Study No.: 49653/020 Title: A Multicentre, Double-Blind, Parallel Group Comparative Study to Evaluate the Efficacy, Safety and Tolerability of

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1 Study No.: 49653/020 Title: A Multicentre, Double-Blind, Parallel Group Comparative Study to Evaluate the Efficacy, Safety and Tolerability of Rosiglitazone vs. Glibenclamide Therapy, When Administered to Patients with Type 2 Diabetes Mellitus. Rationale: Sulphonylureas (SU) act by increasing endogenous insulin secretion. Rosiglitazone (RSG) acts predominantly by increasing insulin sensitivity and this study was to determine if RSG was a viable alternative to glibenclamide in first-line therapy in patients with type 2 diabetes. Phase: IIIa Study Period: 12 October May 1998 Study Design: Multicentre, double blind, parallel group, comparative study. Centres: 25 in France, 16 in Germany, 9 in Italy, 7 in UK, 5 in Belgium, 5 in Sweden, 3 in Ireland, and 1 in the Netherlands Indication: Type 2 diabetes mellitus (T2DM) Treatment: # Denotes treatment regimens approved in the US and at least one country in the European Union After a 6 week run-in (placebo for 4 weeks) eligible patients were randomly assigned to receive either rosiglitazone 2mg bd#, 4mg bd# or glibenclamide for a period of 52 weeks. Glibenclamide was titrated during the first 12 weeks to optimal glycaemic effect, whilst the RSG doses remained constant. After 12 weeks, all doses remained constant. Objectives: To determine the effectiveness of RSG 4mg bd as assessed by reduction in glycosylated haemoglobin (HbA1c) compared with glibenclamide, following 52 weeks of treatment in out-patients with type 2 diabetes mellitus. Primary Outcome/Efficacy Variable: The primary parameter was the comparison of the change from baseline of HbA1c at the end of 52 weeks of treatment between rosiglitazone 4mg bd and glibenclamide treatment groups. Secondary Outcome/Efficacy Variables: The secondary efficacy parameters were analysed at the end of 52 weeks of treatment and included the mean change from baseline of: HbA1c, fasting plasma glucose (FPG), fructosamine, C-peptide, insulin, pro-insulin, split pro-insulin, urinary albumin, albumin excretion rate, and serum lipids including total cholesterol, HDL-cholesterol, LDLcholesterol (calculated), cholesterol/hdl ratio, LDL/HDL ratio, VLDL-cholesterol, triglycerides, free fatty acids and apolipoproteins A1 and B. The proportion of patients that responded to treatment, i.e. HbA1c 0.7% and FPG 30 mg/dl decrease from baseline respectively, were also analysed. The proportions of patients who achieve 140 mg/dl have also been described. Statistical Methods: For the analysis of continuous efficacy variables, an analysis of covariance with terms for regions, treatments and baseline was used. If the assumptions were violated, a model using heterogeneous variance or the Wilcoxon Rank Sum Test was used. For the primary efficacy variable comparison, change in HbA1c at week 52, a two-sided 95% confidence interval (CI) for the difference in treatment means (rosiglitazone 4mg bd -glibenclamide) was constructed. If the upper limit of this CI was 0.5%, a conclusion of 'rosiglitazone 4mg bd is as effective at reducing HbA1c as glibenclamide' was made. Pairwise comparisons using a level of 0.05, unadjusted, were performed to compare the two rosiglitazone groups separately to the glibenclamide group for secondary efficacy variables. The ITT population consisted of all randomised patients who had at least one on-therapy data value for an efficacy parameter (last observation carried forward - LOCF). Additional analyses were conducted to assess the robustness of the results. The safety population is comprised of patients who were randomised and who were dispensed study medication. Study Population: Men and women aged years with type 2 diabetes, with a C-peptide level

2 0.8ng/ml and a fasting plasma glucose 126mg/dL (7.0mmol/L) and 270mg/dL (15.0mmol/l) at 4 and 2 weeks before randomisation. Patients who had diabetic complications requiring treatment, serious renal, hepatic or haematological impairment were excluded Number of Subjects: RSG 2 mg bd RSG 4 mg bd Glibenclamide Planned, N 550 Randomised, N Completed, n (%) 153 (76.5) 158 (82.7) 173 (83.6) Withdrawn, n (%) 47 (23.5) 33 (17.3) 34 (16.4) Withdrawn due to Adverse Events n (%) 12 (6.0) 9 (4.7) 13 (6.3) Withdrawn due to Lack of Efficacy n (%) 22 (11.0) 15 (7.9) 7 (3.4) Withdrawn for other reasons n (%) 6 (3) 3 (1.5) 7 (3.3) Demographics RSG 2 mg bd RSG 4 mg bd Glibenclamide N (ITT) Females: Males 62:133 80:109 60:143 Mean Age, years (SD) 60.4 (8.23) 60.6 (9.27) 60.1 (8.34) White, n (%) 192 (98.5) 183 (96.8) 202 (99.5) Primary Efficacy Results: HbA1c, % RSG 2 mg bd RSG 4 mg bd Glibenclamide N (ITT) Mean Baseline, % (SD) 8.07 (1.296) 8.21 (1.449) 8.15 (1.256) Change from Baseline, % (SD) (1.040) (1.313) (0.996) (95% CI) (-0.42, -0.12) (-0.72, -0.34) (-0.86, -0.58) p-value < < Adjusted mean difference from glibenclamide in change from baseline, % (LOCF) (95% CI) (0.23, 0.65) (-0.01, 0.42) - Secondary Outcome Variables RSG 2 mg bd RSG 4 mg bd Glibenclamide HbA1c Responder Analysis( HbA1c >/= 0.7%), N=195 N=189 N=202 Total Responders n Difference in proportion of Responders compared with glibenclamide 95 % CI (-30.79, - (-20.41, -1.21) 11.74) Odds Ratio (95% CI) (0.25, 0.60) (0.40, 0.92) - FPG, mg/dl N=195 N=189 N=203 Baseline, mean (SD) (56.51) (52.13) (50.17) Change from Baseline at Week 52, mean (SD) (41.98) (45.60) (44.97) (95% CI) (-31.4, -19.5) (-47.3, -34.2) (-36.2, -23.8) Difference from glibenclamide, mean (95% CI) (-2.6, 12.0) (-15.4, -0.6) - FPG Responder Analysis N=195 N=189 N=203 Total Responders (>/= 30mg/dL reduction in FPG), n Difference in proportion of Responders compared with glibenclamide 95% CI -19.6, , Fructosamine, µmol/l N=195 N=189 N=202

3 Baseline, mean (SD) (74.55) (75.12) (73.87) Change from Baseline at Week 52, mean (SD) -5.5 (55.70) (59.79) (60.91) (95% CI) (-13.3, 2.4 ) (-34.1, -16.9) (-43.2, -26.3) Difference from glibenclamide, mean (95% CI) (19.2, 40.0) (1.0, 22.0) - Plasma Insulin, pmol/l N=152 N= 146 N=158 Baseline, mean (SD) (38.73) (57.045) (44.651) Change from Baseline at Week 52, mean (SD) (44.033) (39.753) (47.065) (95% CI) (-13.28, 0.83) (-20.16, -4.76) (8.35, 20.84) Difference from glibenclamide, mean (95% CI) (-29.95, - (-35.54, ) 16.03) C-peptide nmol/l N=195 N=189 N=202 Baseline, mean (SD) (0.3894) (0.4059) (0.3213) Change from Baseline at Week 52, mean (SD) (0.2497) (0.3003) (0.3126) (95% CI) ( , ) (-0.255, ) (-0.015, 0.054) Difference from glibenclamide (mean) % CI , , Pro-insulin, pmol/l N=152 N=145 N=157 Baseline, median Change from Baseline at Week 52, median (95% CI) (-4.00, -1.85) (-5.80, -3.60) (3.45, 6.50) Difference from glibenclamide, median (95% CI) (-9.60, -6.00) (-11.10, -7.70) Split Pro-insulin, pmol/l N=152 N=145 N=157 Baseline, median Change from Baseline at Week 52, median (95% CI) (-6.95, -3.30) (-12.00, -6.75) (0.65, 5.00) Difference from glibenclamide, median (95% CI) (-10.80, -5.00) (-15.00, -8.90) - Total Cholesterol, mg/dl N= 195 N= 189 N= 203 Baseline, median Change from Baseline at Week 52, median (95% CI) (12.0, 21.5 ) (19.5, 31.5) (-6.5, 1.0) Difference from glibenclamide, median (95% CI) (13.0, 25.0) (21.0, 34.0) - HDL-Cholesterol, mg/dl N= 195 N= 189 N= 203 Baseline, median Change from Baseline at Week 52, median (95% CI) (3.5, 6.0) (4.5, 8.5) (2.0, 4.5) Difference from glibenclamide, median (95% CI) (0.0, 3.0) (1.0, 6.0) - Total Cholesterol/HDL ratio N= 195 N= 189 N= 203 Baseline, median Change from Baseline at Week 52, median

4 (95% CI) (-0.265, 0.050) (-0.245, 0.145) (-0.525, ) Difference from glibenclamide, median (95% CI) (0.090, 0.480) (0.110, 0.570) - LDL/HDL ratio N=190 N=185 N=199 Baseline, median Change from Baseline at Week 52, median (95% CI) (-0.265, ) (-0.215, 0.085) (-0.455, ) Difference from glibenclamide, median (95% CI) (0.040, 0.360) (0.090, 0.460) - VLDL, mg/dl N=193 N=189 N=202 Baseline, median Change from Baseline at Week 52, median (95% CI) (1.0, 5.0) (-0.5, 3.0) (-3.0, 0.0) Difference from glibenclamide, median (95% CI) (2.0, 6.0) (0.0, 5.0) - LDL-cholesterol, mg/dl N=190 N=185 N=199 Baseline mean (SD) (33.21) (33.42) (34.40) Change from Baseline at Week 52, mean (SD) 7.9 (27.63) 15.6 (36.26) -3.8 (26.14) (95% CI) (3.9, 11.8) (10.4, 20.9) (-7.5, -0.2) Difference from glibenclamide, mean (95% CI) (7.1, 17.1) (13.6, 25.9) - Triglycerides, mg/dl N=195 N=189 N=203 Baseline mean (SD) (385.94) (120.22) (112.90) Change from Baseline at Week 52, mean (SD) (351.03) 12.3 (91.71) -2.8 (86.02) (95% CI) (-59.8, 39.4) (-0.8, 25.5) (-14.7, 9.1) Difference from glibenclamide, mean (95% CI) (-13.9, 27.4) (-10.9, 30.8) - Free Fatty Acids, mg/dl N=195 N=189 N=202 Baseline mean (SD) (8.7251) (8.5172) (8.0120) Change from Baseline at Week 52, mean (SD) (8.5061) (8.6239) (8.4315) (95% CI) (-6.138, ) (-7.952, ) (-3.659, ) Difference from glibenclamide, mean (95% CI) (-3.442, - (-5.152, ) 2.622) Apolipoprotein A1, mg/dl N=195 N=189 N=202 Baseline mean (SD) (22.86) (22.06) (22.46) Change from Baseline at Week 52, mean (SD) 0.6 (19.52) -4.8 (21.87) 4.1 (18.45) (95% CI) (-2.1, 3.4) (-7.9, -1.6) (1.5, 6.7) Difference from glibenclamide, mean (95% CI) (-6.4, 0.4) (-11.7, -4.1) - Apolipoprotein B, mg/dl N=195 N=189 N=202 Baseline mean (SD) (25.13) (27.85) (28.24) Change from Baseline at Week 52, mean (SD) 6.0 (21.03) 8.6 (26.56) -2.2 (20.54) (95% CI) (3.0, 9.0) (4.8, 12.4) (-5.1, 0.6)

5 Difference from glibenclamide, mean (95% CI) (3.3, 11.0) (5.5, 14.6) - Urinary Albumin Concentration, mg/l N= 173 N= 167 N= 181 Baseline mean (SD) (42.040) (60.301) ( ) Change from Baseline at Week 52, mean (SD) 9.00 (59.304) (48.794) 0.37 (87.507) (95% CI) (0.10, 17.90) (-14.13, 0.78) (-12.46, 13.20) Difference from glibenclamide, mean (95% CI) (-10.51, 13.79) (-25.97, -1.43) - Safety Results: On-therapy events were defined as events starting on or after the start date of coded study medication and on or before the last date of coded study medication. Most Frequent Adverse Events - On-Therapy RSG 2 mg bd RSG 4 mg bd Glibenclamide N Subjects with any AEs, n (%) 150 (75.0) 144 (75.4) 144 (69.6) Oedema 7 (3.5) 17 (8.9) 4 (1.9) Injury 17 (8.5) 16 (8.4) 14 (6.8) Headache 6 (3.0) 15 (7.9) 10 (4.8) Back pain 14 (7.0) 13 (6.8) 13 (6.3) Hypercholesterolaemia 9 (4.5) 12 (6.3) 6 (2.9) Upper respiratory tract infection 6 (3.0) 12 (6.3) 13 (6.3) Viral infection 10 (5.0) 11 (5.8) 11 (5.3) Pharyngitis 12 (6.0) 10 (5.2) 16 (7.7) Bronchitis 20 (10.0) 9 (4.7) 20 (9.7) Respiratory disorder 10 (5.0) 7 (3.7) 9 (4.3) Rhinitis 10 (5.0) 7 (3.7) 2 (1.0) Urinary tract infection 18 (9.0) 6 (3.1) 10 (4.8) Diarrhea 11 (5.5) 5 (2.6) 7 (3.4) Hyperglycaemia 11 (5.5) 3 (1.6) 3 (1.4) Hypoglycaemia 1 (0.5) 3 (1.6) 25 (12.1) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] RSG 2 mg bd RSG 4 mg bd Glibenclamide N Subjects with non-fatal SAEs, n (%) 19 (9.5) 20 (10.5) 13 (6.3) Chest pain 1 (0.5) [0] 2 (1.0) [0] 1 (0.5) [0] Angina pectoris 0 2 (1.0) [0] 0 Injury 4 (2.0) [0] 1 (0.5) [0] 4 (1.9) [0] Therapeutic response increased 2 (1.0) [2] 1 (0.5) [1] 1 (0.5) [1] Breast neoplasm malignant (female) 1 (0.5) [0] 1 (0.5) [0] 0 Abortion 0 1 (0.5) [0] 0 Anemia 0 1 (0.5) [0] 0 Circulatory failure 0 1 (0.5) [0] 0 Claudication intermittent 0 1 (0.5) [0] 0 Gait abnormal 0 1 (0.5) [0] 0 Muscle weakness 0 1 (0.5) [1] 0 Myalgia 0 1 (0.5) [1] 0 Myocardial ischemia 0 1 (0.5) [0] 0

6 Nail disorder 0 1 (0.5) [0] 0 Neoplasm NOS 0 1 (0.5) [0] 0 Paranoid reaction 0 1 (0.5) [0] 0 Pleural effusion 0 1 (0.5) [0] 0 Pneumonia 0 1 (0.5) [0] 0 Respiratory disorder 0 1 (0.5) [0] 0 Skin ulceration 0 1 (0.5) [0] 0 Syncope 0 1 (0.5) [0] 0 Tachycardia supraventricular 0 1 (0.5) [0] 0 Weight increase 0 1 (0.5) [0] 0 Myocardial infarction 2 (1.0) [1] 0 1 (0.5) [1] Abdominal pain 1 (0.5) [0] 0 0 Arrhythmia 1 (0.5) [1] 0 0 Arrhythmia ventricular 1 (0.5) [1] 0 0 Arthropathy 1 (0.5) [0] 0 0 Carcinoma 1 (0.5) [0] 0 0 Cardiac failure left 1 (0.5) [1] 0 0 Cataract 1 (0.5) [0] 0 0 Duodenal ulcer hemorrhagic 1 (0.5) [0] 0 0 Encephalopathy 1 (0.5) [0] 0 0 Hyperpyrexia 1 (0.5) [0] 0 0 Ileus 1 (0.5) [0] 0 0 Ileus paralytic 1 (0.5) [0] 0 0 Infection bacterial 1 (0.5) [0] 0 0 Neuralgia 1 (0.5) [0] 0 0 Neuropathy 1 (0.5) [0] 0 0 Rash 1 (0.5) [1] 0 0 Gastroenteritis (0.5) [0] Gastrointestinal disorder (0.5) [0] Hematemesis (0.5) [0] Hypertonia (0.5) [1] Hypoglycemia (0.5) [1] Muscle contractions involuntary (0.5) [1] Peripheral gangrene (0.5) [0] Sweating increased (0.5) [0] Vertigo (0.5) [1] Subjects with fatal SAEs, n (%) Conclusions: See publications below. Date Updated: 13-Sep-2004 Publications: Charbonnel B, Lonnqvist F, Jones NP et al. Rosiglitazone is superior to glyburide in reducing fasting plasma glucose after one year of treatment in type 2 diabetic patients. Diabetes 1999; 48 (Suppl 1):A Abs poster presented at ADA 1999.

7 Lonnqvist F, Charbonnel B, Jones NP et al. Rosiglitazone is superior to glyburide in reducing fasting plasma glucose in type 2 diabetic patients. Diabetologia 1999; 42 (Suppl 1):A231. Abs 869 presented at EASD Owen S, Charbonnel B, Lonnqvist F et al. Rosiglitazone is an effective alternative to glibenclamide as first-line therapy in type 2 diabetic patients. Diabetologia 1999; 42 (Suppl 1):A231. Abs 868 presented at EASD Jones NP, Charbonnel B, Lonnqvist F et al. Rosiglitazone reduces plasma insulin and its precursors while decreasing glycaemia in type 2 diabetics. Diabetologia 1999; 42 (Suppl 1):A229. Abs 859 presented at EASD Porter LE, Freed MI, Jones NP et al. Rosiglitazone improves beta-cell function as measured by proinsulin/insulin ratio in patients with type 2 diabetes. Diabetes 2000; 49 (Suppl 1):A122. Abs poster presented at ADA Kahn S, Porter L, Freed M et al. Rosiglitazone improves beta-cell function as measured by proinsulin/insulin ratio in patients with type 2 diabetes. Diabetes Res Clin Pract 2000; 50 (Suppl 1). P305 presented at IDF Owen S, Jones NP, Patwardhan R. Rosiglitazone treatment reduces gammaglutamyltransferase levels, a marker for visceral and hepatic fat. Diabetes 2000; 49 (Suppl 1):A120. Abs poster presented at ADA Grunberger G, Dole JF, Freed MI. Rosiglitazone monotherapy significantly lowers HbA1c levels in treatment-naïve type 2 diabetic patients. Diabetes 2000; 49 (Suppl 1):A109. Abs 441 presented at ADA Cranmer H, Jones NP, Patwardhan R. Rosiglitazone is effective in both obese and non-obese patients with type 2 diabetes. Diabetologia 1999; 42 (Suppl 1):A230. Abs 865 presented at EASD Goldstein B, Salzman A. Rosiglitazone is effective in poorly controlled type 2 diabetes patients. Diabetologia 1999; 42 (Suppl 1): A229. Abs 861 presented at EASD Rebuck AS, Weill S, Patwardhan R. Rosiglitazone given once or twice daily is effective first-line treatment for type 2 diabetes mellitus. Diabetologia 1999; 42 (Suppl 1):A231. Abs poster presented at EASD Balfour JA, Plosker GL. Rosiglitazone. Drugs 1999; 57: Porter L. Rosiglitazone reduces proinsulin:insulin ratio and improves ß-cell function in type 2 diabetes. Submitted to Endocr Pract. Awaiting peer review comments, March Abstract: Rosiglitazone is an Effective Alternative to Glibenclamide as First-Line Therapy in Type 2 Diabetic Patients, Owen, S; Charbonnel, B; Lonnqvist, F; Patwardhan, R. Harlow, UK; Nantes, France; Huddinge, Sweden; Collegeville, USA; Brighton; UK. British Diabetic Association Annual Professional Conference. 3/15/2000