1、沙格列汀在腎功能不全型糖尿病有效性Objectives:EfficacyuTo evaluate efficacy of saxagliptin 2.5 mg compared with placebo by assessment of absolute change from baseline in HbA1c and FPGuTo assess the change from baseline in background antihyperglycemic therapy, including daily dose of existing therapy or the addition o

2、f new therapy (OAD therapy or insulin)FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; LT, long-term; OAD, oral antidiabetic; ST, short-term.Objectives:SafetyuTo evaluate the safety and tolerability of saxagliptin 2.5 mg compared with placebo by assessment of: AEs Lab values, including estim

3、ated CrCl (Cockcroft-Gault), estimated GFR, and urinary albumin:creatine ratio ECG, vital signs, body weight, physical examination Doubling of serum creatine or progression to end-stage renal impairmentAE, adverse event; CrCl, creatinine clearance; ECG, electrocardiogram; GFR, glomerular filtration

4、rate. Study Design Stratified enrollment based on degree of renal impairment 69 Sites in 12 European countries and the United StatesPlacebo Lead-in ST Treatment PeriodPlacebo2.5 mg Saxagliptin once daily1:112 Weeks2 WeeksLT Treatment Period40 WeeksContinue allowed stable OAD and/or insulin therapyAd

5、justment of background OAD and/or insulin as neededReference: CSR Figure 1Selected Inclusion and Exclusion CriteriaInclusion CriteriauPatients with T2DM and renal impairment (documented history of CrCl 50 mL/min within 3 months prior to enrollment)Moderate impairment: CrCl 30 50 mL/min Severe impair

6、ment: CrCl 1.5x ULNuBilirubin 1.5x ULNuCK 3x ULNReference: CSR 5.1; CSR 5.3.1; CSP 3.3.2, CSP 3.3.3; CSP Amendment Number 1ALT, alanine transaminase; AST, aspartate aminotransferase; CK, creatine kinase; T2DM, type 2 diabetes mellitus; ULN, upper limit of normal.Subject Disposition:Randomized and tr

7、eated (N = 170)Saxagliptin 5 mg (n = 85)Completed ST period and continued to LT period (n = 61)Discontinued ST and LT (n = 43) AE (n=5) Death (n=3) Incorrect enrollment (n=2) No longer meets study criteria (n=16) Withdrew consent (n=17)Completed LT (n = 42)Moderate (n = 29)Severe (n = 7)End-stage (n

8、 = 6)Placebo (n = 85)Completed ST period and continued to LT period (n = 68)Discontinued ST and LT (n = 35) AE (n=2) Death (n=4) Incorrect enrollment (n=1) No longer meets study criteria (n=13) Other (n=1) Poor/non-compliance (n=4) Withdrew consent (n=10)Completed LT (n = 50) Moderate (n = 27) Sever

9、e (n = 14) End-stage (n = 9)aBefore randomization, total number enrolled=572 and total number excluded=402.Reference: CSR Figure 2Demographic and Baseline Characteristics: Randomized Analysis SetSAXA 2.5 mg (N = 85)PBO(N = 85)Total (N = 170)Age (years)Mean (SD)66.8 (8.3)66.2 (9.1)66.5 (8.7)Range42.0

10、 80.043.0 86.042.0 86.0GenderMale32 (37.6)41 (48.2)73 (42.9)Female53 (62.4)44 (51.8)97 (57.1)Weight (kg)Mean (SD)83.6 (15.7)82.2 (14.4)82.9 (15.1)Range52.0 132.052.0 115.052.0 132.0BMI (kg/m2)Mean (SD)31.2 (6.1)30.2 (6.8)30.7 (6.4)Range 20.8 56.418.6 74.418.6 74.4Renal impairment category, n (%)Mode

11、rate48 (56.5)42 (49.4)90 (52.9)Severe18 (21.2)23 (27.1)41 (24.1)End-stage19 (22.4)20 (23.5)39 (22.9)Reference: CSR Table 11N: number of subjects in each category.PBO, placebo; SAXA, saxagliptin; SD, standard deviation.Baseline Diabetes Characteristics: Randomized Analysis SetSAXA 2.5 mg (N = 85)PBO(

12、N = 85)Total (N = 170)Duration of T2DM (years)Mean (SD)15.1 (7.5)18.2 (8.5)16.7 (8.1)RangeDuration of T2DM categories (years), n (%) 5 years80 (94.1)81 (95.3)161 (94.7) 10 years61 (71.8)67 (78.8)128 (75.3)Baseline HbA1c (%)Mean (SD)8.5 (1.22)8.1 (1.08)8.3 (1.17)Range6.6 11.35.0 11.15.0 11.3Baseline

13、HbA1c categories, n (%) 8.0%34 (40.0)42 (49.4)76 (44.7) 8.0% 9.0%28 (32.9)25 (29.4)53 (31.2) 9.0%23 (27.1)17 (20.0)40 (23.5)FPG (mg/dL)Mean (SD)187.9 (70.4)168.6 (59.2)178.2 (65.5)Range49.0 418.061.8 355.049.0 418.0FPG categories, n (%) 126 mg/dL13 (15.3)21 (24.7)34 (20.0) 126 mg/dL 150 mg/dL13 (15.

14、3)8 (9.4)21 (12.4) 150 mg/dL 220 mg/dL33 (38.8)43 (50.6)76 (44.7) 220 mg/dL 300 mg/dL19 (22.4)9 (10.6)28 (16.5) 300 mg/dL5 (5.9)3 (3.5)8 (4.7)Reference: CSR Table 12HbA1c Change From Baseline to Week 52: LOCF, Full Analysis Set (2 of 2)Adjusted Mean Change FromBaseline HbA1c (%)p0.001 vs PBO.Referen

15、ce: Table 7.2.2bLT; Figure 7.2LTAdjusted Mean Change FromBaseline HbA1c (%)ModerateModerateSevereSevereEnd-stageEnd-stageHbA1c Change From Baseline to Week 52 by Renal Impairment Category: LOCF, Full Analysis Set (3 of 3)ST + LT PeriodMean Change From Baseline HbA1c: LOCF, Full Analysis SetReference

16、: Table 7.2.2dLT; Figure 7.20LTWeeks Mean Change From Baseline HbA1C (%) ST + LT PeriodFPG Change From Baseline to Week 52 by Renal Impairment Category: LOCF, Full Analysis Set (3 of 3)Reference: Table 7.2.1aLT; Figure 7.10LTAdjusted Mean Change FromBaseline FPG (mg/dL)ModerateModerateSevereSevereEn

17、d-stageEnd-stageAll SAXA vs PBO comparisons within each renal impairment category were not significant.ST + LT PeriodSummary of Efficacy Results:HbA1cuMean decrease in HbA1c after 52 weeks of treatment with saxagliptin 2.5 mg once daily was greater than after treatment with placebo (p0.001)uMean dec

18、reases in HbA1c after 52 weeks of treatment with saxagliptin were numerically greater compared with placebo in subjects with moderate or severe renal impairment; mean decreases in subjects with ESRD was comparable between the treatment groupsFPGuThere was a numerically larger reduction in mean fasti

19、ng glucose value after 52 weeks of treatment with saxagliptin 2.5 mg once daily compared with placebo in subjects with moderate or severe renal impairmentuA reduction in FPG was not consistently demonstrated in subjects with ESRDChange in Antihyperglycemic Medications: ST + LT Periodu39/164 (24%) of

20、 subjects in the full analysis set had changes in baseline insulin and/or OAD medication during the 52-week treatment period Saxagliptin: 20/81 (25%) subjects Placebo: 19/83 (23%) subjectsOverall Summary of Adverse Events: Safety Analysis Set AE categoryaSAXA 2.5 mg (N = 85)PBO (N = 85)n (%)n (%)At

21、least 1 AE64 (75.3)60 (70.6)At least 1 AE related to study medication9 (10.6)11 (12.9)Deaths3 (3.5)4 (4.7)At least 1 SAE23 (27.1)24 (28.2)At least 1 SAE related to study medication1 (1.2)2 (2.4)Discontinued study medication due to SAE6 (7.1)6 (7.1)Discontinued study medication due to AE10 (11.8)7 (8

22、.2)Reference: Table 8.1aLTaEvents of hypoglycemia are included in all categories.AE, adverse event; SAE, serious adverse event.ST + LT PeriodMost Common Adverse Events ( 2%) by SOCSOCSAXA 2.5 mg(N = 85)PBO(N = 85)n (%)n (%)Total number of subjects with an AEa54 (63.5)55 (64.7)Infections and infestat

23、ions20 (23.5)22 (25.9)General disorders and administration site conditions10 (11.8)13 (15.3)Vascular disorders10 (11.8)14 (16.5)Gastrointestinal disorders9 (10.6)16 (18.8)Metabolism and nutrition disorders9 (10.6)10 (11.8)Nervous system disorders9 (10.6)10 (11.8)Respiratory, thoracic, and mediastina

24、l disorders9 (10.6)3 (3.5)Skin and subcutaneous tissue disorders8 (9.4)6 (7.1)Cardiac disorders7 (8.2)7 (8.2)Injury, poisoning and procedural complications7 (8.2)7 (8.2)Investigations7 (8.2)9 (10.6)Musculoskeletal and connective tissue disorders6 (7.1)6 (7.1)Blood and lymphatic system disorders5 (5.

25、9)10 (11.8)Renal and urinary disorders4 (4.7)7 (8.2)Eye disorders3 (3.5)2 (2.4)Benign, malignant, and unspecified neoplasms (including cysts and polyps)2 (2.4)0Ear and labyrinth disorders02 (2.4)Reference: Table 8.1kLTaExcluding all events of hypoglycemia.SOC, system organ class.Summary of Deaths: S

26、afety Analysis SetPreferred termSAXA 2.5 mg(N = 85)PBO(N = 85)n (%)n (%)Total number of subjects with an event3 (3.5)4 (4.7)Cardiac arrest1 (1.2)0Cardiac failure01 (1.2)Sudden death1 (1.2)2 (2.4)Cerebrovascular accident1 (1.2)0Sepsis01 (1.2)Reference: Table 8.2aLTST + LT PeriodSAEs ( 2%) by SOC and

27、Preferred Term: Safety Analysis SetSOCSAE (preferred term)SAXA 2.5 mg(N = 85)PBO(N = 85)n (%)n (%)Total subjects with an event23 (27.1)24 (28.2)Infections and infestations6 (7.1)5 (5.9)Pneumonia2 (2.4)0Cardiac disorders4 (4.7)4 (4.7)Myocardial infarction2 (2.4)1 (1.2)Gastrointestinal disorders3 (3.5

28、)1 (1.2)Nervous system disorders3 (3.5)2 (2.4)Vascular disorders3 (3.5)5 (5.9)Eye disorders2 (2.4)0General disorders and administrative site conditions2 (2.4)3 (3.5)Investigations2 (2.4)0Renal and urinary disorders2 (2.4)2 (2.4)Respiratory, thoracic, and mediastinal disorders2 (2.4)0Metabolism and n

29、utrition disorders1 (1.2)5 (5.9)Hypoglycemia02 (2.4)Injury, poisoning, and procedural complications03 (3.5)Reference: Table 8.3aLTST + LT PeriodSummary of Hypoglycemic EventsTreatment groupMajor hypoglycemic eventMinor hypoglycemic eventEvents suggestive for hypoglycemiaNot classifiedTotalSAXA 2.5 m

30、g (N=85)Subjects, N (%)1 (1.2)20 (23.5)7 (8.2)4 (4.7)24 (28.2)Events, N (%)1 (0.8)107 (81.1)13 (9.8)11 (8.3)132 (100.0)PBO (N=85)Subjects, N (%)1 (1.2)18 (21.2)9 (10.6)3 (3.5)25 (29.4)Events, N (%)1 (1.1)66 (73.3)18 (20.0)5 (5.6)90 (100.0)Total (N=170)Subjects, N (%)2 (1.2)38 (22.4)16 (9.4)7 (4.1)49

31、 (28.8)Events, N (%)2 (0.9)173 (77.9)31 (14.0)16 (7.2)222 (100.0)uA total of 12 subjects experienced 25 confirmed hypoglycemic events SAXA 2.5 mg: 8 subjects (9.4%) reported 16 eventsPBO: 4 subjects (4.7%) reported 9 eventsST + LT PeriodSummary of Adverse Events of Interest During ST + LT Period: Sa

32、fety Analysis SetuProportion of subjects with predefined cardiovascular events was similar in the two groups: 5.9% in saxagliptin and 7.1% in placebouProportion of subjects with predefined skin disorders was 2.4% in each treatment groupuProportion of subjects with 1 AE in infections/infestations sys

33、tem organ class: 23.5% saxagliptin subjects, 25.9% placebo subjectsThe only opportunistic infection was oral fungal infection in one placebo subjectuLymphocytopenia (2 subjects), thrombocytopenia (1 subject), hypersensitivity (1 subject), pancreatitis (1 subject) and fracture (2 subjects) were only

34、reported in the placebo group ( by predefined terms)uNo localized edema by predefined lower level terms reportedReference: CSR 8.3.4; CSR 8.3.5; Appendix 8.1LTChanges From Baseline in Serum Creatinine in Subjects With Moderate or Severe Renal Impairment: Safety Analysis SetSerum creatinine (mg/dL)Mo

35、derateSevereSAXA 2.5 mg(N = 85)PBO(N = 85)SAXA 2.5 mg(N = 85)PBO(N = 85)Baselinen48421823Mean (SE)1.90 (0.067)1.95 (0.074)2.88 (0.157)3.04 (0.174)Week 12n37381520Mean (SE) change from baseline0.01 (0.051)0.01 (0.075)0.19 (0.192)0.20 (0.200)Week 28n34341116Mean (SE) change from baseline0.03 (0.064)0.

36、07 (0.074)0.17 (0.212)0.33 (0.199)Week 52n2524714Mean (SE) change from baseline0.20 (0.131)0.23 (0.126)0.30 (0.182)0.76 (0.319)ST + LT PeriodChange From Baseline in Body Weight, BMI, and Waist Circumference: LOCF, Safety Analysis SetSAXA 2.5 mg (N = 85)PBO(N = 85)Body weight (kg)n7882Baseline mean (

37、SE)84.1 (1.84)83.1 (1.58)Week 52 mean (SE)83.4 (1.71)83.0 (1.67)Mean change from baseline (SE)0.7 (0.48)0.1 (0.42)95% CI1.6, 0.30.9, 0.8BMI (kg/m2)n7882Baseline mean (SE)31.5 (0.72)30.5 (0.74)Week 52 mean (SE)31.2 (0.66)30.5 (0.74)Mean change from baseline (SE)0.3 (0.19)0 (0.16)95% CI0.6, 0.10.4, 0.

38、3Waist circumference (cm)n7276Baseline mean (SE)107.1 (1.59)106.8 (1.36)Week 52 mean (SE)106.8 (1.54)106.2 (1.43)Mean change from baseline (SE)0.3 (0.54)0.6 (0.50)95% CI1.4, 0.71.6, 0.3Reference: Table 8.10aLTST + LT PeriodSummary of Safety Results: ST + LT Period (1 of 2)uThe number of subjects exp

39、eriencing any AE, SAE, or discontinuations due to an AE or SAE were similar between the treatment groupsuThere were 3 deaths in the saxagliptin and 4 deaths in the placebo groupuThe number of subjects experiencing any cardiovascular-related AEs were low and similar between the treatment groupsuThere

40、 were few events of special interest and the incidence of these few events was similar in the saxagliptin compared with placebo treatment groupuThe number of subjects with marked abnormality of serum creatinine was not unexpected for this population given the severity of renal diseaseSummary of Safe

41、ty Results: ST + LT Period (2 of 2)uThe proportion of subjects with any hypoglycemia event was similar in the saxagliptin compared with placebo treatment (28.2% vs 29.4%)uThe proportion of subjects who had a minor hypoglycemia event with plasma glucose 20% change (increase or decrease) in prescribed

42、 daily dose Ten or fewer days of a change in antihyperglycemic medication was allowed Time to Study Discontinuation for Lack of Glycemic Control or Change in Dose or Type of Other Antihyperglycemic AgentsaST + LT PeriodReference: CSR Figure 40102030405060708090100BL46121820242832364044485256WeeksPer

43、centage of subjects (%)SAXA 2.5 mgPBONo. of subjects at risk8575695853524946383634333126085827870625855525046444141340SAXA 2.5 mgPBODataset: Safety analysis set.BL, baseline.Summary of Insulin Dose: LOCF, Full Analysis SetInsulin DoseSAXA 2.5 mg (N = 81)PBO(N = 83)na6755Baseline mean (SE)50.49 (3.91

44、8)41.47 (3.128)Week 12 mean (SE)nobservedb5347Mean change from baseline (SE)2.19 (3.265)5.42 (2.559)95% CI8.59, 4.210.40, 10.43Week 28 mean (SE)nobservedb4538Mean change from baseline (SE)7.07 (6.439)7.64 (2.637)95% CI5.55, 19.702.47, 12.81Week 52 mean (SE)nobservedb3324Mean change from baseline (SE

45、)0.18 (3.755)4.22 (2.394)95% CI7.18, 7.540.47. 8.91ST + LT PeriodaFull analysis set including LOCF; bNumber with observed values for the full analysis set.Summary of Exposure to Study Medications: Safety Analysis SetSAXA 2.5 mg (N = 85)PBO(N = 85)Exposure (weeks)Mean (SD)34.4 (20.23)39.2 (17.82)Rang

46、e0.3 54.02.1 53.3Exposure categories (weeks), n (%)0 1020 (23.5)8 (9.4)10 228 (9.4)12 (14.1)22 359 (10.6)8 (9.4)35 485 (5.9)6 (7.1)48 5443 (50.6)51 (60.0)Reference: Table 6.1aLTST + LT PeriodClassification of Hypoglycemic EventsuMajor: a symptomatic event requiring external assistance due to severe

47、impairment in consciousness or behavior, with plasma glucose 63 mg/dL and prompt recovery after glucose or glucagon administrationuMinor: either a symptomatic event, with plasma glucose 63 mg/dL and no need for external assistance, or an asymptomatic plasma glucose measurement 63 mg/dLuEvent suggest

48、ive for hypoglycemia: an event with symptoms associated with hypoglycemia, but no confirmatory plasma glucose measurementuConfirmed: an event with symptoms associated with hypoglycemia with a fingerstick glucose of 50 mg/dLHbA1c Change From Baseline to Week 52: LOCF, Full Analysis Set (1 of 2)HbA1c (%)SAXA 2.5 mg (N = 81)PBO(N = 83)n7882Baseline mean (SE)8.44 (0.134)8.10 (0.120)Week 52 mean (SE)7.41 (0.138)7.9