Clinical Trial Synopsis, NCT# 00225264 Title of Study: A Double-Blind, Randomized, Comparator-Controlled Study in Subjects With Type 2 Diabetes Mellitus Comparing the Effects of Pioglitazone HCl vs Glimepiride on the Rate of Progression of Atherosclerotic Disease as Measured by Carotid Intima-Media Thickness Protocol Number: Name of Sponsor: Takeda Global Research & Development Center, Inc. Name of Active Ingredient: Pioglitazone hydrochloride Name of Finished Product: ACTOS Investigators: 29 investigators Study Centers: 32 sites in the United States Publication (reference): Abstracts of the 66th Scientific Sessions of the American Diabetes Association, June 9-13, 2006, Washington, DC, USA. Diabetes. 2006 Jun;55 Suppl 1:A1-617. Study Period: 01 October 2003 to 03 May 2006 OBJECTIVES Phase of Development: Phase 3b Primary: To compare the effect of treatment with pioglitazone vs glimepiride on absolute change in carotid intimamedia thickness (CIMT) from Baseline to Final Visit in subjects with type 2 diabetes. Secondary: To compare the effect of pioglitazone vs glimepiride on the following: Percent change in CIMT from Baseline to Final Visit. Change in coronary artery calcium (CAC)-volume score from Baseline to Final Visit using electron beam tomography (EBT) of the coronary arteries. Change in abdominal adipose tissue content and distribution from Baseline to Final Visit using EBT of the abdomen. The occurrence of cardiovascular events as a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), and nonfatal stroke. The occurrence of cardiovascular events as a composite of cardiovascular mortality, nonfatal MI, nonfatal stroke, coronary revascularization, carotid endarterectomy/stenting, hospitalization for unstable angina, and hospitalization for congestive heart failure (CHF). Page 1 of 8
METHODOLOGY Each subject who qualified for study entry was randomly assigned to receive either pioglitazone or glimepiride. Treatment randomization was stratified as follows: Subjects naïve to or not taking oral antidiabetic therapy or taking less than 2 mg/day of glimepiride or sulfonylurea equivalent received pioglitazone 15 mg/day or glimepiride 1 mg/day. Subjects taking 2 mg/day or more of glimepiride or sulfonylurea equivalent, metformin monotherapy, or sulfonylurea/metformin combination therapy received pioglitazone 30 mg/day or glimepiride 2 mg/day. Following randomization, subjects entered into a 72-week (18-month) treatment period during which study medication was optimized for glucose control. The dose of pioglitazone or glimepiride was titrated at scheduled study visits or at unscheduled visits if deemed necessary up to a maximum dose of pioglitazone 45 mg/day or glimepiride 4 mg/day. Study visits were scheduled at 4, 8, 16, 24, 32, 40, 48, 60, and 72 weeks after the randomization visit. A posttreatment follow-up visit also occurred 7 days following the last dose of study medication. Subjects were also contacted 30 days after the last dose of study medication to perform assessment of endpoints and adverse events. Subjects who discontinued study medication prior to 72 weeks were contacted at 6-month intervals to perform endpoint assessments, with the last contact occurring 72 weeks from the date of randomization. CIMT ultrasound evaluations were performed at a central location at Screening and at Weeks 24, 48, and 72 (or early termination). EBT evaluations of the coronary arteries and the abdominal adipose tissue were performed at a central location at Screening and Week 72. Occurrence of cardiovascular mortality, nonfatal MI, and nonfatal stroke, coronary revascularization, carotid endarterectomy/stenting, hospitalization for unstable angina, and hospitalization for CHF were assessed at each clinic visit following Screening and at posttreatment contacts. Each endpoint event was assessed and adjudicated by the Clinical Endpoint Committee (CEC). Number of Subjects: Planned: 400 subjects Analyzed: Intent-to-Treat (ITT) Population: 458 subjects (228 glimepiride, 230 pioglitazone); Safety Population: 458 subjects (228 glimepiride, 230 pioglitazone). Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been diagnosed with type 2 diabetes mellitus; aged 45 to 85 years, inclusive; received appropriate counseling on lifestyle modification for type 2 diabetes, including diet and exercise, and naïve to or not currently taking antidiabetic therapy or currently treated with monotherapy or combination antidiabetic therapy; with hemoglobin A1C level 6.0% and <9% if taking antidiabetic medication or 6.5% and <10% if naïve to treatment or not taking antidiabetic medication at Screening. Test Product, Dose and Mode of Administration, Lot Number: Pioglitazone HCl, 15 mg, tablets, oral Lot Number 06056, 06066, Z509H181, Z509H171 Pioglitazone placebo, matching tablets, oral 06026, 00554 Page 2 of 8
Reference Therapy, Dose and Mode of Administration, Lot Number: Lot Number Glimepiride, 1 mg and 2 mg tablets (over-encapsulated), oral 1053664 / O/E 08613.04 1054955 / O/E 08613.05 1068648 / O/E 10816.01 1076764 / O/E 12292.03 1077373 / O/E 12292.04 Glimepiride placebo, matching capsules, oral 08613.01, 07489.01, 12292.01 Duration of Treatment: The study consisted of a Screening period of up to7 weeks, a 72-week (18-month) double-blind treatment period, a 7-day posttreatment follow-up visit, and 30-day posttreatment follow-up contact. Criteria for Evaluation: The primary efficacy variable was the absolute change from Baseline to the Final Visit in the average of the left and right automated posterior (far wall, non-contrast) CIMT mean values for the common carotid artery. The secondary efficacy variables were the percent change in posterior wall CIMT from Baseline to Final Visit, the change in posterior wall CIMT maximum value from Baseline to Final Visit, the change in the average of all automated (posterior and anterior wall) CIMT values from Baseline to Final Visit, the changes from Baseline in EBT-derived CAC volume and score and abdominal adipose tissue content and distribution at Final Visit, the occurrence of cardiovascular events as a composite of cardiovascular mortality, nonfatal MI, and nonfatal stroke, and the occurrence of cardiovascular events as a composite of cardiovascular mortality, nonfatal MI, nonfatal stroke, coronary revascularization, carotid endarterectomy/stenting, hospitalization for unstable angina, and hospitalization for CHF. Other efficacy variables were changes from Baseline in markers of glucose metabolism, in markers of inflammation/atherosclerosis, in lipid profile markers, and in a measure of cardiac function. Safety: Safety variables included adverse events, clinical laboratory test results, vital signs, physical examination findings, and 12-lead electrocardiogram results. Statistical Methods: For the primary variable, treatment comparisons for absolute change from Baseline in posterior wall CIMT mean value were carried out using a 2-way analysis of covariance (ANCOVA) with terms for fixed effects of treatment, center, and Baseline value (as a covariate) in the model. The pooled center by treatment interaction was investigated in an exploratory analysis. The treatment comparison was made at the 0.050 significance level. The mixed-model procedure with all effects fixed and type III sums of squares was used to generate the ANCOVA results. The secondary variables of percent change from Baseline in CIMT mean values, absolute and percent change from Baseline in CIMT maximum value, and absolute and percent change from Baseline in all automated CIMT mean values were analyzed and summarized as described for the primary variable. However, significance of pooled center by treatment interaction was not investigated in the analysis of these secondary variables. EBT-CAC total volume scores were categorized as 0, >0 to 0.1, >0.1 to 0.4, or >0.4. EBT-CAC total scores were categorized as 0, >0 to 100, >100 to 400, or >400. The number of subjects in each category was tabulated by treatment group. At Baseline, the treatment groups were compared using the general association statistics from the Cochran-Mantel-Haenszel test controlling for pooled center. At Final Visit, the treatment groups were compared using the row mean score statistics from the Cochran-Mantel- Haenszel test controlling for pooled center and Baseline category. Page 3 of 8
For change from Baseline to the Final Visit in the remaining EBT data parameters, treatment comparisons were carried out using a 2-way ANCOVA with terms for fixed effects of treatment, center, and Baseline value (as a covariate) in the model. The mixed-model procedure with all effects fixed and type III sums of squares was used to generate the ANCOVA results. The least squares (LS) means and SE on change from Baseline for each treatment group are presented. The LS means treatment difference in change from Baseline and the 95% confidence interval (CI) for this treatment difference are also presented. All analyses and summaries involving the cardiovascular events were based on CEC determinations and the Safety population. The occurrence of each composite event, as well as the occurrence of each individual cardiovascular event, was summarized by treatment group tabulating the number and percentage of subjects. No formal hypothesis testing was done. SUMMARY OF RESULTS Subject Disposition: Of the 1346 subjects screened, 462 subjects were enrolled at 30 centers in this study; 230 were randomized to receive glimepiride 1 to 4 mg once daily (QD), and 232 were randomized to receive pioglitazone 15 to 45 mg QD. Disposition of Subjects, No. (%) Glimepiride (N=230) Pioglitazone (n=232) Completed study 165 (71.7) 158 (68.1) Discontinued from study 65 (28.3) 74 (31.9) Adverse event 19 (8.3) 26 (11.2) Lack of efficacy 8 (3.5) 5 (2.2) Lost to follow-up 10 (4.3) 12 (5.2) Voluntary withdrawal 26 (11.3) 29 (12.5) Other 2 (0.9) 2 (0.9) Subjects were predominantly male (62.7% of glimepiride subjects and 63.5% of pioglitazone subjects) and predominantly Caucasian (65.4% and 59.6% of subjects, respectively). Subjects averaged approximately 60 years of age, with a mean duration of diabetes of approximately 8 years. The majority of subjects were taking a sulfonylurea, metformin, or a sulfonylurea/metformin combination at Baseline. No statistically significant differences were found between the groups in any demographic or Baseline characteristics. The ITT and safety populations consisted of 228 glimepiride subjects and 230 pioglitazone subjects. 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. Results for the primary efficacy variable (change from Baseline in posterior wall CIMT mean value) are shown in the table below: Glimepiride (N=228) Pioglitazone (N=230) P-value N CIMT Value (a) N CIMT Value (a) Baseline, mm 186 0.779 (0.0085) 175 0.771 (0.0085) 0.445 Change from Baseline, mm Week 24 170 0.001 (0.0046) 166-0.006 (0.0046) 0.223 Week 48 186 0.005 (0.0044) 175-0.006 (0.0043) 0.053 Week 72 186 0.012 (0.0043) 175-0.001 (0.0043) 0.017 Treatment difference at Week 72 (95% CI) -- -0.013 (-0.024, -0.002) -- (a) CIMT mean values are LS mean (SE), using the last observation carried forward (LOCF) method. Page 4 of 8
Secondary analyses of CIMT data are shown in the following table: Glimepiride (N=228) Pioglitazone (N=230) P- value N CIMT Value (a) N CIMT Value (a) % Change from Baseline Baseline, mm 186 0.779 (0.0085) 175 0.771 (0.0085) 0.445 % Change at Week 72 186 1.891 (0.5506) 175 0.048 (0.5501) 0.010 Treatment difference at Week 72 (95% CI) -- -1.843 (-3.233, -0.453) -- Change from Baseline in CIMT Maximum Value Baseline, mm 186 1.042 (0.0101) 175 1.038 (0.0101) 0.734 Change at Week 72 186 0.026 (0.0071) 175 0.002 (0.0071) 0.008 Treatment difference at Week 72 (95% CI) -- -0.024 (-0.042, -0.006) -- Change From Baseline in all automated CIMT mean Values Baseline, mm 163 0.811 (0.0101) 146 0.801 (0.0103) 0.437 Change at Week 72 163-0.004 (0.0067) 146-0.008 (0.0068) 0.591 Treatment difference at Week 72 (95% CI) -- -0.005 (-0.002, 0.012) -- (a) CIMT values are LS mean (SE), using the LOCF method In subgroup analyses of the primary CIMT results, the treatment differences in CIMT values were generally consistent within the subgroups. In the subgroup analysis by systolic blood pressure, the treatment difference in subjects with Baseline values of 130 mm Hg or higher was -0.021 mm (P=0.015) in favor of pioglitazone. Statistically significant treatment differences were also seen in subjects aged 64 years, with duration of diabetes >67 months, and with BMI 31.3 kg/m 2. In all of these analyses, glimepiride subjects showed increases in CIMT from Baseline, and pioglitazone subjects showed decreases from Baseline. In determinations of EBT-CAC, results indicated a small shift toward higher volumes and higher scores in both treatment groups during the study. The distributions of volumes and scores were not statistically significantly different between the groups at Baseline or the Final Visit. When analyzed by Baseline category, mean volumes and scores were higher at the Final Visit than at Baseline in all categories. For subjects starting with the higher 2 categories of volumes and scores, the increases were substantially larger in the glimepiride group than in the pioglitazone group. The total abdominal adipose tissue volume increased during the study in both groups, and the difference between the groups was not statistically significant. There was a larger increase in subcutaneous adipose tissue volume for pioglitazone than for glimepiride; the treatment difference was 14.81 cm 3 (P=0.015). The ratio of visceral to total abdominal adipose tissue volume tended to increase in the glimepiride group and decrease in the pioglitazone group, but the difference was not statistically significant (P=0.063). Page 5 of 8
Incidences of cardiovascular events as adjudicated by the CEC are shown in the table below. Ten subjects (4.4%) in the glimepiride group and 4 subjects (1.7%) in the pioglitazone group experienced 1 or more of the prespecified cardiovascular events. In addition, 1 subject in the pioglitazone group died of noncardiovascular causes. Cardiovascular Event or Event Category Glimepiride N=228 Pioglitazone N=230 n (%) n (%) Composite endpoint of cardiovascular mortality, nonfatal MI, and 2 (<1) 0 nonfatal stroke Composite endpoint of cardiovascular mortality, nonfatal MI, 10 (4.4) 4 (1.7) nonfatal stroke, coronary revascularization, carotid endarterectomy/stenting, hospitalization for unstable angina, and hospitalization for CHF Nonfatal MI 1 0 Nonfatal stroke 1 0 Coronary revascularization 8 3 Percutaneous coronary intervention 6 2 Coronary artery bypass graft 2 1 Hospitalization for CHF 0 1 New CHF 0 1 Noncardiovascular mortality 0 1 Changes from Baseline in markers of glucose metabolism are shown below: Glimepiride (N=228) Pioglitazone (N=230) P-value N Value (a) N Value (a) A1C, % Baseline 206 7.36 (0.075) 203 7.42 (0.074) 0.573 Change at Week 72 (b) 206-0.01 (0.079) 203-0.33 (0.077) 0.002 Treatment difference at -- -0.32 (-0.522, 0.124) -- Final Visit (95% CI) Fasting plasma glucose, mg/dl Baseline 211 150.6 (3.66) 217 151.8 (3.59) 0.808 Change at Week 72 (b) 211 6.4 (3.36) 217-4.6 (3.56) 0.022 Treatment difference at -- -11.0 (-20.29, -1.62) -- Final Visit (95% CI) Insulin, µu/ml Baseline 188 25.2 (1.76) 187 28.1 (1.70) 0.199 Change at Final Visit 188 0.9 (1.24) 187-6.5 (1.20) <0.001 Treatment difference at -- -7.4 (-10.49, -4.33) -- Final Visit (95% CI) Pro-Insulin, pmol/ml Baseline 187 39.91 (5.712) 187 53.04 (5.509) 0.068 Change at Final Visit 187-10.76 (1.774) 187-21.74 (1.709) <0.001 Treatment difference at Final Visit (95% CI) -- -10.99 (-15.382, -6.591) -- (a) Values of all glucose metabolism markers are LS mean (SE). (b) LOCF method. Page 6 of 8
Changes from Baseline in selected lipid profile markers are shown in the table below: Glimepiride (N=228) Pioglitazone (N=230) P-value N Value (a) N Value (a) Triglycerides, mg/dl Baseline 206 170.4 (8.13) 201 178.6 (8.10) 0.441 % change, Baseline to Final 206 2.1 (3.25) 201-13.5 (3.24) <0.001 Treatment difference (95% CI) -- -15.6 (-23.98, -7.26) -- Total cholesterol, mg/dl Baseline 206 185.6 (2.74) 201 188.1 (2.73) 0.492 % change, Baseline to Final 206-2.0 (1.34) 201 3.7 (1.34) 0.001 Treatment difference (95% CI) -- 5.7 (2.28, 9.18) -- HDL cholesterol, mg/dl Baseline 206 47.6 (0.91) 201 47.1 (0.90) 0.643 % change, Baseline to Final 206-1.1 (1.29) 201 12.8 (1.29) <0.001 Treatment difference (95% CI) -- 13.9 (10.59, 17.23) -- LDL cholesterol, mg/dl Baseline 206 111.3 (2.42) 200 113.8 (2.42) 0.433 %Change at Final Visit 206 1.0 (2.36) 200 5.8 (2.36) 0.122 Treatment difference (95% CI) -- 4.8 (-1.29, 10.85) -- (a) All lipid values are LS Mean (SE), using the LOCF method. In addition to the above variables, analyses of apolipoprotein B, apolipoprotein A1, and free fatty acid showed no statistically significant differences between the treatment groups. In lipid fractionation results at the Final Visit, the differences between the groups were highly statistically significant for most measures. Changes from Baseline showed a greater increase in large low-density lipoprotein (LDL) and LDL particle size, and greater decreases in LDL particle concentration, mediumsmall LDL, small LDL, and very small LDL, for pioglitazone than for glimepiride. Increases in large and medium-intermediate high-density lipoprotein (HDL) and mean HDL particle concentration and size for pioglitazone were statistically significantly different from the changes for glimepiride, while a greater decrease was seen in small HDL for pioglitazone than for glimepiride. Greater decreases in large and medium-intermediate very-low-density lipoprotein (VLDL) and mean VLDL particle size occurred with pioglitazone than with glimepiride, while small VLDL increased with pioglitazone and decreased with glimepiride. Analysis of changes from Baseline in markers of inflammation showed statistically significant treatment differences in matrix metalloproteinase-9 (a decrease of 28.89 ng/ml for pioglitazone vs an increase of 46.99 ng/ml for glimepiride; P=0.004), plasminogen activator inhibitor-1 (PAI-1) antigen (a decrease of 7.1 ng/ml for pioglitazone vs an increase of 1.5 ng/ml for glimepiride; P<0.001), PAI-1 activity (increases of 3.48 ng/ml for pioglitazone and 0.12 ng/ml for glimepiride; P<0.001), and tissue plasminogen activator (decreases of 2.2 ng/ml for pioglitazone and 1.0 ng/ml for glimepiride; P=0.022). In B-type natriuretic peptide, in the glimepiride group, following a decrease at Week 24 (by 0.4 mg/dl), values at Weeks 48 and 72 were increased over the Baseline value by 0.7 and 4.2 mg/dl, respectively. For pioglitazone, all post-baseline values were increased from Baseline (by 2.2, 3.2, and 9.3 mg/dl at Weeks 24, 48, and 72, respectively). No differences between the groups were statistically significant. 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. Incidences of adverse events were similar between the treatment groups: 89.0% for glimepiride and 89.6% for pioglitazone. In both treatment groups, fewer than half of the subjects with an adverse event had an event that was considered by the investigator to be related to study medication. Severe adverse events occurred in 17.1% and 18.3% of subjects receiving glimepiride and pioglitazone, respectively. Page 7 of 8
Adverse events with incidences of 5% or more in either treatment group are shown below: Preferred Term Glimepiride (N=28) Pioglitazone (N=230) n (%) n (%) Any adverse event 203 (89.0) 206 (89.6) Hypoglycemia 53 (23.2) 45 (19.6) Nasopharyngitis 33 (14.5) 30 (13.0) Edema peripheral 16 (17.0) 30 (13.0) Arthralgia 23 (10.1) 26 (11.3) Upper respiratory tract infection 20 (8.8) 26 (11.3) Headache 23 (10.1) 20 (8.7) Influenza 21 (9.2) 20 (8.7) Cough 15 (6.6) 16 (7.0) Diarrhea 17 (7.5) 16 (7.0) Fatigue 18 (7.9) 16 (7.0) Pain in extremity 13 (5.7) 16 (7.0) Dizziness 22 (9.6) 15 (6.5) Weight increased 10 (4.4) 15 (6.5) Nausea 9 (3.9) 14 (6.1) Hypertension 14 (6.1) 12 (5.2) Back pain 17 (7.5) 11 (4.8) Forty-four subjects were discontinued from the study due to adverse events: 19 (8.3%) in the glimepiride group and 25 (10.9%) in the pioglitazone group. The most common events leading to discontinuation were edema peripheral, dyspnea, and fatigue, accounting for discontinuation of 14 subjects (4 in the glimepiride group and 10 in the pioglitazone group). Serious adverse events occurred in 30 subjects (13.2%) in the glimepiride group and in 25 (10.9%) of those receiving pioglitazone. Aside from coronary artery disease (6 glimepiride subjects and 3 pioglitazone subjects, all undergoing coronary revascularization) and hypoglycemia (2 pioglitazone subjects), no serious adverse event occurred in more than 1 subject in either treatment group. All but 5 serious adverse events were considered by the investigator to be not related to study medication. The exceptions were cases of MI and cholecystitis in the glimepiride group and cases of nephrolithiasis, dizziness, and hypoglycemia in the pioglitazone group. One death occurred: an 80-year-old woman receiving pioglitazone died of malignant hepatic neoplasm and pancreatic carcinoma. The event was considered by the investigator and the sponsor to be unrelated to study medication. In most laboratory tests, the total mean changes from Baseline were small, as were the differences between the treatment groups. In serum chemistry tests, the most common individual abnormalities were fasting serum glucose levels above 250 mg/dl, occurring in 8.8% of glimepiride subjects and 5.7% of pioglitazone subjects, and blood urea nitrogen levels above 30 mg/dl, occurring in 3.5% of glimepiride subjects and 4.3% of pioglitazone subjects. In the urinalysis results, 3.9% of subjects in the glimepiride group had urine blood of 2+ or higher, compared with 5.7% of pioglitazone subjects. In systolic blood pressure, mean changes from Baseline to the Final Visit were -0.3 mm Hg for glimepiride and -2.0 mm Hg for pioglitazone (P=0.266). Corresponding changes in diastolic blood pressure were 0.3 and -2.1 mm Hg, respectively (P=0.023). In both treatment groups, mean increases from Baseline weight were seen at all visits after Week 4. After Week 16, all the increases were larger for pioglitazone than for glimepiride, and these differences were statistically significant from Week 24 through the Final Visit, when mean increases were 1.0 kg for glimepiride and 3.2 kg for pioglitazone (P<0.001). Date of Synopsis: 29 August 2008 Page 8 of 8