The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only.

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1 The clinical trial information provided in this public disclosure synopsis is supplied for informational purposes only. Please note that the results reported in any single trial may not reflect the overall potential risks or benefits of a product which are based on an evaluation of an entire research program. Before prescribing any Takeda products, healthcare professionals should consult prescribing information for the product approved in their country.

2 Clinical Trial Synopsis, NCT Title of Study: PROspective PioglitAzone Clinical Trial in MacroVascular Events (PROactive) Name of Sponsor: Takeda Europe Research & Development Centre, Ltd Name of Active Ingredient: (+)-5[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione hydrochloride (AD-4833) Name of Finished Product: Pioglitazone hydrochloride Study Centers: 321 study sites in 19 countries Publications (references): Bottomley J, Palmer AJ, Williams R, Dormandy J, Massi-Benedetti M. PROactive 03: pioglitazone, type 2 diabetes and reducing macrovascular events - economic implications. British Journal of Diabetes & Vascular Disease 2006;6(2): Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial in MacroVascular Events): a randomised controlled trial. Lancet 2005;366(9493): PMID: Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive): Can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5,238 patients. Diabetes Care 2004;27(7): PMID: Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care 2007;30(11): PMID: Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, PROactive Investigators. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol 2007;49(17): PMID: Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, PROactive Investigators. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08). Diabetes Care 2007;30(11): PMID: Erdmann E, Dormandy J, Wilcox R, Massi-Benedetti M, Charbonnel B. PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study. Vasc Health Risk Manag 2007;3(4): PMID: Erdmann E. Pioglitazone and recurrent myocardial infarction in patients with diabetes and a previous Page 1 of 7

3 myocardial infarction. Cardiology Review 2008;25(1):21-5. Pfutzner A, Forst T. Successful cardiovascular secondary prevention with pioglitazone in patients with type 2 diabetes: results of the PROactive study. Diabetes und Stoffwechsel 2005;14(6): Scheen AJ, Lefebvre PJ. PROactive study: secondary cardiovascular prevention with pioglitazone in type 2 diabetic patients. Rev Med Liege 2005;60(11): PMID: Singaram V, Pratley R. The PROactive trial (PROspective pioglitazone Clinical Trial In macrovascular Events): what does it mean for primary care physicians. Diab Vasc Dis Res 2007;4(3): PMID: Valentine WJ, Bottomley JM, Palmer AJ, Brandle M, Foos V, Williams R, et al. PROactive 06: costeffectiveness of pioglitazone in type 2 diabetes in the UK. Diabet Med 2007;24(9): PMID: Wilcox R, Bousser MG, Betteridge DJ, Schernthaner G, Pirags V, Kupfer S, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke. Results from PROactive (PROspective pioglitazone clinical trial in macrovascular events 04). Stroke 2007;38(3): PMID: Wilcox R, Kupfer S, Erdmann E; PROactive Study Investigators. Effects of pioglitazone on major adverse cardiovascular events in high- risk patients with type 2 diabetes: results from PROspective pioglitazone Clinical Trial In macro Vascular Events (PROactive 10). Am Heart J 2008;155(4): PMID: Study Period (years): Phase of Development: 28 May 2001 to 31 January 2005 Phase 3b OBJECTIVES Primary: To demonstrate that pioglitazone reduces total mortality and macrovascular morbidity in high-risk patients with type 2 diabetes mellitus. Secondary: To further characterize the safety of pioglitazone in this group of type 2 diabetes patients. METHODS This was a multicenter, randomized, double-blind, placebo-controlled, parallel group study. Male and female patients with a diagnosis of type 2 diabetes mellitus, between 35 and 75 years old, inclusive, were screened for eligibility based on results of a medical history, physical examination, and laboratory assessment of alanine aminotransferase (ALT) and glycosylated hemoglobin (A1C). Patients who met eligibility criteria and provided written informed consent were randomized to treatment with either pioglitazone or matching placebo. Randomization was conducted in permuted blocks of 4 using a center-specific computer-generated randomization list prepared by the Statistics Department of Nottingham Clinical Research Limited (NCRL) and installed securely in the study Interactive Voice Response System (IVRS). Subjects began treatment with 15 mg doses of pioglitazone (or matching placebo) taken once daily with current diabetic medications. Doses were titrated from 15 mg to 30 mg at the first month visit, and from 30 mg to 45 mg at the second month visit, the dose that was maintained for the remainder of the study, unless there were tolerability concerns. At any time during the first 3 months and thereafter, upward titration could be suspended or the current dose reduced. Temporary cessation of study medication was also permitted. Treatment was continued for the duration of the study at the highest tolerated dose giving individual subjects an exposure to treatment of between 2.5 and 3.5 years. To maintain the double blind, treatment kits were provided to patients at each follow-up visit after the investigator telephoned a central IVRS to request a kit number at the dose appropriate to the treatment assignment. Concomitant diabetic medications were recorded in full. Use of insulin as sole therapy for glycemic control of diabetes for a minimum of 2 weeks during the 3 months prior to enrollment in the study, current use of a thiazolidinedione (TZD), or known hypersensitivity to a TZD were exclusion criteria. TZDs were not permitted as concomitant medications with study drugs. Investigators were instructed to manage all patients according to International Diabetes Federation (Europe) guidelines, which dictate that concomitant medications be adjusted as necessary to achieve optimal glycemic and lipid control. Page 2 of 7

4 During the first year, clinic visits were scheduled at 1, 2, 4, 6, 8, 10, and 12 months following randomization and then every 3 months thereafter. At each visit, weight, blood pressure, adverse events, concomitant medications taken on the day of the visit, including, photocoagulation treatment for retinopathy, were recorded. Each patient continued study medication until either a minimum of 30 months follow-up was reached or a study total of 760 macrovascular events had been reported and Final Visits were completed. Number of Subjects: Planned: 5000 subjects. Analyzed: Full Analysis Set (Intent-to-Treat [ITT]) 5238 subjects. Diagnosis and Main Criteria for Inclusion: To qualify for study participation, subjects must have had a diagnosis of type 2 diabetes mellitus; been between 35 to 75 years of age, inclusive; were able to comprehend and willing to sign an informed consent form; had a value of A1C above the upper limit of normal (ULN) as determined by the local laboratory at Screening or at any time in the previous 2 months, and had an established history of macrovascular disease defined as 1 or more of the following: myocardial infarction (MI) at least 6 months before entry into the study; stroke at least 6 months before entry into the study; percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) at least 6 months before entry into the study; acute coronary syndrome at least 3 months before entry into the study; objective evidence of coronary artery disease including any 1 of the following: a positive exercise test, angiography showing at least 1 lesion of more than 50% stenosis of positive scintigraphy at any time prior to entry into the study; or symptomatic peripheral arterial obstructive disease. Test Product Dose and Mode of Administration Batch Number Pioglitazone hydrochloride 15 mg tablet, oral E mg tablet, oral E mg tablet, oral E Reference Therapy Dose and Mode of Administration Batch Number Matching placebo 15 mg tablet, oral E mg tablet, oral E mg tablet, oral E Duration of Treatment: The treatment duration was 2.5 to 3.5 years. Criteria for Evaluation: The primary endpoint was time from randomization to first occurrence of any of the events in the following composite: all-cause mortality, non-fatal MI (including silent MI), acute coronary syndrome, cardiac intervention including CABG or PCI, stroke, major leg amputation, and bypass surgery or revascularization in the leg. Secondary endpoints included time from randomization to first occurrence of any of the events in the following composite: all-cause mortality, non-fatal MI (excluding silent MI), and stroke; as well as individual components of the primary endpoint and cardiovascular mortality. Safety: Safety variables included adverse events, clinical laboratory tests to monitor liver and renal function, physical examinations, and measures of blood pressure and body size. Statistical Methods: All efficacy analyses were performed using the intent-to-treat (ITT) population, defined as follows: all patients who were randomized (ie, assigned to a treatment group via a telephone call to the central randomization facility) and who subsequently took at least 1 dose of study medication. The primary Page 3 of 7

5 analysis tested the null hypothesis: Pioglitazone is not different from placebo in reducing total mortality and macrovascular morbidity in high-risk patients with type 2 diabetes mellitus. The analysis of the primary and secondary endpoints was an analysis of time to events. For each endpoint, treatment-group differences were examined using a log rank test without covariates; a Cox proportional hazards model was fitted with treatment as the only independent variable for estimate of the hazard ratio (95% confidence interval [CI]); Kaplan-Meier estimates of the survival functions were used to characterize treatment effects. All subjects who received at least 1 dose of study medication were included in the safety analysis. Serious adverse event summaries are by those that occurred during the period of the study (ie, between date of first dose and the end of study date) and those that occurred while on treatment (ie, between date of first dose and date of last dose). The number of patients reporting a serious adverse event following start of treatment was reported by preferred term, system organ class, treatment group, and relationship to study medication. For commonly occurring events, treatment-group differences were assessed using the chi-square test. Specific preferred terms were grouped into a composite term for events of special interest: transient ischemic attack, carotid disorder, malignancies, and the number of patients reporting at least 1 serious adverse event in each of the following event classes: edema, cardiac ischemia, hypertension, cerebrovascular, and congestive heart failure. Non-serious events of special interest (hypoglycemia, new or worsening heart failure, edema, malignancy, or any other event leading to permanent cessation of study medication) were summarized and the treatment groups compared in a manner identical to that described for serious adverse events. Other non-serious adverse events are summarized by visit. SUMMARY OF RESULTS Subject Disposition: A total of 5238 subjects (mean age of 61.8 years), including 3463 male and 1775 female subjects, were randomized in the study from the 5602 subjects who were screened. A total of 4373 subjects completed the study while receiving study medication. The disposition of subjects is presented in the table below. Category, n (%) Pioglitazone (N=2605) Placebo (N=2633) Total (N=5238) Final status Had a Final Visit 2427 (93.2) 2446 (92.9) 4873 (93.0) Lost to follow-up 1 (0.0) 1 (0.0) 2 (0.0) Died 177 (6.8) 186 (7.1) 363 (6.9) Completed study? Yes 2178 (83.6) 2195 (83.4) 4373 (83.5) No 427 (16.4) 438 (16.6) 865 (16.5) Reason for cessation Adverse event 235 (9.0) 202 (7.7) 437 (8.3) Patient withdrew consent Failure to comply with protocol Exclusion criterion detected 171 (6.6) 179 (6.8) 350 (6.7) 31 (1.2) 38 (1.4) 69 (1.3) 16 (0.6) 18 (0.7) 34 (0.6) Other 53 (2.0) 76 (2.9) 129 (2.5) Page 4 of 7

6 A summary of demographic and baseline characteristics is presented in the table below. Pioglitazone N=2605 Treatment Placebo N=2633 Overall n=5238 Characteristic Gender, n (%) Male 1735 (66.6) 1728 (65.6) 3463 (66.1) Female 870 (33.4) 905 (34.4) 1775 (33.9) Race, n (%) White 2564 (98.4) 2600 (98.7) 5164 (98.6) Black 10 (0.4) 7 (0.3) 17 (0.3) Asian 29 (1.1) 23 (0.9) 52 (1.0) Other 2 (0.1) 3 (0.1) 5 (0.1) Mean (SD) Age (year) 61.9 (7.60) 61.6 (7.75) 61.8 (7.68) Duration of diabetes (year) 9.4 (6.94) 9.6 (7.09) 9.5 (7.02) Weight (kg) 87.6 (15.49) 88.5 (15.63) 88.0 (15.57) Height (m) 1.69 (0.090) 1.69 (0.091) 1.69 (0.091) BMI (kg/m 2 ) 30.7 (4.73) 31.0 (4.79) 30.9 (4.76) Waist circumference (cm) (11.71) (12.08) (11.90) Systolic blood pressure (mmhg) (17.72) (17.82) (17.77) Diastolic blood pressure (mmhg) 82.8 (9.94) 83.2 (9.44) 83.0 (9.70) Ankle blood pressure (mmhg) (34.39) (34.92) (34.65) ABPI (a) 0.93 (0.238) 0.92 (0.239) 0.92 (0.238) ABPI=ankle brachial pressure index, SD=standard deviation. (a) ABPI was collected for subjects who entered the study with peripheral arterial obstructive disease. Data are available for 1267 subjects: 611 in the pioglitazone group and 656 in the placebo group. 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 of the primary composite endpoint analysis showed a 10% relative risk reduction of the first events within the composite for the pioglitazone-treated patients. The Cox proportional hazards model gave an estimate of 0.90 for the hazard ratio comparing pioglitazone with placebo, which did not reach statistical significance (95% CI: 0.80, 1.02; P=0.0954). Results of the analysis of the main secondary composite endpoint, a composite of 3 disease endpoints of the primary endpoint (ie, all-cause mortality, non-fatal MI [excluding silent MI], and stroke) showed a statistically significant 16% relative risk reduction of the events within the composite with pioglitazone treatment. The Cox proportional hazards model gave an estimate of 0.84 (95% CI: 0.72, 0.98; P=0.0277) for the hazard ratio comparing pioglitazone with placebo. The results of the primary and main secondary endpoints were not affected by adjustment of significant baseline covariates in a multivariate model. The analyses of the other secondary endpoints including the time to first event of the individual components of the primary composite endpoint and cardiovascular mortality showed no statistically significant differences between treatment groups. 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. Page 5 of 7

7 Adverse Events The percentage of patients who had any adverse event while in the study was similar for both treatment groups; 81.7% in the pioglitazone group and 80.6% in the placebo group. The percentage of patients who experienced any treatment-emergent adverse event was 80.6% for the pioglitazone group and 78.6% for the placebo group. The most common treatment-emergent adverse events, reported by 3.0% or more of patients in either treatment group, are presented in the table below. System Organ Class Pioglitazone N=2605 Placebo N=2633 Preferred Term n (%) n (%) Total no. of patients with any adverse event 2099 (80.6%) 2069 (78.6%) Cardiac disorders 624 (24.0%) 634 (24.1%) Angina unstable 99 (3.8%) 106 (4.0%) MI 79 (3.0%) 103 (3.9%) Gastrointestinal disorders 420 (16.1%) 455 (17.3%) Diarrhea 92 (3.5%) 94 (3.6%) General disorders and administration site conditions 903 (34.7%) 666 (25.3%) Chest pain 133 (5.1%) 129 (4.9%) Fatigue 74 (2.8%) 84 (3.2%) Edema 689 (26.4%) 397 (15.1%) Infections and infestations 741 (28.4%) 765 (29.1%) Bronchitis 90 (3.5%) 82 (3.1%) Influenza 97 (3.7%) 92 (3.5%) Nasopharyngitis 151 (5.8%) 185 (7.0%) Injury, poisoning and procedural complications 265 (10.2%) 238 (9.0%) Accident 114 (4.4%) 84 (3.2%) Investigations 337 (12.9%) 315 (12.0%) Weight increased 95 (3.6%) 35 (1.3%) Metabolism and nutrition disorders 771 (29.6%) 616 (23.4%) Hypoglycemia 709 (27.2%) 494 (18.8%) Musculoskeletal and connective tissue disorders 600 (23.0%) 595 (22.6%) Arthralgia 142 (5.5%) 150 (5.7%) Back pain 144 (5.5%) 134 (5.1%) Pain in the extremity 166 (6.4%) 150 (5.7%) Nervous system disorders 499 (19.2%) 540 (20.5%) Dizziness 99 (3.8%) 92 (3.5%) Headache 82 (3.1%) 101 (3.8%) Respiratory, thoracic, and mediastinal disorders 294 (11.3%) 261 (9.9%) Cough 78 (3.0%) 88 (3.3%) Dyspnea 85 (3.3%) 56 (2.1%) Surgical and medical procedures 315 (12.1%) 363 (13.8%) Diabetes mellitus management 44 (1.7%) 84 (3.2%) Vascular disorders 307 (11.8%) 299 (11.4%) Hypertension 94 (3.6%) 104 (3.9%) Serious Adverse Events There were 1127 (43.3%) pioglitazone-treated patients and 1181 (44.9%) placebo-treated patients who experienced at least 1 treatment-emergent serious adverse event. For both treatments, the most commonly reported serious adverse events were within the cardiac disorders system organ class (which were experienced by 16.3% of pioglitazone-treated patients and 17.4% of placebo-treated patients). The most frequently reported preferred terms within this class were myocardial infarction, angina pectoris, and angina unstable, each of which was reported more often in the placebo group. The greatest difference between the treatments was for angina pectoris, which was reported for 77 (3.0%) patients in the pioglitazone group and 110 (4.2%) patients in the placebo group. Myocardial infarction was reported for 79 (3.0%) pioglitazone-treated patients and 103 (3.9%) placebo-treated patients. The preferred term atrial fibrillation was reported for 33 (1.3%) pioglitazone-treated patients and 46 (1.7%) placebo-treated patients. Page 6 of 7

8 The preferred terms cardiac failure, cardiac failure congestive, and left ventricular failure were reported for more patients in the pioglitazone group (2.7%, 1.3%, and 0.5%, respectively) than in the placebo group (2.4%, 1.0%, and 0.2%). Serious Adverse Events of Special Interest Additional summaries were prepared for those serious adverse events that were considered to be of special interest. These events are summarized in the table below. While on or Immediately After Permanent Cessation While in the Study of Study Medication (a) Pioglitazone N=2605 Placebo N=2633 Pioglitazone N=2605 Placebo N=2633 Category of Special Interest n (%) n (%) n (%) n (%) Cardiac ischemic 328 (12.6%) 400 (15.2%) 297 (11.4%) 369 (14.0%) Carotid disorders 24 (0.9%) 27 (1.0%) 24 (0.9%) 21 (0.8%) Cerebrovascular 144 (5.5%) 182 (6.9%) 126 (4.8%) 164 (6.2%) Edema 5 (0.2%) 3 (0.1%) 4 (0.2%) 2 (0.1%) Heart failure 149 (5.7%) 108 (4.1%) 127 (4.9%) 96 (3.6%) Hypertension 29 (1.1%) 45 (1.7%) 24 (0.9%) 40 (1.5%) Hypoglycemia 20 (0.8%) 12 (0.5%) 17 (0.7%) 10 (0.4%) Liver disorder 4 (0.2%) 5 (0.2%) 3 (0.1%) 5 (0.2%) Malignancy 97 (3.7%) 99 (3.8%) 93 (3.6%) 97 (3.7%) Transient ischemic attack 34 (1.3%) 39 (1.5%) 30 (1.2%) 36 (1.4%) (a) Includes treatment-emergent serious adverse events, as well as those events that occurred 30 days after permanent cessation of study medication. Deaths There were a total of 177 (6.8%) patients in the pioglitazone group and 186 (7.1%) in the placebo group who died during the study. The most frequently reported primary causes of death were within the special interest category of cardiac ischemia. Thirty (1.2%) patients in the pioglitazone group had a fatal cardiac ischemic event, whereas 45 (1.7%) patients died of such an event in the placebo group. The majority of these deaths were attributed to MI in both groups; 23 (0.9%) in the pioglitazone group and 35 (1.3%) in the placebo group. There were no notable differences between the treatment groups with respect to any other category of special interest. Adverse Events and Serious Adverse Events That Led to Study Medication Discontinuation There were 235 (9.0%) of patients in the pioglitazone group who discontinued study medication because of 1 or more adverse events vs 202 (7.7%) patients in the placebo group. A similar number of patients in both treatment groups experienced 1 or more serious adverse events that led to permanent discontinuation of study medication; 4.2% (110) of patients in the pioglitazone group and 4.1% (109) of patients in the placebo group. Most of the serious adverse events that led to permanent discontinuation of study medication were in the SOC cardiac disorders, and the majority were due to cardiac failure, cardiac failure congestive, or MI. Date of Synopsis: 26 November 2008 Page 7 of 7