A 2-Part Trial in Subjects With Type 2 Diabetes and in Healthy Subjects to Evaluate GSK1614235, a New Glucose Lowering Drug to Treat Type 2 Diabetes
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of Part A of this study is to test whether repeated doses of the study drug
      (GSK1614235) are safe and well tolerated (i.e. do not produce unacceptable side effects) and
      whether we can obtain some preliminary information as to whether it works in lowering blood
      glucose levels. We will do this by comparing the effect of the study drug with placebo (no
      drug present) and against a drug (sitagliptin) known to control blood glucose in the
      treatment of diabetes.

      The purpose of Part B of this study is to determine the how the timing of dosing, relative to
      meals, affects the response to study drug.
    

Detailed description: 
      Part A is a double-blind, randomized, parallel group, dose-ranging study, in subjects with
      type 2 diabetes mellitus to assess safety, tolerability, and to estimate the pharmacodynamic
      effects when subjects receive repeated doses of placebo, sitagliptin (Januvia), or
      GSK1614235. The target is to explore the best doses of GSK1614235 that provide glucose
      control with minimal adverse effects.

      There will be at least 4 cohorts of subjects:

        -  Cohort 1: 8 subjects randomized to receive placebo, 100mg sitagliptin QD, or 1mg
           GSK1612435 BID

        -  Cohort 2: 6 subjects randomized to receive placebo, 100mg sitagliptin QD, or 5mg
           GSK1612435 BID.

        -  Cohort 3: 6 subjects randomized to receive placebo, 100mg sitagliptin QD, or 20mg
           GSK1612435 BID.

        -  Cohort 4: 20-40 subjects randomized to receive placebo, 100mg sitagliptin QD, or
           GSK1612435 BID, (potential doses of 0.25 to 40mg BID), depending on safety,
           tolerability, and glucose results of Cohorts 1, 2, and 3.

        -  Cohort 5: 12 subjects randomized to receive placebo or GSK1614235 BID (potential doses
           of up to 80mg BID), depending on safety, tolerability, and glucose results of Cohorts 1,
           2, 3, and 4.

        -  Cohort 6: 24 subjects randomized to receive GSK1614235 BID (20BID), or sitagliptin
           (100mg QD).

      After subjects have successfully completed the screening procedures, they will be asked to
      discontinue prior anti-diabetic therapy at least 72 h before admission to the research
      facility and remain off of the medications until the completion of the follow-up visit (total
      of ~14 days). Subjects will be admitted to the research facility on the evening of Day -2 in
      preparation to begin baseline assessments, including PD, on Day -1 (for their particular
      cohort). Beginning on Day 1, subjects will receive a single dose of GSK1614235 and undergo PK
      sampling, and on Day 2 through Day 6, subjects will be dosed on a twice daily dosing schedule
      with doses administered immediately before breakfast and the evening meal. Day 6 includes
      intensive assessments of PK and PD parameters in addition to routine safety monitoring.

      Part B is a double-blind, randomized, single-dose, 3-way crossover study in 12 subjects. A
      well-tolerated dose of GSK1614235 that provides a meaningful pharmacodynamic response based
      on data from Part A will be administered in both fed and fasted states. It is not anticipated
      that the dose for Part B will exceed single doses of 40mg.

      Part B will consist of 3 periods. Period 1 will begin after subjects have successfully
      completed screening. They will be admitted to the research facility the evening before dosing
      (Day -1) and will dose the following morning after an overnight (at least 12 hour fast).
      Safety monitoring and PK and PD sampling will be conducted over a 48 hour period. Subjects
      will be discharged from the research facility after the 48 hour PK and PD sample has been
      collected. A washout period of ≥ 5 days period will ensue, and subjects will be admitted to
      the research facility to begin Period 2. Period 3 will follow the same schedule as Period 1
      and Period 2.

      Subjects will be randomized such that, at separate admissions, each subject receives the
      selected GSK1614235 dose or matching placebo as follows.

        -  GSK1614235 before meal and placebo after meal

        -  GSK1614235 30 min after meal and placebo before meal

        -  Placebo - both before meal and 30 min after meal
    

Intervention name(s): GSK1614235; Sitagliptin; Placebo
Intervention type(s): Drug; Drug; Other
Intervention description(s): Glucose lowering in Type 2 Diabetes Mellitus; Glucose lowering in Type 2 Diabetes Mellitus; Comparator
Other intervention name(s): Type 2 Diabetes Mellitus; Type 2 Diabetes Mellitus; Type 2 Diabetes Mellitus
Intervention MeSH terms: Sitagliptin Phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: type 2 diabetes; single dose; 3-O-methylglucose; healthy volunteer; repeat dose