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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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01128621
First Posted: May 24, 2010
Last Update Posted: October 16, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose
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 Intervention Phase
Diabetes Mellitus, Type 2 Drug: GSK1292263 Drug: GSK1292263 matching placebo Drug: Sitagliptin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.

  • Number of Participants With Any AEs and Serious Adverse Events SAEs (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury.

  • Number of Participants With Abnormal Hematology Values of Potential Clinical Importance (PCI) (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    Blood samples for hematology assessments were collected at screening, fasting (Day -1), at 24hr post- dose (morning of Day 2), and at follow-up. Hematology parameter: Total Neutrophil count was assessed for abnormal value of PCI. The range of PCI value was: <0.83 x lower limit normal (LLN) with unit x10^9 per liter

  • Number of Participants With Abnormal Hematology Values of PCI (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Blood samples for hematology assessments were collected at screening, on Day -2 (non-fasting), and prior to breakfast (early in the morning, fasting) on Days 1, 7, and on Day 15 prior to checkout, (=24hrs post-dose), and at follow-up. Hematology parameters: Hematocrit (unit: ratio) and hemoglobin (unit: grams per liter [g/L]), were assessed for abnormal values of PCI. The PCI range for hematocrit was: >0.075 decrease from Baseline (low), >1.02 x upper limit normal (ULN) (high-male), >1.17 x ULN (high-female). The PCI range for hemoglobin was: >25 decrease from Baseline (low), >1.03 x ULN (high-male), >1.13 x ULN (high-female). Data has been presented for the number of participants with hematology data values high from the PCI range in a consolidated format.

  • Number of Participants With Abnormal Clinical Chemistry Values of PCI (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]

    Blood samples for chemistry assessments were collected at screening, fasting (Day -1), at 24hr post- dose (morning of Day 2), and at follow-up.

    Clinical chemistry parameter: Glucose (unit: millimoles per liter [mmol/L]) was assessed for abnormal high value of PCI. The normal range was 3.6 to 5.5 mmol/L


  • Number of Participants With Abnormal Clinical Chemistry Values of PCI (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Blood samples for chemistry assessments were collected at screening, on Day -2 (non-fasting), and prior to breakfast (early in the morning, fasting) on Days 1, 7, and on Day 15 prior to checkout, (=24hrs post-dose), and at follow-up. Clinical chemistry parameters: Aspartate amino transferase (unit: international unit per liter [IU/L]) and Total bilirubin (unit: micromoles per liter (µmol/L) were assessed for abnormal values of PCI. For aspartate aminotransferase the PCI range was >=2 x ULN (high). For total bilirubin the PCI range was >=1.5 x ULN (high).

  • Number of Participants With Abnormal Urinalysis Data Values by Dipstick Method (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    Urinalysis parameters: Urine occult blood, Urine Glucose, Urine ketones and Urine protein were assessed for abnormal findings by dipstick analysis. The abnormalities were presented as trace, 1+, 2+ and 3+. Trace indicates lowest concentration of the mentioned parameters in urine and 3+ indicates highest concentration. Concentration of 3+ indicates worse outcome.

  • Number of Participants With Abnormal Urinalysis Data Values (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Urinalysis parameters: Urine occult blood, Urine glucose, Urine ketones, Urine protein, White blood cells were assessed for abnormal findings by dipstick analysis. The abnormal findings were presented as trace, 1+, 2+ and 3+. Trace indicates lowest concentration of the mentioned parameters in urine and 3+ indicates highest concentration. Concentration of 3+ indicates worse outcome.

  • Mean Value of Urine Albumin at Follow up (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    Urine samples were collected at screening, Day -1, at 24hr post- dose (Day 2), and at follow-up. Urine albumin was assessed using quantitative analysis.

  • Mean Value of Urine Albumin (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Urine samples were collected at screening, on Day -2, and on Days 1, 7, 15 and at follow-up. Urine albumin was assessed using quantitative analysis.

  • Mean Value of Urine pH (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    Urine samples were collected at screening, Day -1, at 24hr post- dose (Day 2), and at follow-up. Urinalysis parameters included urine pH assessed using dipstick analysis. pH is calculated on a scale of 0 to 14, such that, the lower the number, more acidic the urine and higher the number, more alkaline the urine with 7 being neutral.

  • Mean Value of Urine pH (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Urine samples were collected at screening, on Day -2, and on Days 1, 7, 15 and at follow-up. Urinalysis parameters included urine pH assessed using dipstick analysis. pH is calculated on a scale of 0 to 14, such that, the lower the number, more acidic the urine and higher the number, more alkaline the urine with 7 being neutral.

  • Mean Value of Urine Specific Gravity (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    Urine samples were collected at screening, Day -1, at 24hr post- dose (Day 2), and at follow-up. Urinalysis parameter include urine specific gravity. Urinary specific gravity is a measure of the concentration of solutes in the urine . It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine .

  • Mean Value of Urine Specific Gravity (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Urine samples were collected at screening, on Day -2, and on Days 1, 7, 15 and at follow-up. Urinalysis parameter include urine specific gravity. Urinary specific gravity is a measure of the concentration of solutes in the urine . It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine .

  • Number of Participants With Abnormal Vital Signs of PCI (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    Assessment of vital signs (including systolic, diastolic blood pressure and heart rate) was performed at one time point at Screening, at follow-up and pre-breakfast on Day -1. On Day 1, they were taken at pre-breakfast, 1 hour, 3, 4, 6, 10, 16 and 24 hours post-dose. Assessments were made in triplicate at the pre-breakfast time point, and single assessments were made at all other times. Assessments were performed after resting in a supine or semi-supine position for at least 10 minutes. PCI value of systolic blood pressure: <85 and >160 millimeter of mercury (mmHg). PCI value of diastolic blood pressure: <45 and >100 mmHg. PCI value of heart rate: <40 and >110 beats per minute.

  • Number of Participants With Abnormal Vital Signs of PCI (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    Assessment of vital signs (including systolic and diastolic blood pressure and heart rate) was performed at Screening, pre-breakfast on Days -1 to 14 in a fasting state early in the morning (prior to morning dosing on Days 1-14), and at Follow-up. On Days 1, 7 and 14, they were taken at 1, 3, 6, 9, 12 and 24 hours after the morning dose. At each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes.

  • Number of Participants With Abnormal Electrocardiogram (ECG) Findings (Part A) [ Time Frame: Up to 10 days after discharge (Day 2) in Part A ]
    ECGs were taken at Screening, pre-breakfast on Day -1, on Day 1 (pre-breakfast, 1 hour, 2, 3, 4, 6, 8, 13, 24hours post-dose), and at follow-up. Assessments were made in triplicate on Day 1 at the pre-breakfast time point, and single assessments were made at all other times. ECGs were taken in supine position. The data has been presented as abnormal- not clinically significant (NCS) and abnormal-clinically significant (CS).

  • Number of Participants With Abnormal Electrocardiogram (ECG) Findings (Part B) [ Time Frame: Up to 10 days after discharge (Day 15) in Part B ]
    ECGs were taken at Screening, pre-breakfast on Day -1 and at Follow-up. On Days 1, 7 and 14 ECGs were taken pre-breakfast (fasting) and at 1, 2, 4, 6, 8, 12 and 24hours post-dose. Triplicate ECGs were taken at the pre-breakfast time point, and single assessments were taken at all other times. ECGs were taken in supine position. The data has been presented as abnormal- not clinically significant (NCS) and abnormal-clinically significant (CS).

  • 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) [ Time Frame: 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. ]
    Blood samples for the determination of pharmacokinetics (PK) were collected 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. PK samples for 2 participants were not analyzed. The PK parameters were calculated by standard non-compartmental analysis. AUC (0-last) and AUC (0-24) were determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

  • Maximum Observed Concentration (Cmax) Following a Single Dose of GSK1292263 (Part A) [ Time Frame: 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. ]
    Blood samples for the determination of PK were collected 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. PK samples for participants were not analyzed. The PK parameters were calculated by standard non-compartmental analysis. Cmax was determined directly from the raw concentration-time data.

  • 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) [ Time Frame: 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. ]
    Blood samples for the determination of PK were collected 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. PK samples for 2 participants were not analyzed. The PK parameters were calculated by standard non-compartmental analysis. Tmax was determined directly from the raw concentration-time data. Tlag was determined as the time of the sample preceding the first quantifiable concentration, on Day 1 only.

  • Apparent Clearance Following Oral Dosing (CL/F) of GSK1292263 (Part A) [ Time Frame: 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. ]
    Outcome measure was added with caveat "as data permits". The data for CL/F was not collected.

  • Volume of Distribution (V/F) (Part A) [ Time Frame: 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. ]
    Outcome measure was added with caveat "as data permits". The data for V/F was not collected.

  • 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) [ Time Frame: 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. ]
    Outcome measure was added with caveat "as data permits". The data for AUC (0-inf) was not collected.

  • Terminal Phase Half-life (t1/2) Following a Single Dose of GSK1292263 (Part A) [ Time Frame: 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. ]
    Outcome measure was added with caveat "as data permits". The data for t1/2 was not collected.

  • Cmax Following Repeat Dose of GSK1292263 (Part B) [ Time Frame: 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). ]
    Serial blood samples for the determination of the PK of GSK1292263 were collected on Days 1, 7 and 14. Blood samples for PK were collected 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, blood samples for PK were collected at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen). When planned PK sampling resulted in multiple samples at the same time point, only one sample was collected. The PK parameters were calculated by standard non-compartmental analysis. Cmax was determined directly from the raw concentration-time data.

  • Tmax and Tlag Following Repeat Dose of GSK1292263 (Part B) [ Time Frame: 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). ]
    Serial blood samples for the determination of the PK of GSK1292263 were collected on Days 1, 7 and 14. Blood samples for PK were collected 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, blood samples for PK were collected at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen). When planned PK sampling resulted in multiple samples at the same time point, only one sample was collected. The PK parameters were calculated by standard non-compartmental analysis. Tmax was determined directly from the raw concentration-time data. Tlag was determined as the time of the sample preceding the first quantifiable concentration, on Day 1 only.

  • AUC From Time Zero (Pre-dose) to 10 Hours [AUC (0-10)] and AUC (0-24) Following Repeat Dose of GSK1292263 (Part B) [ Time Frame: 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). ]
    Serial blood samples for the determination of the PK of GSK1292263 were collected on Days 1, 7 and 14. Blood samples for PK were collected 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, blood samples for PK were collected at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen). When planned PK sampling resulted in multiple samples at the same time point, only one sample was collected. The PK parameters were calculated by standard non-compartmental analysis. AUC (0-10) and AUC (0-24) were determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

  • T1/2 Following Repeat Dose of GSK1292263 (Part B) [ Time Frame: 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). ]
    Outcome measure was added with caveat "as data permits". The data for T1/2 was not collected.

  • Mean Accumulation Ratio by AUC (0-10), AUC (0-24) and Cmax for GSK1292263 (Part B) [ Time Frame: 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. ]
    Accumulation ratio (Ro) was derived as: Ro = Day 14 morning AUC(0-10)/Day 1 morning AUC(0-10) (for BID regimens only). Ro = Day 14 AUC(0-24)/Day 1 AUC(0-24) (for both BID and once daily regimens). Accumulation ratio (RCmax)= Day 14 Cmax/Day 1 Cmax. RCmax was not computed for each dosing period (morning and evening).

  • Change From Baseline in Mean Fasted Glucose Value (Part A) [ Time Frame: Baseline and at pre-breakfast on Day 1 and 24 h post-dose. ]
    Baseline was considered to be Day 1 pre-breakfast. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline is set to missing as well. If measurements were taken in triplicate, then the mean of the triplicate measurements was used as the Baseline.

  • Change From Baseline in Mean Fasted Insulin Value (Part A) [ Time Frame: Baseline and at pre-breakfast on Day 1 and 24 hours post-dose. ]
    Baseline was considered to be Day 1 pre-breakfast. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline is set to missing as well. If measurements were taken in triplicate, then the mean of the triplicate measurements was used as the Baseline.

  • Change From Baseline in Mean Fasted Glucose Value (Part B) [ Time Frame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose. ]
    Baseline was considered to be Day -1 pre-breakfast value. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline is set to missing as well. If measurements were taken in triplicate, then the mean of the triplicate measurements was used as the Baseline.

  • Change From Baseline in Mean Fasted Insulin Value (Part B) [ Time Frame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose. ]
    Baseline was considered to be Day -1 pre-breakfast value. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline is set to missing as well. If measurements were taken in triplicate, then the mean of the triplicate measurements was used as the Baseline.

  • Mean Post Meal Glucose Value (Part B) [ Time Frame: At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose. ]
    Blood samples were collected on Days -1 and 14, post-breakfast at 0.5, 1, 1.5, 2 and 3 hours post dose. For lunch (approximately 4 hours post morning dose) samples were collected at the following times after starting each meal: 0.5, 1, 1.5, 2 and 3 hours. For the evening meal (approximately 10 hours post morning dose), samples were taken at 0.5, 1, 1.5, 2 and 3 hours post dinner.

  • Mean Post Meal Insulin Value (Part B) [ Time Frame: At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose. ]
    Blood samples were collected on Days -1 and 14, post-breakfast at 0.5, 1, 1.5, 2 and 3 hours post dose. For lunch (approximately 4 hours post morning dose) samples were collected at the following times after starting each meal: 0.5, 1, 1.5, 2 and 3 hours. For the evening meal (approximately 10 hours post morning dose), samples were taken at 0.5, 1, 1.5, 2 and 3 hours post dinner.

  • Change From Baseline in Weighted Mean for Glucose Value (Part B) [ Time Frame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose. ]
    Baseline was considered to be Day -1 pre-breakfast value. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline is set to missing as well. If measurements were taken in triplicate, then the mean of the triplicate measurements was used as the Baseline. Weighted mean were assessed for (0-12) and (0-24). AUC with respect to that time interval was calculated using the linear trapezoidal rule. The weighted mean was determined by dividing the AUC by the observed length of the collection interval (time of last assessment - time of first assessment in hours). In order for the AUC to be calculated, the first and last time points and at least one additional assessment falling between the two must be non-missing.

  • Change From Baseline in Weighted Mean for Insulin Value (Part B) [ Time Frame: Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose. ]
    Baseline was considered to be Day -1 pre-breakfast value. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline is set to missing as well. If measurements were taken in triplicate, then the mean of the triplicate measurements was used as the Baseline. AUC with respect to that time interval was calculated using the linear trapezoidal rule. The weighted mean was determined by dividing the AUC by the observed length of the collection interval (time of last assessment - time of first assessment in hours). In order for the AUC to be calculated, the first and last time points and at least one additional assessment falling between the two must be non-missing.

  • Number of Participants With Relationship Between GSK1292263 Drug Exposures and Pharmacodynamic Parameters (Part B) [ Time Frame: At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose ]
    Data was not collected for this outcome measure.


Enrollment: 66
Actual Study Start Date: November 23, 2009
Study Completion Date: April 12, 2010
Primary Completion Date: April 12, 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Part A
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.
Drug: GSK1292263
Tablet
Placebo Comparator: Part B - PLA
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.
Drug: GSK1292263 matching placebo
Tablet
Active Comparator: Part B - Active
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.
Drug: GSK1292263
Tablet
Active Comparator: Part B - Sitagliptin
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.
Drug: Sitagliptin
Tablet

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01128621


Locations
United States, California
GSK Investigational Site
Chula Vista, California, United States, 91910
United States, Florida
GSK Investigational Site
Miami, Florida, United States, 33169
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Study Data/Documents: Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 113132
For additional information about this study please refer to the GSK Clinical Study Register

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01128621     History of Changes
Other Study ID Numbers: 113132
First Submitted: February 12, 2010
First Posted: May 24, 2010
Results First Submitted: August 10, 2017
Results First Posted: October 16, 2017
Last Update Posted: October 16, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
URL: http://

Keywords provided by GlaxoSmithKline:
Pharmacokinetics
Glucose
Safety
Male
Female
Metformin
Pharmacodynamics
Tolerability
Type II Diabetes

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action