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CONFIDENTIALTheGlaxoSmithKlinegroupofcompaniesH3M1164771Division:WorldWideDevelopmentRetentionCategory:GRS019InformationType:ReportingandAnalysisPlanTitle:ReportingandAnalysisPlanforH3M116477:ProofofMechanismStudytoAssessthePotentialofGSK239512toRemyelinateLesionsinSubjectswithRelapsingRemittingMultipleSclerosisCompoundNumber:GSK239512EffectiveDate:30-SEP-2014Description:ThisdocumentprovidesthereportingandanalysisplanforthisProofofMechanismStudytoAssessthePotentialofGSK239512toRemyelinateLesionsinSubjectswithRelapsingRemittingMultipleSclerosisSubject:RelapsingRemittingMultipleSclerosis,Remyelination,H3inverseagonist,magneticResonanceImaging,MagnetisationTransferRatioAuthor'sName,TitleandFunctionalArea:Manager,NeurosciencesClinicalStatistics;Director,ClinicalPharmacology,ModellingandSimulation.
Approvedviae-mailby:NSClinStatsTAHeadDirector,DevelopmentSciences,NeurosciencesTAUCopyright2014theGlaxoSmithKlinegroupofcompanies.
Allrightsreserved.
Unauthorisedcopyingoruseofthisinformationisprohibited.
2014N204379_00CONFIDENTIALH3M1164772TABLEOFCONTENTSPAGEABBREVIATIONS51.
INTRODUCTION.
72.
STUDYOBJECTIVE(S)ANDENDPOINT(S)72.
1.
StudyObjectivesandEndpoints72.
2.
StatisticalHypotheses.
92.
3.
Pharmacokinetic(PK)andPK/Pharmacodynamic(PD)hypotheses103.
STUDYDESIGN104.
PLANNEDANALYSES114.
1.
InterimAnalyses114.
2.
FinalAnalysis125.
SAMPLESIZECONSIDERATIONS.
125.
1.
SampleSizeAssumptions125.
2.
SampleSizeSensitivity.
145.
3.
SampleSizeRe-estimation.
176.
ANALYSISPOPULATIONS176.
1.
AnalysisDatasets176.
1.
1.
Non-MTRMRIEndpoints.
177.
TREATMENTCOMPARISONS.
187.
1.
DataDisplayTreatmentandOtherSub-groupDescriptors188.
GENERALCONSIDERATIONSFORDATAANALYSES.
188.
1.
MulticentreStudies188.
2.
OtherStrataandCovariates198.
3.
ExaminationofSubgroups.
208.
4.
MultipleComparisonsandMultiplicity208.
5.
GeneticMarkers209.
DATAHANDLINGCONVENTIONS209.
1.
PrematureWithdrawalandMissingData209.
2.
DerivedandTransformedData.
219.
2.
1.
BaselineData219.
2.
2.
DemographicData.
219.
2.
3.
StudyDayDefinition219.
2.
4.
DefiningtheFirstDoseDate.
219.
2.
5.
DefiningtheLastDoseDate229.
2.
6.
DefiningTitrationandMaintenancePeriods.
229.
2.
7.
MRI–MTRData.
239.
2.
8.
MRI–OtherMRIEndpoints.
249.
2.
8.
1.
ConventionalMRIendpointsfromCentralReader249.
2.
8.
2.
MRIendpointstobeDerivedProgrammatically.
252014N204379_00CONFIDENTIALH3M11647739.
2.
9.
CogStateBattery279.
2.
10.
MSQoL54299.
2.
11.
Electrocardiograms(ECGs)319.
3.
AssessmentWindows.
319.
3.
1.
StudyPhases319.
3.
2.
AssessmentWindows.
329.
4.
ValuesofPotentialClinicalImportance.
349.
4.
1.
LaboratoryData.
349.
4.
2.
VitalSigns.
359.
4.
3.
ECGs.
3510.
STUDYPOPULATION.
3510.
1.
DispositionofSubjects.
3610.
2.
ProtocolDeviations.
3610.
3.
DemographicandBaselineCharacteristics.
3710.
3.
1.
Demographics3710.
3.
2.
MedicalHistory3810.
3.
3.
MSDiseaseHistory3810.
3.
4.
SmokingHistory.
3810.
4.
ConcomitantMedications.
3910.
5.
ExposureandTreatmentCompliance.
4210.
5.
1.
Exposure4210.
5.
2.
TreatmentCompliance.
4310.
5.
3.
DoseTitration4311.
EFFICACYANALYSES.
4411.
1.
PrimaryEfficacyAnalyses4411.
1.
1.
SummaryDisplays.
4411.
1.
2.
StatisticalAnalysis.
4511.
2.
SecondaryMRIEfficacyAnalyses4811.
2.
1.
T2LesionMTR4811.
2.
2.
MRILesionCountVariables4911.
2.
2.
1.
SummaryDisplays.
4911.
2.
2.
2.
StatisticalAnalysis.
5011.
2.
3.
MRIVolumeMeasures5211.
2.
3.
1.
SummaryDisplays.
5211.
2.
3.
2.
StatisticalAnalysis.
5211.
3.
OtherEfficacyAnalyses.
5311.
3.
1.
CogStateBattery5311.
3.
1.
1.
SummaryDisplays.
5311.
3.
1.
2.
StatisticalAnalysis.
5411.
3.
1.
3.
SensitivityAnalysisaroundMissingData.
5611.
3.
2.
ExploratoryAnalyses:UnderstandingRelationships5712.
SAFETYANALYSES5712.
1.
AdverseEvents.
5712.
1.
1.
GeneralRulesforAEs5812.
1.
2.
CountingRulesforAEs.
5912.
1.
3.
AECollapsingAlgorithm6012.
1.
4.
AdverseEventReporting.
6012.
1.
5.
AdverseEventsofSpecialInterest6212.
1.
6.
PossibleSuicidalityRelatedAdverseEvents632014N204379_00CONFIDENTIALH3M116477412.
2.
DeathsandSeriousAdverseEvents.
6312.
3.
DeviceIncidentsandNearIncidents.
6312.
4.
AdverseEventsLeadingtoDiscontinuationofInvestigationalProductand/orWithdrawalfromtheStudyandOtherSignificantAdverseEvents.
6412.
5.
Pregnancies.
6412.
6.
ClinicalLaboratoryEvaluations.
6412.
6.
1.
HaematologyandChemistry.
6412.
6.
1.
1.
LiverFunctionTests6512.
6.
2.
UrinalysisResults6612.
7.
MultipleSclerosisSafetyAssessments.
6612.
7.
1.
EDSS.
6612.
7.
2.
MSRelapses6712.
8.
OtherSafetyMeasures.
6812.
8.
1.
VitalSigns.
6812.
8.
2.
ECGAssessments.
6812.
8.
3.
ColumbiaSuicideSeverityRatingScale(C-SSRS)6913.
HEALTHOUTCOMESANALYSES.
7013.
1.
MSQoL547013.
1.
1.
SummaryDisplays.
7013.
1.
2.
StatisticalAnalysis.
7014.
CLINICALPHARMACOLOGYDATAANALYSES.
7114.
1.
PharmacokineticAnalyses.
7114.
2.
Pharmacokinetic/PharmacodynamicAnalyses.
7115.
REFERENCES.
7216.
ATTACHMENTS7316.
1.
TableofContentsforDataDisplaySpecifications.
7316.
2.
DataDisplaySpecifications10116.
3.
LaboratoryNormalRangesandPotentialClinicalConcernRanges.
1022014N204379_00CONFIDENTIALH3M1164775ABBREVIATIONSAEAESAESIALPALTANCOVAASTATCBILBMIbpmBPTCUALCSRDMECGeCRFeC-SSRSAdverseEventAllEvaluableScansAdverseEventofSpecialInterestAlkalinePhosphataseAlanineAminoTransferaseAnalysisofCovarianceAspartateAminoTransferaseAnatomicalTherapeuticClass*TotalBilirubinBodyMassIndexBeatsperMinuteBiostatistics&ProgrammingTeamCumulativeUniqueActiveLesionsClinicalStudyReportDataManagementElectrocardiogramelectronicCaseReportFormelectronicColumbia-SuicideSeverityRatingScaleEDSSFSHFSSGdGdEGGTGMLTGSKHLGTIMVISLTISLT-RiSRCITTkgmMedDRAmmHgMMRMMSMSQoLMTRMRINROBTOCOCLPCCExpandedDisabilitySeverityScale*FunctionalSystemScoreGadoliniumGadolinium-enhancingGamma-GlutanylTransferaseGrotonMazeLearningTestGlaxoSmithKlineHigherLevelGrpoupTermImputedMissingValuesInternationalShoppingListTask–ImmediateRecallInternationalShoppingListTask–DelayedRecallinternalSafetyReviewCommittee*Intention-to-TreatKilogrammetreMedicalDictionaryforRegulatoryAffairsmillimetersofmercuryMixedModelRepeatedMeasuresMultipleSclerosisMultipleSclerosisQualityofLifeMagnetisationTransferRatioMagneticResonanceImagingNon-RandomisedPopulationOneBackTestObservedCaseOneCardLearningPotentialClinicalConcern2014N204379_00CONFIDENTIALH3M1164776PCIPDPKPP*PSRAEPTQCRR&DRAPRRMSRUCAMPotentialClinicalImportancePharmacodynamicsPharmacokineticsPerProtocolPossibleSuicide-RelatedAdverseEventPreferredTermQualityControlRandomisedPopulationResearch&DevelopmentReportingandAnalysisPlanRelapsingRemittingMultipleSclerosisRousselUclafCausalityAssessmentMethodSAESDSOCSeriousAdverseEventStandardDeviationSystemOrganClassSPMSOPSPMSSRTugULNStudyProceduresManualStandardOperatingProcedureSecondaryProgressiveMultipleSclerosisSafetyReviewTeamMicrogramUpperLimitofNormalTrademarkInformationTrademarksoftheGlaxoSmithKlinegroupofcompaniesTrademarksnotownedbytheGlaxoSmithKlinegroupofcompaniesNONEAvonexCopaxoneSAS2014N204379_00CONFIDENTIALH3M11647771.
INTRODUCTIONThisdocumentdetailsthereportingandanalysistobepreparedbytheBiostatisticsandProgrammingTeam,NeuroscienceforthisProofofMechanismStudytoAssessthePotentialofGSK239512toRemyelinateLesionsinSubjectswithRelapsingRemittingMultipleSclerosis.
TheRAPhasbeenwrittenandapprovedwhilsttheprojectteamremainblindedtotreatmentassignments.
Aspertheprotocol,someprojectteammembersmaybeunblindedatthetimeoftheiSRCconductingtheinterimanalysis.
Thissub-teamwillbereviewingdatasummarieswhilstthestudyisconductedandanalysesnotspecifiedinthisRAPmaybeplannedforfinalreporting.
TheseanalyseswillbeidentifiedasbeingplannedafterunblindingintheCSR.
ThisRAPisbasedonGuidancedocumentGUI_00000137354andisinlinewithSOP_00000054838TheRAPreferencestheH3M116477protocol[GlaxoSmithKlineDocumentNumberHM2012N133918_00]andthestudyeCRF.
ThisRAPisintendedforusebyGSKstaffwithinR&DinvolvedinthedeliveryofdatadisplaysforstudyH3M116477.
Version2ofthisRAPwasgeneratedbasedoncommentsfromtheinstreamblindeddatalookandfollowingreviewoftheanalysisofthenovelco-primaryendpointsafterthefutilityinterimanalysisatatimewhentheauthorwasunblindedatthesubjectlevelandtheapproverswereunblindedtothetreatmentgroupresults.
Theupdateshavebeenmadetoprovideaclearreportingstrategyfortheprogrammersonthisstudybasedoninformationlearnedonreviewoftheinterimanalysisresultsfortheimagingandclinicalendpoints.
Theunblindedsub-teamdidnotreviewanygroupedsafetydata.
Whenversion1wasapproved,noblindeddatahadbeenseenfortheco-primaryendpointssoupdatesinSection11arebasedontheopportunitytolearnabouttheirdistributionofthoseendpointsatthetimeoftheinterimanalysis.
2.
STUDYOBJECTIVE(S)ANDENDPOINT(S)2.
1.
StudyObjectivesandEndpointsThestudyobjectivesandendpointsaredetailedinTable1.
Table1ObjectivesandEndpointsPrimaryObjectivesEndpointsEstimationoftheeffectsofGSK239512onlesionremyelinationinsubjectswithRelapsingRemittingMultipleSclerosisonstabletreatmentwithAvonex[interferon-beta1a]orCopaxone[glatirameracetate].
Changesinlesionmyelinationusingtwoexploratorymagnetizationtransferratio(MTR)endpointscomparingplacebotoGSK239512treatedsubjectsin:1)Meanchangeingadolinium(Gd)enhanced(GdE)lesionMTRdifferences(calibratedtoreferencescan[Section6.
3.
1.
1])frombeforeenhancementto2014N204379_00CONFIDENTIALH3M1164778stablerecovery(3monthspostnewGdElesion),and2)MeanchangeinDeltaMTRlesionMTRdifferences(calibratedtoreferencescan)frombeforelesionappearancetostablerecovery(≥3monthspostlesionappearance).
SecondaryObjectivesEndpointsEvaluatetheeffectsofGSK239512onalternatepotentialmarkerofremyelinationoflesions.
ChangefrombaselineinT2lesionMTRatWeek48.
EvaluatetheeffectsofGSK239512onbrainMRIlesioncounts.
CumulativenewandenlargingGdenhancing,T2andCombinedUniqueActivelesionscomparingplacebotoGSK239512treatedsubjects.
EvaluatetheeffectsofGSK239512onoverallneurodegenerationbyassessingbrainvolumes(Total,whitematterandgreymatter)ChangefrombaselineatWeek48intotalbrainvolume,whitemattervolumeandgreymattervolumecomparingplacebotoGSK239512treatedsubjects.
EvaluatetheeffectsofGSK239512onT1hypointenselesiondevelopmentassociatedwithMSCumulativenumberofpersistentblackholesandnew,unenhancingT1lesioncountscomparingplacebotoGSK239512treatedsubjectsovertreatmentdurationuptoWeek48.
ProportionofnewGdElesionsevolvingintochronic(unenhancing)T1lesions(blackholes)comparingplacebotoGSK239512treatedsubjectsovertreatmentdurationuptoWeek48.
EvaluatetheeffectofGSK239512onCognitiveabilityMeanchangefrombaselineinoverallCognitiveimpairmentandcognitivedomainscomparingplacebotoGSK239512treatedsubjects.
EvaluatetheeffectofGSK239512onrelapsesComparisonofRelapseRatesbetweenplaceboandGSK239512treatedsubjects.
ComparisonofTimetoFirstRelapsebetweenplaceboandGSK239512treatedsubjects.
ComparisonoftheproportionofsubjectsRelapseFreebetweenplaceboandGSK239512treatedsubjectsEvaluatetheeffectofGSK239512onDisabilityandFunctionalityProportionofsubjectswithsustainedworseningofExpandedDisabilitySeverityScale(EDSS)over3monthscomparingplacebotoGSK239512treatedsubjects.
MeanchangefrombaselineintheEDSSfunctionalsystemsandasubsetofcomponentassessmentscomparingplacebotoGSK239512treatedsubjects.
2014N204379_00CONFIDENTIALH3M1164779SafetyObjectivesEndpointsEvaluatethesafetyandtolerabilityofGSK239512FrequencyandseverityofAEsandSAEs.
PercentageofsubjectswithdrawingduetoAEs.
SummaryofsuicidebehaviorandideationriskasassessedbytheeC-SSRSandPSRAE.
Changefrombaselineinclinicalchemistry,hematology,andurinalysisparameters.
Frequencyofclinicalchemistry,hematology,andurinalysisparametersofpotentialclinicalconcern.
ChangefrombaselineinvitalsignsandECGparameters.
FrequencyofvitalsignsandECGparametersofpotentialclinicalconcern.
PharmacokineticObjectivesEndpointsEvaluatepharmacokineticsofGSK239512inMSsubjectsPre-dosetroughconcentrationatWk4,Wk24,Wk36andWk48withsparsesampling(1pre-doseand3post-dose)atWk8.
ExploratoryObjectivesEndpointsEvaluatetheeffectofGSK239512onMSsymptomsandqualityoflifeMeanchangefrombaselineintheMultipleSclerosisQualityofLife(MSQoL)54comparingGSK239512andplacebotreatedsubjects2.
2.
StatisticalHypothesesTherearenostatisticalhypothesestobetestedinthisstudy.
TheprimaryobjectivesofthisstudyarearoundestimationoftheeffectsofremyelinationofGSK239512versusplacebo.
Theseobjectiveswillbeassessedbythegenerationofpredictiveprobabilitiesthattheremyelinationofnewlesionsisofaneffectsizegreaterthanzeroandconsideredofpotentialclinicalrelevance.
Thetargeteffectsizeforthisstudyis0.
5.
Tothisextent,inferencewillbecarriedouttoestimatetheposteriorprobabilitythatthedifferencebetweenthemeanofthetesttreatmentandthemeanofthereferencetreatment(GSK239512)-(Placebo),isgreaterthan0foreachco-primaryendpointusingeffectsizes.
Aneffectsizeisdefinedasthedifferenceofthemeansinthetwotreatmentgroupsdividedbythestandarddeviationfromthestatisticalmodel.
TheposteriorprobabilitythatthetrueeffectsizeisgreaterthanzerowillbereferredtoasPP(Δ>0).
Inadditioninthisstudyitisalsoofinteresttoestimatethechangesintheco-primaryendpointsthatareofpotentialclinicalrelevance,definetheirstatisticaldistributions,estimatetheirrelationshipandexplorethemostappropriatestatisticalmethodologytoanalysestheseendpoints.
2014N204379_00CONFIDENTIALH3M116477102.
3.
Pharmacokinetic(PK)andPK/Pharmacodynamic(PD)hypothesesTherearenoPKorPK/PDhypothesestobetestedinthisstudy.
Analyseswillbedescriptiveandexploratory.
3.
STUDYDESIGNThisstudyisrandomized,parallelgroup,andplacebo-controlled.
SubjectswithRRMSonstablebackgroundtreatmentwitheitherAvonex(Interferon-beta1a)orCopaxone(GlatiramerAcetate)areeligibletoparticipate.
Subjectswillberandomizedina1:1ratiobetweenplaceboandGSK239512.
RandomizationwillbestratifiedbyBackgroundDiseaseModifyingTherapy(DMT)ofeitherAvonexorCopaxone.
Thetotaltreatmentperiodis48weeks,includingastandard4weektitrationperiodand44weekmaintenancetreatmentperiod(whichcouldbeadaptedtoa5-weektitrationand43weekmaintenanceperiod,ifneeded[ProtocolSection3.
3]).
Titrationdosesstartat10gandincreaseupto80g(10gfirstweek,20gsecondweek,40gthirdweek,80gfourthweek).
Subjectswillbetitratedtothemaximumtolerateddosewiththeobjectiveoftitratingtothehighestdose(80gGSK239512),wheneverpossible,basedoninvestigatorjudgementoftolerability,asdescribedinProtocolSection5.
3.
Subjectsunabletotitrateto80gwillbeallowedtoremaininthestudy,atthehighestdosethattheywereabletotolerate.
Thepost-treatmentfollow-upperiodwillbeaminimumof2weeksindurationfollowingtheendoftreatmentatWeek48orearlywithdrawal,asappropriate.
SafetydataincludingallsafetyassessmentswillbereviewedthroughoutthestudybytheSafetyReviewTeam(SRT)forGSK239512.
Trendsinclinicalendpointdata(e.
g.
relapse,EDSS,etc.
.
.
)toassesssignalsofdiseaseworseningthatcouldbeindicativeofasafetysignal,willbereviewedandmayinclude,asappropriate,theengagementofexternalexpertconsultation.
Ataminimum,thesereviewswillincludeefficacydataapproximatelyevery3monthsfollowingrandomizationofthefirstsubject.
AninternalSafetyReviewCommittee(iSRC)consistingofGSKpersonnelwhoarenotinvolvedintheconductofthisstudywillbeassembledandcharteredtoanswerspecificquestionsonbehalfofthestudyteam(ProtocolSection6.
4.
9).
Thestudywillbeconductedasa'single-blind'study.
Only,asubsetofindividualsdefinedintheiSRCCharterwillbeunblinded.
ALLsubjectsandnon-GSKpersonnel(includingtheprincipalinvestigator,sub-investigators,andstudysitepersonnel)involvedinmeasuring,monitoringandobtainingdatainthestudywillbeblindedtosubjecttreatmentassignment.
InadditionallGSKandvendorpersonnelinvolvedintheon-sitemonitoringanddirectmanagementofthedataandstudysiteswillalsoremainblindedtoindividualsubjectdata.
Thestudywillbeconductedasa'single-blind'studyduetotheexploratorynatureofthestudyanduseoftheendpoints.
TheinstreamreviewsoftheMRIdatawillbeconductedatintervalsthroughoutthestudywithavailablesubjectdataasdefinedinSection8and2014N204379_00CONFIDENTIALH3M11647711theiSRCCharter,includinginvolvementofexternalMSand/orimagingexpert(s),asappropriate.
TheSRTwillreviewstudydataaspartofthestandardSRTmonitoringandreviewprocessforGSK239512.
Measureswillbetakentoensurethatunblindedinformationisnotprovidedtothesitepersonnel,subjectsoranyGSKandvendorstaffinvolvedinthemanagementofthestudysitesandsubjectdata.
Inaddition,aformalInterimAnalysiswillbeconducted,inaccordancewithProtocolSection8andtheiSRCcharter,toassessthecharacteristicsoftheremyelinationsignalthatmaybedetectableattheendofthestudy.
Thiswillincludeanassessmentoftheprobabilityofachievingtheprimarystudyobjectiveandallowsforthepossibilityofstoppingthestudyforfutility.
Protocolwaiversorexemptionsarenotallowedwiththeexceptionofimmediatesafetyconcerns.
Therefore,adherencetothestudydesignrequirements,includingthosespecifiedintheProtocolTimeandEventsTable,areessentialandrequiredforstudyconduct.
SupplementarystudyconductinformationnotmandatedtobepresentinthisprotocolisprovidedintheaccompanyingStudyProceduresManual(SPM).
TheSPMwillprovidethesitepersonnelwithadministrativeanddetailedtechnicalinformationthatdoesnotimpactsubjectsafety.
Figure1StudyDesignwithTitration4.
PLANNEDANALYSES4.
1.
InterimAnalysesInaddition,aformalInterimAnalysiswillbeconductedwhenapproximatelyhalfthesubjectshaveWeek42MRIdataavailabletoassessthecharacteristicsoftheremyelinationsignalthatmaybedetectableattheendofthestudy.
Thiswillincludean2014N204379_00CONFIDENTIALH3M11647712assessmentoftheprobabilityofachievingtheprimarystudyobjectiveandallowsforthepossibilityofstoppingthestudyforfutility(seeSection5fordetailsonstoppingguidelines).
4.
2.
FinalAnalysisOnceallsubjectshavecompletedthestudy,alldataisinhouse,alldataquerieshavebeenresolvedandprotocolviolatorshavebeendetermined,thedatawillbefrozen,unblindedandalldatadisplaysdescribedinthisanalysisplanwillbegenerated.
DetailsoffinalefficacyanalysesareprovidedinSection11.
Thequalitycontrol(QC)ofthetables,figuresandlistingsgeneratedforthestatisticalreportingandanalysisofthisstudyistheresponsibilityoftheBiostatisticsandProgrammingTeam(BPT).
WhileitisanticipatedthattheBPTwillworkfromafullyqualityassureddatabase,anydataanomaliesdiscoveredduringfinalanalysiswillbecommunicatedtotheDataManagementandClinicalgroups.
TheBPTwillperformaQCreviewoftheresultspriortoreleaseinaccordancewiththeSOP,SOP_55411,(Review/QualityControlofStatisticsandProgrammingPhaseI-IVResults).
5.
SAMPLESIZECONSIDERATIONS5.
1.
SampleSizeAssumptionsThefollowingassumptionshavebeenmadeinthedesignofthisstudy:Thetreatmenteffectforbothco-primaryendpointswillbeexpressedaseffectsizesandarethereforeassumedtohavedistributionsofmean0andstandarddeviation1.
Thetargeteffectsizeforthisstudyis0.
5.
Basedonunpublisheddatainpost-mortembrainsforSPMSsubjects,itisbelievedthataneffectsizeof0.
5isapproximatelyequivalenttoa50%increaseinremyelinationcomparedtothenaturalremyelinationprocessthatwouldbeexpectedintheplacebogroup.
Thecorrelationbetweenthetwoco-primaryendpointsis0.
5.
Thedistributionoftheco-primaryendpointsisdescribedbyaBivariateNormalDistribution.
Analysiswillbeperformedatthesubjectlevelwiththeestimationofremyelinationwithineachlesionaveragedforeachsubject.
Itisassumedthateachsubjectwillhaveatleast1lesionthatcontributestotheanalysisforbothendpoints.
AninterimanalysiswillbeperformedwhenapproximatelyhalfthesubjectshaveWeek42MRIdataavailable.
Thestudywillbeconsideredaspotentiallyfutileifbothco-primaryendpointshaveaPP(Δ>0)0)>80%)forbothco-primaryendpoints.
Anefficacysignalwillalsobe2014N204379_00CONFIDENTIALH3M11647713consideredobservedifoneco-primaryendpointhasaPP(Δ>0)>80%andtheotherco-primaryendpointhasaPP(Δ>0)>70%.
Anegativestudywillbedeclarediftheposteriorprobabilitythatthetrueeffectsize(GSK239512-placebo)isgreaterthanzeroislessthan70%(PP(Δ>0)0)0)0)0)>80%)andNegative"Stop"ResultatStudyEnd(PP(Δ>0)0)0)>80%)andNegative"Stop"ResultatStudyEnd(PP(Δ>0)0)>80%)with50subjectsperarm,ifthetrueeffectis0.
5forbothco-primaryendpointswewilldetectasignalofefficacyinapproximately94%oftrials,anddeclareanegative"Stop"signalin~41%oftrials.
Lessthan1%ofstudieswouldbestoppedforfutilityattheinterimanalysis.
Ifthetrueeffectis0forbothco-primaryendpoints(i.
e.
GSK239512isnobetterthanplacebo)thenthestudieswouldincorrectlydetectasignalin~13%oftrials.
Ifthetrueeffectforbothco-primaryendpointswas0thestudywouldbeconsideredfutileforitsprimaryobjectivein~16%oftrials;andifthetrueeffectforbothco-primaryendpointswas0thestudywouldbeconsiderednegativeforitsprimaryobjectiveatthestudyendin~53%oftrials.
5.
2.
SampleSizeSensitivityAsdiscussedinSection5.
1,itispossiblethatnotallsubjectswillhaveananalyzableGdElesionwhileparticipatinginthestudy.
Itisestimatedthat40-60%ofsubjectswillhaveaGdElesionthatcanbeassessedforremyelination.
Itisbelievedthatbasedonnon-publisheddata[personalcommunication,theprevalenceofdelta-MTRlesionswillbehigherthantheprevalenceofGdElesions.
Therefore,itispossiblethatnotallsubjectswillbeabletocontributetotheanalysesforeitherco-primaryendpoint.
Figure3demonstratesthechanceofstoppingforfutility,ordeclaringapositiveornegativestudy,with30evaluablesubjects/armforarangeofunknowntrueeffectsizes.
2014N204379_00CONFIDENTIALH3M11647715Figure3ChanceofStoppingforFutilityorDeclaringaPositiveorNegativestudywith30evaluablesubjects/armItcanbeseenthatwithfewersubjectsbeingevaluablefortheGdElesionco-primaryendpointreducestheprobabilityofdeclaringapositivestudyandslightlyincreasesthechancesofstoppingthestudyattheinterimanalysisordeclaringanegativestudyforthetargeteffectsizeof0.
5.
Forthisefficacydetection(i.
e.
PP(Δ>0)>80%)with30subjectsperarm,ifthetrueeffectis0.
5forbothco-primaryendpointswewilldetectasignalofefficacyinapproximately84%oftrials,anddeclareanegativesignalin~4%oftrials.
Lessthan1%ofstudieswouldbestoppedforfutilityattheinterimanalysis.
Ifthetrueeffectis0forbothco-primaryendpoints(i.
e.
GSK239512isnobetterthanplacebo)thenwith30subjectsperarmtheoutcomesaresimilarinthatstudieswouldincorrectlydetectasignalin~13%oftrials.
Ifthetrueeffectforbothco-primaryendpointswas0thestudywouldbeconsideredfutileforitsprimaryobjectivein~15%oftrials;andifthetrueeffectforbothco-primaryendpointswas0thestudywouldbeconsiderednegativeforitsprimaryobjectiveatthestudyendin~53%oftrials.
2014N204379_00CONFIDENTIALH3M11647716Table3showstheprobabilityofeachstudyoutcomevaryingthecorrelationcoefficientbetweenthetwoco-primaryendpointsforthesamplesizeof50subjectspergroup.
Itcanbeseenthatwhenthetruetreatmenteffectsizeis0,thestrongerthecorrelationbetweenthetwoco-primaryendpointsthemorelikelythestudywouldeitherstopforfutilityattheinterimanalysisordeclareanegativestudy.
Foratrueeffectsizeof0.
5thereislittleimpactontheoutcomesofthestudywithchangingcorrelationcoefficients.
Asthecorrelationincreases,thereisaslightincreaseintheprobabilityofapositivesignalbeingobserved.
Table3AssessmentofImpactofCorrelationCoefficientsonStudyOutcomesTreatmentDifferenceforbothCo-PrimaryEndpointsPercentageofTrialsinthisscenario(%)DecisionforCo-PrimaryEndpoint2FutileGoGreyStopCorrelationCoefficient:0.
20DecisionforCo-PrimaryEndpoint1Futile11.
27%0.
00%0.
00%0.
00%Go0.
00%5.
31%2.
22%11.
44%Grey0.
00%2.
18%1.
20%6.
37%Stop0.
00%11.
71%6.
59%41.
71%0.
5DecisionforCo-PrimaryEndpoint1Futile0.
02%0.
00%0.
00%0.
00%Go0.
00%89.
80%2.
12%2.
81%Grey0.
00%2.
14%0.
10%0.
11%Stop0.
00%2.
57%0.
13%0.
20%CorrelationCoefficient:0.
50DecisionforCo-PrimaryEndpoint1Futile15.
39%0.
00%0.
00%0.
00%Go0.
00%8.
01%2.
75%8.
21%Grey0.
00%2.
64%1.
40%5.
66%Stop0.
00%8.
44%5.
63%41.
87%0.
5DecisionforCo-PrimaryEndpoint1Futile0.
06%0.
00%0.
00%0.
00%Go0.
00%90.
45%1.
97%2.
31%Grey0.
00%1.
89%0.
24%0.
22%Stop0.
00%2.
15%0.
29%0.
42%CorrelationCoefficient:0.
80DecisionforCo-PrimaryEndpoint1Futile20.
35%0.
00%0.
00%0.
00%Go0.
00%12.
13%2.
98%3.
86%Grey0.
00%2.
97%1.
89%4.
73%Stop0.
00%4.
41%4.
18%42.
50%0.
5DecisionforCo-PrimaryEndpoint1Futile0.
34%0.
00%0.
00%0.
00%Go0.
00%91.
90%1.
51%1.
32%Grey0.
00%1.
43%0.
48%0.
42%Stop0.
00%1.
19%0.
43%0.
98%2014N204379_00CONFIDENTIALH3M116477175.
3.
SampleSizeRe-estimationDuringtheinstreamreviews(ProtocolSection8.
3.
4),anassessmentoftheGdElesionrateandtheabilityofthestudytodetecteffectsofGSK239512wherePP(Δ>0)>80%willbeperformed.
IftheGdElesionoccurrencerateislowerthanexpectedanincreaseinsamplesizeorchangesintheinclusion/exclusioncriteriawillbeconsideredtoincreasethelikelihoodthatsubjectsrecruitedwillcontributelesionstotheprimaryanalysis(ProtocolSection8.
3.
4).
6.
ANALYSISPOPULATIONSFivepopulationsaredefinedforthisstudy:ScreenFailurepopulation:ThiswillconsistofallsubjectswhofailedScreeningandwillbeusedforScreeningFailuredisplaysonly.
Randomisedpopulation:Thiswillconsistofallsubjectsrandomisedtostudymedication.
Intent-to-treat(ITT)population(SafetyPopulation):Thiswillconsistofallrandomisedsubjectswhohavetakenatleastonedoseofstudymedication.
Thispopulationwillbeusedfortheanalysisofallefficacyandsafetydata.
Forsummarytablesandfiguresitwillbedenotedas"Intent-to-Treat/SafetyPopulation"andTable6.
01willbefootnotedtostatethatthe2populationsaredefinedthesame.
ThroughoutthisRAP,thispopulationwillbereferredtoastheITTPopulation.
PK-concentrationpopulation:Thiswillincludeallsubjectsforwhomapharmacokineticsamplewasobtainedandanalysed.
PharmacogeneticsPopulation:ThiswillincludeallsubjectsintheITTpopulationwhoconsentedtoprovidingageneticssample,providedasampleanddidnotwithdrawtheirconsentforgenetictesting.
6.
1.
AnalysisDatasetsTheObservedCase(OC)datasetisdefinedforallendpointsandwillcontainalltheavailablechangefrombaselineresponsesforeachsubjectateachvisit,withoutmissingvaluesbeingestimatedordatacarriedforwardotherthanasdescribedinSection9.
2.
8.
2.
6.
1.
1.
Non-MTRMRIEndpointsFornon-MTRMRIendpointstwoadditionaldatasetsaredefined.
TheAllEvaluableScans(AES)datasetwhichincludesallevaluableon-treatmentMRIscansforeachsubject,thusallowingestimatesoflesionratestobecalculatedacrosstheentireTreatmentPhase.
AscanisevaluableifNeuroRx,thevendorwhoisreadingtheMRIscans,indicateitasevaluableanditwasnotperformedbetween1and7daysoftheconclusionofsteroiddosingforrelapse.
2014N204379_00CONFIDENTIALH3M11647718AnMRIscanwillbeconsideredevaluableifsteroidswereadministeredonthesamedayastheMRIscanwasperformed.
TheImputedMissingValues(IMV)datasetwillbeusedforasensitivityanalysisofMRIparametersonly:intheIMVdataset,missingvaluesforanindividualsubjectwillbeestimatedfromtheotheravailableobservationsforonlythatsubject,allowingestimatesoftreatmenteffecttobemadewiththecompletestudypopulation.
FurtherdetailsonthederivationofbothdatasetsareprovidedinSection9.
2.
8.
2.
7.
TREATMENTCOMPARISONSTheprimarycomparisonsofinterestinthisstudyaretheeffectsofGSK239512relativetoplaceboadministeredadjunctivelytostableBackgroundMSDiseaseModifyingTreatment(AvonexorCopaxone)ontheco-primaryendpointsasspecifiedinSection2.
2.
NoformalhypothesistestingwillbeperformedandnoTypeIErrorRateisnominatedforthisstudy.
Treatmentdifferenceswillbeestimated,standardisedEffectSizeswillbederivedasthetreatmentdifferencedividedbythestandarddeviation(estimatedasthebetweensubjectvariabilityfromtheanalysismodel)ofthetreatmentdifferenceaveragedacrossvisits/RelativeMRIs(bothwithassociated90%confidenceintervals)andposteriorprobabilitiesthatthedifferencebetweentreatmentgroupsisgreaterthanzerowillbepresented.
7.
1.
DataDisplayTreatmentandOtherSub-groupDescriptorsTreatmentgroupswillbeidentifiedinthedatadisplaysas'Placebo'and'GSK239512'.
SpecificdisplayswillalsobeprovidedbydoseofGSK239512andwillbeidentifiedas'GSK23951210ug','GSK23951220ug','GSK23951240ug'and'GSK23951280ug'respectively.
DatadisplayspresentedforallsubjectsandbyBackgroundDiseaseModifyingTherapywillbelabelled:"Stratum:AllSubjects","Stratum:BackgroundDiseaseModifyingTherapy–Avonex"and"Stratum:BackgroundDiseaseModifyingTherapy–Copaxone"8.
GENERALCONSIDERATIONSFORDATAANALYSESAllprogrammingwillbeperformedusingSASversion9.
1.
3orlaterinaLinuxenvironment.
8.
1.
MulticentreStudiesSubjectshavebeenrecruitedintothisstudyfromcentresacrossBulgaria,Canada,CzechRepublic,Germany,Spain,Sweden,UkraineandUnitedKingdom.
Lownumbersofsubjectswererecruitedatsomecentresandthereforecentreswillbepooledwithineachcountry.
Assomecountriesrecruitedfewsubjects,countrygroupswillbefurthercombinedasfollowstocreate2groups:UkraineandOther(Bulgaria,Canada,CzechRepublic,Germany,Spain,SwedenandUnitedKingdom).
Theeffectofcountrygroup2014N204379_00CONFIDENTIALH3M11647719variabilitywillbeassessedasanexploratorycovariatefortheco-primaryendpoints;SeeSection11.
1.
2Throughoutthisdocumentanyreferencestoacentreeffectorgroupingofcentreswillbedenotedas"country".
Approximately35%ofsubjectsinthisstudyhavebeenrecruitedintheUkraine.
Thenumberofsubjectsineachcountrygroupwillbesmallandassuch,anyassessmentofatreatmentbycountryinteractionwouldhaveahighprobabilityofshowingafalseresult(positiveornegative).
Henceformalhypothesistestingofthetreatmentbycountryinteractiontermwillnotbeconducted.
Inter-countryvariabilitymaybeinvestigatedbyreviewingsummarystatisticsoftheco-primaryefficacyparametersbycountrygroup;graphicaldisplayswillalsobeproduced.
DetailsareprovidedinSection8.
3.
8.
2.
OtherStrataandCovariatesThestudydesignincludesstratificationbasedontheMSbackgrounddiseasemodifyingtherapythesubjectisreceiving(AvonexorCopaxone).
AllstatisticalanalyseswillincludeafactorforBackgroundDiseaseModifyingTherapy.
StatisticalanalysesdefinedinSection11willdefinethetermsthatwillbeincludedinthestatisticalanalysismodels.
Asthestudyisrelativelysmall,ifanalysismodelsdonotconvergecovariatesmayberemovedfromthemodelordifferentfactorsofacovariatemaybecombinedtoallowthestatisticalanalysismodeltoconverge.
Ifthisoccurs,detailswillbeprovidedintheCSR.
Theeffectsoffollowingcovariateswillbeassessedinanexploratorysensitivityanalysisoftheco-primaryendpointsandsomekeysecondaryendpointsasappropriatebasedoninitialresults:GenderAgeCountryPresenceofgadolinium-enhancinglesionsonScreeningMRIScan(Presence/Absence)BaselineEDSSScore(≤2.
5/≥3)BaselineT2LesionMTRNormalisedBrainVolumeatScreening\NumberofRelapsesinprevious24monthsbeforeScreening(6yearsBaselineEDSSModifiedVisualScore(≤1/≥2)[CogStateendpointsonly]2014N204379_00CONFIDENTIALH3M11647720BaselineBodyMassIndex(BMI)Lesionsize[MTRCo-primaryendpointsonly]ContinuouscovariateswillbecentredsuchthateachvaluewillhavethebaselinemeanfortheITTpopulationsubtractedfromtheactualvalue.
8.
3.
ExaminationofSubgroupsTwosubgroupswillbeinvestigatedinthisstudy;subjectsreceiving"Avonex"andsubjectsreceiving"Copaxone"astheirbackgroundMSdiseasemodifyingtherapy.
Thesesubgroupswillcontainasmallnumberofsubjectsandthepotentialforfalseresultsisnotcontrolledinthestudy.
Eachsubgroupwillbeinvestigatedforeachco-primaryendpointandCogStateassessments;othersecondaryendpointsmaybeinvestigatedfurtheriftheeffectforthecovariateissignificantinstatisticalmodels.
Inaddition,attherequestoftheSpanishRegulatoryAgency,ifasubstantialnumberofsubjectsdonottitrateuptoDoseLevel4,sensitivityanalysesoftheco-primaryendpointsandkeysecondaryendpointswillalsobeanalysedassessingDoseLevelasacategoricalcovariate.
Forthepurposesofconductingtheseanalyses,asubstantialproportionofsubjectsnotmaintainingDoseLevel4of≥30%willbethecut-offforthisanalysisasisinlinewithpreviousstudiesinthiscompound.
Therefore,ifmorethan70%ofsubjectsstayonDoseLevel4throughtheMaintenancePeriod,theseanalyseswillnotbeconducted8.
4.
MultipleComparisonsandMultiplicityThisisanexploratorystudywithnohypothesistestingsuchthatnoadjustmentformultiplicityisrequired.
8.
5.
GeneticMarkersGeneticmarkersarenotplannedtobeinvestigatedinthisreportingeffort.
AnygeneticanalyseswillbedescribedinaseparateanalysisplanauthoredbytheGSKGeneticsGroup,ordesignate.
9.
DATAHANDLINGCONVENTIONS9.
1.
PrematureWithdrawalandMissingDataAsubjectisconsideredtohavecompletedthestudyiftheycompletethe48weektreatmentperiodandattendthefollow-upvisitspecifiedintheprotocoltobeapproximately2weeksaftertheWeek48visit.
Forsubjectsthatdonotcompletethestudy,detailsofhowtodealwithmissingdataareprovidedinSection6.
1andSection9.
2.
2014N204379_00CONFIDENTIALH3M116477219.
2.
DerivedandTransformedData9.
2.
1.
BaselineDataForsafetyandefficacydatabaselineisconsideredtobethesubject'slastavailableassessmentpriortoinitiationofstudymedicationunlessotherwisestated.
Changefrombaselineforpost-baselinerecordswillbecalculatedbysubtractingthebaselinevaluefromthepost-baselinevalue.
9.
2.
2.
DemographicDataBodyMassIndex(BMI)atscreeningwillbecalculatedusingtheheightandweightatthatvisit:22(m)Height(kg)Weight)(kg/mIndexMassBodyAge(inyears)willbedeterminedattheScreeningvisitusingthedateoftheScreeningvisitasrecordedintheeCRF.
OnlyYearofBirthiscollectedintheeCRFsuchthatthebirthdatewillbeimputedas30JuneoftheyearenteredintheeCRF.
9.
2.
3.
StudyDayDefinitionStudydayfortheassessmentdateofinterestshouldbecalculatedrelativetothefirstdosedateofdouble-blindstudymedicationusingtheappropriateformulabelow:1)Iftheassessmentdateofinterestisonorafterthefirstdosedateofdouble-blindstudymedication:Studyday=assessmentdate–dateoffirstdoseofdouble-blindstudymedication+12)Iftheassessmentdateofinterestisbeforethefirstdosedateofdouble-blindstudymedication:Studyday=assessmentdate–firstdosedateofdouble-blindstudymedication9.
2.
4.
DefiningtheFirstDoseDateThefirstdosedateofdouble-blindmedication(MSTSTDTvariableinMSTONE)isdefinedastheearlieststartdateintheExposuredatasetwithaVISITNUM>=20.
Ifthenumberoftabletstakenisequalto0,thestartdateforthisrowofstudymedicationshouldbeignored.
Thefirstdouble-blinddosedatewillbeusedtopopulatethevariableDMREFDT.
Thisdateisusedforstudydaycalculations.
2014N204379_00CONFIDENTIALH3M116477229.
2.
5.
DefiningtheLastDoseDateThelastdosedateofdouble-blindmedication(MSTENDTvariableinMSTONE)isdefinedas:Ifthetreatmentstopdateispresentonthelastrowofdata,thisshouldbeusedasthestopdateofstudymedication.
Ifthetreatmentstopdateismissingonthelastrowofdatabutastartdateispresentthenthestartdateshouldbeusedasthestopdateofstudymedication.
Inthecasewherenostartorstopdatesareknownonthelastdosingrecordthentheaboveprocessisrepeatedonprevioussetsofdosingrecordsuntilastopdateofstudymedicationisobtained.
Anydosingrecordswhereitcannotbedeterminedthatstudymedicationwastakenwillbeignored.
ItshouldbenotedthattheTreatmentPhasewillend3daysafterthelastdoseofdouble-blindstudymedication.
9.
2.
6.
DefiningTitrationandMaintenancePeriodsTitrationinthestudyisplannedtotake4weeksbutifanadditionalweekoftitrationisrequiredthentheTitrationPeriodcanbeadaptedfrom4weeksto5weeks.
TheTitrationPeriodstartsonthefirstdosedateofdouble-blindmedication(MSTSTDTvariableinMSTONE)asdefinedinSection9.
2.
4.
Ifthesubjectundergoesa4-weekTitrationPeriod(definedasOPTW5TITvariableinOPTTITRDMDatasetbeing"N")then:TheMaintenancePeriodisconsideredtohavestartedonthestartdaterecordedintheeCRFforWeek4(usingEXSTDTvariableinEXPOSUREDMDataset).
Ifthesubjectundergoesa5-weekTitrationPeriod(definedasOPTW5TITvariableinOPTTITRDMDatasetbeing"Y")then:TheMaintenanceperiodisconsideredtohavestartedonthestartdaterecordedintheeCRFforWeek5(usingEXSTDTvariableinEXPOSUREDMDataset).
TheTitrationPeriodisconsideredtohaveendedthedaybeforethestartoftheMaintenancePeriod.
However,ifnoMaintenancePerioddataisavailable,theTitrationperiodwillbeconsideredtohaveendedatthelatestavailablestudymedicationdosingdateavailableandnoMaintenancePeriodstartandstopdateswillbedefinedforthesubject.
TheMaintenancePeriodendsatthesametimeastheTreatmentPhaseendsasdefinedinSection9.
2.
5.
2014N204379_00CONFIDENTIALH3M116477239.
2.
7.
MRI–MTRDataMTRdatawillbeprovidedtoGSKinaformatofonerowofdatapersubjectperlesionperMRIassessment.
Avalueof1isconsideredtobeanormalWhiteMatterMTRvalue,avalueof0isconsideredtobeanormalGreyMatterMTRValue.
Lesionscanoccuratdifferentvisitsinthestudy,totransformlesionstothesamescaleadditionaltimepointvariableswillbederived.
ForeachuniquelesionidentifiedbyNeuroRx,theMRIonwhichitisidentifiedwillbesettobe"LesionDay0"andtheMRIwillbedefinedasthe"ReferenceMRI".
Thereforeforasubjectwithmorethanonelesiontheywillhavemorethanone"ReferenceMRI"andmorethanone"LesionDay0";i.
e.
onesetperlesionidentified.
ForallotherMTRMRIscansforeachlesiontheir"LesionDay"willbecalculatedasMRIdateminusReferenceMRIdate(plus1dayforpostReferenceMRIscans)andMRIswillbeidentifiedrelativetothe"ReferenceMRI"suchpostlesionMTRMRIscanswillbeidentifiedas"PostLesionScan1","PostLesionScan2"etcandMTRMRIscanspriortothe"ReferenceMRI"willbeidentifiedas"PreLesionScan1","PreLesionScan2"etcasshowninTable4forasubjectwithagadolinium-enhancinglesionobservedattheWeek18MRIassessment.
AlesionphaseIDvariablecategorising"Pre-Lesion","ReferenceMRI"and"Post-Lesion"willalsobedefined.
Table4WorkedExampleforDefiningMTRScansStudyMRILesionIDLesionDayRelativeMRILesionPhaseScreeningGdE_Wk18-126Pre-LesionMRI3Pre-LesionWeek6GdE_Wk18-84Pre-LesionMRI2Pre-LesionWeek12GdE_Wk18-42Pre-LesionMRI1Pre-LesionWeek18GdE_Wk180ReferenceMRIReferenceMRIWeek24GdE_Wk1842Post-LesionMRI1Post-LesionWeek30GdE_Wk1884Post-LesionMRI2Post-LesionWeek36GdE_Wk18126Post-LesionMRI3Post-LesionWeek42GdE_Wk18168Post-LesionMRI4Post-LesionWeek48GdE_Wk18210Post-LesionMRI5Post-LesionThechangeinMTRfromtheReferenceMRIiscalculatedasthenon-ReferenceMRIMTRValueminustheReferenceMRIMTRValue.
ThechangeinMTRforPost-LesionMRIscansfromPre-LesionisthechangeineachPost-LesionMRIscansfromtheaveragePre-LesionMRIscans.
Allthesederivationsareconductedatthelesionlevel.
AsapotentialforasensitivityanalysisandtoreducethevariabilitytheMTRValueateachMRIandthechangefrom2014N204379_00CONFIDENTIALH3M11647724ReferenceMRIMTRValuewillbederivedatthesubjectlevelbytakingtheaverage(mean)ofalllesions(gadolinium-enhancinglesionsanddeltaMTRlesionsseparately).
Inaddition,themeanofallPre-LesionMRIscanMTRValuesandPost-LesionMRIScanMTRValueswillbederivedatthelesionlevelandthesubjectlevel.
AsthereisexpectedtobeincreasedvariabilityinMTRValuesaroundthetimeoflesionoccurrencesensitivityanalysestoassesstheimpactofinclusionofMTRdataclosetolesionoccurrencemayberequiredtofullyassesstherobustnessoftheanalysesandtobeabletofullyinterpretthestudy.
AtthetimeofwritingtheprotocolitwasadvisedthatMTRdatafromMRIscanswithin12weeksofalesionbeingobservedshouldbeexcludedduetoincreasedvariability.
Thisanalysisisdefinedastheprimarydatasetasperthestudyprotocol.
AdditionalsensitivityanalysesarealsoincludedinTable5whichwillallowadditionalinvestigationsofthesenovelendpointstobeconducted.
Foralldefinitions,considerationwillbemadeastowhethertheremustbeaminimumof2MRIspre-lesionandpost-lesionassensitivityanalyses.
Table5SummaryofSensitivityAnalysesDefinitionsAnalysisIDPre-LesionMRIScanstoExcludePost-LesionMRIScanstoExclude1[Protocol-specifiedanalysis]Within70daysofReferenceMRIScanWithin70daysofReferenceMRIScan2Within28daysofReferenceMRIScanWithin70daysofReferenceMRIScan3NoscansexcludedNoscansexcluded4Within28daysofReferenceMRIScanWithin28daysofReferenceMRIScan5Within70daysofReferenceMRIScanWithin28daysofReferenceMRIScanNote,forallsensitivityanalysesspecifiedinTable5theaverageMTRValuesshouldbederivedasspecifiedinthissectionatthelesionandsubjectlevelforbothgadolinium-enhancinglesionsanddelta-MTRlesions.
9.
2.
8.
MRI–OtherMRIEndpoints9.
2.
8.
1.
ConventionalMRIendpointsfromCentralReaderThefollowingMRIendpointswillbecollectedbyNeuroRx,thecentralMRIreaderandsenttoGSKintheMRIRESDMDatasetforeachvisit(Weeks6,12,18,24,30,36,42and48)unlessotherwisespecified:Numberofgadolinium-enhancinglesions(AlsoreportedatScreening)Numberofnewgadolinium-enhancinglesionsNumberofnewandenlargingT2lesions2014N204379_00CONFIDENTIALH3M11647725NumberofnewunenhancingT1lesionsNumberofuniqueactionslesions(newGdElesionsandnewenlargingT2lesionsnotassociatedwithGd)Numberofnewgadolinium-enhancinglesionsevolvingintoblackholesatendofstudyfromeachon-treatmentMRINormalisedbrainvolume(Screeningonly*)WholebrainatrophyvolumechangerelativetoScreening(Week48only)Whitemattervolume(Screeningonly*)WhitemattervolumechangerelativetoScreening(PostScreeningMRIsonly)Greymattervolume(Screeningonly*)GreymattervolumechangerelativetoScreening(PostScreeningMRIsonly)*Instead,Week6hasbeenusedasthescanthatwillbeusedforassessingrelativechangesatotherstudyvisits.
ChangesfromScreeningasdescribedinthisRAPwillmeanchangesfromWeek6forthissinglesubject.
Inaddition,thenumberofgadolinium-enhancinglesionsobservedontheScreeningMRIwillalsobedatabased.
9.
2.
8.
2.
MRIendpointstobeDerivedProgrammaticallyAsdefinedinSection6.
1.
1,3datasetsaredefinedforconventionalMRIendpoints.
TheObservedCase(OC)datasetisthedatareportedbyNeuroRxandwillbeusedinlistingsandforsummarystatisticsforactualMRIlesioncountstablesonly.
TheAllEvaluableScans(AES)andImputedMissingValues(IMV)datasetswillbeusedforcumulativeMRIcountsforsummarystatisticsandstatisticalanalyses;theywillalsobelisted.
TheAESdatasetisderivedbycarryingdowncumulativecountsandnumberofevaluablescansfrompreviousvisitstoensureallpatientswithatleast1MRIpriortothatvisitareincludedinthesummarytableasdemonstratedinTable6.
TheIMVdatasetisderivedbyimputingmissingMRIscanlesioncountswiththeaveragenumberoflesionsfornon-missingMRIsforthatsubjectasdemonstratedbyTable6.
Thesederivationswillbeconductedforthefollowingendpointsonly:Numberofnewgadolinium-enhancinglesionsNumberofnewandenlargingT2lesionsNumberofnewunenhancingT1lesions2014N204379_00CONFIDENTIALH3M11647726Numberofuniqueactionslesions(newGdElesionsandnewenlargingT2lesionsnotassociatedwithGd)Numberofnewgadolinium-enhancinglesionsevolvingintoblackholesatendofstudyfromeachon-treatmentMRITable6WorkedExampleforDerivingLesionCountsObservedCaseAllEvaluableScansImputedMissingValuesWeekObservedLesionCountCum.
CountNo.
ofScansCum.
CountNo.
ofScansCum.
CountNo.
ofScansExample1:MissingMRIatWeek246111111112232323218033333324MissingMissingMissing3344301444455362656576421767687480777788Example2:SubjectWithdrawalpriortoWeek24MRI6111111112232323218033333324MissingMissingMissing334430MissingMissingMissing335536MissingMissingMissing336642MissingMissingMissing337748MissingMissingMissing3388Thenormalisedbrainvolume,whitemattervolumeandgreymattervolumeateachpostScreeningMRIwillbederivedusingthefollowingformula:PostBaselineVolume=BaselineVolumeplus(BaselineVolumexRelativeChangePostBaseline)TheChangefromBaselineineachvolumeisthenderivedas:ChangefromBaseline=PostBaselineVolumeminusBaselineVolumeAllBrainVolumemeasurementshavebeensenttoGSKinmm3units.
Reportingwillbeperformedusingcm3andwillbeconvertedbydividingthedataprovidedbyNeuroRxby1,000.
2014N204379_00CONFIDENTIALH3M116477279.
2.
9.
CogStateBatteryTheCogStatebatteryusedinthisstudyconsistsof7'tasks',forwhichmultipleoutcomes'measures'arecollected.
AsdefinedinTable7foreachtask,anoutcome'measure'isdefinedforeach'task'andthat'measure'isusedinthesummarystatistics/statisticalanalysesforthat'task',asapplicable,andusedinthederivationofDomainScoresandtheCogStateBatteryTotalScore.
Thismeasure(denotedasX)is'standardised'bysubtractingtheoverallITTpopulationmeanofthederivedbaselinevalues(mbt)andthendividingbytheoverallITTpopulationstandarddeviationofthederivedbaselinevalues(σbt).
Ifanimprovementinanindividualtaskisdefinedasanegativechangefrombaseline,thiseffectsizewillbemultipliedby-1(seeTable7).
AstandardisedTaskScoreisthereforethedirection-adjusted,standardisedmeasureandateachassessmentiscalculatedasfollows:Whereb=baseline,t=taskandj=week12or24NB:the-1isonlyapplicablewherealowerscoreindicatesanimprovement.
IndividualtaskswhichareflaggedbyCogStateasnothavingbeencompletedwillnotbeusedinthederivationofthestandardised'task'scores,andconsequentlyanycompositescoresorbeanalysed.
Thisstepwillbecompletedbeforeanyderivationsofthedataareconducted.
Thisdatawillbelistedonly.
If>10%oftasksaredefinedasintegrityfailuresbyCogState,apost-hocsensitivityanalysismaybeconductedtoassesstheimpactoftheseintegrityfailuresonthestudyresults.
ThebaselineisderivedastheaverageofthesecondCogStateBatteryassessmentconductedattheScreeningvisitandtheBaseline(Week0)CogStateBatteryassessment.
Ifeitherassessmentismissingthenthederivedbaselinewillbethenon-missingassessment.
Ifbothassessmentsaremissingthenthederivedbaselinewillalsobemissing.
Table7MeasuresforIndividualCogStateTasksTaskShortTaskLabelforreportingCognitiveTestingDomainTaskCodeonCOGTESTdatasetPrimaryMeasureMeasureCodeonCOGTESTdatasetMultiplyby-1ISLTtaskISLTVerbalLearning23NumberofcorrectresponsesCORNoISLTdelayedrecallISLT-RExecutiveFunction/SpatialProblemSolving15NumberofcorrectresponsesCORNoGrotonMazeGMLPsychomotor24TotalTERYes2014N204379_00CONFIDENTIALH3M11647728TaskShortTaskLabelforreportingCognitiveTestingDomainTaskCodeonCOGTESTdatasetPrimaryMeasureMeasureCodeonCOGTESTdatasetMultiplyby-1LearningTestFunction/SpeedofProcessingNumberofErrorsDetectionDETVisualAttention/Vigilance19SpeedofPerformance(logmsec)LMNYesIdentificationIDNVisualLearning&Memory18Speedofperformance(logmsec)LMNYesOne-CardLearningOCLAttention/WorkingMemory42AccuracyofPerformanceACCNoOne-BackOBLVerbalLearningandMemory20SpeedofPerformance(logmsec)LMNYesTable8summarisesthe'tasks'tobeincludedineachCompositeDomain.
EachCompositeDomainScoreandtheCogStateBatteryTotalScore(usesall'tasks')isderivedbytakingtheaverageofall'standardised'directionally-adjusted'task'scores.
InordertocalculateanyCompositeDomainScoreortheCogStateBatteryTotalScoretheremustbeatleast2'tasks'thathavenon-missingdatatobeusedinthecalculation.
IfthiscriterionisnotmetthenasubjectwillhaveamissingCompositeDomainorCogStateBatteryTotalScoreforthatvisit.
Table8SummaryofCogStateBatteryCompositeDomainTasksDomainTaskExecutiveFunctionGrotonMazeLearningTest(GMLT)One-BackTest(OBT)MemoryInternationalShoppingListTask–ImmediateRecall(ISLT)InternationalShoppingListTask–DelayedRecall(ISLT-R)OneCardLearning(OCL)AttentionDetectionIdentificationIftheamountofmissingdataataparticularvisitmeansthatvariouscompositescorescannotbecalculatedbutthereisanotherassessmentwhichslotstothesamevisitfromwhichyoucancalculatemorecompositescores,thentheassessmentwiththelargestnumberofcompositescoresavailablewillbeusedinallsummaries.
Datafromboth2014N204379_00CONFIDENTIALH3M11647729visitswouldbelisted.
CogStatehaveprovidedage-controlledsummarystatisticsfornormativedataforeachCogStateBatterytaskincludedinthisstudy(seeSection16forfilelocationonBPTsharedareanetworkdrive).
Subjectsrecruitedintothisstudywerenotrequiredtohaveanyspecificcognitiveimpairment.
Toenableanassessmentofthepotentialbaselineimpairmentofsubjectsenteringthisstudy,forthederivedBaselineassessmentthescoreforeachtaskwillbecomparedtothenormativedatausingthefollowingformula:BaselineImpairment=(BaselineValueminusNormativeMean)dividedbyNormativeStandardDeviation(SD)Negativevalueswillsuggestthatasubject'stestresultatBaselineisbelowthatofanormalpopulationandpositivevalueswillindicateaBaselineresultthatisaboveaverageforanormalpopulationforthattask.
AcategoricalvariableforeachtaskwillthenbedefinedexpressingtheBaselineValuerelativetotheNormativedata:≥2SDs,450-480>30-603>480-500>604>50010.
STUDYPOPULATIONSubjectswhowererandomisedbutfailedtomeettheIntent-to-Treat(ITT)definitionwillbeincludedintheRandomisedPopulation.
Forthesesubjects,alldatawillbelistedunderthetreatmentgrouptheywererandomisedtoreceive.
Similarlydatafromsubjectswhoreceiveincorrectstudymedication,atanypointduringthestudy,willbesummarisedundertheirrandomisedtreatmentgroup.
2014N204379_00CONFIDENTIALH3M1164773610.
1.
DispositionofSubjectsDispositionofsubjectswillbecoveredbythefollowingsummarytables.
ThesetableswillbepresentedforAllSubjectsandbyStratum(BackgroundDiseaseModifyingTherapy:Avonex/Copaxone).
SummaryofSubjectsbyPopulation(fortheRandomisedpopulation;Table6.
01)SummaryofInclusion/ExclusionDeviations(fortheITTpopulation;Table6.
02)SummaryofSubjectDisposition(fortheITTpopulation;Table6.
03)Table6.
01willgivedetailsofthenumberofsubjectsrandomised,andthenumberincludedintheITT,PKandPGxpopulations.
Alistingofsubjectsexcludedfromthepopulations,andthereasonsfortheexclusion,willbepresentedbytreatmentgroupandsubject(Listing6.
01).
Table6.
02willdetailthenumberofallinclusionandexclusioncriteriaviolationsandwillbesplitbytreatmentgroup.
Inclusion/exclusioncriteriadeviationswillbelistedinListing6.
02.
ThenumberandpercentageofsubjectswhocompletedthestudyandwhowithdrewprematurelyfromthestudywillbepresentedbytreatmentgroupforAllSubjectsandbyStratum.
ReasonsforprematurewithdrawalwillbepresentedintheordertheyaredisplayedintheeCRF.
Inaddition,asummaryofthenumberofsubjectscompletingtheTitrationPeriod(definedasstartingtheMaintenancePeriod)willbeincluded.
ThistablewillbepresentedfortheITTpopulation(Table6.
03).
Alistingofallsubjectsthatwithdrewwillbeprovided(Listing6.
04).
Asummarytableofthenumberofsubjectswhocompletedeachprotocol-specifiedvisitwillbeprovided(Table6.
04);itwillalsoincludeeachup-titrationphonecallthatwasspecifiedintheprotocol.
Allstudyvisits,includingtelephonecallswillbelistedwiththeexceptionofunscheduled-visitspost-randomisation(Listing6.
05).
AsummarytableofthereasonsforScreeningFailuresrecordedintheeCRFwillbeprovided(Table6.
05).
10.
2.
ProtocolDeviationsAsummaryofallprotocoldeviationsrecordedintheeCRFwillbeproducedfortheITTpopulation(Table6.
06).
Thesedatawillbelisted,forallrandomisedsubjects,inListing6.
06.
Thislistingwillidentifythestudyphaseinwhichthedeviationoccurred.
Subjectsforwhomthetreatmentblindwasbroken(asrecordedonthe"Blind"pageoftheeCRF)willbelistedinListing6.
07,andsubjectswhowererandomisedtotheincorrectstratawillbelistedinListing6.
08.
2014N204379_00CONFIDENTIALH3M1164773710.
3.
DemographicandBaselineCharacteristics10.
3.
1.
DemographicsDemographicdatawillbesummarisedbytreatmentgroupfortheITTPopulation(Table6.
07).
Summarystatistics(numberofsubjects,mean,andstandarddeviation,median,minimumandmaximum)willbepresentedforHeight,Weight,BMI,age(atbaseline),andthenumberandpercentageofsubjectswillbepresentedforeachsexandethnicorigincategory.
Demographicdatawillbelistedforallrandomisedsubjects(Listing6.
09).
TwotableswillsummariseraceandracialcombinationsfortheITTpopulationandthedatawillbelisted(Listing6.
10)forallrandomisedsubjects.
Table6.
08willsummariseracebyhighestlevelracecategoriesandracialcombinations.
Thehigh-levelracecategoriesanddesignatedAsiansub-categoriesthatwillbesummarisedare:1.
AfricanAmerican/AfricanHeritage2.
AmericanIndianorAlaskaNative3.
AsianCentral/SouthAsianHeritageJapanese/EastAsianHeritage/SouthEastAsianHeritageMixedAsianHeritage(onlyrequiredifdataexists)4.
NativeHawaiianorotherPacificIslander5.
WhiteCombinationswillberepresentedastheconcatenationofthehighlevelcategoryterms.
Asubjectwillonlyberepresentedinasinglecategory.
Asubjectwhoselectsacombinationofraceswillbecountedinthecombinationofterms,notineachoftheconstituentterms.
Thereforethecountswilladduptothetotalnumberofsubjectswitharesponseandthepercentageswilladdupto100%.
Thesecondofthesetworacesummarieswillsummariseracebysecond-levelracecategoriesandracialcombinations(Table6.
09).
Thesecond-levelracecategoriesthatwillbesummarisedare:1.
AfricanAmerican/AfricanHeritage2.
AmericanIndianorAlaskaNative3.
Asian–Central/SouthAsianHeritage4.
Asian–EastAsianHeritage5.
Asian–JapaneseHeritage6.
Asian–SouthEastAsianHeritage7.
Asian–MixedRace8.
NativeHawaiianorotherPacificIslander9.
White–Arabic/NorthAfricanHeritage10.
White–White/Caucasian/EuropeanHeritage11.
White–MixedRace12.
MixedRace2014N204379_00CONFIDENTIALH3M11647738Asubjectwillonlyberepresentedinasinglecategory.
Asubjectwhoselectsacombinationofraceswillbecountedas'Asian–MixedRace','White–MixedRace'or'MixedRace'butnotineachoftheconstituentterms.
10.
3.
2.
MedicalHistoryMedicalhistorydatawillbesummarised.
PastMedicalconditionswillbesummarisedinTable6.
10andCurrentMedicalconditionswillbesummarisedinTable6.
11,fortheITTpopulationandlistedforallrandomisedsubjects(Listing6.
11).
ConditionswillbesummarisedundereachcategoryspecifiedintheeCRF,withan"OtherConditions"categoryforotherconditionsenteredbytheInvestigators.
Thenumberofsubjectswithafamilyhistoryofcardiovascularrisk-factorswillbesummarised(Table6.
12)andalistingwillbeprovided(Listing6.
12).
10.
3.
3.
MSDiseaseHistoryMSdiseasehistoryiscollectedatScreening.
Asummarytabledisplayingsummarystatistics(fordiseaseduration,timesinceonsetofsymptoms,thenumberofrelapsesintheprevious12months,numberofrelapsesintheprevious24months,totalnumberofrelapses,numberofdayssincethelastrelapseandfrequencycountsfortotalnumberofrelapses,numberofrelapsesinthelast12months,numberofrelapsesinthelast24months,theproportionofsubjectswhohadaMRIscaninthelasttwelvemonthswillbeproduced(Table6.
13)fortheITTPopulation.
ForsubjectsthathadanMRIinthelast12months,frequencycountsofthenumberofMRIscans,numberofscansshowingactiveGdElesionsandthenumberofuniqueactiveGdElesionsdetectedintheMRIscanswillalsobepresentedinTable6.
27;thesesummarieswillusetheproportionofsubjectswithanMRIscaninthepast12monthsasthedenominator.
AswellastheoverallITTpopulationsummaryTable6.
13willshowasummaryofMSdiseasehistorybyrandomisationstratum.
Thefrequencycountofrelapseswillbecategorisedasfollows:0,1,2,3-5,>5relapses.
Datawillalsobelistedforallrandomisedsubjects(Listing6.
13),withaseparatelistingfordatafrombrainMRIscansinthe12monthspriortoScreening(Listing6.
14).
Timesincefirstsymptoms/diseaseduration/laststeroidusewillbedeterminedusingthedateoftheScreeningvisitandthedateoffirstsymptoms/dateofdiagnosis/dateoflaststeroiduseasrecordedontheeCRF.
Ifthedateofdiagnosisorthedateoffirstsymptomsisapartialdatethena'01'willbeusedforthedayand'Jan'willbeusedforthemonth.
Iftheyearoffirstsymptoms/diagnosis/steroiduseismissingthedatewillnotbeimputed.
10.
3.
4.
SmokingHistoryHistoryoftobaccousewillbesummarisedbytreatmentgroup(Table6.
14)fortheITTpopulation.
Alistingoftobaccousewillalsobeprovided(Listing6.
16)forallrandomisedsubjects.
2014N204379_00CONFIDENTIALH3M1164773910.
4.
ConcomitantMedicationsAllprior/concomitantmedicationstakenduringthestudywillberecordedontheeCRF.
MedicationswillbecodedusingtheGSKDrugcodingdictionary,andwillbereportedbyAnatomicalTherapeuticChemical(ATC)classandmedication.
PriorMSdiseasemodifyingmedicationscollectedontheseparateeCRFpageatScreeningwillbesummarisedinTable6.
15andlistedinListing6.
17.
Summariesofpriormedicationsinthepre-treatmentphase(Table6.
16),concomitantmedicationsduringtheTitrationPeriod(Table6.
17),concomitantmedicationsduringMaintenancePeriod(Table6.
18)andanoverallsummaryofconcomitantmedicationsduringthetreatmentphasewillbeproducedbyATClevel1andingredientcombinations(Table6.
19).
TheseTreatmentPhasedisplayswillexcludetheprotocol-specifiedMSDiseaseModifyingBackgroundTherapy(Avonex/Copaxone).
Asummaryofmedicationsinitiatedpost-treatmentwillbeprovided(Table6.
20).
Allprior/concomitantmedicationswillbelisted(Listing6.
18).
AlistingdetailingtherelationshipsbetweenGSK-DrugATCclassificationlevel1(BodySystem),ingredientandtheverbatimtextwillbeprovidedforallverbatimmedicationsadministered(Listing6.
19).
ProhibitedMedicationsForprohibitedmedicationspleaserefertotheProtocolSection5.
10.
2.
Asummarytable(Table6.
21)andlisting(Listing6.
20)ofprohibitedmedicationstakenduringtheTreatmentPhasewillbeprovided.
Prohibitedmedicationswillbeidentifiedviaablindedclinicalreview.
MedicationClassificationPriorandconcomitantmedicationswillbedefinedusingthestartandstopdates,andongoingfieldsrecordedintheCRFsrelativetothefirstandlastdosedatesofrandomisedstudymedication.
Thedefinitionsforprior,concomitantandcorefollow-upmedicationperiodsareshownschematicallyinthediagrambelow.
Table15illustrateshowamedicationisclassifiedasPrior,Concomitant(duringTitrationPeriod),Concomitant(duringMaintenancePeriod)orPost-treatment.
AmedicationisconsideredtobeconcomitantTreatmentPhaseifisassignedtoeithertheconcomitantTitrationorconcomitantMaintenancePeriods(i.
e.
Definedas"Yes"inoneofthetwocorrespondingcolumnsinTable15).
2014N204379_00CONFIDENTIALH3M11647740Table15ExampleMedicationsPre-treatmentOn-treatment(TitrationPeriod)On-Treatment(MaintenancePeriod)Post-TreatmentFollow-UpPriorConco-mitant(Titrat-ion)Conco-mitant(Maint-enance)Post(a)xxTitrationTreatmentStartDateMaintenanceTreatmentStartDateTreatmentStopDateYNNN(b)xxYYNN(c)xxYYYN(d)xxYYYY(e)xxNYNN(f)xxNYYN(g)xxNYYY(h)xxNNYN(i)xxNNYY(j)xxNNNY(k)xYNNN(l)xY*YNN(m)xY*Y*YN(n)xY*Y*Y*Y(o)xYY**Y**Y**(p)xNYY**Y**(q)xNNYY**(r)xNNNY(s)Y***Y***Y***Y***x=start/stopdateofprior/concomitantmedicationY=Yes;N=No=missingstart/stopdateofprior/concomitantmedication*Ifamedicationisstoppedon-treatment(eitherTitrationorMaintenance)orpost-treatmentandnostartdateisrecordeditwillbeassumedthatthemedicationwasongoingfromthepre-treatmentphase**Ifamedicationisstartedpre-treatmentoron-treatmentorduringthepost-treatmentFollow-Upandnostopdateisrecordedthenusagewillbeassumedtobeongoingfortheremainderofthestudy***Ifamedicationhasnostartorstopdateitwillbeassumedthatthemedicationwasongoingfromthepre-treatmentphasetothepost-treatmentFollow-UpphaseIfamedicationisstartedorstoppedonthesamedayoftakingthefirstorthelastdoseofrandomisedstudymedicationplus3daysthenthiswillbeconsideredaconcomitantmedication.
Itshouldbenotedthatthesamemedicationcanbecountedinmorethanonephase.
Ifamedicationisstartedorstoppedonthesamedayoftakingthefirstor,uptoandincluding,thedayofthelastdoseofrandomisedstudymedicationthenthiswillbe2014N204379_00CONFIDENTIALH3M11647741consideredaconcomitantmedication.
Itshouldbenotedthatthesamemedicationcanbecountedinmorethanonephase/period.
PartialDatesNotethatifeitherofthestartdatesorstopdatesofdouble-blindstudymedicationaremissing,theworst,ormostconservative,caseshouldbeconsideredwhenslottingmedications(i.
e.
themedicationsshouldslotintoallpossiblephases).
IfapartialdateisrecordedintheCRF,thefollowingconventionwillbeusedtoassignthemedication:ifthepartialdateisastartdate,a'01'willbeusedforthedayand'Jan'willbeusedforthemonthifthepartialdateisastopdate,a'28/29/30/31'willbeusedfortheday(dependentonthemonthandyear)and'Dec'willbeusedforthemonth.
Therecordedpartialdatewillbedisplayedinlistings.
CountingRulesInthetables,thefollowingrulesapplywhencountingprior/concomitant/follow-upmedications:1.
Ifasubjectreceivesthesameprior/concomitant/follow-upmedication(i.
e.
sameATClevel1classandingredient)morethanonce,theyareonlycountedonceunderthecountforthatingredient.
2.
Ifasubjectreceivesmorethanoneprior/concomitant/follow-upmedicationinaparticularATCclass,theywillonlybeincludedonceinthecountfortheATCclass,butwillappearinthecountforeachappropriateingredientwithintheATCclass(unlessitisthesameingredient,see1.
above).
Therefore,thesumofthenumbersofsubjectswitheachingredientwithinanATCclassmayexceedthenumberofsubjectswithmedicationswithinthatATCclass.
Similarly,thesumoftheATCclasstotalsmayexceedthetotalnumberofsubjectswithatleastonemedication.
Multi-ingredientMedicationsMulti-ingredientmedicationswillbesummarisedaccordingtotheircombinationATCclassificationratherthantheATCclassificationsoftheingredients.
DefinitionofOnsetThefollowingconventionwillbeusedwhencalculatingstudyday:Thestartofmedicationrelativetostudymedicationisthenumberofdaysbetweenthestartofthemedicationandthestartofstudymedication,i.
e.
2014N204379_00CONFIDENTIALH3M116477421)Ifthedateofinterestisonorafterthefirstdosedateofstudymedication:Startofmedicationrelativetostartofstudymedication=startdateofmedication–firstdosedateofstudymedication+12)IfthedateofinterestisbeforethefirstdosedateofIP:Startofmedicationrelativetostartofstudymedication=startdateofmedication–firstdosedateofstudymedication10.
5.
ExposureandTreatmentComplianceAlistingofrandomisedtreatmentbycentrewillbepresentedinListing6.
21.
10.
5.
1.
ExposureAsummaryofexposuretostudymedicationwillbepresented(Table6.
22)fortheITTpopulation.
Thistablewilldisplaysummarystatisticsforthedurationofexposureandcumulativeexposurebytreatmentgroup.
Thesummarystatisticsusedwillbethenumberofsubjects,mean,standarddeviation,median,minimumandmaximum.
Thedurationofexposurewillalsobesummarisedbypresentingthenumber(andpercentage)ofsubjectsineachtreatmentgroupwithdurationofexposureinthefollowingcategories:0days,1-28days,29-56days,57-84days,85-168days,169-252days,253-343daysand344+days.
Allexposuredatawillalsobelisted(Listing8.
22)forallrandomisedsubjects.
Theexpecteddurationis336days(7daysx48weeks).
Thedurationofexposureindayswillbebasedontheformula:Durationofexposureindays=dateoflaststudymedicationdose–dateoffirststudymedicationdose+1Thedurationofexposurewillnotbeadjustedforbreaksindosingofstudymedication.
ThecumulativeexposuretoGSK239512willbebasedontheformula:41*iiitdTotaldosewherei=doselevel;ti=durationofexposureatdoselevel.
ForasubjectonGSK239512thatprogressesthroughthestudyasplanned,theexpectedcumulativeexposurewouldthereforebe25,690g:[10g*7(days)]+[20g*7(days)]+[40g*7(days)]+[80g*315(days[45weeks*7days)]=25,690gThedurationofexposurewillalsobeplottedbytreatmentgroup(Figure6.
01)fortheITTpopulation.
2014N204379_00CONFIDENTIALH3M1164774310.
5.
2.
TreatmentComplianceEachsubjectwasplannedtobedispensedonebottleofIPateachvisitduringtheTitrationandMaintenancePeriodsofthestudy.
EachbottledispensedduringtheTitrationPeriodcontained10tabletsand4or5bottlesweredispensedpersubjectduringtheTitrationPhasedependingonwhetheranadditionalweekoftitrationfromWeek4to5wasrequired.
BottlesdispensedduringtheMaintenancePeriodcontained33tablets.
Allbottleswerelabelledwithauniquecontainernumber.
Thesubjectwasinstructedtotakeonetabletoncedaily,i.
e.
,atotalof1tabletperday.
SubjectsreturnedtheirmedicationforacompliancecheckateachstudyvisitandthenumberoftabletsreturnedineachbottlewasrecordedintheeCRF.
CompliancefortheTreatmentPhase,theTitrationPeriodandtheMaintenancePeriodwillbecalculatedseparatelyusingthefollowingformula:100%*ntontreatmebetoscheduleddaysofno.
}returnedtabletsofno.
total-dispensedtabletsofno.
{totalwhereno.
ofdaysscheduledtobeontreatment=(dateoflastdose–dateoffirstdose)+1day.
Note:thisiscalculatedseparatelyforeachPhase/Period.
SubjectswhohaveanunknownnumberoftabletstakenataspecificvisitduetomissingdataintheCRF,willbeassumedtohavetaken0tabletsbetweenvisitsinthecalculationofcompliance.
Alistingwillbeprovidedofallinvestigationalproductdispensedandthenumberoftabletsreturnedateachvisit(Listing6.
24)forallrandomisedsubjects.
Subjectsareconsideredtobeoverallcompliantifthecalculationforcomplianceis80%and≤120%andtheyhavenoevidenceofanyinterruptionofstudymedicationfor4ormoreconsecutivedays.
Studymedicationcompliance(TreatmentPhase,TitrationPeriodandMaintenancePeriod)andOverallCompliancewillbelisted(Listing6.
24)fortherandomisedpopulationandsummarisedinTable6.
23,Table6.
25andTable6.
26fortheITTPopulationrespectively.
Thesummaryofcompliancewillalsoshowthefrequencycountsforthenumberofsubjectswithcompliance120%.
Asubjectwhoreceivedincorrectstudymedication(incorrectdoselevelorincorrectstudymedication)willbelistedinListing6.
25.
TheinformationforthissecondlistingwillbeprovidedbytheRAMOSco-ordinatorfollowingDBFwhichshouldbeinterpretedalongsidethelistingofProtocolDeviations(Listing6.
06)tofullyinterpretthedata.
10.
5.
3.
DoseTitrationAfrequencytablewillbeprovidedtoshowthenumberofsubjectsateachdoselevelatthestartofeachweekofthetitrationperiod.
Inaddition,thenumberofsubjectsateachdoselevelateachvisitduringtheMaintenanceperiod,andthestartandtheendofthe2014N204379_00CONFIDENTIALH3M11647744Maintenanceperiod,andthemaximumdoselevelattained,andmaintainedforatleast7daysintheMaintenanceperiod,willalsobepresented(Table6.
24).
11.
EFFICACYANALYSESInferenceswillbemadeusingtheintention-to-treat(ITT)population,nootherpopulationisdefinedforefficacyanalyses.
11.
1.
PrimaryEfficacyAnalyses11.
1.
1.
SummaryDisplaysAsummarytablethatshowsthenumberoflesionswithMTRMRIassessmentsforsubjectsateachMRIassessmentwillbeprovided.
Thelesioncategorieswillbe0lesions,1lesion,2,lesions,3lesions,4lesions,5lesions,6-10lesions,and>10lesions(Table7.
01&Table7.
02).
LesionsoccuratdifferenttimesduringthestudysosummarystatisticswillbeprovidedbytheRelativeMRIscanforeachlesionratherthanstudyvisittoenablesimilardatatobegroupedappropriately.
Thenumberofsubjectswithlesionmeasurements,thenumberoflesions,andsummarystatisticsofMTRValue(mean,standarddeviation,median,minimumandmaximum)willbeprovidedateachMRIscanforGdElesionsanddelta-MTRlesionsseparately(Table7.
03&Table7.
04).
SummarystatisticsforthechangefromReferenceMRIateachrelativeMRIforGdElesionsanddeltaMTRlesionswillbepresentedinTable7.
05&Table7.
06.
Itshouldbenotedthatthenumberofsubjectsandthenumberoflesionswillvarydependingonwhenthelesionoccurred.
AllthesesummarytableswillbepresentedforallsubjectsandbyBackgroundMSDiseaseModifyingMedication.
Therawmeanand90%CIforMTRvaluesandchangefromreferenceMRIinMTRValuesand90%CIwillalsobeplotted(Figure7.
01-Figure7.
04).
SummarystatisticsforMTRValuesandchangefromReferenceMRIMTRValueswillalsobeprovidedateachMRIscanforGdElesionsanddelta-MTRlesionsseparatelyatthesubjectlevelwherealllesionsforasubjectareaveragedasperSection9.
2.
7(Table7.
07-Table7.
10).
ProfileplotsoflesionMTRvalueswillalsobeprovidedforGdELesions(Figure7.
05)anddelta-MTRLesions(Figure7.
57).
Thesewillbeplotsof1pagepersubjectandwillusethestudyMRIvisitssuchthatthetimingoflesionoccurrenceforeachsubjectcanbeobserved.
Gadolinium-enhancinglesionswillbepresentedusingsolidredlinesanddelta-MTRlesionswillbepresentedusingdottedbluelines.
Theplotswillbeorderedbytreatmentgroup,BackgroundMSDiseaseModifyingMedication,centreandsubjectnumber.
AllMTRlistingswillbesortedbylesiontype(gadolinium-enhancinglesionordeltaMTRlesion),treatmentgroup,centre,subject,lesionID(lesionsatearliestMRIscanswillbelistedfirst).
AllMTRdatareceivedfromNeuroRxwillbelisted(Listing7.
01),thislistingwillincludedefiningtheReferenceMRIscanandthechangefromReferenceScaninMTRValueforeachMRI.
Aseparatelisting(Listing7.
02)willbeprovidedthat2014N204379_00CONFIDENTIALH3M11647745foreachsubjectlesionsummarisestheaveragepre-lesionMRIMTRValuesandpost-LesionMRIMTRValuesforeachsensitivityanalysis.
Listing7.
03willthenrepeatListing7.
02butusingsubjectleveldata(averagingacrossalllesionsforasubject).
AlistingofsubjectsthathadnoGdEsornodelta-MTRlesionssuchthattheydidnotcontributetoeitherco-primaryendpointwillbeprovided(Listing7.
04).
11.
1.
2.
StatisticalAnalysisAllanalysesdescribedinthissectionmaybeconductedforbothco-primaryendpointsandthecorrespondingdatadisplaysaredetailedinTable16forANCOVAanalysesandTable17forMMRManalyses.
However,whilsteachpotentialsensitivityanalysisisdefined,aniterativeapproachwillbetakentolookatdifferentanalysesbasedonthedatasuchthatnotallspecifiedanalysesmaynecessarilybeconducted.
AnanalysisofcovariancewillbeconductedtoassessthechangeinMTRRecoveryfrompre-lesiontopost-lesionMTRatthelesionlevel.
TheANCOVAmodelwillincludefixedcategoricaltermsfortreatmentgroup,pre-lesionaverageMTRValuelevelandBackgroundMSDiseaseModifyingTherapy.
Toaccountformultiplelesionsoccurringpersubjecta"REPEATED=SUBJECT"termwillbespecifiedtoaccountforpotentialcorrelationinlesionrecoverywithinasubject,acompoundsymmetrycovariancestructurewillbespecified.
However,ifonreviewofdataitappearsthatlesionswithinasubjectareheterogeneous,ortherestrictionresultsinthisanalysisortheBayesiananalysisnotbeingabletoconverge,thenthisrestrictionmayberemoved.
Theimpactoftheremovalofthisrestrictionwillbeinvestigated.
Ifasubjecthasnolesionsthenthatsubjectwillnotcontributetotheanalysis.
AnanalysisofcovariancewillbeconductedtoassessthechangeinMTRRecoveryfrompre-lesiontopost-lesionMTRatthesubjectlevel.
TheANCOVAmodelwillincludefixedcategoricaltermsfortreatmentgroup,pre-lesionaverageMTRValuelevelforalllesionsforthesubjectandBackgroundMSDiseaseModifyingTherapy.
Ifasubjecthasnolesionsthenthatsubjectwillnotcontributetotheanalysis.
Inordertoaidclinicalinterpretationoftheanalyses,theresultsfromtheANCOVAstatisticalmodellingwillalsobecalculatedasstandardisedEffectSizes;withassociated90%confidenceintervalasperthedefinitioninSection7.
TheBayesiananalysiswillbebasedonanon-informativeprior,usingthepriorstatementwithinthemixedprocedureinSAS(withthedefaultJeffreysprioroption).
Atableshowingtheposteriorprobabilities,obtainedfrom500,000simulationsand90%credibleintervalsforthestandardisedEffectSizeforthechangeinMTRValuepost-lesionrelativetopre-lesionatEndofStudybeinggreaterthan0,0.
25and0.
5(seeTable16)willbeproducedalongwithafigureoftheposteriordistributionfortheITTpopulation.
2014N204379_00CONFIDENTIALH3M11647746Table16SummaryofANCOVAAnalysesforCo-PrimaryEndpointsSensitivityAnalysis*GadoliniumEnhancingLesionsDelta-MTRLesionsLesionLevelSubjectLevelLesionLevelSubjectLevel1–ANCOVATable7.
07Table7.
23Table7.
15Table7.
31-Bayesian^Table7.
08Table7.
24Table7.
16Table7.
32Figure7.
06Figure7.
10Figure7.
08Figure7.
121#-ANCOVATable7.
09Table7.
25Table7.
17Table7.
33-Bayesian^Table7.
10Table7.
26Table7.
18Table7.
34Figure7.
07Figure7.
11Figure7.
09Figure7.
132Table7.
11Table7.
27Table7.
19Table7.
353Table7.
12Table7.
28Table7.
20Table7.
364Table7.
13Table7.
29Table7.
21Table7.
375Table7.
14Table7.
30Table7.
22Table7.
38*RefertoRAPSection9.
2.
9forfulldefinition#IncludingLesionswithatleast2MRIMTRAssessmentsPre-andPost-Lesiononly^DenotessensitivityanalyseswhereBayesiananalyseswillalsobeconducted.
Note:AnalysesdefinedasNumbers1,1#and3willbeconductedinitiallyonly.
Theco-primaryendpointswillbeanalysedusingamixedmodelforrepeatedmeasures(MMRM).
Howeveraslightlynonstandardapproachisinitiallyproposed.
Firstthepost-lesionMTRValuechangefromaveragepre-lesionMTRValueforeachlesionismodelledseparatelyacrossvisitswithineachsubject.
Thismeanstherearethreehierarchiclevels,subject,lesionwithinsubject,andvisitwithinlesion-by-subject.
IfthishierarchicapproachmeansthattheMMRMorBayesiananalysesareunabletorun,anditisareasonableassumptiontoconsiderlesionswithinasubjecttobeindependent(i.
e.
heterogeneityinlesionsisobserved)thisrestrictionwillberemovedsuchthatthelevelswithinthemodelwillbelesionandvisitwithinlesion.
Anexplanationfortheneedtoupdatethemodelwillbeinvestigatedwithinthedatastructure.
Atthelesionwithinsubjectlevel,thedateofidentificationofthelesionisseenasthefocusororigin,andallvisitsareseenrelativetothatvisit,describedastheRelativeMRI.
Thefixedeffectspartofthemodelisdefinedastreatmentgroup,averagepre-lesionMTRvalue,RelativeMRI,lesionsize,BackgroundDiseaseModifyingTherapy;interactionsbetweenRelativeMRIandtreatmentgroup,betweenaveragepre-lesionMTRvalueandRelativeMRI,betweenBackgroundDiseaseModifyingTherapyandRelativeMRIandbetweenlesionsizeandRelativeMRI.
Thecovariancestructureatthis2014N204379_00CONFIDENTIALH3M11647747levelismodelledusingasimpleformasweexpectthevariabilitytobeconstantacrosstimeandtheautocorrelationtobenon-complex.
Assuch,weintroduceanAR(1)covariancealongwithasimplerandomeffectatthesubject-by-lesionlevel.
OnereasonforthissimplestructureisthatitisconsistentwiththefixedeffectspartofthemodelfocusingontheRelativeMRI.
Atthesubjectlevelweintroduceanadditionalrandomsubjecteffect.
Inthesituationwherelesionswithinasubjectaretreatedasindependentthemodelwillbedefinedasabovebutthecovariancestructureatthelesionlevelwillbespecifiedasunstructured.
ThemodelwillbeusedtoestimatetreatmenteffectsofGSK239512relativetoplacebo.
Theadjustedmean,standarderror,adjustedtreatmentdifference;andassociated90%confidenceintervalwillbedisplayed.
TheleastsquaresmeanMTRValueateachRelativeMRIwillbeplottedbytreatmentgroup.
RelativeMRIwillbepresentedonthex-axisandtheadjustedmeanMTRValuewillbepresentedonthey-axis.
ThemeanateachRelativeMRIwillbepresentedwithanassociatednominal90%confidenceinterval.
IfthetermforBackgroundDiseaseModifyingTherapyisstatisticallysignificantforananalysis,post-hocanalyseslookingateachstratumseparatelymaybeconducted.
Inordertoaidclinicalinterpretationoftheanalyses,theresultsfromtheMixedModelRepeatedMeasure(MMRM)statisticalmodellingwillalsobecalculatedasstandardisedEffectSizes;withassociated90%confidenceinterval.
TheeffectsizewillbecalculatedasperthedefinitioninSection7.
TheBayesiananalysiswillbebasedonanon-informativeprior,usingthepriorstatementwithintheMCMCprocedureusingtheinverseWishartprioroptioninSASv9.
3oneitheraWindowsorLinuxplatform.
Atableshowingtheposteriorprobabilities,obtainedfrom500,000simulationsand90%credibleintervalsforthestandardisedEffectSizeforthechangeinMTRValuepost-lesionrelativetopre-lesionatEndofStudybeinggreaterthan0,0.
25and0willbeproducedalongwithafigureoftheposteriordistributionfortheITTpopulation.
Table17SummaryofMMRMAnalysestobePerformedSensitivityAnalysis*GadoliniumEnhancingLesionsDelta-MTRLesionsLesionLevelSubjectLevelLesionLevelSubjectLevel1–MMRM(incl.
AdjMeanplots)Table7.
39Table7.
55Table7.
47Table7.
63Figure7.
14Figure7.
22Figure7.
18Figure7.
26-Bayesian^Table7.
40Table7.
56Table7.
48Table7.
64Figure7.
15Figure7.
23Figure7.
19Figure7.
271#-MMRM(incl.
AdjMeanplots)Table7.
41Table7.
57Table7.
49Table7.
65Figure7.
16Figure7.
24Figure7.
20Figure7.
28-Bayesian^Table7.
42Table7.
58Table7.
50Table7.
66Figure7.
17Figure7.
25Figure7.
21Figure7.
292014N204379_00CONFIDENTIALH3M11647748SensitivityAnalysis*GadoliniumEnhancingLesionsDelta-MTRLesionsLesionLevelSubjectLevelLesionLevelSubjectLevel2Table7.
43Table7.
59Table7.
51Table7.
673Table7.
44Table7.
60Table7.
52Table7.
684Table7.
45Table7.
61Table7.
53Table7.
695Table7.
46Table7.
62Table7.
54Table7.
70*RefertoRAPSection9.
2.
9forfulldefinition#IncludingLesionswithatleast2MRIMTRAssessmentsPre-andPost-Lesiononly^DenotessensitivityanalyseswhereBayesiananalyseswillalsobeconducted.
Figureswillbeplotsofposteriorprobabilities.
Note:AnalysesdefinedasNumbers1,1#and3willbeconductedinitiallyonly.
11.
2.
SecondaryMRIEfficacyAnalysesAlistingofcommentsfromNeuroRxprovidedwiththeMRIdatawillbeprovided(Listing6.
26).
11.
2.
1.
T2LesionMTRT2LesionMTRwillbesummarisedusingsummarystatistics(n,mean,standarddeviation,median,minimumandmaximum)ateachvisit(Table7.
147)andforchangefromScreeningateachvisit(Table7.
148).
Aplotofrawmeanand90%CIwillalsobeprovided(Figure7.
54).
AllT2LesionMTRdatawillbelisted(Listing7.
16)ChangefromScreeninginT2LesionMTRwillbeanalysedusingamixedmodelforrepeatedmeasures(MMRM)withrestrictedmaximumlikelihoodestimationandanunstructuredcovariancematrix.
Thestatisticalmodelwilladjustforthefollowingcovariates:treatmentgroup,visit,ScreeningT2LesionMTRValue,BackgroundMSDiseaseModifyingTherapy,interactionsbetweenvisitandtreatmentgroup,betweenvisitandScreeningT2LesionMTRValueandbetweenvisitandBackgroundDiseaseModifyingTherapywillalsobeincludedinthemodel.
Subjectwillbefittedasarandomeffect.
InthecircumstancethatthereareconvergenceproblemswiththeMMRManalysistheSCORING=4optioncouldbeusedintheMIXEDstatement,whichmakesSASuseFisherscoringforthefirst4iterations.
Iftheconvergenceproblemcannotberesolved,theunstructuredcovariancematrixwillbereplacedbyANTE(1)covariancestructureincombinationwitharandomsubjecteffect.
ThemodelwillbeusedtoestimatetreatmenteffectsofGSK239512relativetoplacebo.
Theadjustedmean,standarderror,adjustedtreatmentdifference;andassociated90%confidenceintervalwillbedisplayedfortheITTpopulation(Table7.
149).
Inordertoaidclinicalinterpretationoftheanalyses,theresultsfromtheMixedModelRepeatedMeasure(MMRM)statisticalmodellingwillalsobecalculatedasstandardisedEffectSizes;withassociated90%confidenceinterval.
TheeffectsizewillbecalculatedasperthedefinitioninSection7.
2014N204379_00CONFIDENTIALH3M11647749TheleastsquaresmeanforthechangefromScreeninginT2LesionMTRwillbeplottedbytreatmentgroupoverthetreatmentperiod(Figure7.
55).
Weekofstudywillbepresentedonthex-axisandtheadjustedmeanchangeinT2LesionMTRonthey-axis.
Themeanateachassessmentwillbepresentedwithanassociatednominal90%confidenceinterval.
Thenormalityassumptionswillbeassessedbyinspectionofthefollowingplots:HistogramofmarginalstudentisedresidualsderivedfromtheMMRMmodelNormalprobabilityplotwithsimulationenvelopeTheBayesiananalysis,whichwillonlybeperformediftheMMRManalysesdemonstratetreatmentdifferencesbetweenGSK239512andplacebowillbebasedonanon-informativeprior,usingthepriorstatementwithintheMCMCprocedureusingtheinverseWishartprioroptioninSASv9.
3oneitheraWindowsorLinuxplatform.
Atableshowingtheposteriorprobabilities,obtainedfrom500,000simulationsand90%credibleintervalsforthestandardisedEffectSizeforthechangefromScreeninginT2LesionMTRatEndofStudybeinggreaterthan0,0.
25and0.
5willbeproduced(Table7.
150)alongwithafigureoftheposteriordistributionfortheITTpopulation(Figure7.
56).
11.
2.
2.
MRILesionCountVariables11.
2.
2.
1.
SummaryDisplaysTheactualnumberandcumulativenumberofnewlesionswillbelistedfortheRandomisedpopulation,andsummarisedusingsummarystatistics(n,mean,standarddeviation,median,minimumandmaximum)andfrequencycounts(0lesions,1lesion,2lesions,3lesions,4-10lesions,>10lesions)foreachMRIparameterateachvisitfortheITTpopulationusingtheAESdataset(summarystatisticsonly)asdefinedinTable18.
Table18SummaryofDataDisplaysforSummarisingMRILesionCountEndpointsNewGdElesionsNewenlargingT2lesionsCumulativeUniqueActiveLesionsNewUnenhancingT1LesionsNewGdEEvolvingtoBlackHolesActualLesionCountSumm.
Stats(OC)Table7.
71Table7.
75Table7.
79Table7.
83Table7.
87Freq.
Counts(OC)Table7.
72Table7.
76Table7.
80Table7.
84Table7.
88Cum.
LesionCountsSumm.
Stats(AES)Table7.
73Table7.
77Table7.
81Table7.
85Table7.
892014N204379_00CONFIDENTIALH3M11647750NewGdElesionsNewenlargingT2lesionsCumulativeUniqueActiveLesionsNewUnenhancingT1LesionsNewGdEEvolvingtoBlackHolesFreq.
Counts(AES)Table7.
74Table7.
78Table7.
82Table7.
86Table7.
90MeanProfilePlot(AES)Figure7.
30Figure7.
31Figure7.
32Figure7.
33Figure7.
34Actual&Cum.
LesionCountsListingListing7.
05Listing7.
06Listing7.
07Listing7.
08Listing7.
0911.
2.
2.
2.
StatisticalAnalysisThecumulativenumberofnewlesionsforeachMRIendpointatWeek48willbeanalysedusingtheAESdatasetandtheITTpopulation.
TheseanalyseswillfittreatmentgroupandBackgroundDiseaseModifyingTherapyandbaselinecountofgadolinium-enhancinglesionsascategoricalvariablesusingageneralizedlinearmodel(GLM)assuminganunderlyingnegativebinomialdistributionwithalog-linkfunction,thelogofthenumberofMRIscanswillbeincludedasanoffsetvariable.
Therateratioandassociated90%confidenceintervalwillbepresentedasperTable19.
Theproposedanalysisusingthenegativebinomialmodelassumesthatmissingdataismissingatrandom(MAR).
Toexaminethesensitivityoftheresultsoftheanalysistodeparturesfromthisassumption,furthersensitivityanalysesaredefinedbelow,and,dependentontheobserveddata,maybeexploredusingmultipleimputationmethodsbasedonpatternmixturemodels[Carpenter,2013]usingtheOCdataset.
UsinganunderlyingnegativebinomialmodelpostwithdrawalMRIlesioncountswillbeimputedconditionaluponthesubjectsownobservednumberofeventspriortowithdrawal.
Thisapproachallowsalternativeassumptionsaboutthemissingdatatobeinvestigatedbymodifyingthepost-withdrawalmodel.
Thisapproachinvolvesfirstlyfittingtheprimaryanalysisnegativebinomialgeneralisedlinearmodeltothedata,andsamplingfromtheposteriordistribution(likelihoodfunctionmultipliedbyanon-informativeprior)oftheestimatedparameters(i.
e.
thebetas)associatedwiththeindependentvariables.
ThenumberoflesionsthatwouldhavebeenseenonmissedMRIscansbasedonvariousassumptionsisthenestimatedforsubjectswhowithdrawearly.
ThisnumberiscombinedwiththeobservedlesionsonavailableMRIscansandthedataisanalysedasspecifiedat2014N204379_00CONFIDENTIALH3M11647751thestartofthisSection.
ThisanalysisisrepeatedmultipletimesandtheresultscombinedusingRubin'sformulae[Barnard,1999].
Theassumptionsusedtoimputethemissingpartofthedataforsubjectswhowithdrawearlywillbeasfollows:a)UnconditionalReference.
ThebasisofthisapproachisthatwithdrawalfromtheGSK239512treatmentgrouprepresentsanewperiodforthesubjectandthepreviousMRIresultsarenotusedintheimputationmodelforlesionspost-withdrawal.
InsteadmissingMRIscanlesionresultsforGSK239512areimputedusingtheoverallmeannumberoflesionsperMRIscanfortheplacebotreatmentgroup,conditionalonlyonbaselinecovariates.
Missingdataintheplacebotreatmentgroupareimputedunderrandomised-armMARassumptions.
b)JumptoReference.
MissingcountswillbeimputedconditionaluponthesubjectsownobservednumberoflesionsperMRIscanpriortowithdrawal.
Theimpactofsamplingfromthisconditionaldistributionisthatiftheirlesionratepriortowithdrawalisworsethanwouldbeexpected(positiveresidual)onGSK239512,theirimputedeventrateafterwithdrawalwillbeworsethantheexpectedlesionrateonplacebo.
Missingdataintheplacebotreatmentgroupareimputedunderrandomised-armMAR.
c)CopyReference.
Thewholedistributionevenpriortowithdrawalisassumedtobethesameastheplacebogroup.
Thismimicsthecasewherethosewithdrawingareineffectnon-responders.
ThishasalessextremeimpactthantheJumptoReferenceapproach.
IfasubjectintheGSK239512treatmentgroupishigherthantheplacebomeanthenthispositiveresidualwillfeedthroughintosubsequentobservations,toadegreedeterminedbythecorrelationintheplacebotreatmentgroup.
Missingdataintheplacebotreatmentgroupareagainimputedunderrandomised-armMAR.
Table19SummaryofDataDisplaysforStatisticalAnalysesofMRILesionCountEndpointsNewGdElesionsNewenlargingT2lesionsCumulativeUniqueActiveLesionsNewUnenhancingT1LesionsNewGdEEvolvingtoBlackHolesGLMAnalysis(AES)Table7.
91Table7.
93Table7.
95Table7.
97Table7.
99MIAnalysis(OC)Table7.
92Table7.
94Table7.
96Table7.
98Table7.
1002014N204379_00CONFIDENTIALH3M1164775211.
2.
3.
MRIVolumeMeasures11.
2.
3.
1.
SummaryDisplaysSummarystatistics(n,mean,standarddeviation,median,minimumandmaximum)willbepresentedfortheactualvolumeateachscheduledMRIassessmentandchangefrombaseline(ScreeningMRI)ateachscheduledMRIassessmentasdefinedinTable20fortheITTpopulationusingtheOCdatasetandtheIMVdataset.
ListingsofeachMRIvolumemeasurefortheRandomisedpopulationarealsodefinedinTable20.
Table20SummaryofDataDisplaysforSummarisingMRIVolumeEndpointsNorm.
BrainVolume(Atrophy)WhiteMatterVolumeGreyMatterVolumeActualVolumesSummaryStatistics(OC)Table7.
101Table7.
103Table7.
105ChangefromBaselineSummaryStatistics(OC)Table7.
102Table7.
104Table7.
106MeanProfilePlot(OC)NottobecreatedFigure7.
35Figure7.
36Actual&ChangesListingListing7.
10Listing7.
11Listing7.
1211.
2.
3.
2.
StatisticalAnalysisThechangeinwholebrainatrophyrelativetoScreeningatWeek48willbeanalysedusingtheOCdatasetandtheITTpopulation.
TheanalyseswillfittreatmentgroupandBackgroundDiseaseModifyingTherapyascategoricalvariablesandbaselinenormalisedbrainvolumeatScreeningascovariatesusingageneralizedlinearmodel(GLM).
Thepairwisecomparison,andassociated90%confidenceintervalwillbepresented(Table7.
107).
ThechangeinWhiteMatterandGreyrelativetoScreeningatWeek48willbeanalysedusingtheOCdatasetandtheITTpopulation.
TheanalyseswillfittreatmentgroupandBackgroundDiseaseModifyingTherapyascategoricalvariablesandappropriatebaselinebrainvolumeatScreeningascovariatesusingageneralizedlinearmodel(GLM).
Thepairwisecomparisons,andassociated90%confidenceintervalswillbepresented(Table7.
108andTable7.
109).
Inaddition,thechangefrombaselineforeachWhiteandMattervolumeendpointwillbeanalysedusingamixedmodelforrepeatedmeasures(MMRM)withrestrictedmaximumlikelihoodestimationandanunstructuredcovariancematrixandfortheOCdataset.
Thestatisticalmodelwilladjustforthefollowingcovariates:treatmentgroup,visit,Baselinevolume,BackgroundDiseaseModifyingTherapy,interactionsbetweenvisitandtreatmentgroup,betweenvisitandBaselinevolumeandbetweenBackgroundDiseaseModifyingTherapyandvisitwillalsobeincludedinthemodel.
Subjectwillbefittedasa2014N204379_00CONFIDENTIALH3M11647753randomeffect.
InthecircumstancethatthereareconvergenceproblemswiththeMMRManalysistheSCORING=4optioncouldbeusedintheMIXEDstatement,whichmakesSASuseFisherscoringforthefirst4iterations.
Iftheconvergenceproblemcannotberesolved,theunstructuredcovariancematrixwillbereplacedbyANTE(1)covariancestructureincombinationwitharandomsubjecteffect.
ThemodelwillbeusedtoestimatetreatmenteffectsofGSK239512relativetoplaceboateachMRIvisit.
Theadjustedmean,standarderror,adjustedtreatmentdifference;andassociated90%confidenceintervalwillbedisplayed(Table7.
110&Table7.
111).
Theleastsquaresmeanforthechangefrombaselinewillbeplottedbytreatmentgroupoverthetreatmentperiod(Weeks0-48)forallsubjectsintheITTpopulation(Figure7.
37-Figure7.
38).
Weekofstudywillbepresentedonthex-axisandtheadjustedcumulativenumberofnewlesionswillbepresentedonthey-axis.
Themeanateachassessmentwillbepresentedwithanassociatednominal90%confidenceinterval.
IfthetermforBackgroundDiseaseModifyingTherapyisstatisticallysignificantforananalysis,post-hocanalyseslookingateachstratumseparatelymaybeconducted.
11.
3.
OtherEfficacyAnalyses11.
3.
1.
CogStateBattery11.
3.
1.
1.
SummaryDisplaysTheindividualCogstatetasksdatawillbelistedinListing7.
13,a"*"shallbeusedtodenotetheprimarymeasureforeachCogState'task'anda"^"willbeusedtodenotetasksthatwerecompletionorintegrityfailures.
TheCogStateBatterystandardisedtaskscoreswillbelistedbytreatmentgroup,visitandsubjectfortheallrandomisedpopulation(Listing7.
14).
ThislistingwillincludethecomparisontoahealthypopulationfortheBaselineassessment.
TheCogStateBatteryTotalscoreandcompositescoreswillbelistedbytreatmentgroup,visitandsubjectfortheallrandomisedpopulation(Listing7.
15).
AsummarytableofeachCogStateBatterytaskatbaselinerelativetotheage-matchednormativescoreswillbeprovidedtoaidinterpretationofCogStateBatterydatabyassessingdeficitsatBaseline(Table7.
112).
Thistablewillincludesummarystatisticsandthenumberofsubjects≥2SDs,252Days.
Inaddition,thefollowingdisplayswillalsobeprovidedfortheTitrationPeriodonlybyMSBackgroundDiseaseModifyingTherapyandwillbepresentedforplaceboandeachindividualdoselevelasperSection7.
1:Summaryofalladverseevents(Table8.
09)Summaryof(Investigatorassessed)drug-relatedadverseevents(Table8.
10)Summaryof(Investigatorassessed)drugrelatedadverseeventsbymaximumintensity(Table8.
11)2014N204379_00CONFIDENTIALH3M11647762Summaryofcommonadverseevents(≥5%incidenceinanydosegroup;Table8.
12)Thefollowinglistingswillbeproduced:Listingofalladverseevents(Listing8.
01)Thislistingwilldisplayallcollectedinformationrelatingtoeveryadverseeventrecordedinthestudy,bysubjectnumber.
Basicdemographicinformationisalsoincluded.
Relationshipofadverseeventssystemorganclasses,higherlevelgroupterms,preferredtermsandverbatimtext(Listing8.
02)ThislistingwillshowalistofallSOCs,HLGTs,preferredtermsandverbatimadverseeventtextcollectedandreportedinthisstudy.
Verbatimtextwillbelistedalongsidetheappropriatepreferredterm,andsimilarlythepreferredtermswillbelistedalongsidetheappropriateHLGTandSOC.
Listingofsubjectnumbersforindividualontreatmentadverseevents(Listing8.
03)Thislistingwilldisplaythenumberofsubjectsandsubjectnumbersforeachpreferredtermofadverseevent,splitbySOCandHLGT.
Thefollowingfigureswillbeproduced:DotplotswillbeproducedshowingtherelativerisksofGSK239512vsplaceboforthemostcommonAEs(definedas≥5%withineithertreatmentgroup).
Thepercentageofsubjectswitheachadverseeventwillbedisplayedintheleft-handpanelandtheright-handpanelwillshowtherelativerisk,andasymptotic95%confidenceintervals(Figure8.
01).
12.
1.
5.
AdverseEventsofSpecialInterestAdverseeventsofspecialinterest(AESI)inthisstudyinclude:ConvulsionPerceptualabnormalities(e.
g.
,hypnopompichallucinations)Insomnia/sleepdisordersAbnormaldreams/nightmaresMoodsymptoms(e.
g.
,depressedmood,suicidality,anxiety)FeedingandbodyweightchangeLFTAbnormalitiesToaidwiththeidentificationofadverseeventsofspecialinterest,asetofMedDRAdictionarypreferredtermsandverbatimtermswillbepre-specifiedassearchcriteriafor2014N204379_00CONFIDENTIALH3M11647763eachoftheeventtypes.
Thesewillbestoredinaseparatedocumentandidentifiedpriortotheunblindingofthestudy.
AsummaryofalladverseeventsclinicallyidentifiedasanAESIexcludingLFTabnormalitieswillbepresentedsortedbysystemorganclassandpreferredtermindescendingorderfromthehighesttotalincidencetothelowesttotalincidence(Table8.
13-Table8.
18).
Inaddition,separatetableswillbeprovidedshowingtheactualnumberofoccurrencesofeachAdverseEventofSpecialInterest,andtheircharacteristics(Table8.
19-Table8.
24).
InadditionalistingofallAEdatafortheAESIeventswillbeprovided(Listing8.
04).
ThislistingwillbesortedbyAESI,treatmentgroup,centreandsubject.
ThislistingwillbeasubsetoftheallAdverseEventslisting(Listing8.
01).
ThefollowingthreeadditionaltablesshallalsobeprovidedbyStudyPhase:SummaryofAdverseEvents(AEs)codingtoMedDRAHLGT"Sleepdisordersanddisturbances"(Table8.
25)SummaryofAEscodingtoMedDRAHLGT"Depressedmooddisordersanddisturbances"(Table8.
26)SummaryofAEscodingtoMedDRAHLGT"Suicidalandself-injuriousbehavioursNEC"(Table8.
27)Inaddition,alistingofallAEdataincludedinthese3summarytableswillbeprovided(Listing8.
05).
ThislistingwillbesortedbyHLGTcategory,treatmentgroup,centreandsubject.
ThislistingwillbeasubsetoftheallAdverseEventslisting(Listing8.
01).
12.
1.
6.
PossibleSuicidalityRelatedAdverseEventsAnyadverseeventsthatwerereportedaspossiblesuicidalityrelatedadverseevents(PSRAEs)willbelistedinListing8.
06-Listing8.
09.
12.
2.
DeathsandSeriousAdverseEventsAnydeaththatoccursinthestudyisdefinedasaseriousevent(SAE),andshouldberecordedontheSAEpages.
Asummaryofseriousadverseeventsbytreatmentgroupsplitbyfatal/non-fatalandtreatmentphase(ontreatmentandfollow-up)willbeprovided(Table8.
28).
Fatalandnon-fatalSAEswillbelistedinListing8.
10&Listing8.
11.
AdditionalinformationrecordedintheeCRFforSAE'swillbeprovidedinListing8.
12.
12.
3.
DeviceIncidentsandNearIncidentsNodeviceisbeingusedinthisstudy.
2014N204379_00CONFIDENTIALH3M1164776412.
4.
AdverseEventsLeadingtoDiscontinuationofInvestigationalProductand/orWithdrawalfromtheStudyandOtherSignificantAdverseEventsSubjectscanwithdrawfrominvestigationalproductduetoanadverseeventduringthetreatmentphaseandenterfollow-up.
Asummaryofadverseeventsleadingtowithdrawalofstudydrugorwithdrawalfromstudy,bytreatmentgroupsplitbytreatmentphase:Treatment,TitrationandMaintenancewillbeprovided(Table8.
29).
AllAEsleadingtowithdrawalwillbelisted(Listing8.
13).
ThislistingwillbeasubsetofthelistingofalltreatmentAEs(Listing8.
01).
12.
5.
PregnanciesFemalesubjectsofchildbearingpotentialarebeingrecruitedintothisstudy.
TheyarerequiredtohaveanegativepregnancytestatScreeningandbaseline,andthenateachvisitduringthetreatmentphaseandateveryvisitduringtheFollow-upperiod.
Forpregnanciesthatoccurduringthestudy,theyarefollowedupbytheGCSPgroupandcasenarrativeswillbeprovidedforthestudyreportsonofurtherinformationwillbeprovidedinthisRAP.
ChildBearingpotentialatScreeningwillbelistedinListing6.
03.
12.
6.
ClinicalLaboratoryEvaluations12.
6.
1.
HaematologyandChemistrySummarystatistics(n,mean,standarddeviation,median,minimumandmaximum)forabsolutevaluesandchangefrombaselineateachscheduledpost-baselineassessmentandthemaximumon-treatmentvaluewillbetabulatedbytreatmentgroupforalllaboratoryparameterscollectedateachscheduledassessment(Table8.
30toTable8.
33).
Note:FSHandestradiolwillbelistedonlyandnotincludedinanysummarytables.
Laboratoryvaluesateachassessmentwillbecomparedwithboththeappropriatenormalranges(F1flag)andpotentialclinicalconcern(PCC)ranges(F3flag).
Labvalueswillbepresentedforeachtreatmentgroupusingclassificationbynormalrangesas:withinrange,belowtherange(i.
e.
belowthelowerlimit)orabovetherange(i.
e.
abovetheupperlimit).
Subjectswithactualvaluesorchangesinlabmeasurementsofpotentialclinicalconcern(seeSection9.
4.
1)willbesummarisedseparatelyateachscheduledassessmentandthemaximumon-treatmentvalueforeachtreatmentgroup(Table8.
34toTable8.
37).
Ifareferencerange,orrangeofclinicalconcern,isnotprovided,theparameterwillnotbeincludedinthedatadisplay.
Shifttableswillbeprovidedtoshowthenumberandpercentageofsubjectswithtransitionsfrombaseline(withinnormalrange,abovenormalrangeandbelownormalrange)toeachscheduledpost-baselineassessmentandthemaximumon-treatmentvalue(withinnormalrange,abovenormalrangeandbelownormalrange)ineachtreatment2014N204379_00CONFIDENTIALH3M11647765groupforhaematologydataandchemistrydata.
ThesetableswillusetheF1(normalrange)andberepeatedusingF3flags,asspecifiedinSection9.
4.
1(Table8.
38toTable8.
41).
ParameterswherenoF3flagsarespecifiedwillbeexcludedfromthedatadisplay.
Alistingwillbeproducedshowinglaboratorydatafromallassessmentsforsubjectswhohaveanyvaluesofpotentialclinicalconcernduringthestudy(Listing8.
15).
Inaddition,asubsetlistingwillalsobeprovidedshowingjustthelaboratoryvaluesofpotentialclinicalconcern(Listing8.
14).
Boxplotsofeachhaematologyandchemistryparameterateachscheduledassessmentwillbeprovided;eachparameterwillbepresentedwithvaluesdividedbytheupperlimitofnormal.
Thenumberofsubjectsateachvisitineachtreatmentgroupwillbepresented(Figure8.
02andFigure8.
03).
Toaidinterpretationofeachgraph,anypost-baselineon-treatmentvalue>3xULNwillbesettobe3xULNandwillbeannotatedwiththesubjectnumberandinparenthesestheactualmultipleabovetheULN.
Ashiftplotforeachhaematologyandchemistryparameterwillalsobepresented(Figure8.
04andFigure8.
05).
Thex-axiswillbethebaselinevalue(standardisedbydividingbytheULN)andthey-axiswillbethemaximumon-treatmentvalueforthelaboratoryparameter(standardisedbydividingbytheULN).
AreferencelineofY=Xwillbepresented.
EachtreatmentgroupwillbepresentedusingadifferentcolourandeachBackgroundDiseaseModifyingTherapywillbepresentedusingadifferentsymbol.
Toaidinterpretationofeachgraph,anypost-baselinemaximumon-treatmentvalue>3xULNwillbesettobe3xULNandwillbeannotatedwiththesubjectnumberandinparenthesestheactualmultipleabovetheULN.
12.
6.
1.
1.
LiverFunctionTestsAtableofgradedLFTsforAlanineAminoTransferase(ALT),AspartateAminoTransferase(AST),TotalBilirubin(BIL),AlkalinePhosphatase(ALP)andGammaGlutamylTransferase(GGT)willbeprovidedateachscheduledassessmentandmaximumon-treatmentvalue(Table8.
42).
GradedLFTswillbedefinedbythefollowingcriteria:Grade1:>ULNand≤3xULNGrade2:>3-≤5xULNGrade3:>5-≤20xULNGrade4:>20xULNWhereULN=upperlimitofnormalrangeBoxplotswillbeproducedshowingthedistributionoftheliverfunctiontest(LFT)parameters(ALT,AST,GGT,alkalinephosphataseandtotalbilirubin)ateachscheduledassessmentaspartofFigure8.
05(seeSection12.
6.
1)andthemaximumon-treatmentvalueforeachLFTsidebysidebytreatmentgroup(Figure8.
06).
2014N204379_00CONFIDENTIALH3M11647766By-subjectlistingsofinformationonlivereventsinrelationtotimeoftreatment(Listing8.
16)andforcalculatingtheRUCAMscore(Listing8.
17)willbeproduced.
ListingsofLiverImagingandBiopsydatawillbeproduced(Listing8.
18,Listing8.
19).
12.
6.
2.
UrinalysisResultsUrinalysisdatawillbelistedonly(Listing8.
20).
12.
7.
MultipleSclerosisSafetyAssessments12.
7.
1.
EDSSSummarydisplaysofEDSSassessmentsatscheduledassessmentswillonlyincludeEDSSassessmentsperformedwhenthesubjectwasnotaffectedbyanMSrelapse.
Summarystatistics(numberofsubjects,mean,standarddeviation,median,minimumandmaximum)andafrequencytableofthenumberofsubjectswitheachEDSSscoreateachscheduledassessmentwillbepresentedbytreatmentgroupfortheEDSSsummaryscore(Table8.
43).
SummaryStatisticsandafrequencytableofthenumberofsubjectsineachFunctionalSystemScore:VisualModifiedScore(Table8.
44),BrainstemFunctionalSystemScore(Table8.
45),PyramidalFunctionSystemScore(Table8.
46),CerebellarFunctionalSystemScore(Table8.
47),SensoryFunctionalSystemScore(Table8.
48),Bladder/BowelModifiedFunctionalSystemScore(Table8.
49),CerebralFunctionalSystemScore(Table8.
50)andAmbulatoryScore(Table8.
51)willbeproducedbytreatmentgroupandvisitforthetreatmentphase.
Inaddition,asummaryofthenumberofsubjectsineachtreatmentgroupwithanimproved(by1pointandby2points),unchangedorworsened(by1pointandby2points)EDSSTotalscoreatWeeks12,24,36and48comparedtotheirbaselineassessmentwillbeprovided(Table8.
52).
Inaddition,asummarytableofsubjectswithimproved(by1pointandby2points),unchangedorworsened(by1pointandby2points)FunctionalSystemScores(FSS)sustainedforatleast12weeksatWeek48willbeprovidedbyFSS(Table8.
53).
AscatterplotofbaselineEDSSscoreversusWeek48EDSSscorewillbeprovided(Figure8.
07).
Thex-axiswillbetheBaselineEDSSTotalScoreandthey-axiswillbetheWeek48EDSSTotalScore.
AreferencelineofY=Xwillbepresented.
EachtreatmentgroupwillbepresentedusingadifferentcolourandeachBackgroundDiseaseModifyingTherapywillbepresentedusingadifferentsymbol.
SummarytablesandfiguresofallEDSSdatawillonlyincludeEDSSassessmentsconductedwhenthesubjectwasnotexperiencingthesymptomsofarelapse.
ThiswillbedeterminedbytheresponsetoQuestion12intheeCRF(DMDATA:EDSSSYN.
EDSSRELP)suchthatiftheresponseis"Yes",theEDSSassessmentwillbeexcludedinsummarydisplays;allBaselineEDSSassessmentswillbeincludedinsummarytablesandfigures.
AllEDSSassessmentswillbelisted.
2014N204379_00CONFIDENTIALH3M11647767TheEDSSsummaryscoreandthefunctionalsystemscoreswillbelistedbytreatmentgroup(Listing8.
21).
Listing8.
22-Listing8.
31willlisttheresponsestoeachindividualquestionforeachfunctionalsystem.
12.
7.
2.
MSRelapsesDetailsofrelapsesoccurringduringthestudyandneurologicaldeficitswillbelistedbytreatmentgroupandsubject(Listing8.
32andListing8.
33).
TheEDSSsummaryscoreandtheFunctionalSystemScoresforallEDSSassessmentsmadeatthetimeofrelapsesandthechangeinEDSSscorefromthepreviousscheduledvisitandthefollowingscheduledvisitwillbelistedbytreatmentgroup(Listing8.
34).
Alistingofallsteroidsadministeredtosubjectsduringrelapseswillbeprovided(Listing8.
35).
Thenumberandpercentage(oftheITTpopulation)ofsubjectsexperiencingrelapseswillbesummarisedbytreatmentgroup(Table8.
54)duringthetreatmentphaseandduringtheFollow-upphaseseparatelyforallsubjectsandalsobybaselineEDSSgroup(0-2.
5,≥3;Table8.
55).
Includedinthesummarytablewillbetheproportionofrelapsesthatweretreatedwithmethylprednisoloneorothersteroid,thenumber(percentage)ofrelapsesthatrequiredhospitalisationandsummarystatisticsforthetimespentinhospital.
Asummarytableofthefrequencyofthenumberofsubjectswitheachneurologicaldeficitduringthetreatmentphasewillbepresented(Table8.
56).
Forasubjectwithmultiplerelapseswiththesamedeficitthemostextremestatuswillbepresent,i.
e.
thatsubjectwouldbeincludedinthe"Ongoing"rowratherthanthe"Resolved"row.
Forsubjectsthatrelapsedduringthestudy,historyofpreviouslyimpactedfunctionalsystemsduringrelapseswasalsocollectedintheeCRF.
Thisdatawillbelisted(Listing6.
15).
TherateofrelapsesduringtheTreatmentPhasewillbeanalysedusingmaximumlikelihoodbasedanalysis,assumingtheNegativeBinomialdistribution,withtimeontreatment,measuredindays,asanoffsetvariable.
ThemodelwillincludeadjustmentforBackgroundDiseaseModifyingTherapyandtreatmentgroup,whichwillbefittedasacategoricalvariable.
Theadjustedmeanrelapserateoverthetreatmentperiod,treatmentratioand90%confidenceintervalswillbepresented(Table8.
57).
TheproportionofsubjectsrelapsingduringtheTreatmentPhaseineachtreatmentgroupwillbecomparedusingalogisticregressionadjustedforBackgroundDiseaseModifyingTherapyandtreatmentgroup,whichwillbefittedasacategoricalvariable.
Theoddsratiowithassociated90%confidenceintervalwillbepresented(Table8.
58).
Thetimetofirstrelapse(basedontheearliestsymptomstartdateforasubject'sfirstrelapse)willbecomparedbetweentreatmentgroupsusingaCox'sProportionalHazardsmodeladjustingforBackgroundDiseaseModifyingTherapyandtreatmentgroup,whichwillbefittedasacategoricalvariable.
TieddatawillbehandledusingEfron'smethod[Efron,1977].
Thehazardratiowithassociated90%confidenceintervalwillbepresented(Table8.
59)alongwiththequartilesummarystatistics;wheretheyarenot-estimabletheywillbedenotedas"NA"forNotAvailable.
AKaplanMeierplotoftimetofirstrelapsewillalsobeprovided(Figure8.
08).
Timetofirstrelapsewillbe2014N204379_00CONFIDENTIALH3M11647768calculatedastherelapseonsetdateminusdatestudymedicationwasstartedplusoneday.
Forsubjectsthatdonotrelapse,theirtimetorelapsewillbecensoredatthedateofwithdrawalforsubjectsthatwithdrawfromthestudyduringtheTreatmentPhaseortheWeek48visitdateforsubjectsthatdidnotwithdrawprematurely.
12.
8.
OtherSafetyMeasures12.
8.
1.
VitalSignsThefollowingvitalsignsmeasurementswillbecollectedateachstudyassessment:systolicanddiastolicbloodpressure,heartrateandtemperature.
Heightwillbemeasuredatscreeningonly.
Vitalsignswillbelistedbysubject(Listing8.
36)andsummarisedbytreatmentgroup,treatmentphaseandscheduledassessment(Table8.
60).
Parameterswillbedisplayedintablesinthefollowingorder:SBP,DBP,Weight,HRandtemperature.
Inaddition,asummaryofchangefrombaselineatallscheduledpost-baselineassessmentsinvitalsignswillalsobeproduced(Table8.
61).
Thenumberandpercentageofsubjectsineachdosegroupwithvaluesofbloodpressure,andheartrateoutsidepre-determinedpotentiallyclinicallyimportantrangesandwithchangesfrombaselineofpotentialclinicalconcern(seeSection9.
4.
2fordetailsonabsolutevaluesandchangesfrombaselineofpotentialclinicalconcern)willbetabulatedateachscheduledassessmentandforthemaximumon-treatmentvalues(Table8.
62).
Allvitalsignsdataofpotentialclinicalconcernwillbelisted(Listing8.
37).
Changefrombaselineinvitalsignswillalsobedisplayedgraphically.
Boxplotswillbeproducedforeachparameterthatwilldisplaythedistributionofeachchangeinvitalsignateachscheduledassessmentuptotheendofthefollow-upperiodandthemaximumontreatmentchange(Figure8.
09).
12.
8.
2.
ECGAssessmentsECGsarecollectedandreadbyacentralECGreaderatScreening,andWeeks2,4,12,24,36and48.
AsummaryoftheclinicalinterpretationoftheECGaccordingtotheinvestigator,numberandpercentageofsubjectswhohadabnormaland/orclinicallysignificantECGfindingswillbepresentedbytreatmentgroup(Table8.
63).
AsummaryofECGparameters(HR,PR,RR,QRS,QT,QTcFandQTcB)andchangefrombaselineineachECGparameterwillalsobepresentedbytreatmentgroupandvisit;includingthemaximumon-treatmentvalue(Table8.
64andTable8.
65).
Inaddition,asummaryofthenumberofsubjectswithECGparametersofpotentialclinicalconcernandchangesofpotentialclinicalconcern(seeSection9.
4.
3)willalsobeprovidedbytreatmentgroupandvisit(Table8.
66andTable8.
67).
AlistingofECGvalueswillbepresentedbytreatmentgroupandsubject(Listing8.
39)andalistingofECGinterpretationaccordingtotheinvestigatorwillalsobepresentedbytreatmentgroupandsubject(Listing8.
38).
ThedistributionofchangefrombaselineandthemaximumontreatmentchangeinQTcBandQTcFbytimewillbedisplayedinFigure8.
10.
2014N204379_00CONFIDENTIALH3M1164776912.
8.
3.
ColumbiaSuicideSeverityRatingScale(C-SSRS)TheelectronicColumbia–SuicideSeverityRatingScale(eC-SSRS)isameasureofsuicidalideationandbehaviourcompletedbythesubjectasanautomatedtelephoneinterview.
ThefollowingoutcomesareeC-SSRScategoriesandhavebinaryresponses(yes/no).
Thecategorieshavebeenre-orderedfromtheactualscaleinanincreasingorderofseverityfrom1to9tofacilitatethedefinitionsofthecomparativeendpoints.
Category1–WishtobeDeadCategory2–Non-specificActiveSuicidalThoughtsCategory3–ActiveSuicidalIdeationwithAnyMethods(NotPlan)withoutIntenttoActCategory4–ActiveSuicidalIdeationwithSomeIntenttoAct,withoutSpecificPlanCategory5–ActiveSuicidalIdeationwithSpecificPlanandIntentCategory6–PreparatoryActsorBehaviourCategory7–AbortedAttemptCategory8–InterruptedAttemptCategory9–ActualAttempt(non-fatal)ThefollowingoutcomesarenumericalscoresderivedfromtheeC-SSRScategories.
Thescoresarecreatedateachassessmentforeachpatient.
SuicidalIdeationScore:Themaximumsuicidalideationcategory(1-5ontheeC-SSRS)presentattheassessmentforallassessmentsfollowingtheBaselineassessment(theassessmentatBaselineisalifetimescore).
Assignascoreof0ifnoideationispresent.
SuicidalBehaviourScore:Themaximumsuicidalbehaviourcategory(6-9ontheeC-SSRS)presentattheassessmentforallassessmentsfollowingtheBaselineassessment(theassessmentatBaselineisalifetimescore).
Assignascoreof0ifnobehaviourispresent.
SuicidalIdeationorBehaviourScore:Themaximumsuicidalideationorbehaviourcategory(1-9ontheeC-SSRS)presentattheassessmentforallassessmentsfollowingtheBaselineassessment(theassessmentatBaselineisalifetimescore).
Assignascoreof0ifnoideationorbehaviourispresent.
Asummarytableofthenumber(andpercentage)ofsubjectswithineachcategoryforSuicidalIdeation,SuicidalBehaviourandSuicidalIdeationorBehaviourScorewillbeprovided(Table8.
68)forcompletedeC-SSRSassessments.
AlleC-SSRSCategoriesdatawillbelistedforcompletedeC-SSRSassessments(Listing8.
40toListing8.
42).
AseparatelistingofincompleteeC-SSRSassessmentswillbeprovided(Listing8.
43).
IftheeC-SSRScouldnotbecompletedthenanInvestigatorledassessmentwastobeconducted,allInvestigatorledassessmentswillbelistedseparately(Listing8.
44).
2014N204379_00CONFIDENTIALH3M1164777013.
HEALTHOUTCOMESANALYSES13.
1.
MSQoL5413.
1.
1.
SummaryDisplaysAllMSQoL54datawillbelistedfortheRandomisedPopulation.
Listing9.
01willlistallresponsesandscoresforeachadministrationofMSQoL54.
Thelistingwillbesortedbytreatmentgroup,centre,subject,visitandsubscaleorderedasperTable9inSection9.
2.
10.
Listing9.
02willlisteachsubscalescoreorderedasperlisting9.
01.
Listing9.
03willlisttheCompositeScores.
Foreachlisting,a"*"willbeusedtodenotepost-baselineMSQoL54assessmentsthatwereconductedatleast14daysafterthelastdoseofstudymedicationwastaken.
Summarystatistics(n,mean,standarddeviation,median,minimumandmaximum)foreachMSQoL54subscalewillbeprovidedateachvisit,andforchangefrombaselineatWeek48inTable9.
01.
Afrequencycountofthenumbersubjectsrespondingineachcategoryforthetwosingle-itemswillbeprovided(Table9.
02).
SummarystatisticsfortheCompositeScoreswillbesummarisedateachvisitandforthechangefrombaselineinTable9.
03.
Inaddition,asummarytableofthenumberofsubjectsatWeek48thatshowedanimprovement(by≥10point,by<10-≥5point,<5-≥3pointand<3pointincreases),worsening(by≥10point,by<10-≥5point,<5-≥3pointand<3pointdecreases)orunchangedrelativetotheirbaselineassessmentforeachCompositeScorewillbeprovided(Table9.
04).
13.
1.
2.
StatisticalAnalysisThechangefrombaselineinMSQoL54CompositeScoresatWeek48willbeanalysedusingaparametricanalysisofcovariance(alinearmodelassumingnormalerrors)whichwillincludetermsforthebaselineMSQoL54CompositeScore(asappropriate),BackgroundDiseaseModifyingTherapyandtreatmentgroup(fittedasacategoricalvariable).
PairwisecomparisonswillbeconductedforGSK239512versusplacebo(Table9.
05andTable9.
06).
Thenormalityassumptionsunderpinningtheanalysiswillbeassessedbyinspectionofthefollowingplots:HistogramofmarginalstudentisedresidualsderivedfromtheMMRMmodelQ-QPlotsScatterplotofstudentisedresidualsagainstfittedvaluesScatterplotofstudentisedresidualsagainsteachofthemodelcovariatesNormalprobabilityplotwithsimulationenvelopeIftheresidualsindicatenon-normalityofthemodel,thevanElterenextensiontotheWilcoxonranksumtest,stratifyingforBackgroundDiseaseModifyingTherapymaybeperformedasanonparametricsensitivityanalysis.
2014N204379_00CONFIDENTIALH3M1164777114.
CLINICALPHARMACOLOGYDATAANALYSESPKanalysisandPK/PDexplorationanalysiswillbeconductedunderthemanagementofClinicalPharmacologyModelling&Simulation(CPMS).
Sincethisisasingledoselevelstudy,populationPKandpopulationPK/PDanalysesarenotplanned.
TheproposedPKtables,figuresandlistingsforPKandPK/PDareshowninSection16oftheRAP14.
1.
PharmacokineticAnalysesThereconciliationofthePKCaseReportForm(CRF)andSMS2000datawillbeperformedby,orunderthedirectauspicesofClinicalDataManagement(CDM),GlaxoSmithKline.
ThemergingofPKconcentrationdata,randomisationandCRFdatawillbeperformedby,orunderthedirectauspicesoftheBiostatisticsandProgrammingTeam(BPT),GlaxoSmithKline.
Pre-dosetroughconcentrationsofGSK239512willbesummarizeddescriptivelybyweek(i.
e.
4,8,24,36and48)andbydoselevel.
ConcentrationsofGSK239512atweek8willbesummarizeddescriptivelybynominalsamplingtime(i.
e.
pre-doseandat0.
5,2and6hourspost-dose)anddoselevel.
14.
2.
Pharmacokinetic/PharmacodynamicAnalysesTherelationshipbetweentheco-primarystudyendpointsandtheGSK239512troughconcentrationsduringthemaintenancestagewillbeexploredgraphically.
Inthepresenceofarelationship,aPK/PDmodelingapproachmaybeusedtoquantifytherelationship.
Forthosesubjectswhosedoseremainedconstantduringthemaintenance,thetroughconcentrationtobeusedPK/PDanalysiswillbetheaveragetroughconcentrationduringthemaintenancephase.
Foranysubjectwhosedosechangedduringthemaintenancephase,theGSK239512troughconcentrationswillbetheconcentrationoraveragetheconcentrationatthedoselevelthatthesubjectwasonatthetimethatthelesionoccurredandisdeemedtoreflecttheGSK239512doseduringtheremyelinationperiod.
2014N204379_00CONFIDENTIALH3M1164777215.
REFERENCESBarnardJ,RubinD.
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Biometrika.
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CarpenterJR,RogerJH,KenwardMG.
AnalysisofLongitudinalTrialswithProtocolDeviations:aFrameworkforRelevant,AccessibleAssumptions,andInferenceviaMultipleImputation.
JournalofBiopharmaceuticalStatistics(acceptedforpublication).
2013;23:6:1352-1371.
EfronB,TheefficiencyofCox'slikelihoodfunctionforcensoreddata.
JournaloftheAmericanStatisticalAssociation.
1977;72,557-565.
GlaxoSmithKlineClinicalProtocolDocumentNumberHM2012N133918_00;ProofofMechanismStudytoAssessthePotentialofGSK239512toRemyelinateLesionsinSubjectswithRelapsingRemittingMultipleSclerosisH3M116477.
EffectiveDate:26July2012VickreyBG,HaysRD,HarooniR,MyersLW,EllisonGW.
Ahealth-relatedqualityoflifemeasureformultiplesclerosis.
QualLifeRes.
1995;4(3):187-206.
2014N204379_00CONFIDENTIALH3M1164777316.
ATTACHMENTS16.
1.
TableofContentsforDataDisplaySpecificationsStudyPopulationTablesTableNo.
PopTableTitleTemplateReference6.
001RSummaryofSubjectsbyPopulationSA16.
002ITTSummaryofInclusion/ExclusionCriteriaDeviationsIE16.
003ITTSummaryofSubjectDispositionES16.
004ITTSummaryofSubjectVisitsSP16.
005NRSummaryofReasonsforScreeningFailuresSP26.
006ITTSummaryofProtocolDeviationsDV1B6.
007ITTSummaryofDemographicCharacteristicsDM16.
008ITTSummaryofRaceandRacialCombinationsDM56.
009ITTSummaryofRaceandRacialCombinationDetailsDM66.
010ITTSummaryofPastMedicalConditionsMH16.
011ITTSummaryofCurrentMedicalConditionsMH16.
012ITTSummaryofFamilyHistoryofCardiovascularRiskFactorsSP36.
013ITTSummaryofMSMedicalHistoryatScreeningNS_P026.
014ITTSummaryofSmokingHistorySU16.
015ITTSummaryofPriorMSDiseaseModifyingTherapiesCM16.
016ITTSummaryofPriorMedicationsCM16.
017ITTSummaryofConcomitantMedications(excludingrequiredMSDiseaseModifyingTherapy)takenduringtheTitrationPeriodCM16.
018ITTSummaryofConcomitantMedications(excludingrequiredMSDiseaseModifyingTherapy)takenduringtheMaintenancePeriodCM16.
019ITTSummaryofConcomitantMedications(excludingrequiredMSDiseaseModifyingTherapy)takenduringtheTreatmentPhaseCM16.
020ITTSummaryofMedicationsInitiatedduringtheFollow-UpPeriodCM16.
021ITTSummaryofProhibitedMedicationstakenduringtheTreatmentPhaseCM16.
022ITTSummaryofExposureSAT012014N204379_00CONFIDENTIALH3M11647774TableNo.
PopTableTitleTemplateReference6.
023ITTSummaryofTreatmentComplianceNS_COMP16.
024ITTSummaryofDoseTitrationSP36.
025ITTSummaryofTreatmentComplianceduringtheTitrationPeriodNS_COMP16.
026ITTSummaryofTreatmentComplianceduringtheMaintenancePeriodNS_COMP16.
027ITTSummaryofMSMedicalHistoryatScreeningforSubjectswithanMRIinthe12MonthsPriortoScreeningSeeiSRC.
StudyPopulationListingsListingNoPopListingTitleTemplateReference6.
001RListingofSubjectsExcludedfromPopulationsSA3a6.
002RListingofInclusion/ExclusionCriteriaDeviationsIE36.
003RListingofChildBearingPotentialatScreening(FemaleSubjectsonly)SP086.
004RListingofSubjectWithdrawalsES26.
005RListingofSubjectVisitsNS_P076.
006RListingofProtocolDeviationsDV26.
007RListingofSubjectsforWhomtheTreatmentBlindwasBrokenBL16.
008RListingofSubjectsRandomisedtotheIncorrectStrataBL16.
009RListingofDemographicCharacteristicsDM26.
010RListingofRaceDM96.
011RListingofMedicalHistoryMH26.
012RListingofFamilyHistoryofCardiovascularRiskFactorsSP46.
013RListingofMSMedicalHistoryatScreening.
SP076.
014RListingofMSMedicalHistoryatScreening:SummaryofMrainMRIScansinPrevious12MonthsSP07a6.
015RListingofPreviouslyImpactedFunctionalSystemsduringRelapsesforSubjectsRelapsingintheStudySP56.
016RListingofSmokingHistorySU26.
017RListingofPriorMSDiseaseModifyingTherapiesCM36.
018RListingofPrior/ConcomitantMedicationsCM32014N204379_00CONFIDENTIALH3M11647775ListingNoPopListingTitleTemplateReference6.
019RRelationshipbetweenATCLevel1,IngredientandVerbatimTextCM66.
020RListingofProhibitedMedicationstakenduringtheTreatmentPhaseCM36.
021RListingofSubjectsReceivingInvestigationalProductTA16.
022RListingofExposureDataEX36.
023RListingofStudyMedicationDispensedandTabletsReturnedEX36.
024RListingofComplianceDataSPL136.
025RListingofSubjectsReceivingIncorrectStudyMedicationSPL15StudyPopulationFiguresFigureNoPopListingTitleTemplateReference6.
001ITTSummaryofDurationofExposuretoStudyMedicationSAF01EfficacyTablesTableNo.
PopTableTitleTemplateReferenceMTRSummaryDisplays7.
001ITTFrequencyCountofNumberofGadolinium-EnhancingLesionswithMTR-AssessmentsatEachMRIAssessmentNS_TE067.
002ITTFrequencyCountofNumberofdelta-MTRLesionswithMTR-AssessmentsatEachMRIAssessmentNS_TE067.
003ITTSummaryStatisticsofMTRValuesforGadolinium-EnhancingLesionsbyRelativeMRIScanNS_TE077.
004ITTSummaryStatisticsofMTRValuesfordelta-MTRLesionsbyRelativeMRIScanNS_TE077.
005ITTSummaryStatisticsofChangeinMTRValuesfromReferenceMRIScanMTRValueforGadolinium-EnhancingLesionsbyRelativeMRIScanNS_TE077.
006ITTSummaryStatisticsofChangeinMTRValuesfromReferenceMRIScanMTRValueforfordelta-MTRLesionsbyRelativeMRIScanNS_TE072014N204379_00CONFIDENTIALH3M11647776TableNo.
PopTableTitleTemplateReferenceMTRANCOVAAnalyses7.
007ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
008ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
009ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
010ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
011ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
012ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsNS_TE017.
013ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE017.
014ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE017.
015ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
016ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
017ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceforLesionswithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
018ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost22014N204379_00CONFIDENTIALH3M11647777TableNo.
PopTableTitleTemplateReference7.
019ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
020ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsNS_TE017.
021ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE017.
022ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE017.
023ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
024ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
025ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
026ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
027ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
028ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectNS_TE017.
029ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE012014N204379_00CONFIDENTIALH3M11647778TableNo.
PopTableTitleTemplateReference7.
030ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE017.
031ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
032ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
033ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceforLesionswithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
034ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
035ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
036ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectNS_TE017.
037ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE017.
038ITTSummaryoftheStatisticalAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE01MTRMMRMAnalyses7.
039ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
040ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost22014N204379_00CONFIDENTIALH3M11647779TableNo.
PopTableTitleTemplateReference7.
041ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
042ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
043ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
044ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsNS_TE017.
045ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE017.
046ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE017.
047ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
048ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
049ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceforLesionswithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
050ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
051ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE012014N204379_00CONFIDENTIALH3M11647780TableNo.
PopTableTitleTemplateReference7.
052ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsNS_TE017.
053ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE017.
054ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE017.
055ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
056ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
057ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
058ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
059ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
060ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectNS_TE017.
061ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE012014N204379_00CONFIDENTIALH3M11647781TableNo.
PopTableTitleTemplateReference7.
062ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE017.
063ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceNS_TE017.
064ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceand90%CredibleIntervalsPost27.
065ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrenceforLesionswithatLeast2MRIAssessmentsPre-andPost-LesionNS_TE017.
066ITTPosteriorProbabilitybasedontheRepeatedMeasuresAnalysisofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-Lesionand90%CredibleIntervalsPost27.
067ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysPriortoLesionOccurrenceand70DaysPostLesionOccurrenceNS_TE017.
068ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectNS_TE017.
069ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin28DaysofLesionOccurrenceNS_TE017.
070ITTSummaryoftheRepeatedMeasuresAnalysisoftheChangeinMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsaveragedforeachSubjectExcludingMRIScansWithin70DaysPriortoLesionOccurrenceand28DaysPostLesionOccurrenceNS_TE01ConventionalMRI7.
071ITTSummaryStatisticsoftheActualNumberofNewGadoliniumEnhancingLesions(OCDataset)NS_TE042014N204379_00CONFIDENTIALH3M11647782TableNo.
PopTableTitleTemplateReference7.
072ITTFrequencyTableoftheActualNumberofNewGadolinium-EnhancingLesions(OCDataset)NS_TE057.
073ITTSummaryStatisticsoftheCumulativeNumberofNewGadoliniumEnhancingLesions(AESDataset)NS_TE047.
074ITTFrequencyTableoftheCumulativeNumberofNewGadolinium-EnhancingLesions(OCDataset)NS_TE057.
075ITTSummaryStatisticsoftheActualNumberofNewEnlargingT2Lesions(OCDataset)NS_TE047.
076ITTFrequencyTableoftheActualNumberofNewEnlargingT2Lesions(OCDataset)NS_TE057.
077ITTSummaryStatisticsoftheCumulativeNumberofNewEnlargingT2Lesions(AESDataset)NS_TE047.
078ITTFrequencyTableoftheCumulativeNumberofNewEnlargingT2Lesions(OCDataset)NS_TE057.
079ITTSummaryStatisticsoftheActualNumberofCumulativeUniqueActiveLesions(OCDataset)NS_TE047.
080ITTFrequencyTableoftheActualNumberofCumulativeUniqueActiveLesions(OCDataset)NS_TE057.
081ITTSummaryStatisticsoftheCumulativeNumberofCumulativeUniqueActiveLesions(AESDataset)NS_TE047.
082ITTFrequencyTableoftheCumulativeNumberofCumulativeUniqueActiveLesions(OCDataset)NS_TE057.
083ITTSummaryStatisticsoftheActualNumberofNewUnenhancingT1Lesions(OCDataset)NS_TE047.
084ITTFrequencyTableoftheActualNumberofNewUnenhancingT1Lesions(OCDataset)NS_TE057.
085ITTSummaryStatisticsoftheCumulativeNumberofNewUnenhancingT1Lesions(AESDataset)NS_TE047.
086ITTFrequencyTableoftheCumulativeNumberofNewUnenhancingT1Lesions(OCDataset)NS_TE057.
087ITTSummaryStatisticsoftheActualNumberofNewGadoliniumEnhancingLesionsEvolvingintoBlackHolesbyWeek48(OCDataset)NS_TE047.
088ITTFrequencyTableoftheActualNumberofNewGadolinium-EnhancingLesionsEvolvingintoBlackHolesbyWeek48(OCDataset)NS_TE052014N204379_00CONFIDENTIALH3M11647783TableNo.
PopTableTitleTemplateReference7.
089ITTSummaryStatisticsoftheCumulativeNumberofNewGadoliniumEnhancingLesionsEvolvingintoBlackHolesbyWeek48(AESDataset)NS_TE047.
090ITTFrequencyTableoftheCumulativeNumberofNewGadolinium-EnhancingLesionsEvolvingintoBlackHolesbyWeek48(OCDataset)NS_TE057.
091ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofNewGadolinium-EnhancingLesionsatWeek48(AESDataset)NS_TE017.
092ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofNewGadolinium-EnhancingLesionsatWeek48usingMultipleImputationMethods(OCDataset)NS_TE01a7.
093ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofNewEnlargingT2LesionsatWeek48(AESDataset)NS_TE017.
094ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofNewEnlargingT2LesionsatWeek48usingMultipleImputationMethods(AESDataset)NS_TE01a7.
095ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofCumulativeUniqueActiveLesionsatWeek48(AESDataset)NS_TE017.
096ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofCumulativeUniqueActiveLesionsatWeek48usingMultipleImputationMethods(AESDataset)NS_TE01a7.
097ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofUnenhancingT1LesionsatWeek48(AESDataset)NS_TE017.
098ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofUnenhancingT1LesionsatWeek48usingMultipleImputationMethods(AESDataset)NS_TE01a7.
099ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofNewGadolinium-EnhancingLesionsEvolvingintoBlackHolesatWeek48(AESDataset)NS_TE017.
100ITTSummaryoftheStatisticalAnalysisoftheCumulativeNumberofNewGadolinium-EnhancingLesionsEvolvingintoBlackHolesatWeek48usingMultipleImputationMethods(AESDataset)NS_TE01aConventionalMRIVolumes7.
101ITTSummaryStatisticsofNormalisedBrainVolume(OCDataset)NS_TE047.
102ITTSummaryStatisticsofWholeBrainAtrophyVolumeChangefromScreening(AESDataset)NS_TE047.
103ITTSummaryStatisticsofWhiteMatterVolumeateachMRI(OCDataset)NS_TE042014N204379_00CONFIDENTIALH3M11647784TableNo.
PopTableTitleTemplateReference7.
104ITTSummaryStatisticsofChangefromScreeninginWhiteMatterVolumeateachMRI(AESDataset)NS_TE047.
105ITTSummaryStatisticsofGreyMatterVolumeateachMRI(OCDataset)NS_TE047.
106ITTSummaryStatisticsofChangefromScreeninginGreyMatterVolumeateachMRI(AESDataset)NS_TE047.
107ITTSummaryoftheAnalysisofCovarianceoftheWholeBrainAtrophyVolumeChangefromScreeningatWeek48(AESDataset)NS_TE017.
108ITTSummaryoftheAnalysisofCovarianceofWhiteMatterVolumeChangefromScreeningatWeek48(AESDataset)NS_TE017.
109ITTSummaryoftheAnalysisofCovarianceofGreyMatterVolumeChangefromScreeningatWeek48(AESDataset)NS_TE017.
110ITTSummaryofRepeatedMeasuresAnalysisoftheChangefromScreeninginWhiteMatterVolumeateachMRI(AESDataset)NS_TE017.
111ITTSummaryofRepeatedMeasuresAnalysisoftheChangefromScreeninginGreyMatterVolumeateachMRI(AESDataset)NS_TE01CogState7.
112ITTSummaryofCogStateBatteryTaskPrimaryMeasureBaselineRawScoresRelativetoaNormalPopulationNS_CG017.
113ITTFrequencyCountofCogStateBatteryTasksateachAssessmentMeetingCompletionorIntegrityFailureCriterionNS_CG027.
114ITTSummaryofCogStateBatteryTaskPrimaryMeasureRawScoresbyVisitEFT017.
115ITTSummaryofCogStateBatteryTaskPrimaryMeasureStandardisedScoresbyVisitEFT017.
116ITTSummaryofCogStateBatteryTotalScorebyVisitEFT017.
117ITTSummaryofCogStateBatteryExecutiveFunctionCompositeScorebyVisitEFT017.
118ITTSummaryofCogStateBatteryMemoryCompositeScorebyVisitEFT017.
119ITTSummaryofCogStateBatteryAttentionCompositeScorebyVisitEFT017.
120ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryTotalScoreCG27.
121ITTPosteriorProbabilityforChangefromBaselineinCogStateBatteryTotalScoreand90%CredibleIntervalsatWeek48Post22014N204379_00CONFIDENTIALH3M11647785TableNo.
PopTableTitleTemplateReference7.
122ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryTotalScorebyBackgroundDiseaseModifyingTherapyStratumCG27.
123ITTSummaryofAnalysisofCovarianceofCogStateBatteryTotalScoreatWeek48CG27.
124ITTSummaryofAnalysisofCovarianceofCogStateBatteryTotalScoreatWeek48(MultipleImputedDataset–MAR,CDCandDeltaapproaches)CG2a7.
125ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryExecutiveFunctionCompositeScoreCG27.
126ITTPosteriorProbabilityforChangefromBaselineinCogStateBatteryExecutiveFunctionCompositeScoreand90%CredibleIntervalsatWeek48Post27.
127ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryExecutiveFunctionCompositeScorebyBackgroundDiseaseModifyingTherapyStratumCG27.
128ITTSummaryofAnalysisofCovarianceofCogStateBatteryExecutiveFunctionCompositeScoreatWeek48CG27.
129ITTSummaryofAnalysisofCovarianceofCogStateBatteryExecutiveFunctionCompositeScoreatWeek48(MultipleImputedDataset–MAR,CDCandDeltaapproaches)CG2a7.
130ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryMemoryCompositeScoreCG27.
131ITTPosteriorProbabilityforChangefromBaselineinCogStateBatteryMemoryCompositeScoreand90%CredibleIntervalsatWeek48Post27.
132ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryMemoryCompositeScorebyBackgroundDiseaseModifyingTherapyStratumCG27.
133ITTSummaryofAnalysisofCovarianceofCogStateBatteryMemoryCompositeScoreatWeek48CG27.
134ITTSummaryofAnalysisofCovarianceofCogStateBatteryMemoryCompositeScoreatWeek48(MultipleImputedDataset–MAR,CDCandDeltaapproaches)CG2a7.
135ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryAttentionCompositeScoreCG27.
136ITTPosteriorProbabilityforChangefromBaselineinCogStateBatteryAttentionCompositeScoreand90%CredibleIntervalsatWeek48Post27.
137ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryAttentionCompositeScorebyBackgroundDiseaseModifyingTherapyStratumCG22014N204379_00CONFIDENTIALH3M11647786TableNo.
PopTableTitleTemplateReference7.
138ITTSummaryofAnalysisofCovarianceofCogStateBatteryAttentionCompositeScoreatWeek48CG27.
139ITTSummaryofAnalysisofCovarianceofCogStateBatteryMemoryCompositeScoreatWeek48(MultipleImputedDataset–MAR,CDCandDeltaapproaches)CG2a7.
140ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryGrotonMazeLearningTestStandardisedTestScoreCG27.
141ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryOneBackTestStandardisedTestScoreCG27.
142ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryInternationalShoppingList-ImmediateRecallTaskStandardisedTestScoreCG27.
143ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryInternationalShoppingList-DelayedRecallTaskStandardisedTestScoreCG27.
144ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryOneCardLearningTaskStandardisedTestScoreCG27.
145ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryDetectionTaskStandardisedTestScoreCG27.
146ITTSummaryofRepeatedMeasuresAnalysisofChangefromBaselineinCogStateBatteryIdentificationTaskStandardisedTestScoreCG2T2LesionMTR7.
147ITTSummaryStatisticsofT2LesionMTRValuesbyVisitNS_TE077.
148ITTSummaryStatisticsofChangefromScreeninginT2LesionMTRValuesbyVisitNS_TE077.
149ITTSummaryofRepeatedMeasuresAnalysisofChangefromScreeninginT2LesionMTRValuesCG27.
150ITTPosteriorProbabilityforChangefromScreeninginT2LesionMTRValuesand90%CredibleIntervalsatWeek48Post2EfficacyListingsListingNoPopListingTitleTemplateReference7.
001RListingofMTRValueDataEL17.
002RListingofDerivedLesionLevelMTRValueDataEL22014N204379_00CONFIDENTIALH3M11647787ListingNoPopListingTitleTemplateReference7.
003RListingofDerivedSubjectLevelMTRValueDataEL27.
004RListingofSubjectswithnoLesionsforMTRAnalysesEL37.
005RListingofNumberofNewGadoliniumEnhancingLesionsNS_LE027.
006RListingofNumberofNewEnlargingT2LesionsNS_LE027.
007RListingofNumberofCumulativeUniqueActiveLesionsNS_LE027.
008RListingofNumberofNewUnenhancingT1LesionsNS_LE027.
009RListingofNumberofGadolinium-EnhancingLesionsEvolvingtoBlackHolesatWeek48NS_LE027.
010RListingofNormalisedBrainVolumeandChangefromScreeninginAtrophyatWeek48NS_LE037.
011RListingofWhiteMatterVolumeNS_LE037.
012RListingofGreyMatterVolumeNS_LE037.
013RListingofCogStateBatteryTaskData7.
014RListingofCogStateBatteryStandardisedTaskScores7.
015RListingofCogStateBattery7.
016RListingofT2LesionMTRDataEL1EfficacyFiguresFigureNoPopListingTitleTemplateReferenceMTR7.
001ITTRawMeanMTRValueand90%ConfidenceIntervalforGadolinium-EnhancingLesionsbyRelativeMRIScanFE01a7.
002ITTRawMeanMTRValueand90%ConfidenceIntervalfordelta-MTRLesionsbyRelativeMRIScanFE01a7.
003ITTRawMeanChangefromReferenceMRIMTRValueand90%ConfidenceIntervalforGadolinium-EnhancingLesionsbyRelativeMRIScanFE01a7.
004ITTRawMeanChangefromReferenceMRIMTRValueand90%ConfidenceIntervalfordelta-MTRLesionsbyRelativeMRIScanFE01a7.
005ITTProfilePlotofallGadolinium-EnhancingLesionswithMTRMeasurementsbySubjectNone2014N204379_00CONFIDENTIALH3M11647788FigureNoPopListingTitleTemplateReference7.
057ITTProfilePlotofalldelta-MTRLesionswithMTRMeasurementsbySubjectNone7.
006ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforgadolinium-enhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceBasedonANCOVAStatisticalAnalysisFig17.
007ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforgadolinium-enhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionBasedonANCOVAStatisticalAnalysisFig17.
008ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceBasedonANCOVAStatisticalAnalysisFig17.
009ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionBasedonANCOVAStatisticalAnalysisFig17.
010ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforgadolinium-enhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectBasedonANCOVAStatisticalAnalysisFig17.
011ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforgadolinium-enhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectwithatLeast2MRIAssessmentsPre-andPost-LesionBasedonANCOVAStatisticalAnalysisFig17.
012ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectBasedonANCOVAStatisticalAnalysisFig17.
013ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectwithatLeast2MRIAssessmentsPre-andPost-LesionBasedonANCOVAStatisticalAnalysisFig17.
014ITTAdjustedMeanChangeinMTRValueateachRelativeMRIforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencefromMixed-ModelRepeatedMeasuresAnalysis2014N204379_00CONFIDENTIALH3M11647789FigureNoPopListingTitleTemplateReference7.
015ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceBasedonMMRMAnalysisFig17.
016ITTAdjustedMeanChangeinMTRValueateachRelativeMRIforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionfromMixed-ModelRepeatedMeasuresAnalysis7.
017ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionBasedonMMRMAnalysisFig17.
018ITTAdjustedMeanChangeinMTRValueateachRelativeMRIfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrencefromMixed-ModelRepeatedMeasuresAnalysis7.
019ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceBasedonMMRMAnalysisFig17.
020ITTAdjustedMeanChangeinMTRValueateachRelativeMRIfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionfromMixed-ModelRepeatedMeasuresAnalysis7.
021ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionBasedonMMRMAnalysisFig17.
022ITTAdjustedMeanChangeinMTRValueateachRelativeMRIforGadolinium-EnhancingLesionsAveraginglesionsforaSubjectExcludingMRIScansWithin70DaysofLesionOccurrencefromMixed-ModelRepeatedMeasuresAnalysis7.
023ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectBasedonMMRMAnalysisFig17.
024ITTAdjustedMeanChangeinMTRValueateachRelativeMRIforGadolinium-EnhancingLesionsAveraginglesionsforaSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionfromMixed-ModelRepeatedMeasuresAnalysis2014N204379_00CONFIDENTIALH3M11647790FigureNoPopListingTitleTemplateReference7.
025ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionforGadolinium-EnhancingLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectwithatLeast2MRIAssessmentsPre-andPost-LesionBasedonMMRMAnalysisFig17.
026ITTAdjustedMeanChangeinMTRValueateachRelativeMRIfordelta-MTRLesionsAveraginglesionsforaSubjectExcludingMRIScansWithin70DaysofLesionOccurrencefromMixed-ModelRepeatedMeasuresAnalysis7.
027ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectBasedonMMRMAnalysisFig17.
028ITTAdjustedMeanChangeinMTRValueateachRelativeMRIfordelta-MTRLesionsAveraginglesionsforaSubjectExcludingMRIScansWithin70DaysofLesionOccurrencewithatLeast2MRIAssessmentsPre-andPost-LesionfromMixed-ModelRepeatedMeasuresAnalysis7.
029ITTPosteriorProbabilityofMTRValuePostLesionrelativetoPreLesionfordelta-MTRLesionsExcludingMRIScansWithin70DaysofLesionOccurrenceaveragedforeachSubjectwithatLeast2MRIAssessmentsPre-andPost-LesionBasedonMMRMAnalysisFig1ConventionalMRILesions7.
030ITTRawMeanNumberofCumulativeNumberofNewGadoliniumEnhancingLesions(AES)FE017.
031ITTRawMeanNumberofCumulativeNumberofNewEnlargingT2Lesions(AES)FE017.
032ITTRawMeanNumberofCumulativeNumberofUniqueActiveLesions(AES)FE017.
033ITTRawMeanNumberofCumulativeNumberofNewUnenhancingT1Lesions(AES)FE017.
034ITTRawMeanNumberofCumulativeNumberofNewGadoliniumEnhancingLesionsEvolvingintoBlackHolesatWeek48(AES)FE01ConventionalMRIVolumes7.
035ITTRawMeanChangefromScreeninginWhiteMatterVolumeateachMRI(AES)FE017.
036ITTRawMeanChangefromScreeninginGreyMatterVolumeateachMRI(AES)FE012014N204379_00CONFIDENTIALH3M11647791FigureNoPopListingTitleTemplateReference7.
037ITTAdjustedMeanChangefromScreeninginWhiteMatterVolumeateachMRIfromMixed-ModelRepeatedMeasuresAnalysis(AESDataset)7.
038ITTAdjustedMeanChangefromScreeninginWhiteMatterVolumeateachMRIfromMixed-ModelRepeatedMeasuresAnalysis(AESDataset)CogState7.
039ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryTotalScorebyVisit(MMRMResults)Fig27.
040ITTPosteriorProbabilityofChangefromBaselineinCogstateBatteryTotalScoreatWeek48Fig17.
041ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryExecutiveFunctionCompositeScorebyVisit(MMRMResults)Fig27.
042ITTPosteriorProbabilityofChangefromBaselineinCogstateBatteryExecutiveFunctionCompositeScoreatWeek48Fig17.
043ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryMemoryCompositeScorebyVisit(MMRMResults)Fig27.
044ITTPosteriorProbabilityofChangefromBaselineinCogstateBatteryMemoryCompositeScoreatWeek48Fig17.
045ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryAttentionCompositeScorebyVisit(MMRMResults)Fig27.
046ITTPosteriorProbabilityofChangefromBaselineinCogstateBatteryAttentionCompositeScoreatWeek48Fig17.
047ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryGrotonMazeLearningTestStandardisedScoresbyVisit(MMRMResults)Fig27.
048ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryOneBackTestStandardisedScoresbyVisit(MMRMResults)Fig27.
049ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryInternationalShoppingListTask–ImmediateRecallTaskStandardisedScoresbyVisit(MMRMResults)Fig27.
050ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryInternationalShoppingListTask–DelayedRecallTaskStandardisedScoresbyVisit(MMRMResults)Fig27.
051ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryOneCardLearningTaskStandardisedScoresbyVisit(MMRMResults)Fig22014N204379_00CONFIDENTIALH3M11647792FigureNoPopListingTitleTemplateReference7.
052ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryDetectionTaskStandardisedScoresbyVisit(MMRMResults)Fig27.
053ITTAdjustedMeanChangefromBaseline(90%CI)inCogStateBatteryIdentificationTaskStandardisedScoresbyVisit(MMRMResults)Fig2T2LesionMTR7.
054ITTRawMeanChangefromScreeninginT2LesionMTRValueateachMRI7.
055ITTAdjustedMeanChangefromBaseline(90%CI)inT2LesionMTRValuebyVisit(MMRMResults)Fig27.
056ITTPosteriorProbabilityofChangefromBaselineT2LesionMTRValueatWeek48Fig1SafetyTablesTableNo.
PopTableTitleTemplateReferenceAdverseEvents8.
001ITTSummaryofAllAdverseEventsbyStudyPhaseAE18.
002ITTSummaryofDrug-relatedAdverseEventsbyStudyPhaseAE18.
003ITTSummaryofAdverseEventsbyMaximumIntensityandStudyPhaseAE58.
004ITTSummaryofAdverseEventsconsideredtobeDrug-RelatedbyMaximumIntensityandStudyPhaseAE58.
005ITTSummaryofCommonAdverseEventsOccurringin≥5%ofSubjectsinEitherTreatmentGroup.
AE18.
006ITTSummaryof(Investigatorassessed)studymedicationrelatedCommonAdverseEventsOccurringin≥5%ofSubjectsinEitherTreatmentGroup.
AE18.
007ITTSummaryofCharacteristicsofAdverseEventsbyStudyPhaseESI18.
008ITTSummaryofAdverseEventsbyTimeofFirstOccurrenceAE68.
009ITTSummaryofAllAdverseEventsOccurringintheTitrationPeriodbyGSK239512DoseAE18.
010ITTSummaryofDrug-relatedAdverseEventsOccurringintheTitrationPeriodbyGSK239512DoseAE12014N204379_00CONFIDENTIALH3M11647793TableNo.
PopTableTitleTemplateReference8.
011ITTSummaryofAdverseEventsconsideredtobeDrug-RelatedOccurringintheTitrationPeriodbyMaximumIntensityGSK239512DoseAE58.
012ITTSummaryofCommonAdverseEventsOccurringin≥5%ofSubjectsOccurringintheTitrationPeriodbyGSK239512DoseAE18.
013ITTSummaryofAdverseEventsofSpecialInterestRelatedtoConvulsionsbyStudyPhaseAE18.
014ITTSummaryofAdverseEventsofSpecialInterestRelatedtoPerceptualAbnormalitiesbyStudyPhaseAE18.
015ITTSummaryofAdverseEventsofSpecialInterestRelatedtoInsomnia/SleepDisordersbyStudyPhaseAE18.
016ITTSummaryofAdverseEventsofSpecialInterestRelatedtoAbnormalDreams/NightmaresbyStudyPhaseAE18.
017ITTSummaryofAdverseEventsofSpecialInterestRelatedtoMoodSymptomsbyStudyPhaseAE18.
018ITTSummaryofAdverseEventsofSpecialInterestRelatedtoFeedingandBodyWeightChangebyStudyPhaseAE18.
019ITTSummaryofCharacteristicsofAdverseEventsofSpecialInterestRelatedtoConvulsionsbyStudyPhaseESI18.
020ITTSummaryofCharacteristicsofAdverseEventsofSpecialInterestRelatedtoPerceptualAbnormalitiesbyStudyPhaseESI18.
021ITTSummaryofCharacteristicsofAdverseEventsofSpecialInterestRelatedtoInsomnia/SleepDisordersbyStudyPhaseESI18.
022ITTSummaryofCharacteristicsofAdverseEventsofSpecialInterestRelatedtoAbnormalDreams/NightmaresbyStudyPhaseESI18.
023ITTSummaryofCharacteristicsofAdverseEventsofSpecialInterestRelatedtoMoodSymptomsbyStudyPhaseESI18.
024ITTSummaryofCharacteristicsofAdverseEventsofSpecialInterestRelatedtoFeedingandBodyWeightChangebyStudyPhaseESI18.
025ITTSummaryofAdverseEvents(AEs)codingtoMedDRAHLGT"Sleepdisordersanddisturbances"byStudyPhaseAE18.
026ITTSummaryofAEscodingtoMedDRAHLGT"Depressedmooddisordersanddisturbances"byStudyPhaseAE18.
027ITTSummaryofAEscodingtoMedDRAHLGT"Suicidalandself-injuriousbehavioursNEC"byStudyPhaseAE18.
028ITTSummaryofInvestigator-ReportedSeriousAdverseEventsbyStudyPhaseAE12014N204379_00CONFIDENTIALH3M11647794TableNo.
PopTableTitleTemplateReference8.
029ITTSummaryofAdverseEventsLeadingtoPermanentDiscontinuationofStudyDrugand/orWithdrawalfromStudybyStudyPhaseAE1LaboratoryData8.
030ITTSummaryofHaematologyLaboratoryValuesLB18.
031ITTSummaryofChemistryLaboratoryValuesLB18.
032ITTSummaryofChangefromBaselineinHaematologyLaboratoryValuesLB18.
033ITTSummaryofChangefromBaselineinChemistryLaboratoryValuesLB18.
034ITTSummaryofHaematologyLaboratoryValuesoutsidetheNormalRange(F1flag)LB28.
035ITTSummaryofChemistryLaboratoryValuesoutsidetheNormalRange(F1flag)LB28.
036ITTSummaryofHaematologyLaboratoryValuesoutsidetheClinicalConcernRange(F3flag)LB28.
037ITTSummaryofChemistryLaboratoryValuesoutsidetheClinicalConcernRange(F3flag)LB28.
038ITTSummaryofChangesinHaematologyLaboratoryValuesfromBaselinewithrespecttotheNormalRages(F1Flag)LB48.
039ITTSummaryofChangesinChemistryLaboratoryValuesfromBaselinewithrespecttotheNormalRages(F1Flag)LB48.
040ITTSummaryofChangesinHaematologyLaboratoryValues(usingClinicalConcernRanges)LB48.
041ITTSummaryofChangesinChemistryLaboratoryValues(usingClinicalConcernRanges)LB48.
042ITTSummaryofGradedLFTValuesLV01MSSpecificSafetyEndpoints8.
043ITTSummaryofExpandedDisabilityStatusScale(EDSS)TotalScoreNS_SAF018.
044ITTSummaryofExpandedDisabilityStatus(EDSS):VisualModifiedScoreNS_SAF018.
045ITTSummaryofExpandedDisabilityStatus(EDSS):BrainstemFunctionalSystemScoreNS_SAF018.
046ITTSummaryofExpandedDisabilityStatus(EDSS):PyramidalFunctionSystemScoreNS_SAF018.
047ITTSummaryofExpandedDisabilityStatus(EDSS):CerebellarFunctionalSystemScoreNS_SAF012014N204379_00CONFIDENTIALH3M11647795TableNo.
PopTableTitleTemplateReference8.
048ITTSummaryofExpandedDisabilityStatus(EDSS):SensoryFunctionalSystemScoreNS_SAF018.
049ITTSummaryofExpandedDisabilityStatus(EDSS):Bladder/BowelModifiedFunctionalSystemScoreNS_SAF018.
050ITTSummaryofExpandedDisabilityStatus(EDSS):CerebralFunctionalSystemScoreNS_SAF018.
051ITTSummaryofExpandedDisabilityStatus(EDSS):AmbulatoryScoreNS_SAF018.
052ITTSummaryofChangefromBaselineinExpandedDisabilityStatusScale(EDSS)NS_SAF048.
053ITTSummaryofSustainedChangesinFunctionalSystemScoresatWeek48NS_SAF028.
054ITTSummaryofRelapsesNS_SAF038.
055ITTSummaryofRelapsesbyBaselineEDSSScoreandStudyPhaseNS_SAF038.
056ITTSummaryofNeurologicalDeficitsNS_SAF058.
057ITTSummaryofStatisticalAnalysisoftheRelapseRateduringtheTreatmentPhaseNS_TE028.
058ITTSummaryofStatisticalAnalysisoftheProportionofSubjectsRelapsingduringtheTreatmentPhaseNS_SAF068.
059ITTSummaryofStatisticalAnalysisoftheTimetoFirstRelapseduringtheTreatmentPhaseNS_SAF07OtherSafetyEndpoints8.
060ITTSummaryofVitalSignsVS18.
061ITTSummaryofChangefromBaselineinVitalSignsVS18.
062ITTSummaryofVitalSignswithrespecttotheReferenceRangeandChangefromBaselineCriteriaVS28.
063ITTSummaryofECGFindingsEG18.
064ITTSummaryofECGValuesEG28.
065ITTSummaryofChangefromBaselineinECGValuesEG28.
066ITTSummaryofECGValuesofPotentialClinicalConcernLB28.
067ITTSummaryofChangefromBaselineinECGValuesofPotentialClinicalConcernLB28.
068ITTSummaryoftheNumberofSubjectswithineachCategoryoftheColumbiaSuicideSeverityRatingScale.
ECSSR12014N204379_00CONFIDENTIALH3M11647796SafetyListingsListingNoPopListingTitleTemplateReference8.
001RListingofAllAdverseEventsAE88.
002RRelationshipofAdverseEventsSystemOrganClasses,HigherLevelGroupTerms,PreferredtermsandVerbatimTextAE28.
003RListingofSubjectNumbersforIndividualOn-TreatmentAdverseEventsAE78.
004RListingofAdverseEventsofSpecialInterestAE88.
005RListingofHLGTAdverseEventsofSpecialInterestAE88.
006RListingofPossibleSuicidality-RelatedAdverseEvents(Section1-Section2)PSRAE18.
007RListingofPossibleSuicidality-RelatedAdverseEvents(Section3)PSRAE28.
008RListingofPossibleSuicidality-RelatedAdverseEvents(Section4)PSRAE38.
009RListingofPossibleSuicidality-RelatedAdverseEvents(Section5-Section8)PSRAE48.
010RListingofFatalAdverseEventsAE88.
011RListingofNon-FatalSeriousAdverseEventsAE88.
012RListingofAdditionalInformationforSAEsNS_LS018.
013RListingofAllAdverseEventsLeadingtoPermanentDiscontinuationofStudyDrugand/orWithdrawalfromStudyAE8R8.
014RListingofLaboratoryDataofPotentialClinicalConcernLB58.
015RListingofLaboratoryDataforSubjectswithAbnormalitiesofPotentialClinicalConcernLB58.
016RListingofLiverEventsinRelationtoTimeLIVER58.
017RListingofLiverEventsInformationforRUCAMScoreLIVER68.
018RListingofLiverBiopsyLIVER78.
019RListingofLiverImagingDetailsLIVER88.
020RListingofUrinalysisDataUR18.
021RListingofEDSSTotalScoreandFunctionalSystemScoresNS_LSAF012014N204379_00CONFIDENTIALH3M11647797ListingNoPopListingTitleTemplateReference8.
022RListingofEDSSVisualFSSQuestionsNS_LOV18.
023RListingofEDSSBrainstemFSSQuestionsNS_LOV28.
024RListingofEDSSPyramidalFSSQuestions-ReflexesNS_LOV3a8.
025RListingofEDSSPyramidalFSSQuestions-LimbsNS_LOV3b8.
026RListingofEDSSPyramidalFSSQuestions–SpasticityandMotorPerformanceNS_LOV3c8.
027RListingofEDSSCerebellarFSSQuestionsNS_LOV48.
028RListingofEDSSSensoryFSSQuestionsNS_LOV58.
029RListingofEDSSBladder/BowelFSSQuestionsNS_LOV68.
030RListingofEDSSMentalFSSQuestionsNS_LOV78.
031RListingofEDSSAmbulationQuestionsNS_LOV88.
032RListingofSubjectswithRelapsesNS_LSAF068.
033RListingofDetailsofRelapses(NeurologicalDeficits)NS_LSAF078.
034RListingofExpandedDisabilityStatus(EDSS)ScoresattheTimeofRelapsesNS_LSAF018.
035RListingofSteroidsadministeredtoSubjectsduringRelapsesCM38.
036RListingofVitalSignsVS48.
037RListingofVitalSignsDataforSubjectswithAbnormalitiesofPotentialClinicalConcernVS48.
038RListingofECGFindingsEG58.
039RListingofECGValuesEG38.
040RListingofeC-SSRSSuicidalIdeationandBehaviourDataforCompletedeC-SSRSAssessmentsOnlyECSSRS48.
041RListingofeC-SSRSSuicidalBehaviourDetailsforCompletedeC-SSRSAssessmentsOnlyECSSRS58.
042RListingofDetailsofMostSevereSuicidalIdeationatEacheC-SSRSAssessmentforCompletedeC-SSRSAssessmentsOnlyECSSRS68.
043RListingofeC-SSRSSuicidalIdeationandBehaviourDataforIncompleteeC-SSRSAssessmentsOnlyECSSRS42014N204379_00CONFIDENTIALH3M11647798ListingNoPopListingTitleTemplateReference8.
044RListingofC-SSRSSuicidalIdeationandBehaviourDataforCompletedC-SSRSAssessmentsOnlyCSSRS4SafetyFiguresFigureNoPopFigureTitleTemplateReference8.
001ITTDotplotofMostFrequentOn-TreatmentAdverseEventsbyRelativeRisk(GSK239512vsplacebo)AE108.
002ITTBoxplotofChemistyParametersbyvisitLB98.
003ITTBoxplotofHaematologyParametersbyvisitLB98.
004ITTScatterPlotofMaximumOn-TreatmentValueforeachChemistryLaboratoryParameterversusBaselineNone8.
005ITTScatterPlotofMaximumOn-TreatmentValueforeachHaematologyLaboratoryParameterversusBaselineNone8.
006ITTBoxplotofMaximumOn-TreatmentLFTsLB108.
007ITTScatterPlotofWeek48EDSSScoreversusBaselineEDSSScoreNone8.
008ITTKaplanMeierPlotofTimetoFirstRelapseTTE108.
009ITTBoxplotofChangefromBaselineinVitalSignsbyvisitLB98.
010ITTBoxplotofChangefromBaselineinQTcBandQTcFEG8HealthOutcomesTablesTableNo.
PopTableTitleTemplateReference9.
001ITTSummaryStatisticsforMSQoL54SubscaleScoresHO19.
002ITTFrequencyCountsfortheMSQoL54Single-itemMeasuresHO29.
003ITTSummaryStatisticsforMSQoL54CompositeScoresHO19.
004ITTSummaryofChangesfromScreeninginMSQoL54CompositeScoresatWeek48HO39.
005ITTSummaryoftheStatisticalAnalysisoftheChangefromScreeningatWeek48inMSQoL54PhysicalHealthCompositeScore(AESDataset)HO42014N204379_00CONFIDENTIALH3M11647799TableNo.
PopTableTitleTemplateReference9.
006ITTSummaryoftheStatisticalAnalysisoftheChangefromScreeningatWeek48inMSQoL54MentalHealthCompositeScore(AESDataset)HO4HealthOutcomesListingsListingNoPopListingTitleTemplateReference9.
001RListingofMSQoL54ScaleResponsesHO59.
002RListingofMSQoL54ScaleSubscaleScoresHO69.
003RListingofMSQoL54ScaleCompositeScoresHO7PharmacokineticTablesTableNo.
PopTableTitleTemplateReference10.
001PKSummarystatisticsforGSK239512troughplasmaconcentrations(ng/mL)byweekandbydoseBPTresponsible10.
002PKSummarystatisticsforGSK239512plasmaconcentrations(ng/mL)bynominaltimeatWeek8andbydoseBPTresponsible10.
003PKSummarystatisticsforGSK239512averagetroughplasmaconcentrationusedforPK/PDanalysesbydoseCPMStoprovideindividualvaluestoBPTforsummarisingPharmacokineticListingsListingNo.
PopTableTitleTemplateReference10.
001PKListingofindividualGSK239512troughplasmaconcentrations(ng/mL)byweekandbydoseBPTresponsible10.
002PKListingofindividualGSK239512plasmaconcentrations(ng/mL)bynominaltimeatWeek8andbydoseBPTresponsible2014N204379_00CONFIDENTIALH3M116477100ListingNo.
PopTableTitleTemplateReference10.
003PK/PDListingofindividualGSK239512averagetroughplasmaconcentrationusedforPK/PDanalysesbydoseCPMStoprovideindividualvaluestoBPTforsummarisingPharmacokineticFiguresFigureNo.
PopTableTitleTemplateReference10.
001PKIndividualGSK239512troughplasmaconcentrations(ng/mL)byweekandbydose.
CPMSresponsible.
10.
002PKIndividualGSK239512plasmaconcentrations(ng/mL)bynominaltimeatWeek8andbydoseCPMSresponsible10.
003PKBoxplotofGSK239512troughconcentrations(ng/mL)byweekandbydoseCPMSresponsiblePharmacokinetic/PharmacodynamicFiguresFigureNo.
PopTableTitleTemplateReference10.
001PK/PDMTRprimary1)versusaveragetroughconcentrationCPMSresponsible.
10.
002PK/PDMTRprimary2)versusaveragetroughconcentrationCPMSresponsible2014N204379_00CONFIDENTIALH3M11647710116.
2.
DataDisplaySpecificationsTemplateShells477Study2014N204379_00CONFIDENTIALH3M11647710216.
3.
LaboratoryNormalRangesandPotentialClinicalConcernRangesLabTestCodeAlgorithmTypeLowClinicalConcernValueHighClinicalConcernValueALB_PLCA26.
000065.
0000ALP_PLC+NR.
3.
0000ALT_PLC+NR.
3.
0000AST_PLC+NR.
3.
0000BILT_PLCA.
44.
0000CA_PLCA1.
89622.
7000CRT_PLCA.
176.
8000EOS_BLCA.
1.
0000GGT_PLC+NR.
3.
0000GLUC_PLCA2.
790012.
0000HB_BLC+NR0.
85001.
1500HCT_BLQ+NR0.
85001.
1500K_PLCA3.
00006.
0000LYMPH_BLCA0.
60005.
0000MONO_BLCA.
2.
0000NA_PLCA127.
0000151.
0000NEUT_BLCA1.
5000.
PLT_BLCA100.
0000600.
0000RETIC_BLC+NR0.
75001.
2000TP_PLC+NR0.
80001.
2000WBC_BLCA3.
000016.
0000BASO_BLC+NR2BILD_PLC+NR1.
5CK_PLC+NR2LDH_PLC+NR2MCHC_BLC+NR0.
751.
2MCH_BLC+NR0.
751.
2MCV_BLV+NR0.
751.
2RBC_BLC+NR0.
751.
2UREA_BLC+NR0.
82Note:A=AbsoluteValue;+NR=MultipleofNormalrange2014N204379_00