Comparison of TAK-875 to Placebo and Sitagliptin in Combination With Metformin in Participants With Type 2 Diabetes

TAK-875 is being developed at Takeda Global Research and Development, Inc. as an adjunct to
diet and exercise to improve glycemic control in participants with Type 2 Diabetes Mellitus
(T2DM) whose blood glucose level is inadequately controlled with metformin.

This study will evaluate the efficacy of TAK-875 (25 mg and 50 mg) plus metformin compared
to placebo plus metformin and sitagliptin plus metformin on glycemic control as measured by
change from baseline in glycosylated hemoglobin (HbA1c) over a 24-week Treatment Period.
Participants completing the 24-week Treatment Period may enter an optional 80-week extension
period for a total of 104 weeks of treatment.

Inclusion Criteria:

1. The participant is male or female and 18 years of age or older with a historical
diagnosis of type II diabetes mellitus.

2. The participant meets one of the following criteria:

1. The participant has an HbA1c level ≥7.5 and <10.5%, and has been on a stable
daily dose of ≥1500 mg (or documented maximum tolerated dose [MTD]) of metformin
for at least 2 months prior to Screening. This participant will immediately
enter the Placebo Run-in Period according to Study Schedule A, or;

2. The participant has an HbA1c level ≥7.5 and <10.5%, and has been on a stable
daily dose of <1500 mg of metformin without documented MTD for at least 2 months
prior to Screening. After completing the Screening Visit, this participant will
have their metformin dose immediately increased to ≥1500 mg (or MTD) for an
8-week Titration Period according to Study Schedule B. Following this 8-week
period, the participant must qualify for entry into the Placebo Run-in Period by
completing the Week -3 procedures including having an HbA1c level ≥7.5 and
<10.5%.

3. The participant has had no treatment with antidiabetic agents other than metformin
within 2 months prior to Screening (Exception: if a participant has received other
antidiabetic therapy for ≤7 days within the 2 months prior to Screening).

4. The participant has a body mass index (BMI) ≤45 kg/m² at Screening.

5. Participants regularly using other, non-excluded medications, must be on a stable
dose for at least 4 weeks prior to Screening. However, PRN (as needed) use of
prescription or over-the-counter medications is allowed at the discretion of the
investigator.

6. The participant is able and willing to monitor glucose with a home glucose monitor
and consistently record his or her own blood glucose concentrations and complete
subject diaries.

Exclusion Criteria:

1. The participant donated or received any blood products within 12 weeks prior to
Screening or is planning to donate blood during the study.

2. Hemoglobin ≤12 g/dL (≤120 g/L) for males and ≤10 g/dL (≤100 g/L) for females at
Screening Visit.

3. The participant has systolic blood pressure ≥160 mm Hg or diastolic pressure ≥95 mm
Hg at Screening Visit. (If the participant meets this exclusion criterion, the
assessment may be repeated once at least 30 minutes after the initial measurement.)

4. The participant has a history of laser treatment for proliferative diabetic
retinopathy within 6 months prior to Screening.

5. The participant has had treatment for gastric banding or gastric bypass surgery
within one year prior to Screening.

6. The participant had coronary angioplasty, coronary stent placement, coronary bypass
surgery, myocardial infarction, unstable angina pectoris, clinically significant
abnormal ECG, cerebrovascular accident or transient ischemic attack within 3 months
prior to or at Screening.