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Synopsis Name of the sponsor Takeda Pharmaceutical company Limited Name of the finished product Actos Tablets 15&30 Name of active ingredient Title of the study Pioglitazone Post-marketing Clinical Trial of Actos Tablets A Study of Preventive Effects on the Onset and Recurrence of Macrovascular Events Study centers 20 centers Related publications Kaku K, Daida H, Kashiwagi A, Yamashina A, Yamazaki T, Momomura S, Iwase T, Yamasaki Y, Nagatsuka K, Kitagawa K, Kawamori R. Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity. Curr Med Res Opin, 2009; 25: 2925-32. Yamasaki Y, Katakami N, Furukado S, Kitagawa K, Nagatsuka K, Kashiwagi A, Daida H, Kawamori R, Kaku K. Long-term effects of pioglitazone on carotid atherosclerosis in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity. J Atheroscler Thromb. 2010 Nov 27;17(11):1132-40. Study period 26 April 2002-13 June 2006 (Date of obtaining first subject s informed consent - Date of completing the study treatment in the last subject) Phase of development: Phase 4 Objective of the study Primary objective: The preventive effects of pioglitazone on the onset and recurrence of macrovascular events in type 2 diabetes mellitus patients were exploratory investigated using pioglitazone-untreated patients as the control group. Secondary objectives: [1] Using the carotid intima-media thickness (IMT) as the index, the prevention of arteriosclerosis by pioglitazone in type 2 diabetes mellitus patients was investigated using pioglitazone-untreated patients as the control group. [2] The long-term safety of pioglitazone in type 2 diabetes mellitus patients was investigated. Method of the study A multicenter, prospective, randomized, open, blinded end-point 1
Number of subjects (planned and analyzed) Planned Enrolled subjects: 550 subjects (275 in each group) Evaluable subjects: 500 subjects (250 in each group) Analyzed Efficacy analysis set: (Full analysis set) pioglitazone group: 293 subjects, pioglitazone-untreated (Per protocol set) pioglitazone group: 292 subjects, pioglitazone-untreated Safety analysis set: pioglitazone group: 293 subjects, pioglitazone-untreated Main entrance criteria [Indication Studied] Type 2 diabetes mellitus [Main Inclusion Criteria] (1) Subjects whose HbA1C rate was 6.5% (2) Subjects who met at least two of the following conditions 1) Subjects with hypertension 2) Subjects with hyperlipidemia 3) Subjects with a smoking habit 4) Obesity (3) Subjects aged 35 to <75 years (at the time of informed consent) (4) Subjects who were capable of giving consent to participate in the study and were also capable of reading and understanding the written informed consent form [Main Exclusion Criteria] (1) Subjects who were diagnosed with type 1 diabetes mellitus (2) Subjects with severe ketosis, diabetic coma or precoma (3) Subjects with a BMI of <22 and a fasting IRI of <5 µu/ml (4) Subjects who required insulin therapy to control the blood glucose of diabetes mellitus, or who were on insulin therapy (5) Subjects with serious hepatic function disorder or serious renal impairment (6) Subjects with a history of hepatic function disorder due to the use of thiazolidinediones (7) Subjects currently on pioglitazone therapy (8) Subjects who had cardiac failure or a history thereof (9) Subjects with cardiovascular disorders 1) Subjects with onset of myocardial infarction within 6 months 2) Subjects who received hospital treatment for acute coronary syndrome within 3 months 3) Subjects who underwent coronary artery bypass surgery or percutaneous transluminal coronary angioplasty within 6 months (10) Subjects with the complication of severe arrhythmia (11) Subjects with cerebrovascular disorders (12) Subjects who needed management of their blood glucose by insulin injection, due to severe infection, before or after operation, or serious traumatic injury (13) Subjects with scheduled coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, or surgery for leg ischemia (14) Subjects with a history of hypersensitivity to thiazolidinediones (15) Subjects with malignant tumors 2
Test product, dose and mode of administration [Investigational medical product, dose] Tablets containing 15 mg or 30 mg of pioglitazone per tablet (commercially obtained). [Mode of administration] Using Actos Tablets containing 15 mg or 30 mg of pioglitazone per tablet, pioglitazone 15 to 30 mg was orally administered once daily before or after breakfast. The dosage was adjusted according to the patient s sex, age and symptoms, up to the maximum daily dose of 45 mg. Duration of Treatment Endpoint Statistical Methods 2.5 to 4 years [Primary endpoint] Time to the onset of any of the following macrovascular events from the start of the treatment period [1] Death (endogenous) [2] Myocardial infarction (non-fatal) [3] Silent myocardial infarction [4] Acute coronary syndrome [5] Coronary intervention (percutaneous vascular intervention, coronary artery bypass surgery) [6] Cerebrovascular disorder (excluding TIA) [7] Lower limb (leg down to the ankle) amputation [8] Lower limb bypass surgery or angioplasty [9] Onset or worsening of angina pectoris [10] Arteriosclerosis obliterans [Secondary endpoints] Changes in IMT, occurrence of adverse events [Analysis of primary endpoint] Time to the first onset of a macrovascular event (Subjects analyzed) Full analysis set (Analytical method) For the time to the first onset of a macrovascular event from the study initiation day, survival time was analyzed. The ratio of event-free subjects was estimated for each group by the Kaplan-Meier method, and was compared between the groups by a logrank test. The number of events and the number of censored cases were presented for each group. (Events) The presence/absence of an event was defined as follows: In subjects in whom pioglitazone treatment was discontinued, events that occurred during the observation period after discontinuation were also included in the analysis. In subjects who had no events, the observation period was also included in the event-free period (time to censored observation). [Analyses of secondary endpoints] Changes in IMT (Subjects analyzed) Full analysis set (Analytical method) Among the full analysis set, subjects for whom data obtained at the start of the treatment period (Week 0) and at one or more time points during the treatment period were available, were subjected to the following analyses. For the test values obtained every 24 weeks and their changes from the values 3
obtained at the start of the treatment period, summary statistics were calculated by group, and the time courses and box plots of means ± SD were prepared For reference, the 2-sample t-test was performed between the groups, and the changes were examined by the 1-sample t-test for each group. [Safety analysis] Analysis of adverse events (Analysis items) The frequency of adverse events in the pioglitazone group and in the pioglitazone-untreated group was calculated. Two-sided 95% confidence intervals (CI) were calculated for the incidence by treatment group and for the inter-group difference [(Value in the pioglitazone group) (Value in the pioglitazone-untreated group)]. In addition, the incidence was compared between the groups by the contingency table χ 2 test. Summary of Results [Efficacy Results] (1) Primary endpoint The cumulative incidence of macrovascular events was 3.56% in the pioglitazone group and 4.49% in the pioglitazone-untreated group. No significant difference in the incidence of macrovascular events was observed between the two groups (logrank test: p=0.5512). (2) Secondary endpoint The IMT of the right and left common carotid arteries during the treatment period tended to decrease in both the pioglitazone and pioglitazone-untreated groups, showing no differences between the treatment groups. Changes in the IMT of the right and left carotid artery bifurcations to the internal carotid artery were similar between the pioglitazone and pioglitazone-untreated groups. [Safety Results] The number of subjects with adverse events and the number of adverse events in the pioglitazone and pioglitazone-untreated groups were as follows. A total of 1948 events occurred in 286 subjects in the pioglitazone group, with an incidence of 97.6% (286 of 293 subjects), whereas a total of 1969 events occurred in 285 subjects in the pioglitazone-untreated group, with an incidence of 96.9% (285 of 294 subjects). [Conclusions] The onset of macrovascular events tended to be delayed in the pioglitazone group compared with the pioglitazone-untreated group, but there were no significant differences between the two groups. In addition, the IMT of the right and left common carotid arteries tended to decrease in both the pioglitazone and pioglitazone-untreated groups during the treatment period, showing no differences between the treatment groups. There were no major differences in the incidence of adverse events between the treatment groups. Thus, no new safety concerns have been identified. HbA1C, fasting blood glucose, proinsulin and fasting IRI decreased significantly in the pioglitazone group compared with the pioglitazone-untreated group. Pioglitazone has been confirmed to provide good and stable blood glucose control over a long period of time, and also showed a trend toward reducing the need for insulin. Date of Report 2011/07/07 4