Safety and Efficacy of S-707106 in Subjects With Type 2 Diabetes Mellitus and Inadequate Glycemic Control With Metformin Therapy

• Serial pharmacokinetic (PK) assessments [ Time Frame: 5 days ] [ Designated as safety issue: No ]
  Serial pharmacokinetic sampling at Visit 6 prior to dosing, at Visit 7 prior to dosing and at 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after dosing, at Visit 8, at Visit 9, and Early Termination Visit
• Sparse pharmacokinetic assessments [ Time Frame: 5 days ] [ Designated as safety issue: No ]
  Sparse pharmacokinetic sampling at Visit 6 and Visit 7 prior to dosing, at Visit 6 or Visit 7 one additional post-dose sample, at Visit 8, at Visit 9, and Early Termination Visit
• Percent of subjects with Hemoglobin A1c < 7.0% at Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Hemoglobin A1c
• Change from Baseline at Week 12 in: Fasting plasma glucose, 1,5-Anhydroglucitol, Fructosamine, Glycoalbumin, C-peptide, Beta-cell function and insulin resistance indices using Homeostatic Model Assessment, and Postprandial glucose test [ Time Frame: Baseline and at 12 weeks ] [ Designated as safety issue: No ]
  Fasting plasma glucose, 1,5-Anhydroglucitol, Fructosamine, Glycoalbumin, C-peptide, Beta-cell function and insulin resistance indices using Homeostatic Model Assessment, and Postprandial glucose test
• Safety assessments [ Time Frame: 5-6 months ] [ Designated as safety issue: Yes ]
  Safety will be assessed by monitoring of treatment-emergent adverse events, serious adverse events, treatment-emergent adverse events leading to study drug discontinuation, clinical laboratory evaluations, vital signs, 12-lead electrocardiograms (ECGs), adrenal axis hormones, and treatment-emergent adverse events of hypoglycemia, hyperglycemia, confirmed hypoglycemia or hyperglycemia

• Percent of subjects with Hemoglobin A1c (HbA1c) < 7.0% at Week 12 [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Hemoglobin A1c
• Change from Baseline at Week 12 in Fasting plasma glucose [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Fasting plasma glucose

The purpose of this study is to evaluate the safety and efficacy of S-707106 co-administered with metformin in subjects with type 2 diabetes mellitus.

Based on the unmet clinical need for more safe and effective type 2 diabetes mellitus therapies, together with the nonclinical efficacy and safety profile of S-707106, Shionogi USA, Inc. is initiating studies to further assess the efficacy, clinical pharmacology and safety profile of S-707106 in preparation for full clinical development as a novel treatment for type 2 diabetes mellitus. It is anticipated that S-707106 will provide clinicians and patients with a new therapeutic option to treat type 2 diabetes mellitus with potential advantages over existing therapy.

• Drug: S-707106 dose 1
  One S-707106 dose 1 tablet and 3 Placebo A tablets matching S-707106 dose 1- and dose 2 tablets and metformin
• Drug: S-707106 dose 2
  One S-707106 dose 2 tablet and 3 Placebo A tablets matching S-707106 dose 1- and dose 2 tablets and metformin
• Drug: S-707106 dose 3
  Four S-707106 dose 2 tablets and metformin
• Drug: Placebo
  Four Placebo A tablets matching S-707106 dose 1- and dose 2 tablets and metformin

• Experimental: S-707106 dose 1 plus metformin
  S-707106 tablets concurrently with their usual metformin dose for 12 weeks
  Intervention: Drug: S-707106 dose 1
• Experimental: S-707106 dose 2 plus metformin
  S-707106 tablets concurrently with their usual metformin dose for 12 weeks
  Intervention: Drug: S-707106 dose 2
• Experimental: S-707106 dose 3 plus metformin
  S-707106 tablets concurrently with their usual metformin dose for 12 weeks
  Intervention: Drug: S-707106 dose 3
• Placebo Comparator: Placebo plus metformin
  Placebo tablets concurrently with their usual metformin dose for 12 weeks
  Intervention: Drug: Placebo

Main Inclusion Criteria:

• Subjects with type 2 diabetes mellitus receiving a stable dose of metformin for the past 3 months (with no other medication for glycemic control) and who are clinically stable as determined by medical history
• Body mass index (BMI) ≥25.0 and <45.0 (kg/m2) using http://www.bmicalculator.org/ as the BMI calculator
• No clinically significant abnormal laboratory tests as determined by the investigator except Hemoglobin A1c level ≥7.5% and ≤11.0% and C peptide level >1.0 ng/mL

Main Exclusion Criteria:

• Type 1 diabetes mellitus or gestational diabetes mellitus within last 6 months
• Use of any medication for glycemic control other than metformin during the past 3 months or thiazolidinediones within the past year
• Congestive heart failure as defined by New York Heart Association class III or IV
• Fasting glucose >270 mg/dL
• Creatinine clearance is <60 mL/minute
• History of myocardial infarction within the past 3 months, history of clinically significant cardiac arrhythmia, clinically significant hypotension or hypertension, or clinically significant abnormal electrocardiogram as determined by the investigator