Synopsis. Name of the sponsor Name of the finished product Name of active ingredient Study ID. Title of the study. Investigators and study centers:

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1 Synopsis Name of the sponsor Name of the finished product Name of active ingredient Study ID Title of the study Investigators and study centers: Related publications Takeda Global Research & Development Center, Inc. N/A TAK-379 TAK-379_201 A Phase II, Randomized, Double-Blind, Placebo- and Active- Controlled, Multi-center Study to Determine the Efficacy and Safety of TAK-379 in Subjects with Type 2 Diabetes Investigator: Julio Rosenstock, MD et al Study Sites: Subjects were screened at 96 sites and randomized at 83 sites: 59 sites in the United States, 9 sites in Mexico, 1 site in Guatemala, 2 sites in Chile, and 12 sites in Peru N/A Study period 03 July 2008 to 29 May 2009 (early termination 21 April 2009) Phase of development: Objective of the study Method of the study Number of subjects (planned and analyzed) Main entrance criteria Phase II The primary objective of this study was to evaluate the effect of TAK-379 administered as 25, 100 and 200 mg QD on glycemic control over a 12-week treatment period in subjects with T2DM inadequately controlled by diet and exercise or on a stable dose of metformin. Eligible subjects were randomly assigned in a 1:1:1:1:1 ratio to one of the following treatments: TAK , 100, or 200 mg; placebo; or pioglitazone 30 mg QD for 12 weeks. The study was terminated early because the TAK-379 program was terminated by the sponsor. Planned: Approximately 300 subjects Analyzed: Full Analysis Set 323 subjects; Safety Analysis Set 323 subjects To qualify for study participation, subjects must have been men or nonpregnant, nonlactating women; aged 18 to 80 years, inclusive; had either a historical diagnosis of T2DM without the chronic use (defined as >7 days) of antidiabetic therapy and an 8-week history of diet and exercise at Screening or a historical diagnosis of T2DM on a stable dose of metformin as monotherapy for at least 3 months prior to Screening; had an HbA1c level between 7.5% and 10.0%, inclusive; been able to understand and willing to sign an informed consent form; been able and willing to monitor his or her own blood glucose concentrations with a home glucose monitor; and had no known hypersensitivity to TAK-379 or its excipients. Women of childbearing potential who were sexually active must have agreed to use adequate contraception from Screening throughout the duration of the study and for 1 month after the last dose of

2 Test product, dose and mode of administration, and lot number Contrast product, dose and mode of administration, and lot number Duration of Treatment Endpoints Statistical Methods study drug. TAK mg tablet, oral Z TAK mg tablet oral Z Pioglitazone 30 mg tablet, oral Z509I263 Placebo pioglitazone tablet, oral Z509F222 and Z509F282 Placebo TAK-379 tablet, oral Z weeks The primary efficacy variable was the change from Baseline in HbA1c at Week 12/Early Termination (ET). The secondary efficacy variables were the change from Baseline in HbA1c at Weeks 4, and 8; the change from Baseline in fasting plasma glucose at Weeks 1, 2, 4, 8, and 12/ET; the change from Baseline in body weight at Weeks 4, 8, and 12/ET; the incidence of alanine aminotransferase (ALT) >3 times the upper limit of normal ( ULN) at Weeks 1, 2, 4, 6, 8, and 12/ET; and the plasma concentrations of TAK-379 and its metabolite M-I via a sparse sampling population approach. Safety variables were adverse events, clinical laboratory test results (serum chemistry, hematology, and urinalysis), vital sign measurements, physical examination findings, and electrocardiogram (ECG) results. Signs and symptoms of new or worsening lower limb edema during treatment and initiation of or increase in diuretic treatment due to new or worsening lower limb edema were assessed by the investigators based on a questionnaire at each visit. Incidence of hypoglycemia (blood glucose <70 mg/dl [3.33 mmol/l] in the presence of symptoms or blood glucose <60 mg/dl [2.78 mmol/l] regardless of symptoms). Primary Efficacy Analysis The primary efficacy variable was the change from Baseline in HbA1c at Week 12/ET and was analyzed using an analysis of covariance (ANCOVA) with treatment and center as fixed effects and baseline value as a covariate. Treatment comparison for each active treatment (TAK , 100, and 200 mg and pioglitazone 30 mg) with placebo and each TAK-379 dose with pioglitazone 30 mg was performed within the framework of the ANCOVA with treatment and center as fixed effects and baseline HbA1c as a covariate using 2-sided test at 5% significance level. Missing data were imputed using the last observation carried forward (LOCF) method. Secondary Efficacy Analyses The secondary efficacy variables were the change from Baseline in HbA1c at Weeks 4,, and 8; the change from Baseline in fasting plasma glucose at Weeks 1, 2, 4,, 8, and 12/ET; the change from Baseline in body weight at Weeks 4, 8, and 12/ET; and the incidence of ALT >3 ULN at Weeks 1, 2, 4, 6, 8, and 12/ET. The secondary efficacy variables were analyzed using a method that was similar to that used to analyze the primary efficacy

3 Summary of Results variable but was performed only on available observed data. A logistic regression model with treatment, center, and baseline as effects was used to analyze the incidence of ALT >3xULN; the analysis was performed using available observed data, and the odds ratio and the 95% confidence interval (CI) of the odds ratio were calculated. A total of 323 subjects entered the Double-Blind Treatment Period. Of these, 119 subjects completed study drug and 204 subjects prematurely discontinued study drug. The number of subjects who prematurely discontinued study drug was similar across the treatment groups, as were the reasons that subjects prematurely discontinued study drug; the most common reasons were study termination by the sponsor (150 subjects), adverse event (17 subjects), and lost to follow-up (15 subjects). Primary Efficacy Variable The following least squares (LS) mean changes from Baseline in HbA1c at Week 12/ET were statistically significant (P<0.05): TAK mg (-0.60%) vs placebo (-0.10%); TAK and 200 mg (-0.91% and -1.04%, respectively) vs placebo and pioglitazone 30 mg (-0.31%). Secondary Efficacy Variables The following LS mean changes from Baseline in HbA1c were statistically significant (P<0.05): Week 4: None. Week 8: TAK mg (-0.63%) vs placebo (-0.22%); TAK and 200 mg (-1.03% and -1.23%, (-0.54%). The following LS mean changes from Baseline in fasting plasma glucose were statistically significant (P<0.05): Week 1: TAK and 200 mg (-17.5 and mg/dl, (2.4 and mg/dl, respectively). Week 2: TAK mg (-11.8 mg/dl) vs placebo (4.9 mg/dl); TAK and 200 mg (-28.9 and mg/dl, (-1.3 mg/dl). Week 4: TAK mg (-30.3 mg/dl) vs placebo (6.4 mg/dl); TAK and 200 mg (-46.4 and mg/dl, (-19.9 mg/dl); pioglitazone 30 mg vs placebo. Week 6: TAK mg (-27.4 mg/dl) vs placebo (2.7 mg/dl); TAK and 200 mg (-48.8 and mg/dl, (-29.1 mg/dl); pioglitazone 30 mg vs placebo. Week 8: TAK mg (-21.7 mg/dl) vs placebo (-4.6 mg/dl); TAK and 200 mg (-52.8 and mg/dl,

4 (-24.1 mg/dl); pioglitazone 30 mg vs placebo. Week 12/ET: TAK and 100 mg (-20.3 and mg/dl, respectively) vs placebo (19.7 mg/dl); TAK mg (-69.3 mg/dl) vs placebo and pioglitazone 30 mg (-37.8 mg/dl); pioglitazone 30 mg vs placebo. The following LS mean changes from Baseline in body weight were statistically significant (P<0.05): Week 4: None. Week 8: TAK , 100, and 200 mg (2.5, 2.9, and 5.1 kg, (0.0 and 0.5 kg, respectively); pioglitazone 30 mg vs placebo. Week 12/ET: TAK mg (7.3 kg) vs placebo and pioglitazone 30 mg (0.4 and 1.4 kg, respectively). The incidence of ALT 3 ULN was 1.5% (1/66 subjects) in the TAK mg group at Baseline. Safety Results: Overall, 50.5% of subjects (163/323) experienced 1 or more adverse events. No relationship was observed between the percentage of subjects who experienced adverse events and TAK-379 dose. The percentage of subjects who experienced adverse events was 45.5% (30/66) in the TAK mg group, 61.5% (40/65) in the TAK mg group, 57.1% (36/63) in the TAK mg group, 40.6% (26/64) in the pioglitazone 30 mg group, and 47.7% (31/65) in the placebo group. Edema peripheral, edema, and weight increased occurred more frequently in the TAK-379 groups than in the pioglitazone 30 mg and placebo groups. The percentage of subjects who experienced edema peripheral was 7.6% to 16.9% in the TAK-379 groups vs 3.1% and 4.6% in the pioglitazone 30 mg and placebo groups, respectively. The percentage of subjects who experienced edema was 4.6% to 12.7% in the TAK-379 groups vs 1.6% and 0% in the pioglitazone 30 mg and placebo groups, respectively. The percentage of subjects who experienced weight increased was 7.7% to 12.7% in the TAK-379 groups vs 0% and 1.5% in the pioglitazone 30 mg and placebo groups, respectively. A total of 6 serious adverse events (SAEs) that occurred during or <30 days after treatment with double-blind study drug (including 1 death) were reported for 5 subjects. One SAE was considered by the investigator to be possibly related to study drug (syncope in a subject in the TAK mg group), and 2 SAEs were considered by the investigator to be probably related to study drug (myocardial ischemia in a subject in the placebo group and cardiac failure congestive in a subject in the TAK mg group). All other SAEs were considered by the investigator to be not related to study drug.

5 Date of Report 09 September 2011 One death occurred (multiple trauma in a subject in the placebo group); the death was considered by the investigator to be not related to study drug.