A Study in Type 2 Diabetic Subjects on Stable Metformin Therapy to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Co-administering Single and Multiple Oral Doses of GSK1292263

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 2

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: GSK1292263 matching placebo; Drug: GSK1292263; Drug: Sitagliptin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01128621

113132

Details and patient eligibility

About

A study in type 2 diabetic subjects on stable metformin therapy to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of co-administering single and multiple oral doses of GSK1292263

Full description

This study will investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK1292263 when co-administered with metformin. The study will be in 2 parts. Part A will determine the PK of GSK1292263 following single day dosing of type 2 diabetes (T2DM) subjects on metformin. Part B will investigate the effects of 14d of co-dosing of GSK1292263 BID, 50mg BID of sitagliptin or placebo to 48 T2DM subjects taking metformin.

Enrollment: 66 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female subjects, 18 - 65 years of age, inclusive.
• Females of non-childbearing potential.
• Male subjects willing to employ appropriate contraception.
• Except as noted elsewhere, subjects should have no significant known medical conditions other than T2DM that would affect the safety of the subject or the objectives of the study.
• BMI (body mass index) within the range 21.8-37.5 kg/m2.
• T2DM diagnosed by American Diabetes Association criteria for at least 3 month prior to screening.
• Currently on stable metformin therapy.
• Fasting plasma glucose <= 250mg/dL.
• HbA1c between 6.5 and 11.0%.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Average QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with right bundle branch block. Subjects with left bundle branch block are not eligible.
• AST and ALT < 2xULN; alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Subjects with Gilbert's syndrome are allowed to participate in the study.

Exclusion criteria

• Positive for Hepatitis B or C, or HIV.
• History of uncorrected thyroid dysfunction or an abnormal thyroid function test.
• History of ketoacidosis or lactic acidosis.
• Fasting triglycerides > 450mg/dL.
• For females a hemoglobin < 11.5g/dL, and for males a hemoglobin < 12.5g/dL.
• Positive drug/alcohol screen.
• Smoking.
• If female is pregnant or has a positive pregnancy test or is lactating.
• Significant renal disease.
• Significant ECG abnormalities.
• Systolic blood pressure > 150mmHg or <80mmHg or diastolic blood pressure > 95mmHg or <60mmHg at screening.
• Previous use of insulin as a treatment within 3 months of screening, or for >2 weeks when used for acute illness in the last 12 months prior to screening, or if used for more than 1 year when associated with gestational diabetes mellitus.
• History of: clinically significant symptoms of gastroparesis; symptomatic cholelithiasis or obstructive or inflammatory gallbladder disease within 3 months prior to screening; gastrointestinal disease that could affect fat or bile acid absorption, or the pharmacokinetics or pharmacodynamics of the study drugs, including inflammatory bowel disease, chronic diarrhea, Crohn's or malabsorption syndromes within the past year; gastrointestinal surgery that may affect the pharmacokinetics or pharmacodynamics of the study drugs; or, chronic or acute pancreatitis.
• History of regular alcohol consumption within 6 months.
• Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months.
• Has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication.
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Is taking prohibited medications. In Parts A and B, subjects will not be allowed to wash-off of unapproved anti-diabetic medications in order to qualify for participation in this study. • Subjects must wash out from the following medications during the 7-day period prior to first dose, and must remain off these medications through discharge on Day 2 (Part A) or Day 15 (Part B): all statin agents, fat absorption blocking agents, bile acid sequestrants. Fibrates must be washed out for a 14-day period prior to first dose. • Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication.
• Unwilling to abstain from: Caffeine-or xanthine-containing products from Day -7 until D2 (Part A) or Day -7 through Day 15 (Part B); use of illicit drugs or nicotine-containing products; alcohol from Day -7 prior to dosing until D2 (Part A) or Day -7 through Day 15 (Part B); Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication until collection of the final pharmacokinetic blood samples.
• History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation. This includes sensitivity to heparin or heparin-induced thrombocytopenia, if heparin will be used to maintain catheter patency.
• Where participation in the study would result in donation of blood in excess of approximately 500mL within a 56 day period.
• Subject is either an immediate family member of a participating investigator, study coordinator, employee of an investigator; or is a member of the staff conducting the study.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Subject is mentally or legally incapacitated.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Single Blind

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66 participants in 4 patient groups, including a placebo group

Part A

Other group

Description:

Part A is open label, in T2DM subjects on established metformin monotherapy. Subjects will receive a single dose of GSK1292263 with food. This will permit a comparison of GSK1292263 exposures in this cohort with those observed in study GPR111598 in which T2DM subjects were drug naïve or washed off prior anti-diabetic medications.

Treatment:

Drug: GSK1292263

Part B - PLA

Placebo Comparator group

Description:

Part B is a single-blind, randomized, placebo-controlled, 4-arm cohort of 48 subjects dosed for 14 days with one of two doses of GSK1292263 BID, placebo BID or open-label sitagliptin 50mg BID. It is being conducted to assess safety, tolerability, PK and PD of GSK1292263 and open-label sitagliptin after 14-days of dosing in T2DM subjects already taking metformin monotherapy.

Treatment:

Drug: GSK1292263 matching placebo

Part B - Active

Active Comparator group

Description:

Part B is a single-blind, randomized, placebo-controlled, 4-arm cohort of 48 subjects dosed for 14 days with one of two doses of GSK1292263 BID, placebo BID or open-label sitagliptin 50mg BID. It is being conducted to assess safety, tolerability, PK and PD of GSK1292263 and open-label sitagliptin after 14-days of dosing in T2DM subjects already taking metformin monotherapy.

Treatment:

Drug: GSK1292263

Part B - Sitagliptin

Active Comparator group

Description:

Part B is a single-blind, randomized, placebo-controlled, 4-arm cohort of 48 subjects dosed for 14 days with one of two doses of GSK1292263 BID, placebo BID or open-label sitagliptin 50mg BID. It is being conducted to assess safety, tolerability, PK and PD of GSK1292263 and open-label sitagliptin after 14-days of dosing in T2DM subjects already taking metformin monotherapy.

Treatment:

Drug: Sitagliptin