醫(yī)學交流課件：Post-ATS FLAME MSL deck and Q A

FLAMESummaryFLAMEispartoftheUltibroIGNITEprogramFLAMEStudylocations3356locationsin43countriesItaly–19Japan–30Korea–11Latvia–4Lithuania–12Mexico–7Netherlands–10Norway–10Philippines–3Poland–7Portugal–11Romania–18Russia–11Serbia–4Slovakia–16SouthAfrica–11Spain–32Sweden–8Taiwan–8Thailand–4Turkey–8UK–20Argentina–30Austria–11Belgium–22Brazil–10Bulgaria–9Canada–17Chile–4China–23Colombia–4Croatia–3Czechia–18Denmark–9Egypt–1Estonia–3Finland–6France–17Germany–75Greece–11Guatemala–3HongKong–3Hungary–6Iceland–1India–23FLAMEStudyoverview4Source:Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385StudydetailInformationPIJornOssumGronertPrimaryendpointRateofall(mild/mod/severe)

COPDexacerbations(non-inferiorityover52weeks)SecondaryendpointsRateofallCOPDexacerbations(potentialsuperiorityover52wks)TimetofirstCOPDexacerbationRateofmod/severeexacerbations(requiringantibiotics/systemicsteroids/hospitalisation)LungfunctionHealthstatusSafety&tolerabilityToevaluatetheeffectofUltibro?vs.salmeterol/fluticasone(SFC)onexacerbationsinmoderatetoverysevereCOPDpatientswithahistoryofexacerbations(GOLDBandD)ToshowthatUltibro?isnon-inferiortoSFCforannualrateofallCOPDexacerbations(mild/moderate/severe)ToevaluatepotentialsuperiorityofUltibro?vs.SFCforannualrateofallexacerbationsToevaluatetherateof(andtimetofirst)moderate/severeCOPDexacerbations,lungfunction,healthstatus,safetyandtolerabilityObjectiveKeydatesStudyinitiationJuly2013StudycompletionPrimaryendpointSep20151Initialresultspressrelease17thNovember2015Keynotepresentation16thMay2016(ATS)Fullresultspublished16thMay2016(NEJM)2ScreeningperiodRun-inperiodTiotropium18μgq.dIND/GLY110/50μgq.d(Breezhaler)SFC50/500μgb.i.d(Accuhaler)Pre-randomizationperiodDouble-blindtreatmentperiod30-daypost-safetyfollow-upDay-35toDay-29Day-28toDay-1Day1toDay365Day366toDay395Visit1Visit101Visit20112clinicvisits5328

Patientsscreened4942

Patientsenteredrun-in3362

Patientsrandomized2760Completed52weeksExacerbationswereclassifiedfollowingcriteriaofAnthonisenetal.1

5Anthonisenetal.(1987)AnnInternMed;106:196-204Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385CategoryDescriptionMildCOPDexacerbationsweredefinedasaworseningofdyspnea,sputumpurulenceorsputumvolumeforatleasttwoconsecutivedays,orasaworseningofanyoneoftheabovealongwithanincreaseinanyoneofsorethroat,colds(nasaldischargeand/ornasalcongestion),feverwithoutothercause,coughorwheezeforatleast2consecutivedays1Mildexacerbationsinvolvedworseningofsymptomsfor>2consecutivedaysbutnotleadingtotreatmentwithsystemicglucocorticoidsorantibiotics2ModerateAsabove,butleadingtotreatmentwithsystemicglucocorticoids,antibiotics,orboth2SevereAsabove,butleadingtohospitaladmissionoravisittotheemergencydepartmentthatlasted>24hoursinadditiontotreatmentwithsystemicglucocorticoids,antibiotics,orboth2FLAMEPatientpopulation6Source:Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385Age:≥40yearsHistory:Ahistoryof≥1exacerbationrequiringantibioticsand/orsystemicglucocorticosteroidsinthepast12monthsCurrentorex-smokerswithasmokinghistoryofatleast10pack-yearsTakingstableCOPDmedication(atleast60days)Lungfunction/diseasecharacteristics:Post-bronchodilatorFEV1of≥25%and<60%ofpredictednormalvaluePost-bronchodilatorFEV1/FVC<0.70mMRCgrade≥2InclusioncriteriaPatientswhohavehadaCOPDexacerbationthatrequiredtreatmentwithantibioticsand/orsystemiccorticosteroidsand/orhospitalizationinthe6weekspriortoscreening(PatientswhodevelopaCOPDexacerbationofanyseverity(mild/moderate/severe)betweenscreeningandtreatmentwillnotbeeligiblebutwillbepermittedtobere-screenedafteraminimumof6weeksaftertheresolutionoftheCOPDexacerbation)Patientswhohavehadarespiratorytractinfectionwithin4weekspriortoscreeningPatientswhodeveloparespiratorytractinfectionbetweenscreeningandpriortotreatmentwillnotbeeligible,butwillbepermittedtobere-screened4weeksaftertheresolutionoftherespiratorytractinfectionPatientsrequiringlongtermoxygentherapyprescribedfor>12h/dayPatientswithanyhistoryofasthmaPatientswithabloodeosinophilcount>600/mm3atscreeningPatientswithanonsetofrespiratorysymptoms,includingaCOPDdiagnosispriortoage40yearsSelectexclusioncriteria7FLAMEPatientpopulation1:Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa151638519.3%55.5%24.4%56.3%usingICSatscreening39.6%

currentsmokers44.1%

predictedPBFEV141.6%PBFEV1/FVC76%

male65averageage7.3yearssincediagnosisBaselinecharacteristics24.4%ofpatientsintherandomizedpopulationwereGOLDgroupB,0.1%wereinGOLDC,and74.8%inGOLDD133.4%ofpatientshadmoderateairflowlimitation(GOLDII),58.1hadsevereairflowlimitation(GOLDIII)and7.6%hadverysevereairflowlimitation(GOLDIV)1Patientswereusing4puffs/dayonaverageofrescuemedication1Althoughthree-quartersofpatientsintheFLAMEstudywereinGOLDGroupD,only19.3%ofpatientsoverallhadahistoryof2ormoremoderateorsevereexacerbationsintheprevious12months18FLAMEOutcomes:Primaryandsecondaryendpoints=sig.improvement/superior=nodifference=worsening/inferiorEndpointFLAMEResultRateofall(mild/moderate/severe)exacerbations(non-inferiority)Rateofall(mild/moderate/severe)exacerbations(superiority)LungfunctionRateof(andtimetofirst)moderatetosevereexacerbationsTimetofirstCOPDexacerbation(mild/moderate/severe)Rateof(andtimetofirst)moderatetosevereexacerbationsrequiringsystemiccorticosteroidsRateof(andtimetofirst)moderatetosevereexacerbationsrequiringantibioticsRateofsevereexacerbationsrequiringhospitalisationTimetofirstCOPDexacerbationrequiringhospitalisationHealthstatus(SGRQ-C)RescuemedicationusePneumonia=primaryendpointWedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385(alloutcomesover52weeks)9Results–AllExacerbationsWedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385Ultibromettheprimaryendpointofnon-inferiority,anddemonstratedsuperioritytoSeretideasakeysecondaryendpoint,reducingtherateofallexacerbations(mild/moderate/severe)by11%overoneyearoftreatment1AnnualizedrateofallexacerbationsRR=0.89,p=0.003IND/GLY110/50μgq.d.SFC50/500μgb.i.d.10Results–Allexacerbations-subgroupanalysis1.:Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385Inasubgroupanalysisoftherateofallexacerbations,Ultibrodidnotshowsuperiorityvs.Seretideinpatientswithahistoryof2ormoreexacerbationsintheprevious12months.Itisalsoimportanttonotethatthesepatientsmadeuponly19.3%ofthefullstudypopulation111Results–ModeratetosevereexacerbationsWedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385AnnualizedrateofmoderateorsevereexacerbationsIND/GLY110/50μgq.d.SFC50/500μgb.i.d.RR=0.83,p<0.001TheannualrateofmoderatetosevereCOPDexacerbations(i.e.,exacerbationsthatrequiredtheuseofhealthcareservices)was17%lowerintheUltibrogroupthanintheSeretidegroup(RR=0.83;p<0.001)112Results–TimetoFirstExacerbationWedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385Ultibroprolongedtimetofirstexacerbation(mild/mod/severe),representinga16%lowerriskoveroneyearoftreatment(p<0.001)1ThetimetofirstmoderateorsevereexacerbationwassignificantlyprolongedinpatientstakingUltibro,equatingtoa22%riskreduction1AlthoughthetimetofirstsevereexacerbationwassignificantlygreaterinpatientstakingUltibro(p=0.046),theannualrateofsevereexacerbationsrequiringhospitalisationwasnotdifferentbetweentheUltibroandSeretidegroups(p=0.23)1IND/GLY110/50μgq.d.SFC50/500μgb.i.d.10005226050Probabilityofexacerbation(%)WeekModerateorSevereAnySevereHR=0.84p<0.001HR=0.78p<0.001HR=0.81p=0.04613Results–LungFunctionIND/GLY110/50μgq.d.SFC50/500μgb.i.d.Δ=0.62mLp<0.001Adjustedmeanchangefrombaselineinpre-dosetroughFEV1(mL)Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385Asexpectedwhencomparingadual-bronchodilatortoanICS/LABA,thechangefrombaselineintroughFEV1wassignificantlygreaterintheindacaterol–glycopyrroniumgroupthaninthesalmeterol–fluticasonegroup,withabetween-groupdifferenceof62mlatweek52(p<0.001)114Results–Eosinophils1.Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385TheFLAMEstudyanalysedtherateofall(mild/moderate/severe)exacerbationsandmoderateandsevereexacerbationsaccordingtobaselinebloodeosinophils(<2%vs.≥2%)1Amongpatientswithbaselinebloodeosinophilcountslowerthan2%,therateofallexacerbationswassignificantlylowerintheLAMA/LABAcomparedwiththeICS/LABAgroup(RR=0.84;p=0.004);amongpatientswithbaselinebloodeosinophilcountsof2%orhigher,theratewasalsosignificantlylowerintheLAMA/LABAgroupthanintheICS/LABAgroup(RR=0.90;p=0.03)1Amongpatientswithbaselinebloodeosinophilcountslowerthan2%,therateofmoderatetosevereexacerbationswassignificantlylowerintheLAMA/LABAcomparedwiththeICS/LABAgroup(RR=0.80;p=0.004);amongpatientswithbaselinebloodeosinophilcountsof2%orhigher,theratewasalsosignificantlylowerintheLAMA/LABAgroupthanintheICS/LABAgroup(RR=0.85;p=0.01)1However,nootheranalyses,includingtheeffectofeosinophilsontherateofexacerbationsrequiringhospitalisation,orusingdifferentbloodeosinophilthresholds(eitherabsolutecountorpercentage),havebeenpublished1EOS<2%EOS≥2%RR=0.85,p=0.01RR=0.80,p=0.004EOS<2%EOS≥2%RR=0.84,p=0.004RR=0.90,p=0.03Therateofmoderatetosevereexacerbations

bybaselinebloodEOS%Therateofallexacerbations

bybaselinebloodEOS%IND/GLY110/50μgq.d.SFC50/500μgb.i.d.15Results–SGRQ-C1.Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385TheimprovementovertimeinSGRQ-CtotalscorewasgreaterintheUltibrogroupthanintheSeretidegroup,withbetween-groupdifferencesrangingfrom?1.2pointsatweek12to?1.8pointsatweek52(p<0.01forbothcomparisons)1However,neithertreatmentimprovementmettheMCIDof4pointsvs.baselineover52weeks1IND/GLY110/50μgq.d.SFC50/500μgb.i.d.AdjustedmeanSGRQ-CtotalscoreTime(days)Improvement16Results–RescueMedication1.Wedzichaetal.(2016)NEnglJMed.DOI:10.1056/NEJMoa1516385Patientswereusing4puffs/dayonaverageofrescuemedicationatbaseline(3.95puffs/dayintheUltibroarmvs.4.12intheSeretidearm)1Changefrombaselineindailyrescuemedicationuseoverthe52-weektreatmentperiodwasanalysedusingamixedmodel,whichcontainedtermsoftreatment,baselinemeandailyuseofrescuemedication,smokingstatusatbaseline,COPDseverity,region,andhistoryofICSuseasfixedeffects,withcentrenestedwithinregionasarandomeffect1Rescuemedicationusedecreasedby1.01puffsperdaywithUltibroandby0.76puffsperdaywithSeretide,withatreatmentdifferenceof0.25(95%CI,–0.38to–0.12;p<0.001)1TherewasanincreaseinthepercentageofdayswithnorescuemedicationusewithUltibro(13.0%)andSeretide(8.3%),withatreatmentdifferenceof4.7%(95%CI,2.7to6.7;p<0.001)1IND/GLY110/50μgq.d.SFC50/500μgb.i.d.Adjustedmeanchangefrombaselineinrescuemedicationuse(puffs/day)Δ=-0.25p<0.00117Results–Adverseevents1.We