Pharmacokinetics and Pharmacodynamics of TAK-875 in Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Sequential, Multiple Ascending-Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of TAK-875 in Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: TAK-875


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 68 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: TAK-875<br>* Randomized, multiple ascending-dose sequence over 14 consecutive days to include the following: TAK-875 25 mg tablets, orally TAK-875 50 mg tablets, orally TAK-875 100 mg tablets, orally TAK-875 200 mg tablets, orally TAK-875 400 mg tablets, orally TAK-875 placebo-matching tablets, orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TAK-875 maximum observed plasma concentration (Cmax) |  | Day 14 | 
| TAK-875 time at which Cmax occurred (Tmax) |  | Day 14 | 
| TAK-875 area under the plasma concentration-time curve from time 0 to time tau, where tau is the length of a dosing interval AUC(0-tau) |  | Day 14 | 
| TAK-875 renal clearance (CLr) |  | Day 14 | 
| TAK-875 metabolite (M-I) Cmax |  | Day 14 | 
| TAK-875 M-I Tmax |  | Day 14 | 
| TAK-875 M-I AUC(0-tau) |  | Day 14 | 
| TAK-875 M-I renal clearance CLr |  | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TAK-875 Cmax |  | Day 1 | 
| TAK-875 Tmax |  | Day 1 | 
| TAK-875 AUC(0-tau) |  | Day 1 | 
| TAK-875 renal clearance CLr |  | Day 1 | 
| M-I Tmax |  | Day 1 | 
| M-I Cmax |  | Day 1 | 
| M-I AUC(0-tau) |  | Day 1 | 
| M-I renal clearance CLr |  | Day 1 | 
| TAK-875 and M-I Cmax ratio |  | Day 1 | 
| TAK-875 and M-I Cmax ratio |  | Day 14 | 
| TAK-875 and M-I AUC(0-tau) ratio |  | Day 1 | 
| TAK-875 and M-I AUC(0-tau) ratio |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4-hour concentration values for plasma glucose |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4- hour concentration values for insulin |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4- hour concentration values for proinsulin |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4- hour concentration values for C-peptide |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4- hour concentration values for glucagon |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4- hour concentration values for total gastric inhibitory polypeptide (GIP) |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 4- hour concentration values for total glucagon-like peptide-1 (GLP-1) |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24-hour concentration values for plasma glucose |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24- hour concentration values for insulin |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24- hour concentration values for proinsulin |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24- hour concentration values for C-peptide |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24- hour concentration values for glucagon |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24- hour concentration values for total gastric inhibitory polypeptide (GIP) |  | Day 14 | 
| Percent changes from baseline to Day 14 in mean 24- hour concentration values for total glucagon-like peptide-1 (GLP-1) |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4-hour concentration values for plasma glucose |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4- hour concentration values for insulin |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4- hour concentration values for proinsulin |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4- hour concentration values for C-peptide |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4- hour concentration values for glucagon |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4- hour concentration values for total gastric inhibitory polypeptide (GIP) |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 4- hour concentration values for total glucagon-like peptide-1 (GLP-1) |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24-hour concentration values for plasma glucose |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24- hour concentration values for insulin |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24- hour concentration values for proinsulin |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24- hour concentration values for C-peptide |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24- hour concentration values for glucagon |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24- hour concentration values for total gastric inhibitory polypeptide (GIP) |  | Day 14 | 
| Absolute changes from baseline to Day 14 in mean 24- hour concentration values for total glucagon-like peptide-1 (GLP-1) |  | Day 14 | 
| Percent change from baseline to 24-hours post Day 13 dose in homeostasis model assessment of ß-cell function |  | Day 13 | 
| Percent change from baseline to 24-hours post Day 14 dose in homeostasis model assessment of ß-cell function |  | Day 14 | 
| Absolute change from baseline to 24-hours post Day 13 dose in homeostasis model assessment of ß-cell function |  | Day 13 | 
| Absolute change from baseline to 24-hours post Day 14 dose in homeostasis model assessment of ß-cell function |  | Day 14 | 
| Percent change from baseline to Day 14 in insulinogenic index |  | Day 14 | 
| Absolute change from baseline to Day 14 in insulinogenic index |  | Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Non Insulin Dependent, Diabetes Mellitus, Type II, Type 2 Diabetes Mellitus, Drug Therapy