwiththoseplannedinrandomizedtrialsofmildstrokes(PRISMSTrial,P. Khatri (PI), Sponsor: Genentech). This will permit future data aggregation andinterpretation.Aim1b.Determinethereliabilityofanautomatedpatientreportedoutcome(PRO).Inadditiontothetelephone‐basedinterviewstoassessoutcomes,wewillevaluatethefeasibilityofemployingaself‐accessedweb‐based,patientreportedoutcomemeasure(PRO).Inordertodothis,asubsetof100randompatientsidentifiedatbaselineashavinginternetaccessfromhomewillbeinvitedtocompleteaweb‐basedPROthatincludesthemRS,BI,SIS‐16,andEQ‐5D. Thesewill be compared for alternate form reliabilitywith their own telephone‐basedresponses,usingaKappastatisticforthemRSandcorrelationcoefficientsfortheSIS‐16andEQ‐5D.Inthismanner,wewilldetermineifanautomatedweb‐basedPROcanbestandardizedandscaled.Ifthisprovedtobethecase,differentformatsofPROcanbeenvisioned,suchasoneaccessedthroughasmartphone.Aim 2:Determine the predictors forworse 90‐day outcomes in patientswithmildstrokesymptomsorrapidlyimprovingstrokesymptoms.Theworkinghypothesisisthatcertaindemographicvariables(i.e.age),clinicalvariables(rapidfluctuationsinNIHSS),strokemechanism(i.e. largearterydisease), and typeof symptoms (i.e. aphasia,hemiparesis andataxia) will be strong predictors for poor outcomes. This aim will be accomplished byevaluatingcurrentGWTGdemographic,riskfactor,andclinicalpresentationvariables,aswellasnewlycollectedin‐hospitalvariablesincludingindividualcomponentsofthebaselineNIHSS,serial in‐hospitalNIHSS, qualitative assessments of pre‐hospital and in‐hospital neurologicfluctuations,andtheTOASTstrokeclassification.Thevariablesusedinthepredictionmodelsinclude:1. Demographic: age, gender, race/ethnicity. These are currently collected in the GWTG

registry.2. Clinical:traditionalstrokeriskfactors,prioruseofantithrombotic,antihypertensiveand

antilipidemicagents,timefromonsettoarrival.ThesearecurrentlycollectedintheGWTGregistry.

3. Symptomatology:evaluatedbytheNationalInstitutesofHealthStrokeScale(NIHSS).Thisisawell‐validated,reliablescale,availableinvariouslanguages,andisusedbothintheresearchsettingandinclinicalpracticeasawaytoestimatethemagnitudeofneurologicimpairment by quantifying the neurologic examination. Its use is established forneurologists, non‐neurologists and nurses. Although low NIHSS scores have been


associated with good outcomes and used as criteria for excluding patients fromthrombolytictreatment,onlyverylowfinalNIHSSarecorrelatedwithverygoodfunctionalrecovery(46),andspecificcomponentsof theNIHSSsuchasaphasiacanbeassociatedwith a poor outcome. TheNIHSSwill be recorded on arrival, at the time of treatmentdecision(standardofcare),atanytimeofclinicaldeteriorationwithin24hours,at24+/‐4hoursfromsymptomonset,andatday3(ordischargeifbeforeday3).Wewilltesttheglobalscore,itschangeoverthefirstdays,andeachindividualcomponentoftheNIHSSaspotentialpredictorsofoutcome.The individual componentsof theNIHSSand its serialcollectionarenotcurrentlyencompassedintheGWTGregistry.SiteinvestigatorswillbecertifiedintheperformanceoftheNIHSS.InadditiontotheNIHSS,wewillcollectanewqualitativeassessmentofpre‐hospitalandin‐hospitalneurologicfluctuationtocorrelatewithoutcomes.

4. Mechanism:definedbytheTrialofOrg10172inAcuteStrokeTreatment(TOAST)strokeclassification; TOAST iswidely used to classify themechanisms that underlie ischemicstroke(47)withgoodinter‐raterreliability(48).Thepotentialforearlydeteriorationafterstrokeiscorrelatedwiththestrokemechanism,andlargearterydiseasecanresultinearlyrecurrence.

Predictionmodelsandriskscoresformildandrapidlyimprovingstrokewillbecreatedandevaluatedfortheprimaryoutcome(mRSat90‐days),secondaryoutcomes(90‐dayBI,SIS‐16,EQ‐5D), and30and90‐daymortality,basedondemographicvariables, strokemechanism,presentingsymptoms,andchangesinneurologicstatus. Asmortality,themRSandBIwillbetreatedasdichotomousoutcomesasdefinedpreviouslyand logistic regression prediction models will be created. The SIS‐16 and EQ‐5D will betreated as continuous measures and analyzed using linear models. We will first confirmvariableandmodelassumptionsregardingnormality,andwhennecessaryoutcomevariableswillbetransformedtoachievenormality.Potentialpredictorvariableswillbeexaminedbothcontinuouslyandcategorically inrelation to theoutcomes,and included in finalpredictionmodelsappropriately.Initialmodelswillincludeallpotentialpredictorssimultaneously,andmoreparsimoniousmodelswillbecreatedusingbackwardsselectionkeepingallvariablesassociatedwiththeoutcomesataveryliberalcriteriaofp<0.20.Aim3:Amongpatientswithmildorrapidlyimprovingstrokesymptoms,comparethesafety and efficacy outcomes of intravenous thrombolysis compared to non‐thrombolyzedpatientsafteradjustingfortreatmentpredictors.Itisanticipatedthatthemildorrapidlyimprovingstrokepatientstreatedwiththrombolysiswillhavealowrateofsymptomatichemorrhagictransformation,lesssubsequentworseningrequiringendovascularrescuetherapy,andbetter90‐dayoutcomesthanthosenottreatedwithrtPA.Wewillcomparethe safety outcomes and efficacy in those treatedwith orwithout IV rtPA, accounting forpotentialconfoundersincludingimportantdeterminantsoftreatment.Themainsafetyoutcomemeasureforthisaimissymptomatichemorrhagictransformation.Thisisdefinedasanyneurologicaldeteriorationthat,inthejudgmentofthesiteinvestigator,is related to intracranial hemorrhage confirmed by CT or MRI. It has traditionally beenconsidered as deterioration by at least 4 NIHSS points within 36 hours of IV rtPAadministration.Secondarysafetyoutcomemeasuresarethe30and90‐daymortality.


ThemainefficacyoutcomemeasureforthisaimisamRS2‐6.Secondaryefficacyoutcomemeasures include the 30‐day mRS and the 90‐day BI, EQ‐5D, and SIS‐16, as well asendovascularacutestrokerescuetreatmentwithin24hours.5.2STATISTICALCONSIDERATIONSA)ANALYSISPLANBy analyzing the interaction between predictors of poor outcomes and rtPA treatment inrelationtothe90‐dayoutcomes,itispossiblethatpotentialsubgroupsofpatientswithmildorrapidlyimprovingsymptomscanbeidentifiedbybaselinepresentationthatmaybenefitfromthrombolytictreatment.Asmentionedabove,thedichotomousoutcomes,symptomatichemorrhagictransformation,mortality,themRSandBI,willbeanalyzedusinglogisticregressionpredictionmodels.TheSIS‐16andEQ‐5Dwillbetreatedascontinuousmeasuresandanalyzedusinglinearmodelsandtransformedifnecessarytosatisfynormalityassumptions.Confoundingbyindicationisthegreatestthreattothevalidityofthisanalysis.Toovercomethispotentialimportantsourceofbiaswewilluseapropensityscoreanalysistocontrolfortreatmentpredictors.First,wewillcreatealogisticregressionpredictionmodelfortreatmentwithIVrtPAusingallavailableGWTGdataatadmission.Wewillusethismodeltocontrolfortreatmentpredictorsinourfinallogisticregressionmodelsandgeneralizedlinearmodelstopredict our outcomes of interest. We will separately and additionally control for allparticularlyrelevantpossibleconfoundingvariables,includingriskfactorsfortheoutcomesintheGWTGdatabase.Asequenceoffinalmodelswillbecreated.First,wewillexaminetheunadjustedassociationbetweenIVrtPAtreatmentandtheoutcomes.Next,wewillcontrolfordemographicvariablesonly.Lastly,ourfullmultivariatemodelswillincludethepropensityscoreincludingclinicaland symptomatology variables associatedwith IV rtPA treatment. In the finalmultivariatemodelwewillexplorepotentialeffectmodificationbetweenIVrtPAtreatmentandcovariatesinrelationtotheoutcomesofinterestusinginteractionterms.Ifeffectmodificationisdetectedwithaliberalp<0.10stratifiedanalyseswillbeperformed.B)SAMPLESIZECALCULATIONWe estimate that a total of 2650 patientswill need to be recruited to detect a significantdifferencein90‐dayoutcomesacrosstreatmentgroupsforaim4,with80%powerandatwo‐sidedalphalevelof0.05.Thiscalculationisbasedonthefollowingassumptions: ProportionofmildStroke&RIS:31%ofthosearrivingwithin2hours(14),probablylarger

proportionofthosearrivingwithin4.5hours. Proportion ofmild Stroke& RIS treatedwith IV rtPA: 10%. This is based on the SITS

registry(21)andtheUSGWTGdata:3,139patientswithNIHSS<5receivedIVrtPA,while


29,200withmild and rapidly improving stroke did not, for a 9.7% rate ofmild stroketreatedwithIVrtPA(E.Smith,personalcommunication).

OutcomeinuntreatedmildStroke&RIS:62%willhaveamRS0‐1.ThisisbasedonthePRISMS estimate. Also, in GWTG, 62% were not discharged home (Smith 2011); it isassumed that some of those discharged from rehabilitation (16%) will have goodoutcomes,whilesomeofthosedischargedhomewillhavepooroutcomesat90days.

OutcomeintreatedmildStroke&RIS:71%willhaveagoodoutcome.ThisisbasedontheSITSregistryandourowndataanalysisofdischargeoutcomesinthosetreatedwithIVrtPAwithbaselineNIHSS<5(4,21).

5.3STUDYORGANIZATIONA)STAFFROSTERUniversityofMiamiCoordinatingandDataCenter:JoseRomano,MD,FAHA,FANA,PrincipalInvestigatorProfessorofClinicalNeurologyChief,StrokeDivisionUniversityofMiamiMillerSchoolofMedicine1120NW14thStreet,Suite1357MiamiFL33136Tel:305‐243‐9911Fax:305‐243‐[email protected]‐Bustillo,MPH,ProjectManagerAssistantScientistUniversityofMiami,MillerSchoolofMedicineCerebrovascularDivision1120NW14thSt.suite1361Miami,FL33136Tel:305‐243‐8018Fax:305‐243‐[email protected],ScD,BiostatisticianAssistantScientistUniversityofMiami,MillerSchoolofMedicine1120NW14thStreet,Suite1370MiamiFL33136Tel:305‐243‐9283Fax:305‐243‐[email protected]


AmericanHeartAssociation:YosefKhan,MD,MPH,PhD,MACEClinicalRegistryandResearchInformaticsManager/BioinformaticsSpecialistAmericanHeartAssociation‐NationalCenter7272GreenvilleAveDallas,[email protected],MD,FAHAViceChairman,MassachusettsGeneralHospital,NeurologyDirector,MassachusettsGeneralHospital,AcuteStrokeServicesProfessorofNeurology,HarvardMedicalSchoolDirector,PartnersTeleStrokeCenter,MassachusettsGeneralHospitalTel:617‐726‐8459Fax:617‐724‐[email protected],MD,MPH,FRCPC,FAHAAssistantProfessor,Dept.ofClinicalNeurosciencesJointAssistantProfessor,Dept.ofRadiologyMember,HotchkissBrainInstituteMedicalDirector,CognitiveNeurosciencesClinicStrokeNeurologist,CalgaryStrokeProgramUniversityofCalgaryTel:403‐944‐1594Fax:403‐283‐2270Eric.Smith@albertahealthservices.caEdnaKavumaManagerQualityResearchProjectsAmericanHeartAssociation‐NationalCenter7272GreenvilleAvenueDallas,TX75231Email:Edna.Kavuma@heart.orgNikeshaRileyMaRISSProjectCoordinatorAmericanHeartAssociation‐NationalCenter7272GreenvilleAvenueDallas,TX75231Email:[email protected],MPHProjectCoordinatorAmericanHeartAssociation‐NationalCenter


7272GreenvilleAvenueDallas,TX75231Email:[email protected])MaRISSSteeringCommittee TheMaRISSSteeringCommitteemonitorstheproject’soveralldirection,studyperformancemetricsanddatacollectiontoassurethatfinalresultsareaccurate,aswellasthattherightsand welfare of human subjects are protected. The Steering Committee Members havequarterly conference calls and annual in‐person meetings to review study progress andprovide recommendations on study status, data collection, anddata analysis. The SteeringCommittee provides UM with advice on the general conduct of the study, data collectionpracticesandprocedures,andproposedchangesinstudyprocedures.TheMaRISSSteeringCommitteeiscomposedbythefollowingmembers: JoseRomano,MD,FAHA,FANA UniversityofMiami,DepartmentofNeurology [email protected]

IszetCampo‐Bustillo,MPH,CCRP UniversityofMiami,DepartmentofNeurology [email protected]

HannahGardener,ScD UniversityofMiami,DepartmentofNeurology [email protected]

RalphSacco,MD,MS,FAAN,FAHA UniversityofMiami,DepartmentofNeurology

[email protected]

LeeH.Schwamm,MD,FAHA Massachusetts General Hospital, Department ofNeurology

[email protected]

EricE.Smith,MD,MPH,FRCPC,FAHA UniversityofCalgary,Dept.ofClinical Neurosciences

[email protected]

PoojaKhatri,MD,MSc UniversityofCincinnati,DepartmentofNeurology [email protected]


C)CORECENTERSUniversityofMiami:ClinicalCoordinatingCenterandDataManagementCenterThe University of Miami (UM) is the leader and coordinating center of this study. UM isresponsibleforprotocoldesignandthedevelopmentofthestudymanualinaccordancewithGoodClinicalPractice(GCP)guidelines.UMwillmaintainoverallsupervisionoftheconductofthestudy.UMisalsothedatamanagementcenterand,throughanagreementwithOutcomeScience,Inc.(thedatamanagementcompanyforallGWTGprograms),willreceiveMaRISSdatain a limiteddata set toperformstudyanalysis.UMwill receive reportsof serious adverseeventsandothersignificantadverseeventsrelatedtoIVrtPAandreportthemtothefundingagency. It is responsible for principal manuscript generation. UM reports to the MaRISSSteeringCommittee.AmericanHeartAssociationTheAmericanHeartAssociation(AHA)isthemaincollaborator intheMaRISSproject.TheAHA is responsible forcoordinatingwithOutcomeSciences themodificationof theGWTG‐Stroke database to include MaRISS‐specific research fields and providing detailed codinginstructionstosupportthesedatafields;AHApersonnelwillreviewnewdatafieldsandcodinginstructions during their training of each recruiting site. As necessary, the AHA will hostwebinarstoinstructrecruitingsitesondataabstraction.TheAHAhoststheMaRISSwebsiteand web‐based training tool, provides CE/CMEs for training completion, and monitorscompletionandmaintenanceoftrainingandcertificationforrecruitingsiteinvestigatorsandcoordinators. It is also responsible for creating the web‐based Patient Reported Outcome(PRO).TheAHAwillcontactandcompletesubcontractswithrecruitingsites,andhaveoverallresponsibilityforissuesrelatedtoparticipatingsitemanagement.UMandAHAwillhavebimonthlyconferencecallstoevaluateMaRISSprogressincludingbutnotlimitedtosubcontracting,IRBandcertificationstatusaswellasenrollmentgoals.D)PARTICIPATINGSITES1.ParticipatingsitecharacteristicsProspectivesiteswillhavethefollowingeligibilitycharacteristics: Annual stroke discharges >300: these centerswill have the ability to recruit sufficient

number of patients, and are likely to have a dedicated stroke team and coordinator toensurethesuccessfulcompletionoftheaddedoutcomemeasuresproposedinthisstudy.Exceptionstostrokevolumerequirementwillbemadeonacase‐by‐casebasis.

Baseline completion rate forNIHSS>60% in thosepatients treatedwithAlteplase thatarrivedwithin4.5hours fromsymptomonset:goodGWTGperformancemeasureswillassure that the centers have adequate staffing, expertise, and quality in rapid strokeevaluation.

2.ParticipatingsiteselectionOnehundredeligiblehospitalsthatcurrentlyparticipateinGWTG‐Swillbeselectedtoensureadequaterecruitmentandrepresentationbasedontypeofhospitalandgeographiclocation.


Selectionwill bebasedon an initial stratificationby geographic area (Northeast,Midwest,South,West) and then by academic vs. non‐academic status. Within each of these 8 sub‐categories, each site will be ranked by annual discharges and baseline NIHSS completionperformance. The top hospitals within each category will be selected in order to achievesimilarproportionsoflargewell‐performinghospitalswithineachcategory.3.Participatingsiteresponsibilities1. Designationofsiteprincipalinvestigatorandstudycoordinator.

a. Site principal investigator is responsible for communicating and disseminatingMaRISSeligibility criteriaamongst the restof the strokegroup,willparticipate inpatient enrollment and consent, and will complete the TOAST classification atdischarge or designate an experienced practitioner to complete the TOASTclassification.

b. Study coordinator: it is suggested and anticipated that inmost centers the strokecoordinatorwillserveas theMaRISScoordinator.However, thedesignationoftheMaRISScoordinatoris lefttothediscretionofeachparticipatingcenter.Thestudycoordinatorwillparticipateinpatientenrollmentandconsent,performtheMaRISS‐requiredNIHSSat1and3days(ordischargeifearlier),completethe30and90‐daytelephoneinterviews,andentertheMaRISSspecificdataintotheGWTG‐Sregistry.

2. Obtain local IRB approval;when a local IRB is not required or available,MaRISSwillfacilitateIRBapprovalthroughacentralcommercialIRB.

3. Identifying,screeningandrecruitingparticipants.Theaveragerecruitmentisanticipatedtobe30patientsperhospital,orabout2patientspermonths.Hospitalsthatrecruitlessthan6patientsinthefirstyearwillnotberenewedforthesecondyear.

4. Protectingparticipants'rights.5. Obtaininginformedconsentfromeachparticipantpriortoperforminganystudy‐specific

activityorassessment.6. Collectingstudydataandfollowingparticipantsthroughstudycompletion.7. EnteringstudydataintheresearchtabofGWTG‐StrokeRegistry.8. Maintainingthestudyregulatorybinderandtheparticipant’sClinicalResearchFormsup

todate.9. Retainingstudyregulatoryandpatient’srecordsfor10years.10. ProvidingAHAandCoordinatingCenterwithIRBapprovalsupportingdocumentation.11. ReportingtoUMseriousadverseeventsandotheradverseeventsofinterestrelatedto

theuseofIVrtPA.4.CommunicationwithsitesPriortositeactivation,AHApersonnelwillcommunicateonaregularbasiswithparticipatingsitestomonitorprogresswithcontracting,IRBapprovalandtrainingcompletion.Oncethestudy is operational, routine telephone calls with the clinical site coordinators to discussprotocoladherence,adequateenrollmentandregulatorycompliancemonthlyandasfrequentasneeded.


5.4PARTICIPATINGSITETRAININGANDCERTIFICATIONTheresearchteameachparticipatingsiteisrequiredtobetrainedinthestudyspecifics,theoutcomemeasurestoolsandtheprotectionofhumansubjectspriortothesiteinitiation.UMandtheAHAresearchteamshavedevelopedofaMaRISStrainingmoduletoensurethatallstudyoutcomesdataareaccuratelycollectedandallstudyproceduresarereliablyperformed.TheMaRISStrainingmoduleislocatedat:learn.heart.org,andrequiresapasswordprovidedbytheAHAtoeachsiteresearchteam.Thetrainingmodulecomponentsinclude:MaRISSprotocoland logistics:Briefoulineof thestudyprotocol, scheduleofactivities,CRFcompletionanddataacquisition.Outcomemeasures: ModifiedRankinScale (mRS):This scalemeasures the functional levelafter stroke.See

attachment1. Barthel Index (BI): This 10‐item index measures the extent to which individuals can

performactivitiesofdailyliving.Seeattachment2. EuroQoL/EQ‐5D:Thisinstrumentassessqualityoflifeinfivedomains:mobility,selfcare,

usualactivities,pain/discomfortandanxiety/depression.Seeattachment3. StrokeImpactScale‐16(SIS‐16):Thisscalemeasuresstrokeoutcomesinactivitiesofdaily

living, mobility, communication, memory and strength, with emphasis of motorimpairment.Seeattachment4.

Otherscales: NIH Stroke Scale (NIHSS) measures the severity of the infarct by quantifying the

neurologicalexam.Seeattachment5. TOASTclassification(seeattachment6)evaluatesthestrokemechanismandincludesfive

subtypes of ischemic stroke: large‐artery atherosclerosis, cardioembolism, small‐vesselocclusion,strokeofotherdeterminedetiology,strokeofundeterminedetiology.

HumanSubjectsProtection:Siteinvestigatorsandstudycoordinatorsmustbeknowledgeableoftheesentialelementsofthehumansubjectsprotection.Theymustprovidedocumentationofcompleting their institutionalHSprotectioncourse, if theyarecertified.Otherwise, theymustcompleteanabbreviated3modulesessiondevelopedbytheCollaborativeInstitutionalTrainingInitiative(CITI)Program.Assessment of gained knowledge: a series of knowledge and case scenarios to evaluateproficiencyinstudyprocedures.Oncetraininghasbeensuccessfullycompleted,studypersonnelwillreceiveacertificationofcompletionandCE/CMEcredits.Figure1showstheMaRISSTrainingflowchartandrequiredmodulesfortheparticipatingsiteprincipalinvestigatorandstudycoordinator.


Figure1.MaRISStrainingflowchart


5.5STUDYPROCEDURESA)Summary:Thisprospectiveobservationalregistrywillrecruitatotalof2650patientswithmild and/or rapidly improving stroke symptoms. In addition to information currentlycollectedinGWTG‐S,afterinformedconsentisobtained,participantswillhavethefollowingMaRISS‐specificinterventions: NIHSS performed at 24 +/‐ 4 hours from onset of symptoms (or before if neurologic

deteriorationbefore24hours)andat3days(ordischargeifearlier). Stroke mechanism determination through the TOAST classification at the time of

discharge. Telephonecallat30daystoevaluatethemRS. Telephonecallat90daystodeterminethemRS,BI,SIS‐15,EQ‐5D. A randomly selected subgroup of 100 patientswill be asked to complete aweb‐based

patientself‐reportedoutcomemeasure.Thetotalstudydurationis90days.MaRISS‐specificactivitiesandtheirtimingareoutlinedbelow:Activities StudyVisits

Visit1Baseline

Visit224hours+/‐4hours

Visit3Day3(oratD/Cif<72h)

Visit4Day30+/‐7

days(Telephone)

Visit5 Day90+/‐10days

(Telephone)Screening,informedconsentandenrollment x

Contactinformation x x x

Initialphysicianassessment x

Neurologicfluctuationassessment

x(pre‐

hospital) x

(in‐hospital)

NIHSS x* x** x

TOAST(Neurologist) x

Outcomeassessment(telephone) mRSmRS,BI,SIS‐16,EuroQoL

Selectparticipants(N=100)completeWeb‐basedPRO x

GWTG‐ResearchCRFs x x x x x

(*)Both thebaselineNIHSS recordedonarrivalaswellas theNIHSSperformed justbeforetreatmentdecision,ifavailable,shouldberecorded.

(**)RepeatNIHSS<24hifclinicalchange


B)ELIGIBILITYCRITERIAPatientswillbeinvitedtoparticipateinthisresearchregistrystudyafterthedecisiontotreatstrokewithIVrtPAornothasbeenalreadymadebytheattendingphysicianandpatientshavereceivedtherecommendedstandardofcareacutetreatment.Inclusioncriteria:1. Patients with mild or spontaneously rapidly improving acute ischemic stroke defined

clinically. Mild stroke is defined as an NIHSS 0‐5. MaRISS does not define RapidlyImproving Stroke Symptoms for purposes of enrollment. It enrolls patients after thedeterminationtotreatornottotreathasbeenmade,inordernottoinfluencetreatmentdecisions.

2. Absenceofnon‐ischemic conditionsonneuro‐imaging (i.e. absenceofhemorrhageoramass on non‐contrast brain CT, or more advanced imaging obtained according toparticipatingsite’simagingprotocol).

3. Age18yearsorolder.4. Arrivaltothehospitalwithin4.5hoursaftertheonsetofstrokesymptoms.5. Patientorlegallyauthorizedrepresentativeprovidesconsentwithin24hoursofarrival.

Obtainingconsentbeyond24hwillbeallowedifthepatientarrivedtothehospitalwithin4.5hoursoftheonsetofsymptomsandtheNIHSSisperformedasstandardofcareat24hours +/‐ 4 hours from onset of symptoms (or before if the patient has neurologicaldeterioration) by a certified practitioner and provided that the NIHSS sub‐scoresinformationisreadilyavailableandcanberecordedintheparticipant’sstudyrecord.

6. Availablebytelephoneandwillingtoreceivetwofollow‐uptelephonecallsoverthenext3months.

ExclusionCriteria:1. Acutestrokepatientsarrivingtothehospitalbeyond4.5hoursfromsymptomonset.2.Unabletoobtainconsentfromeitherpatientorlegallyauthorizedrepresentative.3.Pre‐morbidmodifiedRankinscalegreaterthan1.4.Notavailablebytelephone.C)SCREENINGThestudyteamwillactivelysearchforpatientsthatmeetalltheinclusioncriteriaandnoneoftheexclusioncriteria.TheParticipatingSitewillmaintainaMaRISSScreeningLog.Thislogwill include documentation of all potential study participants that are reviewed for studyeligibility. It will contain an identification number and individuals’ initials, age, gender,screeningdate,andeligibilitystatus: Eligibleforstudyparticipationanddateenrolled. Ineligibleforstudyparticipationandreason. Consentrefusedandwhy.


D)RECRUITMENTTheaveragerecruitment is anticipated to be 30 patients per hospital, or about 2 patients per monthswithanoverallrecruitmentof2650participantsat100participatingsites.Moresitesmaybeincludedinthecaseofslowrecruitment.Hospitalsthatrecruitlessthan6patientsinthefirstyear will not be renewed for the second year. The recruitment of study participants atparticipatingsiteswillbeginaftertrainingiscompletedandthesitestudycoordinatorshavebeencertifiedintheMaRISSstudyrelatedactivities.Patients will be invited to participate in this research registry study by the site strokecoordinator/strokenurseafterthedecisiontotreatstrokewithtPAornothasbeenmadebytheattendingphysicianandpatientshavereceivedthestandardofcareacutetreatment.TherationaleforthisistoavoiddelaysinacutetreatmentwithIVrtPAineligiblepatients.Thestrokecoordinator/strokenursewillpersonallyapproachpatientandwillinvitehim/hertoparticipate.Apatient's legallyauthorizedrepresentativeorproxywillbeapproachedifthepatientiscognitivelyimpairedasdeterminedbythetreatingphysician.E)RETENTIONAvoidanceoflossestofollow‐uporwithdrawalofconsentisahighpriorityinachievingstudysuccess.Thestudy/strokecoordinatorshouldmakeeveryefforttoretainstudyparticipantswithoutbeingcoercive.Thus, it is importantthatseveralcontactsare identifiedduringthescreeningprocess.Specificstrategiestoensureretentioninclude:a) At the time of conducting the informed consent process collect alternative contact

informationincluding: Home,work,mobiletelephonenumbers. Emailaddress. Mailingaddress. Contactinformationforfriendsandfamilymemberswhomaybeabletoassistinlocating

participants.b)Atthetimeofhospitaldischarge: Provide study participant with the proposed date/time in which the 30 and 90 days

telephonecallswillbeperformed. Verifyparticipantandalternativecontactinformation.c)Atthetimeofthe30‐daytelephonecall: Remindparticipantthats/hewillbecalledagaininapproximately2months. Getintouchwithalternativecontactifunabletoreachstudyparticipant.d)Atthetimeofthe90‐daycall: Getintouchwithalternativecontactifunabletoreachstudyparticipant.


F)INFORMEDCONSENTPROCESSANDHIPAAFORMInformedConsentProcessOncethesitecoordinator,investigator,orothersitestaffmemberidentifiesanindividualthatmeets inclusion criteria, the informed consent process will be initiated and the expresspermissiontoparticipatemustbeobtainedfrompatient.Ifthestudycandidateisdeterminedtobecognitivelyimpaired,informedconsenttoparticipateinthestudywillbeobtainedfromaLAR.ThosewhoseprimarylanguageisSpanishwillbeapproachedbyastudyteammemberthat speaks Spanishor an institutional translatorwill be requested.The informed consentprocesswillbeconductedbyastudyteammemberwhowill: Providepotentialparticipantswithadequateinformationconcerningthestudyobjectives,

proceduresanddurationofthestudy. Provideadequateopportunityforanindividualtoconsiderparticipation. Respondtoindividuals’questionsandconcerns. Ensurethateachindividualunderstandsallinformationprovided. Clearlyinformpatientorlegallyappointedrepresentative(LAR)thatparticipationinthe

studyisvoluntaryandthathis/herdecisionofwhethertoparticipateornotwillnotaffectpatient’s care in any way. Specifically, the study investigator designee will informparticipant/LARthats/heisnotobligatedtoparticipateinthestudy,stressthattherearenoconsequencesfornotparticipatingintheMaRISSresearchregistrystudy,thathis/herstandardtreatmentwillnotbeaffectedinanyway,andthatparticipantcanwithdrawthepermissiontoparticipateatanytime.

Obtaintheindividual'sorLARwrittenvoluntaryconsenttoparticipate. AsignedanddatedinformedconsentformmustbeobtainedpriortoundergoingMaRISS

specificinterventionssuchassubsequentNIHSSandstudydatacollection.InformedConsentDocumentationTheinformedconsentshouldbedistributedinthefollowingmanner:1. The investigatormustmaintainasignedoriginalof the informedconsentdocument for

eachparticipantinthestudy.2. Thestudyparticipantorlegalrepresentativewillreceiveacopyofthesignedanddated

informedconsentform.3. Acopyofthesignedanddateddocumentmustbefiledinthepatient’smedicalrecordand

anotemustbeincludedinthemedicalrecordandintheparticipantCRFthatconsentforMaRISSwasobtained.Asuggestedannotationis:

“Patientwas invitedtoparticipate intheMaRISSResearchRegistry.Thepurpose,procedures,risks,benefits,andalternativeswereexplainedtopatient/proxyandallthequestionsansweredtopatient/proxy’ssatisfaction.Freelygiven informedconsentwasobtainedandacopyofthesigneddocumenthasbeenfiledinthepatient’smedicalrecord.Nostudyactivitiesorassessmentsweredonepriortoobtainingconsentfromtheparticipantandsignatureoftheinformedconsentformbyboththestudyparticipant(andlegallyauthorizedrepresentative)andamemberofthestudyteam.”


HIPAAProceduresAlltheRecruitingSitesmustcomplywiththeHIPAAPrivacyRule,whichprotectstheprivacyofindividuallyidentifiablehealthinformation.AHIPAAformwillbepresentedtoapotentialparticipant for signature inaddition to the InformedConsentFormunless the institution’sprivacyregulationsallowthatthenecessaryassurancesareincorporatedintotheInformedConsentForm.TheoriginalsignedanddatedHIPAAformwillbefiledalongwiththeoriginalsignedinformedconsentformintheparticipants’CRFs.6.SPECIFICMEASUREMENTSANDOUTCOMES6.1DEFININGMILDSTROKE

MildstrokeisdefinedasNIHSS0‐5.6.2DEFININGRAPIDLYIMPROVINGSTROKERapidly improving stroke (prior to thrombolysis) is determined by the treating team. Thechoices for classifying Rapidly Improving Stroke Symptoms in the MaRISS data collectionformsare:

NIHSS improvement in absolute points from baseline: for example, patient arrivedaphasiaandhemiplegicwithanNIHSSof17,nowimprovedspeech,onlydysarthriaandhemiparesis,NIHSS7,foroverall10pointimprovement.

ProportionorpercentimprovementinNIHSSfrombaseline:Forexample,theNIHSSimprovedby50%from16to8.

Final NIHSS value regardless of baseline NIHSS: for example, patient arrived withhemineglect, gazedeviationand lefthemiplegiawithaNIHSSwas18and in theEDimprovedtoonlymildhemiparesiswithafinalNIHSSof3.

Improvement toanon‐disablingcondition: forexample,patient improved fromnondominanthemiplegiatominimalclumsinessofnon‐dominanthand.

Other(needtospecify).

Morethanoneoptionmaybeused;allapplicablereasonsshouldberecorded.Acopyoftheinitialphysicianassessmentdatacollectionformisincludedinattachment7.6.3CODINGPRE‐HOSPITALFLUCTUATIONSPatient’sneurologicsymptomsmayfluctuateaftersymptomonsetbutpriortohospitalarrival.As there are no validated methods to ascertain and quantify this change, it has to be aqualitativeassessment.Researchteamwillobtaininformationofsignificantchanges,eitherimprovementordeterioration,thatoccurredaftersymptomonsetbutpriortohospitalarrivalfrompatient,familyorEMSreports.AcopyoftheMaRISSPre‐hospitalarrivalfluctuationcollectionformisincludedinattachment8.6.4CODINGIN‐HOSPITALFLUCTUATIONS


Patient’s neurologic symptoms after hospital arrival will be recorded at Day 3 or at discharge if prior to day 3. As there are no validated methods to ascertain and quantify this change, it has to be a qualitative assessment. Research teamwill obtain information of significant changes, eitherimprovement or deterioration, that occurred after hospital arrival from patient, family or medical record reports. AcopyoftheMaRISSPost‐hospitalarrivalfluctuationcollectionformisincludedinattachment9.6.5ASSESSINGTHENIHSSSCORETheresearchteamwillcollectinformationofthestandardofcarebaselineNIHSSperformedathospitalarrivalaswellas theNIHSSdoneby the treatingphysicianat the timeofacutetreatmentdecision.TheNIHSSwillbeperformedat24+/‐4hours fromonsetofsymptomsandat3days(ordischarge if earlier) aswell as at the timeofneurologicaldeteriorationasMaRISS‐specificassessments.AcopyoftheMaRISSNIHStrokeScaleisincludedinattachment5.6.6OBTAININGTHETOASTCLASIFICATIONTheTOASTClassificationofSubtypesofAcuteIschemicStrokeassessmentmustbedonebytheNeurologist(orbyanexperiencedpractitionerdesignatedbythePI)atDay3oratthetimeofdischargeifpriortoDay3.Thefollowingcriteriawillbeused:

Large‐arteryatherosclerosis(embolus/thrombosis)(Evidencebyimagingof≥50%stenosisofextraorintracranialarteryinthedistributionorthestroke)

a.ExtracranialICA/Vertebralartery b.IntracranialLargeVesselStenosis c.AorticArchatheroscleroticdisease

Cardioembolism(high‐risk/medium‐risk):a.Leftatrialthrombusb.Leftventricularthrombusc.Atrialfibrillationd.ParoxysmalAtrialFibrillatione.SickSinusSyndromef.SustainedAtrialFlutterg.RecentMyocardialInfarction(within1month)h.Rheumatoidmitraloraorticvalvediseasei.Bioprostheticandmechanicalheartvalvej.Chronicmyocardialinfarctiontogetherwithlowejectionfraction<28%k.Symptomaticcongestiveheartfailurewithejectionfraction<30%


l.Dilatedcardiomyopathym.Nonbacterialthromboticendocarditisn.Infectiveendocarditiso.Papillaryfibroelastomap.Leftatrialmyomaq.Othercardioembolicsource

Small‐vesselocclusion(lacune) Strokeofundeterminedetiology:

a.Multipleetiologiesseemlikelyb.Undeterminedetiologydespitethoroughevaluationc.Evaluationincomplete

Otherdeterminedetiologya.Hypercoagulablestates:

1. Malignancy2. Antiphospholipidantibodysyndrome3. Inheritedthrombophilia

b.Iatrogenicc.Arterialdissection(carotid,vertebral)d.Other

AcopyoftheMaRISSTOASTClassificationofSubtypesofAcuteIschemicStrokedatacollectionformisincludedinattachment6.6.7THEMODIFIEDRANKINSCALETheModifiedRankin Scale (mRS) is theMaRISSPrimaryOutcomeMeasure: proportionofpatientswithamRS=or>2at90days.Thestudycoordinator/strokecoordinatorwillperforma5‐10minutestelephonecallatday30(+/‐7days)tocompleteamodifiedRankinScale.Atthistimeinformationaboutanynewhospitalizationornewischemiceventwillbeobtainedaswell.ThemRSwillbecompletedoverthephoneduringtheMaRISS90‐daytelephonecall.6.8THEBARTHELINDEX,THESTROKEIMPACTSCALE‐16,THEEUROPEANQUALITYOFLIFEEQ‐5DSCALETheBarthelIndex(BI),theStrokeImpactScale‐16(SIS‐16)andtheEuropeanQualityofLifeEQ‐5DscalearetheMaRISSSecondaryOutcomeMeasures.Thestudycoordinator/strokecoordinatorwillcallstudyparticipantat90days(+/‐10days)tocompletetheBI,SIS‐16andEQ‐5D.Atthistimeinformationaboutanynewhospitalizationornewischemiceventwillbeobtainedaswell.Inthis25‐30minutestelephonecallamodifiedRankinScalewillbecompletedaswell.


7.EVALUATIONSANDDATACOLLECTIONThe study specific evaluations and data collection begin after screening enrollment andinformedconsent,andoncethedecisiontousethrombolyticshasbeenmadeinordernottodelay or influence treatment decisions. Please note thatMaRISS specific data needs to becollectedinadditiontoGWTG‐Sdatapoints.MaRISSCRFsaretobekeptonfile,senttoUM,andusedassourcedocumentationtocompletetheGWTG‐SMaRISSfields.TheMaRISSCRFsare included in Attachment 10. The flowchart in Figure 3 depicts the timing of MaRISSevaluations.7.1STUDYFLOWCHARTFigure3.MaRISSflowchart

Performedasstandardofcare MaRISS‐specificassessments

(**)

(*)


(*)Consentshouldbeobtainedwithin24hoursofarrival.Consentafter24hoursisallowedonlyifthefollowingconditionsareallmet:a)theNIHSSisobtainedat24hours+/‐4hoursaspartofstandardofcareprocedures;b)theNIHSSsub‐scoresareavailabletobeenteredintotheMaRISSdatacollectionforms;c)theNIHSSisperformedbyacertifiedpractitioner.(**)NIHSSperformedat24hours+/‐4hoursfromonsetofsymptoms.7.2MaRISSGWTG‐SRequiredItemsElementsalreadyrequiredintheGWTG‐SRegistry:

• Age• Gender• Race• HispanicEthnicity• Symptomtimeline• Admissiondateandtime• Finalstrokediagnosis(IS,TIA,non‐stroke)• Modeofarrival• Previouslyknownmedicalhistory• InitialNIHSS• IVthrombolytictherapyatthishospital• Date/TimeIVtPAinitiated• Contraindicationsthrombolytic0‐3hr• ComplicationsofThrombolyticTherapy• Dischargedate• Dischargedispositionondayofdischarge&mortality

ExistingelementsintheGWTG‐SRegistryrequiredtobecompletedforMaRISS:

• Insurance• Medicationspriortoadmission(onlycholesterolmandatorynow)• Ambulatorystatuspriortoarrival• Wherewaspatientcaredforandbywhom• Initialexamfindings• Contraindicationsthrombolytics3‐4.5hr• Ifnodocumentedcontraindicationsorwarnings,Hospital‐RelatedorOtherFactors• IAcatheterbasedreperfusioninthishospital• Ambulationstatusatdischarge

7.3MaRISSSTUDYVISITS VISIT1:BASELINEVISITThebaselinevisithasvariouscomponents:1. Confirmeligibility:seesection5.5.B

2. Obtainconsent:seesection5.5.F


3. Collectcontactinformation:TheStudyCoordinator/StrokeCoordinatorwillcollectthepatient’sandalternativecontactinformation,including:

• Telephonenumbershome,work,mobile.• Emailaddress.• Mailingaddress.• Contactinformationforfriendsandfamilymemberswhomaybeabletoassistinlocating

participants.4. Initialphysicianassessment:Determinationofmildstrokeandrapid improvement is

discussed in section 6. In the baseline visit CRF and in the GWTG‐SMaRISS fields, thedefinition that most closely approximates the reason to code Mild Stroke or RapidlyImproving Stroke should be given. In order to code correctly, the coordinator shouldcontactthetreatingphysiciantoassesswhichofthesecriteriawhereusedbythephysiciantodeterminerapidimprovement.

5. Pre‐hospital fluctuation: Some patient’s neurologic symptoms may fluctuate aftersymptomonsetbutpriortohospitalarrival.Astherearenovalidatedmethodstoascertainandquantifythischange,thiswillbeaqualitativeassessment.Answerthisquestionbasedon patient, family or EMS reports of significant changes, either improvement ordeterioration, that occurred after symptom onset but prior to hospital arrival. Do notconsiderchangesthatoccurafterpatientisfirstevaluatedbyhospitalpersonnel.Ifmorethanonesignificantfluctuationoccurs,pleasenoteso.However,inthecaseof2sequentialchangesinthesamedirection(i.e.improvementfollowedbyimprovement,orworseningfollowedbyworsening)onlyrecordthedirectionofchangeorasingledirectionalchange.Thedatacollectionform(seeattachment8)asksthefollowingquestion:

Did neurologic status change between onset of symptoms but prior to hospital arrival? ☐No☐YesIf YES, please note if they improved () or worsened ().Noteifmorethanonefluctuation.

☐☐☐

Example1:Patienthasremainedunchangedwithmildarmandlegweaknessontheleftandslurredspeech.Didneurologicstatuschangebetweenonsetofsymptomsbutpriortohospitalarrival?No☐YesExample2:Initiallyunabletospeakormoverightsidebutimprovedduringambulancerideandnowliftingarmandlegandspeaking,althoughstillslurred.Didneurologicstatuschangebetweenonsetofsymptomsbutpriortohospitalarrival?☐NoYes


If YES, please note if they improved () or worsened ()Noteifmorethanonefluctuation.

BaselineNIHSS:PleasenotethattheindividualcomponentsoftheNIHSSneedtobe

recordedintheCRFandintheGWTG‐SMaRISSfields.

NIHSS prior to treatment decision: In addition to the baseline NIHSS on arrival(baseline),arepeatNIHSSshouldbeperformedifpatientisbeingconsideredforacuteischemic stroke treatment. That NIHSS and its individual components need to becollected.

VISIT2:24HOURSThe investigator or the study coordinator/stroke coordinatorwill perform aNIHSSat24hours(+/‐4hours)fromsymptomonsetorbeforeifneurologicalworseningoccurswithin24 hours to document potential in hospital fluctuations. The total score its individualcomponentsneedtobecollected. VISIT3:DAY3OREARLIERIFDISCHARGEPRIORTODAY3The3rdvisitshouldbecompletedonthe3rddayoratdischargeifthisoccurspriortoday3.Thisvisitconsistsofthefollowing:1. NIHSSatday3ordischarge:recordthetotalscoreandtheindividualcomponents.2. TOAST classification to determine the stroke mechanism. The TOAST should be

completedbytheinvestigatorinconsultationwiththetreatingneurologist,andisbasedontheclinical,imagingandcardiacevaluationsperformed.

3. Post‐hospitalfluctuation:InadditiontothesequentialNIHSS,pleaserecordifsignificant

changes, either improvement or deterioration, occurred after hospital arrival. Do notconsiderchanges thatoccurredprior toarrival. Ifmore thanonesignificant fluctuationoccurs,pleasenoteso.However,inthecaseof2sequentialchangesinthesamedirection(i.e. improvementfollowedbyimprovement,orworseningfollowedbyworsening)onlyrecordthedirectionofchangeorasingledirectionalchange.TheCRFasksthefollowingquestion:

Did neurologic status change after arrival to hospital? ☐No☐YesIf YES, please note if they improved () or worsened ().Noteifmorethanonefluctuation.

☐☐☐4. RecordAdverseEvents:Reportingislimitedtothefollowingsituations:

a) OnlythosetreatedwithAlteplasethathaveAEneedtobereported;and


b) OnlySeriousAdverseEvents(SAE)relatedtotheuseofAlteplase,aswellasalldeaths,pregnancyandtransmissionofinfectiousagentthroughtheadministrationofIVrtPAneedtobereported.

Seesection8forAdverseEventreporting.AdverseEventsneedtobereportedwithin24hoursoftheresearchteambeingmadeawareofevent.

5. Confirmcontactinformation:ensurethatthebaselinecontactinformationforpatient,

legallyauthorizedrepresentativeandalternativecontactsarecorrect.VISIT4:DAY30+/‐7DAYS‐TELEPHONECALLThisbrief(approximately5‐10minutes)telephonecallshouldincludethefollowing:1. PerformthemodifiedRankinScale.2. Askifpatienthasbeenre‐hospitalizedsincedischargeandthereason(Stroke,TIA,

cardiovascularsymptoms,other).3. Askifpatienthashadaseriousadverseeventasdefinedinsection8.4. Verifyparticipant/alternativephonenumbers.5. Remindparticipantofthe90‐dayphonecall.VISIT5:DAY90+/‐10DAYS‐TELEPHONECALLThisextended(approximately20minutes)telephonecallshouldincludethefollowing:1. PerformthemodifiedRankinScale.2. ObtaintheBarthelIndex.3. ObtaintheStrokeImpactScale‐16.4. ObtaintheEuroQOL.5. Askifpatienthasbeenre‐hospitalizedsincedischargeandthereason(Stroke,TIA,

cardiovascularsymptoms,other).6. Askifpatienthashadaseriousadverseeventasdefinedinsection8.7. Thankparticipantandinformthathis/herparticipationinthestudyfinished.8. Arandomlyselectedgroupof100participantswillparticipateinaweb‐basedPatient Self-Reported Outcome (PRO). If a participant is pre-selected for PRO, direct them to this website. All theresearchelementswillbeentered into theGetWithTheGuidelines‐StrokeRegistryalongwiththeusualrequireditems.8.ADVERSEEVENTREPORTINGAlthoughMaRISSisnotaninterventiontrial,doesnotdictatetheuseofaspecifictreatment,and enrolls patients after treatment decision has been made, some patients will receivethrombolyticsandthereforeSAEneedtobereported.However,reportingislimitedtothosetreatedwithAlteplasethathavereportableAdverseEvents.CONDITIONSTHATNEEDTOBEREPORTEDinALTEPLASE‐TREATEDPATIENTS:A.SeriouseventsthatarerelatedorcausedbyAlteplase:


• Symptomatic intracranial hemorrhage: neurological deterioration by 4 NIHSS pointswithin36hoursoftreatment.

• Systemichemorrhagethatrequirestransfusion,pressorsorsurgery.• Othereventsthatarelifethreatening.• Eventsthatcausesignificantandpersistentdisabilityorincapacity.• Eventsthatprolonghospitalization.B.Othereventsregardlessofcausalassociation:• Alldeaths.• Allpregnanciesthatoccurduringthestudyperiodorevenbeyondifthestudyteamismade

awareofit.• BirthdefectorcongenitalabnormalityininfantborntomothertreatedwithAlteplase.• TransmissionofaninfectionthroughtheadministrationofAlteplase(i.e.Hepatitis,HIV,

etc.)DeterminationofcausalityorrelationtoIVrtPA/Alteplase• ItistemporallyrelatedtotheadministrationofAlteplase(i.e.36hours).• It isnotreadilyexplainedbythesubject’sclinicalstate, thestroke,orotherconcurrent

therapies.• ItisaknownpatternofresponsetoAlteplase(i.e.hemorrhage,orolingualangioedema)DeterminationofSeriousAdverseEvent• Theeventisfatal.• Theeventislifethreatening.• Theeventprolongshospitalizations.• Theeventresultsinpersistentandsignificantdisabilityorincapacity.ReportingAdverseEvents• ReportableeventsshouldbefaxedtotheUniversityofMiamiwithin24hoursofthestudy

teambeingmadeawareofevent.• Completethe“SeriousAdverseEvent”MaRISSCRF.Acopyisincludedasattachment11.• Collectsupportingmaterial(i.e.CTreport,labs,etc.)• FaxCRFandsupportingmaterialtothenumberprovidedtoMaRISSsitesoremailto

[email protected]• ForquestionsrelatedtowhicheventsarereportableorhowtocompleteCRFcall305‐243‐

8018.


9.MONITORING,COMPLIANCE,FORMS,DATAQUALITYCONTROL9.1MONITORINGRESPONSIBILITIESAHAwillberesponsibleforthedirectmonitoringoftheParticipatingSites.Monitoringperformanceofthestudyincludesreviewof: Participantrecruitment. Flowofdata. Qualitycontrolofthedata. Adverseeventreporting. Adherencetoprotocol.9.2COMPLIANCEWITHSTUDYPROTOCOLThe followingprocedureswillbe implemented tomaximizeadherence to theprotocolandenhanceparticipantretention: Comprehensivetraining. Earlyreviewofthedata. Routinecommunicationswiththesites.Protocolviolationsincludebutarenotlimitedtothefollowing: Enrollmentofanineligibleparticipant. Failuretoobtaininformedconsent. FailuretokeepIRBapprovaluptodate.Studystaffshouldreportaviolationassoonasitisdiscovered.TheCoordinatingCenterwillmaintainalogofprotocoldeviationsand/orviolationsandwillreportthemroutinelytotheSteeringCommittee.OccasionalviolationswillrequireanexplanationfromtheRS.Siteswithseriouscontinualproblemsmaybeterminated.9.3DATACOLLECTIONANDSTUDYFORMSUserTrainingTheparticipatingsitestudystaffwithaccesstotheGWTG‐StrokeRegistrywillbetrainedintheuseof the researchelements inGWTG‐S. Trainingwill includeexplanationsofhow toaccessthesystemandadiscussionoftheneedfor,andimportanceof,systemsecurity.SourceDocumentationTodocumentstudy‐specificdatarequirements,sourcedatawillbetranscribedtoapapercasereportform(CRF)andsubsequentlyenteredintotheGWTG‐SResearchRegistry.AllessentialstudydocumentsincludingCRFsmustberetainedbythestudyinvestigator.Thefollowingareconsideredparticipantfiledocuments: Casereportforms. Sourcedocuments(NIHSS,mRankin,BarthelIndex,EuroQoL5D,SIS16,Toast

classification). SignedparticipantconsentandHIPAAforms.


StudyForms(CRFs)Copy of MaRISS CRFs and outcome measures data collection forms are included in theattachmentssection.DataFlowMaRISS Participating Sites will enter the research registry data into the GWTG‐S PatientManagementTool(PMT).Through its relationshipwith Outcome Sciences/Quintiles, AHAwill provide University ofMiami study team access to the MaRISS data fields in the GWTG‐S registry by way of apassword protected super‐user account. To perform the statistical analysis, UM will begrantedaccessfortheclinicalleveldataofpatientsthathaveprovidedinformedconsenttoparticipateinthestudy.RetentionofStudyDocumentsAllMaRISSstudyfilesandsourcedocumentsaretobemaintainedattheParticipatingSiteforatotalof10years.AdministrativeFormsFacsimileTransmittalSheet‐coverpageforallfaxes,asrequiredbyMaRISSstudy.1. TelephoneContactLogtorecordthetelephonecallswithparticipantsregardingthe

study.2. ScreeningLogtomaintainarecordofindividualswhoarescreenedforparticipationin

thestudy.Itshouldbearrangedchronologicallyandbekeptuptodate.3. ParticipantIdentificationListrecordseachparticipant'sname,medicalrecordnumber,

studyidentificationnumberandstudyentryandexitdates.Thisisconfidentialinformation.ItshouldbemaintainedinasecuredlocationapartfromCRFsanddatafilesatthestudysite.

4. CRFTransmittalSheet:thecoverpageforeachpacketofCRFssubmittedtotheCoordinatingCenter.

5. SignatureLog:thisdocumentmustcontainthesignatureofallmembersofthesitestudyteam.ThePrincipalInvestigatororhis/herdelegate(ClinicalResearchCoordinator/StrokeCoordinator)isresponsibleforlistingtheresearchpersonnelapprovedtoparticipateintheMaRISSstudy,includinginitialsandsignature,aswellasnotingthedateeachstudyteammemberbecomesinvolvedinthestudyandtheterminationdate.

6. SiteVisitLog:AllparticipatingsitesmustmaintainaSiteVisitlogtorecordthesiteinitiation,everymonitoringvisitperformed,training,andstudyclose‐out.

9.4DATAMANAGEMENTDataTrackingToprovidethestatusofParticipatingSiteresearchteamtrainingandcertification,participantenrollment,numberof formscompletedatthesites,andnumberof formsenteredintotheGWTG‐StrokeResearchRegistryasappropriate,theAHAwillaccountforparticipantsaccrued,


enteredandcompletedintheGWTG‐StrokeResearchRegistrybytheRecruitingSitesandwillinformUnivofMiami,MaRISSCoordinatingCenter,onamonthlybasis.DataEntry:Tominimizeerrors,theMaRISSCRFswillbesimilartothedataentryscreensintheGWTG‐StrokePMT.AllcollectedinformationwillbeenteredintheGWTG‐Sregistrywithin15daysofcompletingthestudyvisit.9.5QUALITYCONTROLPROCEDURESDataqualitycontrolchecksincludethefollowingtypesofreview: AlldatareceivedfromparticipatingRS Nomissingformsordata Uniqueidentification(ID)numberforeachstudyparticipantisconsistentacrossall

formsandvisits CorrectnumbersinthesiteIDandparticipant’sIDnumber Legibledata Consistentandlogicaldatesovertime Datawithinacceptableranges Dataconsistentacrossformsandvisits Allfieldsofa"completedform"actuallycompletedorreasonfornodatanoted Allrequiredformscompletedorreasonfornodatanoted.MonitoringThe AHA Project Coordinator will supervise the Participating Sites performance throughperiodicmonitoringsitevisitsduringthecourseofthestudy.Thefrequencyofvisitsdependsupon site performance and the number of participants enrolled. The purposes of thesemonitoringvisitsare:

1.Assuretherightsandsafetyofparticipants2.ConfirmthatstudyconductfollowstheguidelinesofGoodClinicalPractice(GCP)3.Assuremaintenanceofrequireddocuments 4.Verifyadherencetotheprotocol5.Monitorthequalityofdatacollected6.Assureaccuratereportinganddocumentationofalloutcomemeasures

Thedatarecordedonthestudyformswillbereviewedandverifiedagainstthestudysourcedocumentsand/orstudydatabaseduringthemonitoringvisitstoverifythat:

Informedconsenthasbeenobtainedanddocumentedpriortoperforminganystudyspecificactivity.

Theinformationrecordedontheformsiscompleteandaccurate. Therearenoomissionsinthereportsofspecificdataelements. Missingassessmentsareindicatedontheforms.

SiteinvestigatorsmustallowtheAHAprojectcoordinatoraccesstothestudydocuments,includinginformedconsentformsandsourcedocuments,pertinenthospitalormedicalrecords.Oncethesitevisitiscomplete,asitemonitoringreportwillprovidefeedback


regardinganyproblemsorissuesthatmayhavebeenuncoveredduringthevisit.Atimelinewillbeincludedinthereporttoensurethatfollow‐upoftheissuesiscompletedandimplemented.ReportsOncethestudybegins,routinereportspreparedbytheAHAstudycoordinatorwilldescribeparticipantsenrolledbysiteandinaggregate.Enrollmentreportswilldescribeparticipantsscreened,enrolled,refusedparticipation,completed,andlosttofollow‐up.10.STUDYCOMPLETIONANDCLOSEOUTPROCEDURESParticipatingSitesCloseoutProceduresOnce the study target enrollment is achieved, study closeout activitieswill be initiated toconfirmthatthesiteinvestigator’sstudyobligationshavebeenmetandpoststudyobligationsareunderstood.ThefollowingcloseoutactivitieswillbeperformedattheParticipatingSitesandsupervisedbyAHAandtheCoordinatingCenter: Completionofstudyproceduresanddatacollection. Resolutionofanystandingdataqueries. AssurancethatIRBcorrespondenceandstudyfilesareaccessibleforexternalaudit. Ascertaintoinvestigatorsoftheongoingresponsibilitytomaintainstudyrecordsfor10

years. Assurethatsiteinvestigatorshavecompletedrequiredregulatoryobligations InstitutionalIRB(orcommercialIRBifapplicable)isnotifiedofstudycompletion ObtainingacopyoftheIRBstudyclosurenotification.The AHA study teamwill recognize sites that enrolled adequately and had a high level ofperformancethroughouttheconductoftheresearchregistrystudy.


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12.RELEVANTWEBSITESMaRISSwebsite:http://www.heart.org/HEARTORG/HealthcareResearch/GetWithTheGuidelinesHFStrokeResus/GetWithTheGuidelinesStrokeHomePage/MaRISS_UCM_452130_SubHomePage.jspUniversityofMiamihttp://neurology.med.miami.eduAmericanHeartAssociation/AmericanStrokeAssociationhttp://www.heart.orgNIH:

http://ohrp.osophs.dhhs.gov/polasur.htm(Office of Human Research Protections’ Regulations on conducting research with humansubjects)http://www.nih.gov/sigs/bioethics/IRB.html(BioethicsResourcesontheWeb)DHHSOfficeforCivilRights‐HIPAAInformation:http://www.hhs.gov/ocr/http://privacyruleandresearch.nih.gov(ProtectingPersonalHealthInformationinResearch:UnderstandingtheHIPAAPrivacyRule)FoodandDrugAdministration(FDA):

http://www.fda.gov/oc/gcp/regulations.html(FDAGoodClinicalPracticeregulations)http://www.fda.gov/cder/(FDACenterforDrugEvaluationandResearch)http://www.fda.gov/ora/compliance_ref/part11/Default.htm(FDAregulationsonelectronicrecordsandelectronicsignatures)


13.ATTACHMENTSATTACHMENT1ModifiedRankinScale(mRS‐9Q)


ATTACHMENT2BarthelIndex(BI)


ATTACHMENT3EuropeanQualityofLife5D(EQ‐5D)Page1


ATTACHMENT3EuropeanQualityofLife5D(EQ‐5D)Page2


ATTACHMENT4StrokeImpactScale16(SIS‐16)


ATTACHMENT5NIHStrokeScale(NIHSS) Page1


ATTACHMENT5NIHStrokeScale(NIHSS)Page2


ATTACHMENT6TOASTClassificationofSubtypesofAcuteIschemicStroke


ATTACHMENT7CriteriaforcodingRapidlyImprovingStroke(RIS)


ATTACHMENT8Pre‐hospitalarrivalneurologicfluctuations


ATTACHMENT9In‐hospitalneurologicfluctuationsATTACHMENT10MaRISSCRF


ATTACHMENT11AdverseEventReportingForm