Efficacy and Safety of TAK-875 in Subjects With Type 2 Diabetes Mellitus

TAK-875 is under clinical development for the treatment of type 2 diabetes mellitus in humans. Non-clinical as well as Phase I clinical data suggest that TAK-875 stimulates insulin secretion only at elevated blood glucose levels.

This study is being conducted to study glycemic effects and safety of TAK-875 compared with placebo and glimepiride in subjects with type 2 diabetes who are inadequately controlled on a stable dose of metformin as monotherapy.

Subjects participating in this study are required to fast for 8 hours prior to each study visit, and will be educated in recognition and self-management of hypoglycemia. In addition, during this Run-in Period compliance with study medication will be documented. Subjects who are less than 80% or more than120% compliant with the single-blind, placebo regimen during the run-in period will not be randomized.

At the conclusion of the Run-in period, appropriate subjects will be randomized into the 12 week double-blind treatment period.

Inclusion criteria

• Participant meets 1 of the following criteria:

• A historical diagnosis of type 2 diabetes mellitus without the chronic use of antidiabetic therapy within 8 weeks prior to Screening, and with at least an 8-week documented history of a diet and exercise plan at Screening.
• A historical diagnosis of mellitus and stable on at least 1500 mg per day or the respective (individually) maximal tolerated dose of metformin as monotherapy for at least 2 months prior to Screening.
• Has a glycosylated hemoglobin level at Screening between 7.5% and 10.0%, inclusive, if on metformin and greater than or equal to 7.5% to less than 11% if treated with diet and exercise alone.
• Has a fasting plasma glucose level less than 260 mg/dL, at Screening.
• Has a fasting C-peptide concentration greater than or equal to 0.8 ng/mL at Screening.
• If participant takes any chronic medications, the dose of these medications must have been stable (no change in dose or drug) for at least 4 weeks prior to Screening.
• Participant's body mass index at Screening is greater than or equal to 23 and less than or equal to 45 kg/m2.
• Is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations.
• Females of childbearing potential who are sexually active must agree to use a medically accepted means of contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study and for 1 month after the last dose of study drug.
• Compliance with single-blind study medication during the Run-in Period is at least 80% and does not exceed 120% based on tablet counts performed by the study staff.

Exclusion criteria

• Has systolic blood pressure greater than 160 mm Hg or diastolic pressure greater than 100 mm Hg at Screening or Baseline (as confirmed by repeat measurement 30 minutes after initial measurement).
• Has history of cancer that has been in remission for less than 5 years prior to Screening. A history of basal cell carcinoma or stage 1 squamous cell carcinoma of the skin is allowed.
• Has a creatine phosphokinase level greater than or equal to 5 times the upper limit of normal at Screening.
• Has a hemoglobin level of less than or equal to 12 g/dL (120 gm/L) for men and less than or equal to 10 g/dL (100 gm/L) for women at Screening.
• Has alanine aminotransferase and aspartate aminotransferase levels greater than or equal to 2.5 times upper limit of normal at Screening.
• Has a total bilirubin level greater than or equal to 1.5 mg/dL at Screening.
• The subject has a serum triglyceride concentration greater than or equal to 400 mg/dL at Screening.
• Has an estimated glomerular filtration rate less than or equal to 60 mL/min using the Modification of Diet in Renal Disease equation at Screening.
• Has abnormal thyroid-stimulating hormone levels.
• Has a positive test result for hepatitis B surface antigen or hepatitis C antibody or human immunodeficiency virus.
• Has macro-albuminuria at Screening
• Has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
• Has diabetic gastroparesis that in the investigator's opinion is moderate or severe and hence may impair absorption of study medication.
• Has had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal electrocardiogram, cerebrovascular accident or transient ischemic attack within 6 months prior or at Screening.
• Has a history of any hemoglobinopathy that may affect determination of glycosylated hemoglobin.
• Received treatment with probucol within 1 year of randomization.
• Donated or received any blood products within 12 weeks prior to Screening.
• Received treatment for more than 7 days within 4 weeks or 8 weeks (depending on the medication) prior to Screening.
• Is on any insulin treatment.
• Received any investigational drug within 4 weeks prior to Screening.
• Is hypersensitive to TAK-875, its excipients or glimepiride.
• Has a history of drug abuse or a history of alcohol abuse within 2 years prior to Screening.
• 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 subject according to the protocol.
• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

• Probucol
• Chronically used insulin
• Chronically used oral or parenteral glucocorticoids
• Chronically used over-the-counter or prescription weight-loss medications and/or Orlistat Niacin more than 200 mg/day, including niacin-containing products such as Advicor®
• Chronically used peroxisome proliferator-activated receptor agonists, ezetimibe, oral or injectable hypoglycemic agents other than metformin bile-acid binding agents such as cholestyramine and colesevelam
• Investigational medications
• Warfarin and phenytoin