12-Week Study of DS-8500a in Subjects With Type 2 Diabetes Mellitus on Metformin

Inclusion Criteria:

- Able to provide written informed consent and adhere to the study visit schedule and
treatment

- Diagnosed with Type 2 diabetes mellitus as defined in the American Diabetes
Association Standards of Medical Care in Diabetes 2015

- Male or female ≥ 18 and ≤ 70 years of age

- Screening fasting C-peptide > 0.5 ng/mL

- Women of child bearing potential (WOCBP) must be willing to use double-barrier
contraception for the entire study

- WOCBP must have a negative pregnancy test (human chorionic gonadotropin, beta subunit
[βhCG]) before entering the Lead-in Period

- Body mass index ≥ 25 kg/m2 and ≤ 45 kg/m2 at the Screening Visit

- On stable (≥ 8 weeks) metformin monotherapy ≥ 1000 mg/day

- Screening HbA1c ≥ 7.0% and ≤ 10%

- Taking ≥ 80% and ≤ 120% of both dispensed DS-8500a placebo tablets and sitagliptin
placebo capsules during the Lead-in Period

Exclusion Criteria:

- History of type 1 diabetes and/or history of ketoacidosis

- History of insulin use for > 2 weeks within 2 months prior to the Screening Visit

- Two or more readings of fasting Self-monitoring of Blood Glucose (SMBG) > 240 mg/dL or
worsening symptoms of hyperglycemia with one SMBG level of > 240 mg/dL during the
second week of Lead-in Period, confirmed by laboratory measurement

- Screening hemoglobin <12 g/dL for males and <11 g/dL for females

- Blood donation within 2 months prior to the Screening Visit or plans to donate blood
or blood products during the study

- Subjects after bariatric surgery or any gastric bypass

- Screening thyroid stimulating hormone (TSH) levels not within normal range (based on
reference laboratory values )

- Screening Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) > 2.0 x
upper limit of normal (ULN), and/or total bilirubin > 1.5 x ULN. If a subject has
total bilirubin > 1.5 ULN, unconjugated and conjugated bilirubin fractions should be
analyzed and only subjects documented to have Gilbert's syndrome may be enrolled

- Screening Serum creatinine ≥ 1.5 mg/dL for males and ≥ 1.4 mg/dL for females, or
creatinine clearance (CrCl) < 50 mL/min for both males and females

- Screening Creatine kinase (CK) > 3.0 × ULN

- History of unstable angina, myocardial infarction, cerebrovascular accident, transient
ischemic attack, peripheral arterial event or any revascularization procedure during
the 6 months prior to the Screening Visit or planned vascular procedures or surgery
during study period

- History of congestive heart failure (CHF)

- Exclusionary concomitant medications:

a. Eight weeks prior to screening and throughout the duration of the study:

- Any diabetes medication other than metformin; any prescription or over the counter
medication for weight-loss.

- Systemic corticosteroids (including nasal and inhaled), with the exception of use of
topical and ophthalmic corticosteroids.

- Rosuvastatin > 20 mg daily. b. During treatment periods, additional medications will
be prohibited based on potential drug-drug interaction (DDI) (see Section 5.6)

- Subjects with anticipated interruption in metformin or study drug use during the
course of the clinical trial (e.g., due to an imaging procedure involving iodinated
contrast media)

- Subjects in whom treatment with sitagliptin 100 mg is contraindicated ( e.g., known
hypersensitivity or intolerance to sitagliptin) or may not be medically advisable
(e.g., history of pancreatitis)

- Abuse of or dependence on prescription medications, illicit drugs, or alcohol within
the last 1 year

- Any history of a malignancy other than basal cell carcinoma within the past 5 years

- Pregnancy or breast-feeding, or intent to become pregnant during the study period

- Known (or evidence of) infection with human immunodeficiency virus

- Any condition, laboratory abnormality, or concomitant therapy which, in the opinion of
the Investigator, might pose a risk to the subject or make participation not in the
subject's best interest

- Subject is currently enrolled in or has not yet completed at least 30 days since
ending another investigational device or drug study or is receiving other
investigational agents

- A direct or familial relationship with the Sponsor, Investigator, or site personnel
affiliated with the study