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

This study has been completed.
Sponsor:
Information provided by:
Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:
NCT00949091
First received: July 28, 2009
Last updated: June 9, 2010
Last verified: June 2010
History of Changes
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus, Type 2
 Drug: TAK-875
 Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: 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

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:
  • TAK-875 maximum observed plasma concentration (Cmax) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 time at which Cmax occurred (Tmax) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • 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) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 renal clearance (CLr) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 metabolite (M-I) Cmax [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 M-I Tmax [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 M-I AUC(0-tau) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 M-I renal clearance CLr [ Time Frame: Day 14 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • TAK-875 Cmax [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • TAK-875 Tmax [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • TAK-875 AUC(0-tau) [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • TAK-875 renal clearance CLr [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • M-I Tmax [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • M-I Cmax [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • M-I AUC(0-tau) [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • M-I renal clearance CLr [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • TAK-875 and M-I Cmax ratio [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • TAK-875 and M-I Cmax ratio [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • TAK-875 and M-I AUC(0-tau) ratio [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
  • TAK-875 and M-I AUC(0-tau) ratio [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4-hour concentration values for plasma glucose [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4- hour concentration values for insulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4- hour concentration values for proinsulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4- hour concentration values for C-peptide [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4- hour concentration values for glucagon [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4- hour concentration values for total gastric inhibitory polypeptide (GIP) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 4- hour concentration values for total glucagon-like peptide-1 (GLP-1) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24-hour concentration values for plasma glucose [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24- hour concentration values for insulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24- hour concentration values for proinsulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24- hour concentration values for C-peptide [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24- hour concentration values for glucagon [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24- hour concentration values for total gastric inhibitory polypeptide (GIP) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent changes from baseline to Day 14 in mean 24- hour concentration values for total glucagon-like peptide-1 (GLP-1) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4-hour concentration values for plasma glucose [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4- hour concentration values for insulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4- hour concentration values for proinsulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4- hour concentration values for C-peptide [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4- hour concentration values for glucagon [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4- hour concentration values for total gastric inhibitory polypeptide (GIP) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 4- hour concentration values for total glucagon-like peptide-1 (GLP-1) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24-hour concentration values for plasma glucose [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24- hour concentration values for insulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24- hour concentration values for proinsulin [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24- hour concentration values for C-peptide [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24- hour concentration values for glucagon [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24- hour concentration values for total gastric inhibitory polypeptide (GIP) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute changes from baseline to Day 14 in mean 24- hour concentration values for total glucagon-like peptide-1 (GLP-1) [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent change from baseline to 24-hours post Day 13 dose in homeostasis model assessment of ß-cell function [ Time Frame: Day 13 ] [ Designated as safety issue: No ]
  • Percent change from baseline to 24-hours post Day 14 dose in homeostasis model assessment of ß-cell function [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute change from baseline to 24-hours post Day 13 dose in homeostasis model assessment of ß-cell function [ Time Frame: Day 13 ] [ Designated as safety issue: No ]
  • Absolute change from baseline to 24-hours post Day 14 dose in homeostasis model assessment of ß-cell function [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Percent change from baseline to Day 14 in insulinogenic index [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  • Absolute change from baseline to Day 14 in insulinogenic index [ Time Frame: Day 14 ] [ Designated as safety issue: No ]

Enrollment: 60
Study Start Date: January 2009
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: TAK-875

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.

Detailed Description:

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

Ages Eligible for Study:   18 Years to 68 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00949091

Sponsors and Collaborators
Takeda Global Research & Development Center, Inc.
Investigators
Study Director: Medical Director Clinical Science Takeda Global Research & Development Center, Inc.
  More Information

No publications provided

Responsible Party: Sr. VP, Clinical Science, Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier: NCT00949091     History of Changes
Other Study ID Numbers: TAK-875_102, U1111-1114-2888
Study First Received: July 28, 2009
Last Updated: June 9, 2010
Health Authority: United States: Food and Drug Administration

Keywords provided by Takeda Global Research & Development Center, Inc.:
Diabetes Mellitus, Non Insulin Dependent
Diabetes Mellitus, Type II
Type 2 Diabetes Mellitus
Drug Therapy

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on May 16, 2013