pharmacokinetics and pharmacodynamics of tak-875 in subjects with type 2 diabetes

Conditions: Diabetes Mellitus, Type 2

Summary: the purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending-doses of tak-875 in subjects with type 2 diabetes mellitus.

tak-875 is being developed as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. nonclinical data suggest that tak-875 stimulates insulin secretion only at elevated blood glucose levels, with the potential for low hypoglycemic side effects. the purpose of this phase 1, multiple ascending-dose study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of once daily oral doses of tak-875 for 14 days in subjects with type 2 diabetes mellitus. participants will be housed for a total of 8 consecutive overnight stays in the clinic, and will undergo oral glucose tolerance tests and standardized meal tests with multiple blood sampling throughout their clinic stay.

Eligibility criteria:
inclusion criteria: * participants with type 2 diabetes who are newly diagnosed, managed with diet and exercise alone, or taking up to 2 oral antidiabetic agents (except thiazolidinediones) and willing to discontinue the antidiabetic medication(s) 2 weeks prior to randomization. * meets one of the following glycosylated hemoglobin criteria (diagnosis must be based on current american diabetes association criteria) at screening: * if treatment naïve, should have a glycosylated hemoglobin concentration greater than or equal to 6.5% and less than or equal to 10.0%. * if on a single antidiabetic agent (stable dose for at least 28 days), should have a glycosylated hemoglobin greater than or equal to 6% and less than or equal to 9.5%. * if on a combination of up to 2 antidiabetic agents (stable doses for at least 28 days), should have a glycosylated hemoglobin greater than or equal to 6% and less than or equal to 9.0%. * has fasting plasma glucose greater than 126 mg/dl and less than 260 mg/dl if not on any antidiabetic medication, or less than 220 mg/dl if on any single antidiabetic agent, and less than 200 mg/dl if on any combination of 2 oral antidiabetic agents at screening. * has fasting c-peptide concentration greater than or equal to 0.8 ng/ml at screening. * weighs at least 50 kg (110 lb) and has a body mass index between 18 and 40 kg/m2, inclusive at screening. * has not received treatment with weight-loss drugs within the 3 months prior to screening. * has a systolic blood pressure less than or equal to 160 mm hg and a diastolic blood pressure of less than or equal to 100 mm hg at screening and at check-in (day -2). * female participant is not of child-bearing potential (ie, surgically sterile \[hysterectomy, bilateral oophorectomy, or 2 years post-tubal ligation\] or postmenopausal \[2 years since last menses\]). * is able and willing to monitor blood glucose concentrations with a home glucose monitor during the washout interval and record results in the daily diary. * has negative test results at screening and check-in for selected substances of abuse, including alcohol and cotinine. * has screening and check-in clinical laboratory evaluations \[including fasting clinical chemistry, hematology, and complete urinalysis (excluding glucose results)\] within the reference range for the testing laboratory, unless the investigator deems the out-of-range results to be not clinically significant. * has negative test results for hepatitis b surface antigen and antibody to hepatitis c virus, and no known history of human immunodeficiency virus. * is willing to refrain from strenuous exercise from 72 hours before check-in and throughout the study. * is considered by the investigator to be in a good health (other than being diabetic) as determined during the medical history review, physical examination findings, electrocardiogram and vital sign results, and clinical laboratory evaluations. * has creatinine clearance greater than 60 ml/min at screening and check-in. exclusion criteria: * has a history of abdominal surgery (except laparoscopic cholecystectomy or uncomplicated appendectomy), thoracic, or nonperipheral vascular surgery within 6 months prior to check-in. * has a known hypersensitivity to tak-875, or other related compounds. * has a history of cardiac arrhythmia, systolic dysfunction congestive heart failure, angina, myocardial ischemia or infarction, or stroke within 1 year prior to screening, or the presence of an abnormal electrocardiogram that, in the investigator's opinion, is clinically significant. * has a history of drug abuse or a history of alcohol abuse within 2 years prior to screening. * has used any tobacco (ie, nicotine) products within 90 days prior to check-in, and is unwilling to abstain from these products for the duration of the study. * has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. this criterion does not apply to basal cell or stage i squamous cell carcinoma of the skin. * has an alanine aminotransferase, alkaline phosphatase or aspartate aminotransferase level greater than or equal to 2 times the upper limit normal for the testing laboratory, active liver disease, or jaundice at screening or check-in. * has a total bilirubin greater than 2 mg/dl at screening or check-in. * has donated blood or experienced acute blood loss (including plasmapheresis) of greater than 500 ml within 90 days prior to the first dose of study drug. * participant is on any insulin treatment. * the subject has a history of proteinuria greater than 300 mg/day on a 12- or 24-hour urine collection or an albumin/creatinine ratio greater than 300 μg/mg at screening. if elevated, the subject may be rescreened within 1 week, and may be included in study with agreement between principal investigator and the takeda global research and development medical monitor. * has a history of any clinically significant retinopathy, which is defined as more than moderate nonproliferative diabetic retinopathy or any stage of proliferative diabetic retinopathy or any history of laser-treated retinopathy. * has history of treated or clinically significant peripheral or autonomic neuropathy. * the subject has a history of ulcerative colitis or crohn's disease, or has undergone gastric resection. * the subject has a history of a psychiatric disorder that will affect the subject's ability to participate in the study. * has a history of angioedema. * had an acute, clinically significant illness within 30 days prior to check-in, or any other condition or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study. * participant took or requires the use of any restricted medication or products within the timeframes listed. * is participating in another investigational study or has taken any investigational drug within 30 days prior to check-in. * has poor venous access. * has been randomized in a previous tak-875 study within 6 months prior to the first dose of study drug.

Keywords: diabetes mellitus, non insulin dependent diabetes mellitus, type ii type 2 diabetes mellitus drug therapy