沙格列汀在肾功能不全2型糖尿病的有效性ppt课件

Saxagliptin,StudytoEvaluatetheTreatmentEffectofSaxagliptinComparedWithPlaceboinAdultPatientsWithType2DiabetesandRenalImpairment,Objectives:,EfficacyToevaluateefficacyofsaxagliptin2.5mgcomparedwithplacebobyassessmentofabsolutechangefrombaselineinHbA1candFPGToassessthechangefrombaselineinbackgroundantihyperglycemictherapy,includingdailydoseofexistingtherapyortheadditionofnewtherapy(OADtherapyorinsulin),FPG,fastingplasmaglucose;HbA1c,glycatedhemoglobin;LT,long-term;OAD,oralantidiabetic;ST,short-term.,Objectives:,SafetyToevaluatethesafetyandtolerabilityofsaxagliptin2.5mgcomparedwithplacebobyassessmentof:AEsLabvalues,includingestimatedCrCl(Cockcroft-Gault),estimatedGFR,andurinaryalbumin:creatineratioECG,vitalsigns,bodyweight,physicalexaminationDoublingofserumcreatineorprogressiontoend-stagerenalimpairment,AE,adverseevent;CrCl,creatinineclearance;ECG,electrocardiogram;GFR,glomerularfiltrationrate.,StudyDesign,Stratifiedenrollmentbasedondegreeofrenalimpairment69Sitesin12EuropeancountriesandtheUnitedStates,PlaceboLead-in,STTreatmentPeriod,Placebo,2.5mgSaxagliptinoncedaily,1:1,12Weeks,2Weeks,LTTreatmentPeriod,40Weeks,ContinueallowedstableOADand/orinsulintherapy,AdjustmentofbackgroundOADand/orinsulinasneeded,Reference:CSRFigure1,SelectedInclusionandExclusionCriteria,InclusionCriteriaPatientswithT2DMandrenalimpairment(documentedhistoryofCrCl1.5xULNBilirubin1.5xULNCK3xULN,Reference:CSR5.1;CSR5.3.1;CSP3.3.2,CSP3.3.3;CSPAmendmentNumber1,ALT,alaninetransaminase;AST,aspartateaminotransferase;CK,creatinekinase;T2DM,type2diabetesmellitus;ULN,upperlimitofnormal.,SubjectDisposition:,Randomizedandtreated(N=170),Saxagliptin5mg(n=85),CompletedSTperiodandcontinuedtoLTperiod(n=61),DiscontinuedSTandLT(n=43)AE(n=5)Death(n=3)Incorrectenrollment(n=2)Nolongermeetsstudycriteria(n=16)Withdrewconsent(n=17),CompletedLT(n=42)Moderate(n=29)Severe(n=7)End-stage(n=6),Placebo(n=85),CompletedSTperiodandcontinuedtoLTperiod(n=68),DiscontinuedSTandLT(n=35)AE(n=2)Death(n=4)Incorrectenrollment(n=1)Nolongermeetsstudycriteria(n=13)Other(n=1)Poor/non-compliance(n=4)Withdrewconsent(n=10),CompletedLT(n=50)Moderate(n=27)Severe(n=14)End-stage(n=9),aBeforerandomization,totalnumberenrolled=572andtotalnumberexcluded=402.,Reference:CSRFigure2,DemographicandBaselineCharacteristics:RandomizedAnalysisSet,Reference:CSRTable11,N:numberofsubjectsineachcategory.PBO,placebo;SAXA,saxagliptin;SD,standarddeviation.,BaselineDiabetesCharacteristics:RandomizedAnalysisSet,Reference:CSRTable12,HbA1cChangeFromBaselinetoWeek52:LOCF,FullAnalysisSet(2of2),Reference:Figure7.1LT;Table7.2.2aLT,p0.001vsPBO.,ST+LTPeriod,Reference:Table7.2.2bLT;Figure7.2LT,HbA1cChangeFromBaselinetoWeek52byRenalImpairmentCategory:LOCF,FullAnalysisSet(3of3),ST+LTPeriod,MeanChangeFromBaselineHbA1c:LOCF,FullAnalysisSet,Reference:Table7.2.2dLT;Figure7.20LT,ST+LTPeriod,FPGChangeFromBaselinetoWeek52byRenalImpairmentCategory:LOCF,FullAnalysisSet(3of3),Reference:Table7.2.1aLT;Figure7.10LT,AllSAXAvsPBOcomparisonswithineachrenalimpairmentcategorywerenotsignificant.,ST+LTPeriod,SummaryofEfficacyResults:,HbA1cMeandecreaseinHbA1cafter52weeksoftreatmentwithsaxagliptin2.5mgoncedailywasgreaterthanaftertreatmentwithplacebo(p0.001)MeandecreasesinHbA1cafter52weeksoftreatmentwithsaxagliptinwerenumericallygreatercomparedwithplaceboinsubjectswithmoderateorsevererenalimpairment;meandecreasesinsubjectswithESRDwascomparablebetweenthetreatmentgroupsFPGTherewasanumericallylargerreductioninmeanfastingglucosevalueafter52weeksoftreatmentwithsaxagliptin2.5mgoncedailycomparedwithplaceboinsubjectswithmoderateorsevererenalimpairmentAreductioninFPGwasnotconsistentlydemonstratedinsubjectswithESRD,ChangeinAntihyperglycemicMedications:ST+LTPeriod,39/164(24%)ofsubjectsinthefullanalysissethadchangesinbaselineinsulinand/orOADmedicationduringthe52-weektreatmentperiodSaxagliptin:20/81(25%)subjectsPlacebo:19/83(23%)subjects,Reference:CSR7.1.4,OverallSummaryofAdverseEvents:SafetyAnalysisSet,Reference:Table8.1aLT,aEventsofhypoglycemiaareincludedinallcategories.AE,adverseevent;SAE,seriousadverseevent.,ST+LTPeriod,MostCommonAdverseEvents(2%)bySOC,Reference:Table8.1kLT,aExcludingalleventsofhypoglycemia.SOC,systemorganclass.,ST+LTPeriod,SummaryofDeaths:SafetyAnalysisSet,Reference:Table8.2aLT,ST+LTPeriod,SAEs(2%)bySOCandPreferredTerm:SafetyAnalysisSet,Reference:Table8.3aLT,ST+LTPeriod,SummaryofHypoglycemicEvents,Atotalof12subjectsexperienced25confirmedhypoglycemiceventsSAXA2.5mg:8subjects(9.4%)reported16eventsPBO:4subjects(4.7%)reported9events,Reference:Table8.6.1mLT;Table8.6.1aLT,ST+LTPeriod,SummaryofAdverseEventsofInterestDuringST+LTPeriod:SafetyAnalysisSet,Proportionofsubjectswithpredefinedcardiovasculareventswassimilarinthetwogroups:5.9%insaxagliptinand7.1%inplaceboProportionofsubjectswithpredefinedskindisorderswas2.4%ineachtreatmentgroupProportionofsubjectswith1AEininfections/infestationssystemorganclass:23.5%saxagliptinsubjects,25.9%placebosubjectsTheonlyopportunisticinfectionwasoralfungalinfectioninoneplacebosubjectLymphocytopenia(2subjects),thrombocytopenia(1subject),hypersensitivity(1subject),pancreatitis(1subject)andfracture(2subjects)wereonlyreportedintheplacebogroup(bypredefinedterms)Nolocalizededemabypredefinedlowerleveltermsreported,Reference:CSR8.3.4;CSR8.3.5;Appendix8.1LT,ChangesFromBaselineinSerumCreatinineinSubjectsWithModerateorSevereRenalImpairment:SafetyAnalysisSet,ST+LTPeriod,Reference:Table8.7.1.4fLT,ChangeFromBaselineinBodyWeight,BMI,andWaistCircumference:LOCF,SafetyAnalysisSet,Reference:Table8.10aLT,ST+LTPeriod,SummaryofSafetyResults:ST+LTPeriod(1of2),ThenumberofsubjectsexperiencinganyAE,SAE,ordiscontinuationsduetoanAEorSAEweresimilarbetweenthetreatmentgroupsTherewere3deathsinthesaxagliptinand4deathsintheplacebogroupThenumberofsubjectsexperiencinganycardiovascular-relatedAEswerelowandsimilarbetweenthetreatmentgroupsTherewerefeweventsofspecialinterestandtheincidenceofthesefeweventswassimilarinthesaxagliptincomparedwithplacebotreatmentgroupThenumberofsubjectswithmarkedabnormalityofserumcreatininewasnotunexpectedforthispopulationgiventheseverityofrenaldisease,SummaryofSafetyResults:ST+LTPeriod(2of2),Theproportionofsubjectswithanyhypoglycemiaeventwassimilarinthesaxagliptincomparedwithplacebotreatment(28.2%vs29.4%)Theproportionofsubjectswhohadaminorhypoglycemiaeventwithplasmaglucose20%change(increaseordecrease)inprescribeddailydoseTenorfewerdaysofachangeinantihyperglycemicmedicationwasallowed,Reference:CSR5.7.1.1;CSR5.7.2.3,TimetoStudyDiscontinuationforLackofGlycemicControlorChangeinDoseorTypeofOtherAntihyperglycemicAgentsa,ST+LTPeriod,Reference:CSRFigure4,Dataset:Safetyanalysisset.BL,baseline.,SummaryofInsulinDose:LOCF,FullAnalysisSet,Reference:Table7.2.3dLT,ST+LTPeriod,aFullanalysissetincludingLOCF;bNumberwithobservedvaluesforthefullanalysisset.,SummaryofExposuretoStudyMedications:SafetyAnalysisSet,Reference:Table6.1aLT,ST+LTPeriod,ClassificationofHypoglycemicEvents,Major:asymptomaticeventrequiringexternalassistanceduetosevereimpairmentinconsciousnessorbehavior,withplasmaglucose63mg/dLandpromptrecoveryafterglucoseorglucagonadministrationMinor:eitherasymptomaticevent,withplasmaglucose63mg/dLandnoneedforexternalassistance,oranasymptomaticplasmaglucosemeasurement63mg/dLEventsuggestiveforhypoglycemia:aneventwithsymptomsassociatedwithhypoglycemia,butnoconfirmatoryplasmaglucosemeasurementConfirmed:aneventwithsymptomsassociatedwithhypoglycemiawithafingerstickglucoseof50mg/dL,Reference:CSR8.3.4.7;CSP4.7.4.1,HbA1cChangeFromBaselinetoWeek52:LOCF,FullAnalysisSet(1of2),Reference:Table7.2.2aLT,aDifferenceinadjustedchangefrombasel