Clinical trial NCT01128621: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 2
Keywords: Pharmacokinetics
Glucose
Safety
Male
Female
Metformin
Pharmacodynamics
Tolerability
Type II Diabetes
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-05-24
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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

Detailed 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.

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.

Primary outcomes:
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Number of Participants With Any AEs and Serious Adverse Events SAEs (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Number of Participants With Abnormal Hematology Values of Potential Clinical Importance (PCI) (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Number of Participants With Abnormal Hematology Values of PCI (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Number of Participants With Abnormal Clinical Chemistry Values of PCI (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Number of Participants With Abnormal Clinical Chemistry Values of PCI (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Number of Participants With Abnormal Urinalysis Data Values by Dipstick Method (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Number of Participants With Abnormal Urinalysis Data Values (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Mean Value of Urine Albumin at Follow up (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Mean Value of Urine Albumin (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Mean Value of Urine pH (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Mean Value of Urine pH (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Mean Value of Urine Specific Gravity (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Mean Value of Urine Specific Gravity (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Number of Participants With Abnormal Vital Signs of PCI (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Number of Participants With Abnormal Vital Signs of PCI (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings (Part A)
timeFrame: Up to 10 days after discharge (Day 2) in Part A
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings (Part B)
timeFrame: Up to 10 days after discharge (Day 15) in Part B
measure: Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours [AUC (0-24)] and AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-last)] Following a Single Dose of GSK1292263 (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Maximum Observed Concentration (Cmax) Following a Single Dose of GSK1292263 (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) and Time of Occurrence of Cmax (Tmax) Following a Single Dose of GSK1292263 (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Apparent Clearance Following Oral Dosing (CL/F) of GSK1292263 (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Volume of Distribution (V/F) (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-inf]) Following a Single Dose of GSK1292263 (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Terminal Phase Half-life (t1/2) Following a Single Dose of GSK1292263 (Part A)
timeFrame: On Day 1 Immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13, 24 and 48 hours post-dose.
measure: Cmax Following Repeat Dose of GSK1292263 (Part B)
timeFrame: On Days 1 and 14, at immediately pre-morning dose, 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18, 24 and 48 hours post-morning dose. On Day 7, at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen).
measure: Tmax and Tlag Following Repeat Dose of GSK1292263 (Part B)
timeFrame: On Days 1 and 14, at immediately pre-morning dose, 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18, 24 and 48 hours post-morning dose. On Day 7, at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen).
measure: AUC From Time Zero (Pre-dose) to 10 Hours [AUC (0-10)] and AUC (0-24) Following Repeat Dose of GSK1292263 (Part B)
timeFrame: On Days 1 and 14, at immediately pre-morning dose, 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18, 24 and 48 hours post-morning dose. On Day 7, at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen).
measure: T1/2 Following Repeat Dose of GSK1292263 (Part B)
timeFrame: On Days 1 and 14, at immediately pre-morning dose, 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18, 24 and 48 hours post-morning dose. On Day 7, at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen).
measure: Mean Accumulation Ratio by AUC (0-10), AUC (0-24) and Cmax for GSK1292263 (Part B)
timeFrame: On Days 1 and 14, at immediately pre-morning dose, 1, 2, 4, 6, 8, 10, 11, 12, 14, 16, 18, 24 and 48 hours post-morning dose.
measure: Change From Baseline in Mean Fasted Glucose Value (Part A)
timeFrame: Baseline and at pre-breakfast on Day 1 and 24 h post-dose.
measure: Change From Baseline in Mean Fasted Insulin Value (Part A)
timeFrame: Baseline and at pre-breakfast on Day 1 and 24 hours post-dose.
measure: Change From Baseline in Mean Fasted Glucose Value (Part B)
timeFrame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.
measure: Change From Baseline in Mean Fasted Insulin Value (Part B)
timeFrame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.
measure: Mean Post Meal Glucose Value (Part B)
timeFrame: At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.
measure: Mean Post Meal Insulin Value (Part B)
timeFrame: At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.
measure: Change From Baseline in Weighted Mean for Glucose Value (Part B)
timeFrame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.
measure: Change From Baseline in Weighted Mean for Insulin Value (Part B)
timeFrame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.
measure: Number of Participants With Relationship Between GSK1292263 Drug Exposures and Pharmacodynamic Parameters (Part B)
timeFrame: At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose
Secondary outcomes:
Other outcomes:
Locations:
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Nunez DJ, Bush MA, Collins DA, McMullen SL, Gillmor D, Apseloff G, Atiee G, Corsino L, Morrow L, Feldman PL. Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies. PLoS One. 2014 Apr 3;9(4):e92494. doi: 10.1371/journal.pone.0092494. eCollection 2014.