Clinical Trial Synopsis, NCT#00762736 Title of Study: A Phase II, Double-Blind, Randomized, Placebo-Controlled, Proof-of-Concept Study of the Efficacy, Safety, and Tolerability of Pioglitazone HCl (ACTOS ) in Combination With TAK-536 in Subjects With Type 2 Diabetes Name of Sponsor: Takeda Global Research & Development Center, Inc. (TGRD) Name of Active Ingredient: Pioglitazone HCl (hereafter referred to as pioglitazone) in combination with TAK-536 Investigators: 127 investigators in the United States and Latin America Publication (reference): None Study Period (years): 28 July 2004 to 06 October 2005 Study Centers: 127 centers in the United States and Latin America Phase of Development: Phase 2 OBJECTIVES Primary: The primary objective of this study was to determine the effect of pioglitazone HC1 in combination with TAK-536 on glycemic control in subjects with type 2 diabetes. Secondary: The secondary objectives of this study were to determine the effects of pioglitazone in combination with TAK-536 on fasting plasma glucose (FPG), lipid profile, body weight, edema, systolic blood pressure (SBP) and diastolic blood pressure (DBP), microalbuminuria, and inflammatory markers (ie, high-sensitivity C-reactive protein [HS-CRP] and matrix metalloproteinase-9 [MMP-9]), and to determine the safety and tolerability of pioglitazone in combination with TAK-536. METHODOLOGY This was a phase 2, multicenter, randomized, parallel, double-blind, placebo-controlled, proof-of-concept study in subjects with moderately-controlled type 2 diabetes. Subjects received 15 mg of pioglitazone once daily (QD) for up to 6 days during the screening period (Screening). Eligible subjects were randomized to 1 of 6 double-blind treatment groups, and were instructed to take QD combinations of study drug over 24 weeks of treatment. The treatment groups were: Pioglitazone 15 mg plus placebo. Pioglitazone 15 mg plus TAK-536 5 mg. Pioglitazone 15 mg plus TAK-536 40 mg. Pioglitazone 45 mg plus placebo. Page 1 of 8
Pioglitazone 45 mg plus TAK-536 5 mg. Pioglitazone 45 mg plus TAK-536 40 mg. If a subject experienced intolerance, the investigator was able to reduce the number of tablets. Specifically, subjects were allowed to down-titrate from 40 mg to 20 or 10 mg of TAK-536 while maintaining the blind. Subjects in the placebo groups or TAK-536 5 mg blinded dosing regimens were allowed to reduce the number of tablets but were not allowed to change the total daily dose. Number of Subjects: Planned: 660 subjects (110 per treatment group). Treatment Group: Analyzed: Intent-to-Treat Population Analyzed: Safety Population Pioglitazone 15 mg plus placebo: 111 118 Pioglitazone 15 mg plus TAK-536 5 mg: 114 118 Pioglitazone 15 mg plus TAK-536 40 mg: 105 113 Pioglitazone 45 mg plus placebo: 113 118 Pioglitazone 45 mg plus TAK-536 5 mg: 114 117 Pioglitazone 45 mg plus TAK-536 40 mg: 110 114 Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been subjects with type 2 diabetes; aged 18 years or older; been able to comprehend and willing to sign an informed consent form. The following additional inclusion criteria applied: The subject had a glycosylated hemoglobin A (A1C) value of greater than or equal to 8.0% or less than 10.0% at Screening. If the subject was receiving antihypertensive therapy, he or she must have been taking a stable dose for a minimum of 8 weeks prior to Screening. The subject had clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory unless the results were deemed not clinically significant by the investigator or sponsor. The subject had been on a stable diet and exercise program and oral antiglycemic therapy including sulfonylurea or metformin for 8 weeks prior to Screening. Test Product, Dose and Mode of Administration/Lot Number: TAK-536 5 mg tablets, oral: TAK-536 10 mg tablets, oral: Tablet Batch Number(s): Z5569021 Z556A022 Placebo for TAK-536 tablets: Z5567032, Z5567034, Z5567041 Duration of Treatment: The treatment duration included a 7-day Screening (pioglitazone 15 mg unblinded lead-in) and a 24-week double-blind treatment period. Page 2 of 8
Reference Therapy, Dose and Mode of Administration, Batch Number: Tablet Batch Number(s): Overencapsulated Tablet Batch Number(s) Pioglitazone 15 mg tablets, oral: Z59H161 11014.01, 11692.01 Pioglitazone 45 mg tablets, oral: P45345ZE, C10220 11014.03, 11692.02 Criteria for Evaluation: Efficacy: The primary variable was the change from Baseline in A1C. The secondary variables were the changes from Baseline in FPG, lipid profile, body weight, edema (peripheral), SBP/DBP, microalbuminuria, and inflammatory markers (HS-CRP and MMP-9). Safety: The safety of pioglitazone plus TAK-536 was measured by the incidence of adverse events and by laboratory safety parameters. Statistical Methods: Efficacy parameters were analyzed using the intent-to-treat (ITT) population. The treatment comparisons for change from Baseline for A1C and other efficacy endpoints were carried out using 2-way analysis of covariance with terms for treatment and pooled center as factor and Baseline as covariate in the model. In addition to descriptive statistics, least-squares (LS) means were presented for change from Baseline by visit. Two-sided 95% confidence intervals (CIs) of the LS mean differences in endpoint change from Baseline between the active treatment groups and corresponding placebo were presented. Comparisons among the 6 treatment groups were provided. For HbA1c and weight, the primary analysis pooled across the pioglitazone (PIO) treatment groups (ie, Placebo + and, TAK-536 5 mg + and 45 mg, and TAK-536 40 mg + and 45 mg). Interactions between TAK-536 and PIO were to be investigated; if the interaction was statistically significant at the α=0.05 level, then treatment comparisons for each TAK-536 dose versus placebo were to be performed for Pioglitazone 15 mg and 45 mg separately. These comparisons were made using a 2-sided t-test. No adjustment was made for multiple comparisons. SUMMARY OF RESULTS Subject Disposition: A total of 704 subjects were randomized for treatment in 127 centers in the United States and Latin America. One hundred fifteen to 119 subjects were randomized to each of the 6 treatment groups, and 113 to 118 in each treatment group received double-blind medication. Six-hundred sixty-seven subjects were included in the ITT population. Subject Disposition is summarized in the following table. Page 3 of 8
Category Number of subjects discontinued from study Primary Reason for discontinuation PIO 15mg + Placebo PIO 15mg + TAK- 536 5 mg PIO 15mg + TAK- 536 40 mg 25 (21.0%) 23 (19.3%) 22 (19.1%) PIO 45mg +Placebo PIO 45mg + TAK- 536 5 mg PIO 45mg + TAK- 536 40 mg 14 (11.9%) 24 (20.3%) 19 (16.5%) Adverse Event (s) 1 (0.8%) 3 (2.5%) 2 (1.7%) 2 (1.7%) 6 (5.1%) 2 (1.7%) Lack of Efficacy 2 (1.7%) 6 (5.0%) 0 (0.0%) 1 (0.8%) 1 (0.8%) 1 (0.9%) Lost to Follow-Up 5 (4.2%) 3 (2.5%) 8 (7.0%) 1 (0.8%) 4 (3.4%) 1 (0.9%) Investigator 1 (0.8%) 0 (0.0%) 0 (0.0%) 1 (0.8%) 2 (1.7%) 3 (2.6%) Discretion Study Terminated 1 (0.8%) 3 (2.5%) 3 (2.6%) 4 (3.4%) 1 (0.8%) 1 (0.9%) Protocol Violation 4 (3.4%) 1 (0.8%) 1 (0.9%) 3 (2.5%) 2 (1.7%) 0 (0.0%) Voluntary 8 (6.7%) 4 (3.4%) 5 (4.3%) 2 (1.7%) 6 (5.1%) 9 (7.8%) Withdrawal (by patient) Pregnancy 1 (0.8%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Other 2 (1.7%) 3 (2.5%) 3 (2.6%) 0 (0.0%) 2 (1.7%) 2 (1.7%) Demographic and Other Baseline Characteristics No significant differences were observed across the treatment groups for any demographic characteristics, except for the proportion of male and female subjects within different treatment groups (P=0.006). Demographic data are summarized in the following table. Page 4 of 8
Characteristic Sex +Placebo (N=111) Male, n (%) 64 (57.7) Female, n (%) 47 (42.3) Mean age, yr (SD) Race American Indian or Alaskan Native, n (%) 56.3 (11.14) 12 (10.8) Asian, n (%) 1 (0.9) Black or African American, n (%) 9 (8.1) Multiracial, n (%) 3 (2.7) White, n (%) 86 (77.5) Mean BMI (SD) 30.4 (4.82) Mean A1C (SD) 8.81 (0.730) Mean SBP (SD) 128.5 (13.86) Mean DBP (SD) 78.8 (8.30) 5 mg (N=114) 42 (36.8) 72 (63.2) 58.7 (10.59) 14 (12.3) 0 (0.0) 7 (6.1) 3 (2.6) 90 (78.9) 29.0 (4.85) 8.86 (0.634) 130.1 (12.47) 79.7 (8.44) 40 mg (N=105) 42 (40.0) 63 (60.0) 56.1 (10.52) 6 (5.7) 0 (0.0) 6 (5.7) 3 (2.9) 90 (85.7) 30.6 (4.73) 8.82 (0.708) 129.8 (14.41) 79.5 (7.44) Treatment +Placebo (N=113) 63 (55.8) 50 (44.2) 56.3 (10.90) 14 (12.4) 0 (0.0) 10 (8.8) 1 (0.9) 88 (77.9) 29.9 (4.60) 8.72 (0.787) 128.8 (13.37) 78.4 (7.85) 5 mg (N=114) 50 (43.9) 64 (56.1) 56.3 (10.89) 14 (12.3) 1 (1.9) 10 (8.8) 3 (2.6) 86 (75.4) 30.4 (5.07) 8.96 (0.772) 130.1 (13.32) 80.6 (7.86) 40 mg (N=110) 50 (45.5) 60 (54.5) 56.1 (11.04) 13 (11.8) 1 (0.9) 10 (9.1) 2 (1.8) 84 (76.4) 29.8 (4.19) 8.90 (0.731) 129.5 (12.33) 79.0 (7.37) Efficacy Results: The therapeutic effect observed in clinical trials of a drug cannot be directly compared to the effects found in clinical trials of other drugs and may not reflect the therapeutic effects observed in practice. In addition, therapeutic effects observed in a single clinical trial may not reflect the overall therapeutic effects observed in all clinical trials of a drug. The primary variable was change from Baseline in A1C. As shown in the following table, greater reductions in A1C were observed when pioglitazone was coadministered with TAK-536 5 or 40 mg compared to pioglitazone only. At 16 and 20 weeks of treatment, the treatment differences (in LS mean change from Baseline) were statistically significantly greater for pioglitazone plus TAK-536 40 mg compared to pioglitazone plus placebo, based on the pooled analysis of pioglitazone groups. Page 5 of 8
Visit Change From Baseline in A1C (%) (Pooled Pioglitazone Groups) PIO+Placebo PIO 5 mg PIO 40 mg N=224 N=228 N=215 Baseline (a) 8.78 (0.052) 8.90 (0.050) 8.88 (0.052) Week 12 (b) -0.93 (0.090) -0.90 (0.089) -1.05 (0.092) Week 16 (b) -1.00 (0.094) -1.07 (0.092) -1.29* (0.096) Week 20 (b) -1.02 (0.099) -1.08 (0.097) -1.36* (0.101) Week 24 (b) -1.00 (0.101) -1.01 (0.099) -1.25 (0.102) Treatment effect (c) -0.012 (-0.3, 0.3) -0.245 (-0.5, 0.0) (a) LS mean (standard error). (b) LS mean change from Baseline (standard error). (c) LS mean difference from placebo at Week 24 (CI). *=Statistically significant at P<0.05. Subgroups of subjects with moderately poor to poor glycemic control (Screening A1C values 8% or 9%, respectively) were analyzed without regard to pioglitazone dose. In these analyses, the combination of pioglitazone (either dose) plus TAK-536 40 mg reduced A1C by 0.32% or 0.60%, respectively, compared to pioglitazone alone. The addition of TAK-536 5 or 40 mg to pioglitazone reduced FPG levels at all weeks measured (up to 40.0 mg/dl). However, no statistically significant differences were observed in the comparisons of TAK-536 with matching placebo treatments. Comparison of pioglitazone 15 mg plus TAK-536 40 mg treatment with pioglitazone 45 mg plus placebo treatment showed statistically significant FPG reductions at Weeks 6, 8, and 24 (P 0.037). Treatment with pioglitazone 15 or 45 mg alone (ie, the 2 placebo groups) reduced fasting plasma insulin levels at both weeks measured (up to 3.6 µiu/ml), as did addition of TAK-536 5 or 40 mg to each pioglitazone regimen in most instances (up to 2.8 µiu/ml). A statistically significant difference in the comparison of pioglitazone 45 mg plus TAK-536 40 mg treatment with the matching placebo treatment was observed at Week 12 (P=0.024). Comparison of pioglitazone 15 mg plus TAK-536 40 mg treatment with pioglitazone 45 mg plus placebo treatment showed a significant difference at Week 12 (P 0.008). Microalbuminuria was decreased from Baseline to the final visit by all TAK-536 treatments (up to 52.8 mg/dl), but not by treatment with either dose of pioglitazone alone. Statistically significantly significant reductions from Baseline were observed with both TAK-536 5 mg groups compared with matching placebo treatments (P 0.016). In the pooled analysis of pioglitazone groups, statistically significant mean increases in body weight (up to 2.76 kg) were observed at Weeks 6, 12, and 20 for the PIO + TAK-536 40 mg group compared with PIO + placebo (P 0.035). By Week 8, treatment with pioglitazone 15 mg plus TAK-536 5 or 40 mg achieved statistically significant reductions in sitting DBP (up to 6.3 mmhg) that persisted through Week 24 compared with matching placebo treatments (P 0.049). By Week 2, treatment with pioglitazone 45 mg plus TAK-536 5 or 40 mg resulted in statistically significant reductions (up to 5.6 mmhg) at all weeks (except Week 8 for TAK-536 5 mg) compared with matching placebo treatments (P 0.016). By Week 6, treatment with pioglitazone 15 mg plus TAK-536 5 or 40 mg achieved statistically significant reductions in sitting SBP (up to 8.0 mmhg) that persisted through Week 24 compared with matching placebo treatments (P 0.033). By Week 2, treatment with pioglitazone 45 mg plus TAK-536 5 or 40 mg resulted in statistically significant reductions (up to 9.2 mmhg) at all weeks (except Week 8 for TAK-536 5 mg) compared with matching placebo treatments (P 0.028). No statistically significant treatment differences were observed for lipid parameters (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), peripheral edema, or the inflammatory markers HS-CRP and MMP-9 for any treatment group. Page 6 of 8
Safety Results: Adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of other drugs and may not reflect the rates observed in practice. In addition, the rates observed in a single clinical trial may not reflect the overall rates observed in all clinical trials of a drug. A total of 422 subjects experienced adverse events in the study (approximately 60% of subjects in each treatment group). Between 22.9% and 36.8% of subjects in each treatment group experienced adverse events considered by the investigator to be related to study medication. The majority of adverse events were considered by the investigator to be mild or moderate in severity. The incidence of adverse events that occurred in at least 5% of subjects it any treatment group is summarized in the following table. Treatment n (%) System Organ Class Preferred Term + Placebo N=118 5 mg N=118 40 mg N=113 +Placebo N=118 5 mg N=117 40 mg N=114 Any adverse event 68 (57.6) 76 (64.4) 69 (61.1) 68 (57.6) 68 (58.1) 73 (64.0) Gastrointestinal disorders Diarrhea 7 (5.9) 9 (7.6) 7 (6.2) 6 (5.1) 9 (7.7) 4 (3.5) Abdominal pain 3 (2.5) 2 (1.7) 4 (3.5) 6 (5.1) 3 (2.6) 1 (0.9) Constipation 0 2 (1.7) 0 1 (0.8) 3 (2.6) 6 (5.3) General disorders and administration site conditions Edema peripheral 6 (5.1) 9 (7.6) 5 (4.4) 6 (5.1) 10 (8.5) 10 (8.8) Infections and infestations Influenza 3 (2.5) 6 (5.1) 4 (3.5) 8 (6.8) 8 (6.8) 6 (5.3) Nasopharyngitis 6 (5.1) 2 (1.7) 1 (0.9) 5 (4.2) 7 (6.0) 4 (3.5) Pharyngitis 4 (3.4) 2 (1.7) 1 (0.9) 6 (5.1) 2 (1.7) 3 (2.6) Urinary tract 2 (1.7) 2 (1.7) 1 (0.9) 3 (2.5) 8 (6.8) 5 (4.4) infection Investigations Weight increased 1 (0.8) 1 (0.8) 4 (3.5) 2 (1.7) 6 (5.1) 2 (1.8) Metabolism and nutrition disorders Hypoglycemia 1 (0.8) 6 (5.1) 2 (1.8) 4 (3.4) 6 (5.1) 4 (3.5) Musculoskeletal and connective tissue disorders Arthralgia 4 (3.4) 9 (7.6) 2 (1.8) 4 (3.4) 9 (7.7) 6 (5.3) Back pain 4 (3.4) 6 (5.1) 2 (1.8) 4 (3.4) 4 (3.4) 7 (6.1) Nervous system disorders Headache 7 (5.9) 10 (8.5) 11 (9.7) 12 (10.2) 8 (6.8) 8 (7.0) Dizziness 4 (3.4) 11 (9.3) 13 (11.5) 5 (4.2) 4 (3.4) 14 (12.3) Respiratory, thoracic, and mediastinal disorders Cough 5 (4.2) 1 (0.8) 3 (2.7) 4 (3.4) 3 (2.6) 7 (6.1) Vascular disorders Hypotension 0 4 (3.4) 6 (5.3) 1 (0.8) 4 (3.4) 9 (7.9) Page 7 of 8
Twenty-four subjects experienced serious adverse events during the study. SAEs that occurred in more than 1 subject were hypoglycemia (4 subjects), myocardial infarction (2 subjects), and cerebrovascular incident (2 subjects). Five SAEs were considered by the investigator to be related to study medication: hypoglycemia (2 subjects), cholelithiasis, cholecystitis, and syncope. Thirty-two subjects (4.6%) discontinued the study due to an adverse event. Adverse events that led to study discontinuation in more than 1 subject were vision blurred (3 subjects), edema peripheral (3 subjects), dizziness (3 subjects), diarrhea (2 subjects), dyspepsia (2 subjects), weight increased (2 subjects), hyperglycemia (2 subjects), and headache (2 subjects). Two deaths, sudden cardiac death (pioglitazone 45 mg plus TAK-536 5 mg) and hemorrhagic stroke (pioglitazone 15 mg plus placebo), were reported in the study; neither death was considered related to study drug. Date of Synopsis: 28 October 2008 draft Page 8 of 8