Efficacy and Safety of TAK-875 in Combination With Sitagliptin in Participants With Type 2 Diabetes Mellitus

TAK-875 is being developed at Takeda Global Research and Development, Inc. as an adjunct to
diet and exercise to improve glycemic control in patients with T2DM.

Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4) approved as an adjunct to diet
and exercise to improve glycemic control in adults with T2DM.

This study will investigate the effects of the combination of TAK-875 with a DDP-4 inhibitor
on glycosylated hemoglobin reduction.

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and
complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable
representative signs and dates a written, informed consent form and any required
privacy authorization prior to the initiation of any study procedures.

3. The participant has either:

- A historical diagnosis of Type 2 Diabetes (T2DM) without the chronic use
(defined as >7 days) of anti-diabetic therapy within 8 weeks prior to Screening,
and with at least an 8-week documented history of a diet and exercise plan at
Screening OR,

- A historical diagnosis of T2DM and stable on at least 1500 mg per day (or
maximum tolerated dose) of metformin as monotherapy for at least 8 weeks at
Screening. Participants on a stable dose of metformin who enter the study will
continue on the same dose of metformin throughout the duration of the study.

4. The participant is a man or woman and aged 18 to 80 years, inclusive.

5. The participant's body mass index (BMI) (kg/m2) at Screening is ≥23 and ≤45.

6. The participant has an glycosylated hemoglobin (HbA1c) level at Screening between
7.5% and 10.0%, inclusive, if on metformin and between 7.5% to 10.9%, inclusive, if
treated with diet and exercise alone.

7. The participant has a fasting plasma glucose level <14.4 mmol/L (<260 mg/dL), at
Screening.

8. The participant has a fasting C-peptide concentration ≥0.26 nmol/L (≥0.8 ng/mL) at
Screening.

9. If the participant takes any chronic, non-excluded medications, the dose of these
medications must have been stable (no change in dose or drug) for at least 4 weeks
prior to Screening.

10. The participant is able and willing to monitor their glucose levels with a home
glucose monitor and consistently record his or her own blood glucose concentrations
according to the given instructions.

11. A male participant who is nonsterilized and sexually active with a female partner of
childbearing potential agrees to use adequate contraception from signing of informed
consent throughout the duration of the study and for 30 days after last dose.

12. A female participant of childbearing potential who is sexually active with a
nonsterilized male partner agrees to use routinely adequate contraception from
signing of informed consent throughout the duration of the study.

13. A female participant of childbearing potential must have a negative serum human
chorionic gonadotropin (HCG) pregnancy test at Screening (Visit 1) and at Placebo
Run-in (Visit 2). A negative urine HCG pregnancy test is also required at
Randomization (Visit 3), prior to administration of the first dose of double-blind
study medication.

14. The participant's compliance with single-blind study medication during the run-in
phase is at least 80% and does not exceed 120% based on tablet counts performed by
the study staff.

Exclusion Criteria:

1. The participant has received any investigational compound within 4 weeks prior to
Screening.

2. The participant has been enrolled in a previous TAK-875 study.

3. The participant is an immediate family member, study site employee, or is in a
dependent relationship with a study site employee who is involved in conduct of this
study (eg, spouse, parent, child, sibling) or may consent under duress.

4. The participant has a history of hypersensitivity or allergies to TAK-875 or
sitagliptin, or their excipients.

5. The participant has a history of drug abuse (defined as any illicit drug use) or a
history of alcohol abuse within 2 years prior to the Screening visit.

6. The participant has a history of cancer that has been in remission for <5 years prior
to Screening (a history of basal cell carcinoma or stage 1 squamous cell carcinoma of
the skin is allowed).

7. The participant has systolic blood pressure ≥150 mm Hg or diastolic pressure ≥90 mm
Hg at Screening (Visit 1) or Baseline (Visit 3) (as confirmed by repeat measurement
30 minutes after initial measurement).

8. The participant has a creatine phosphokinase (CPK) level ≥5x the upper limit of
normal (ULN) at Screening.

9. The participant has a hemoglobin level of ≤12 g/dL (120 gm/L) for men and ≤10 g/dL
(100 gm/L) for women at Screening.

10. The participant has ALT and/or AST levels ≥2.5x ULN at Screening.

11. The participant has a total bilirubin level > ULN at Screening.

12. The participant has a serum triglyceride concentration ≥4.5 mmol/L (≥400 mg/dL) at
Screening.

13. The participant has an estimated glomerular filtration rate ≤60mL/min using the
Modification of Diet in Renal Disease (MDRD) equation at Screening.

14. The participant has a documented history or concurrent signs of uncontrolled (not
euthyroid) thyroid disease (eg, autoimmune thyroid diseases such as Graves disease
and Hashimoto thyroiditis or active thyroid nodules).

15. The participant has a history of pancreatitis.

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

17. The participant has a history of gastric bypass surgery or has diabetic gastroparesis
that in the investigator's opinion is moderate or severe and hence may impair
absorption of study medication.

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

19. The participant has a history of any hemoglobinopathy that may affect determination
of HbA1c.

20. The participant has a positive test result for hepatitis B surface antigen and
antibody to hepatitis C virus, and/or has known history of human immunodeficiency
virus at Screening.

21. The participant has donated or received any blood products within 12 weeks prior to
Screening.

22. The participant received medication prior to Screening as listed in the excluded
Medications section.

23. If female, the participant is pregnant or lactating or intending to become pregnant
before, during, or within 1 month after participating in this study; or intending to
donate an ova during such time period.

24. If male, the participant intends to donate sperm during the course of this study or
for 30 days thereafter.

25. The participant has any other physical or psychiatric disease or condition that in
the judgment of the investigator may affect life expectancy or may make it difficult
to successfully manage and follow the participant according to the protocol.