Clinical Trial Synopsis TL-OPI-516, NCT#

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1 Clinical Trial Synopsis, NCT# Title of Study: A Double-Blind, Randomized, Comparator-Controlled Study in Subjects With Type 2 Diabetes Mellitus Comparing the Effects of Pioglitazone HCl Versus Glimepiride on the Rate of Progression of Coronary Atherosclerotic Disease as Measured by Intravascular Ultrasound Name of Sponsor: Takeda Global Research & Development Center, Inc. (TGRD) Name of Active Ingredient: Pioglitazone Hydrochloride (HCl) Name of Finished Product: ACTOS Investigators who Enrolled Subjects: There were 162 investigators in this study who enrolled subjects. Study Sites that Enrolled Subjects: 152 centers in the United States, Canada, Argentina, and Chile received drug. Subjects were enrolled at 97 centers. Publication (reference): Nissen SE, Nicholls SJ, Wolski K, et al. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. Jama. 2008;299(13): PMID# Study Period : 21 July 2003 to 18 October 2007 Phase of Development: Phase 3b OBJECTIVES Primary: The primary objective of the study was to compare the effect of treatment with pioglitazone HCl vs glimepiride on the nominal change in percent atheroma volume of the identified target coronary artery segment in subjects with type 2 diabetes from baseline after 18 months of treatment as measured by intravascular ultrasound (IVUS) imaging of the coronary arteries. Secondary: The secondary objectives of this study were to compare the effect of pioglitazone vs glimepiride on the following: The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. The occurrence of cardiovascular events in the following composite endpoints: (a) cardiovascular mortality, nonfatal myocardial infarction (MI), or nonfatal stroke; (b) cardiovascular mortality, nonfatal MI, nonfatal stroke, coronary revascularization, carotid endarterectomy/carotid stenting, hospitalization for unstable angina, or hospitalization for congestive heart failure (CHF); and (c) cardiovascular mortality, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or hospitalization for CHF. Page 1 of 7

2 METHODOLOGY This was a phase 3b, multicenter study in subjects with type 2 diabetes mellitus undergoing coronary angiography with or without coronary intervention. The purpose of this study was to compare the effect of pioglitazone or glimepiride on the coronary artery atheroma volume using IVUS of the coronary arteries following up to 18 months of treatment. The study consisted of up to a 2-week Screening Period followed by a 72-week (18-month) Double-Blind Treatment Period, a 7-day posttreatment Follow-up Visit, and a 30-day posttreatment Follow-up Contact. Subjects presenting at the investigational site requiring diagnostic coronary angiography or percutaneous coronary intervention (PCI) signed a consent form and were screened prior to cardiac catheterization. At the beginning of the Screening Period, the protocol inclusion and exclusion criteria were reviewed with the subject. If the subject appeared eligible for the study based on initial evaluation, and was undergoing angiography, he or she continued to be evaluated for participation in the trial. Coronary angiography was performed and if there was at least a 20% diameter stenosis in any native proximal coronary artery by visual inspection at coronary angiography, and the subject qualified by all of the other angiographic criteria, the IVUS procedure was performed after the coronary angiogram in order to determine baseline total plaque volume and whether the subject required PCI. If a percutaneous transluminal coronary angioplasty or stent placement was performed as a result of the qualifying coronary angiogram, the IVUS evaluation was performed immediately after the percutaneous procedure on the day of the catheterization. The IVUS videotape obtained at the time of the qualifying angiogram or the PCI (if performed) was sent to the IVUS Core Laboratory for evaluation. If the IVUS procedure was acceptable by the IVUS Core Laboratory at the Cleveland Clinic Cardiovascular Coordinating Center (C5) and the subject met all other entry criteria, then he or she was eligible for randomization. All subjects were randomized at the earliest appropriate date following acceptable screening results, including acceptable IVUS image quality and IVUS interrogation protocol adherence, as determined by the IVUS Core Laboratory s assessment. At the Randomization Visit, subjects were assigned to the initial dose level of study drug according to their oral antidiabetic medication status, and then randomized to pioglitazone or glimepiride. Following randomization, subjects entered a 72-week (18-month) treatment period during which study drug 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 45 mg/day pioglitazone or 4 mg/day glimepiride. The goal of titration was to maximize the dose of study drug to achieve and maintain glucose control. Study visits occurred at 4, 8, 16, 24, 32, 40, 48, 60, and 72 weeks after the Randomization Visit. The Follow-up Visit occurred 7 days after the last dose of study drug.. Subjects were contacted 30 days after the last dose of study drug to perform an assessment of endpoints and adverse events (AEs). Subjects who discontinued study drug prior to 72 weeks (18 months) were contacted at 6-month intervals to perform endpoint assessments, with the last contact occurring 72 weeks from the date of randomization. The IVUS was performed at screening and at 72 weeks (18 months) after randomization or earlier if a subject s clinical condition warranted a diagnostic angiography before the 72-week (18-month) scheduled observation. Subjects received standard therapy for coronary artery disease, which included angiotensin-converting enzyme (ACE) inhibitors, β-blockers, angiotensin receptor blockers, statins, nitrates, anticoagulants, and antiplatelet agents. Number of Subjects: Planned: 440 (220 subjects per treatment group) Analyzed: Intent-to-treat (ITT) population: 543 subjects (273 glimepiride, 270 pioglitazone); Safety population: 543 subjects (273 glimepiride, 270 pioglitazone); IVUS population: 360 subjects (181 glimepiride, 179 pioglitazone). Page 2 of 7

3 Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have been between the ages of 35 and 85 years, inclusive, had coronary artery disease and type 2 diabetes, presented for cardiac catheterization with or without intervention, and were capable of understanding and willing to sign the informed consent. Subjects who were naïve to or not currently taking antidiabetic therapy or who were currently treated with monotherapy or combination antidiabetic therapy were included. Subjects had to have a glycosylated hemoglobin level at screening of 6.0% and <9% if taking antidiabetic medication or 6.5% and <10% if naïve to or not taking antidiabetic medication. Test Product, Dose and Mode of Administration/Lot Number: Pioglitazone 15 mg tablets, oral Pioglitazone placebo, matching tablets, oral Page 3 of 7 Batch/Lot Number 06056, 06066, Z509H161, Z509H171, Z509H181, Z509H191, Z509H , 06026, 06036, Z509F171 Reference Therapy, Dose and Mode of Administration, Batch Number: Batch/Lot Number Glimepiride, 1 and 2 mg tablets /O/E , /O/E (overencapsulated [O/E]), oral , /O/E , /O/E , /O/E , /O/E , /O/E , /O/E , /O/E , /O/E , /O/E , /O/E Glimepiride placebo, matching capsules, oral , , , , , Duration of Treatment: The study consisted of up to a 2-week Screening Period followed by a 72-week (18-month) Double-Blind Treatment Period, a 7-day posttreatment Follow-up Visit, and a 30-day posttreatment Follow-up Contact. Criteria for Evaluation: Efficacy: The primary efficacy endpoint was the nominal change from baseline at the Final Visit in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. The secondary efficacy variables were as follows: Nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. Time to the first occurrence of any of the cardiovascular events in the composite of cardiovascular mortality, nonfatal MI, or nonfatal stroke. Time to the first occurrence of any of the cardiovascular events in the composite of cardiovascular mortality, nonfatal MI, nonfatal stroke, coronary revascularization, carotid endarterectomy/carotid stenting, hospitalization for unstable angina, or hospitalization for CHF. Time to the first occurrence of any of the cardiovascular events in the composite of cardiovascular mortality, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, or hospitalization for CHF.

4 Potential endpoint events were assessed at each clinic visit and at each posttreatment contact. For each event, a dossier was compiled for review by the Clinical Endpoint Committee (CEC). The CEC was composed of independent cardiologists or internists with cardiology expertise. They reviewed all serious adverse events (SAEs) and clinical endpoints reported by the sites, including such items as initial cardiovascular diagnosis, laboratory values, electrocardiograms (ECGs), CRFs, and hospital records to determine the occurrence of clinical endpoints. The CEC s assessment of each potential endpoint was documented in the clinical database and was used in the endpoint analysis. Safety: Safety evaluation including summary of AEs, laboratory tests, vital signs, abdominal and hip girth measurements, and 12-lead electrocardiogram were based on the safety population, which consisted of all subjects who received at least 1 dose of double-blind study drug. Statistical Methods: Percent atheroma volume values were summarized for each treatment group by descriptive statistics (N, mean, SD, median, minimum maximum). The treatment comparisons for nominal change from baseline 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 treatment comparison was made at the significance level. The mixed model procedure with all effects fixed and Type III sums of squares were used to generate the ANCOVA results. The least squares (LS) mean and its standard error of the nominal change from baseline is presented for each treatment group. The LS mean treatment difference in change from baseline and the 95% confidence interval for this treatment difference were also reported for each endpoint. Nominal change from baseline in normalized total atheroma volume values were analyzed and summarized as described above for the primary endpoint (nominal change from baseline in percent atheroma volume values). All analyses and summaries involving the cardiovascular events were based on CEC determinations and the safety population. For each adjudicated cardiovascular event time-to variable, survival analysis methodolgy (Kaplan-Meier) was used to estimate the probability of experiencing the event during the study. All events within 30 days after the last dose of study drug were included and time to data for subjects who did not experience the event being analyzed within 30 days post-treatment, were censored at the last dose of study drug + 30 days. The 2 treatment groups were compared using a log-rank test. The number and percentage of subjects with each of the composite endpoints, as well as each cardiovascular event that comprised the composite endpoints are also presented. SUMMARY OF RESULTS Baseline Demographics and Characteristics: Of the 547 subjects enrolled in the study, a total of 273 subjects were randomized to receive glimepiride 1 to 4 mg once daily (QD), and 274 were randomized to receive pioglitazone 15 to 45 mg QD. Four subjects who were assigned to treatment with pioglitazone group did not receive study drug. The majority of the 543 subjects who received drug were male (65.9% of glimepiride subjects and 68.9% of pioglitazone subjects) and predominantly Caucasian (80.6% of glimepiride subjects and 83.3% of pioglitazone subjects). Black subjects made up approximately 10% of the population, and approximately 25% of subjects identified themselves as being of Hispanic ethnicity. Subjects averaged approximately 60 years of age, with a mean duration of diabetes of approximately 8 years and a mean duration of coronary artery disease (CAD) of over 3 years. The majority of subjects were taking either a sulfonylurea, metformin, or a sulfonylurea/metformin combination to treat their diabetes. No statistically significant differences were found between the treatment groups in any demographic or baseline characteristics analyzed. Subject Disposition: The distribution of subjects who were enrolled and who prematurely discontinued the study are presented by treatment in the following table. The mean treatment duration was 56.3 weeks for glimepiride and 56.5 weeks for pioglitazone (P=0.992). Page 4 of 7

5 Glimepiride n (%) (N=273) Pioglitazone n (%) (n=274) Completed study 178 (65.2) 177 (64.6) Discontinued from study 95 (34.8) 97 (35.4) Adverse event a 34 (12.5) 30 (10.9) Lack of efficacy 1 (0.4) 4 (1.5) Lost to follow-up 6 (2.2) 4 (1.5) Investigator s discretion 8 (2.9) 6 (2.2) Protocol violation 3 (1.1) 6 (2.2) Voluntary withdrawal 34 (12.5) 40 (14.6) Other 9 (3.3) 7 (2.6) a Includes 5 deaths that occurred during the study (2 glimepiride group, 3 pioglitazone group). None of these deaths were considered related to study drug by the investigator. 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. A statistically significant difference between treatment groups in favor of pioglitazone was observed in the primary and supportive analyses of the primary efficacy endpoint (nominal change from baseline in percent atheroma volume). Results for the primary efficacy variable in the IVUS population are shown in the table below: Glimepiride (N=273) Pioglitazone (N=270) P-value N PAV a N PAV a Baseline (0.6663) (0.6925) Nominal Change from baseline (0.2017) (0.2095) Treatment difference (95% CI) at Final Visit b ( , ) a PAV=percent atheroma volume. b Mean change from baseline and mean treatment difference in change from baseline are the least squares (LS) means from the ANCOVA model. Secondary analyses of IVUS findings are shown in the following table. Statistically significant differences were observed in favor of pioglitazone for the secondary IVUS measures of average maximum plaque thickness and normalized percent atheroma volume. Glimepiride Pioglitazone P-value N Value N Value Nominal change from baseline in normalized total atheroma volume IVUS Population Baseline, mm (7.0030) (7.2778) Change from baseline, mm (1.5370) (1.5989) Treatment difference (95% CI) at Final Visit a ( , ) Nominal change from baseline in average maximum plaque thickness IVUS Population Baseline, mm (0.0194) (0.0202) Change from baseline, mm (0.0055) (0.0058) Treatment difference (95% CI) at Final Visit a ( , ) a Mean change from baseline and mean treatment difference in change from baseline are the least squares (LS) means from the ANCOVA model. Page 5 of 7

6 Secondary analyses of the time to the first occurrence (time to event) of cardiovascular events /cardiovascular-related hospitalizations in this study had non-estimable confidence intervals (due to the low number of subjects experiencing the composite endpoint). No statistically significant differences based on log-rank tests were observed for these primary and secondary time-to-event analyses utilizing Kaplan Meier methodolgy. The incidences of cardiovascular events as adjudicated by the CEC are shown in the table below: Cardiovascular Event or Event Category Glimepiride N=273 Pioglitazone N=270 n (%) n (%) Composite endpoint of cardiovascular mortality, nonfatal MI, or 6 (2.2) 5 (1.9) nonfatal stroke Composite endpoint of cardiovascular mortality, nonfatal MI, 41 (15.0) 40 (14.8) nonfatal stroke, coronary revascularization, carotid endarterectomy/stenting, hospitalization for unstable angina, or hospitalization for CHF Composite endpoint of cardiovascular mortality, nonfatal MI, 13 (4.8) 11 (4.1) nonfatal stroke, hospitalization for unstable angina, or hospitalization for CHF Cardiovascular mortality 1 (0.4) 3 (1.1) Nonfatal MI 4 (1.5) 2 (0.7) Nonfatal stroke 1 (0.4) 0 Coronary revascularization a 30 (11.0) 29 (10.7) PCI 28 (10.3) 25 (9.3) Coronary artery bypass graft 2 (0.7) 5 (1.9) Carotid endarterectomy/stenting 0 1 (0.4) Hospitalization for unstable angina 2 (0.7) 4 (1.5) Hospitalization for CHF a 5 (1.8) 4 (1.5) New CHF 2 (0.7) 4 (1.5) Exacerbated CHF 3 (1.1) 0 Noncardiovascular mortality 1 (0.4%) 0 a Categories are not mutually exclusive. Page 6 of 7

7 Safety Results: Adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in cclinical 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. Adverse events with incidences higher than 5% in either treatment group are shown below: Preferred Term Glimepiride N=273 Pioglitazone N=270 n (%) n (%) Any AE 230 (84.2) 234 (86.7) Oedema (combined) a 37 (13.6) 51 (18.9) Oedema peripheral 30 (11.0) 48 (17.8) Oedema 8 (2.9) 5 (1.9) Hypoglycaemia 101 (37.0) 41 (15.2) Non-cardiac chest pain 31 (11.4) 32 (11.9) Coronary artery disease 23 (8.4) 28 (10.4) Weight increased 15 (5.5) 28 (10.4) Dizziness 21 (7.7) 26 (9.6) Angina pectoris 33 (12.1) 19 (7.0) Headache 17 (6.2) 19 (7.0) Arthralgia 15 (5.5) 17 (6.3) Fatigue 14 (5.1) 17 (6.3) Urinary tract infection 19 (7.0) 17 (6.3) Hyperglycaemia 16 (5.9) 16 (5.9) Nausea 18 (6.6) 16 (5.9) Pain in extremity 19 (7.0) 15 (5.6) Upper respiratory tract infection 16 (5.9) 15 (5.6) Influenza 9 (3.3) 14 (5.2) Hypertension 24 (8.8) 13 (4.8) Nasopharyngitis 22 (8.1) 13 (4.8) Diarrhoea 14 (5.1) 11 (4.1) a Aggregate term including preferred terms oedema peripheral and oedema. Sixty-seven subjects were discontinued from the study due to AEs: 35 (12.8%) in the glimepiride group and 32 (11.9%) in the pioglitazone group. The most common events leading to discontinuation in either treatment group were CAD, increased weight, and peripheral edema. SAEs occurred in 77 (28.2%) of the subjects in the glimepiride group and in 76 (28.1%) of those receiving pioglitazone. The most frequently reported SAEs were CAD (16 glimepiride subjects and 20 pioglitazone subjects), angina pectoris (4 glimepiride subjects and 8 pioglitazone subjects), coronary artery stenosis (5 glimepiride subjects and 5 pioglitazone subjects), unstable angina (3 glimepiride subjects and 4 pioglitazone subjects), congestive cardiac failure (5 glimepiride subjects and 5 pioglitazone subjects), MI (3 glimepiride subjects and 5 pioglitazone subjects), noncardiac chest pain (5 glimepiride subjects and 15 pioglitazone subjects), and pneumonia (6 glimepiride subjects and 1 pioglitazone subject). Five deaths occurred during the study. In the glimepiride group, 1 subject died of injuries from a motorcycle accident and 1 subject died of cardiac arrest. In the pioglitazone group, 1 subject died of MI, 1 subject died of methadone toxicity, and 1 subject died of acute pulmonary edema. None of the deaths were considered related to study drug, as assessed by the investigator. In both treatment groups, mean increases from baseline weights were seen at Week 4 and all subsequent visits. Statistically significantly larger weight gains were observed in subjects receiving pioglitazone at Week 48 (P=0.008), Week 60 (P=0.001), Week 72 (P=0.003), and at Final Visit (P=0.002). Date of Synopsis: 17 October 2008 Page 7 of 7