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
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: GSK1292263; GSK1292263 matching placebo; Sitagliptin
Intervention description: Tablet; Tablet; Tablet
Intervention MeSH terms: Sitagliptin Phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Single (Investigator)
Enrollment: 66.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Pharmacokinetics; Glucose; Safety; Male; Female; Metformin; Pharmacodynamics; Tolerability; Type II Diabetes

Summary:

      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
    

Eligibility criteria:

        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.