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

NCT01128621 | Completed Phase 2 Results

• 1 other identifier: 113132
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 2

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

Conditions

Diabetes Mellitus, Type 2

Keywords

Pharmacokinetics; Glucose; Safety; Male; Female; Metformin; Pharmacodynamics; Tolerability; Type II Diabetes

Outcome Measures

Primary Outcomes (39)

• Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs) (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.

  Up to 10 days after discharge (Day 2) in Part A

• Number of Participants With Any AEs and Serious Adverse Events SAEs (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.

  Up to 10 days after discharge (Day 15) in Part B

• Number of Participants With Abnormal Hematology Values of Potential Clinical Importance (PCI) (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

  Up to 10 days after discharge (Day 2) in Part A

• Number of Participants With Abnormal Hematology Values of PCI (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.

  Up to 10 days after discharge (Day 15) in Part B

• Number of Participants With Abnormal Clinical Chemistry Values of PCI (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

  Up to 10 days after discharge (Day 2) in Part A

• Number of Participants With Abnormal Clinical Chemistry Values of PCI (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).

  Up to 10 days after discharge (Day 15) in Part B

• Number of Participants With Abnormal Urinalysis Data Values by Dipstick Method (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.

  Up to 10 days after discharge (Day 2) in Part A

• Number of Participants With Abnormal Urinalysis Data Values (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.

  Up to 10 days after discharge (Day 15) in Part B

• Mean Value of Urine Albumin at Follow up (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.

  Up to 10 days after discharge (Day 2) in Part A

• Mean Value of Urine Albumin (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.

  Up to 10 days after discharge (Day 15) in Part B

• Mean Value of Urine pH (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.

  Up to 10 days after discharge (Day 2) in Part A

• Mean Value of Urine pH (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.

  Up to 10 days after discharge (Day 15) in Part B

• Mean Value of Urine Specific Gravity (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 .

  Up to 10 days after discharge (Day 2) in Part A

• Mean Value of Urine Specific Gravity (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 .

  Up to 10 days after discharge (Day 15) in Part B

• Number of Participants With Abnormal Vital Signs of PCI (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.

  Up to 10 days after discharge (Day 2) in Part A

• Number of Participants With Abnormal Vital Signs of PCI (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.

  Up to 10 days after discharge (Day 15) in Part B

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings (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).

  Up to 10 days after discharge (Day 2) in Part A

• Number of Participants With Abnormal Electrocardiogram (ECG) Findings (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).

  Up to 10 days after discharge (Day 15) in Part B

• 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)

  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.

  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.

• Maximum Observed Concentration (Cmax) Following a Single Dose of GSK1292263 (Part A)

  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.

  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.

• 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)

  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.

  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.

• Apparent Clearance Following Oral Dosing (CL/F) of GSK1292263 (Part A)

  Outcome measure was added with caveat "as data permits". The data for CL/F was not 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.

• Volume of Distribution (V/F) (Part A)

  Outcome measure was added with caveat "as data permits". The data for V/F was not 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.

• 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)

  Outcome measure was added with caveat "as data permits". The data for AUC (0-inf) was not 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.

• Terminal Phase Half-life (t1/2) Following a Single Dose of GSK1292263 (Part A)

  Outcome measure was added with caveat "as data permits". The data for t1/2 was not 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.

• Cmax Following Repeat Dose of GSK1292263 (Part B)

  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.

  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).

• Tmax and Tlag Following Repeat Dose of GSK1292263 (Part B)

  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.

  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).

• AUC From Time Zero (Pre-dose) to 10 Hours [AUC (0-10)] and AUC (0-24) Following Repeat Dose of GSK1292263 (Part B)

  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.

  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).

• T1/2 Following Repeat Dose of GSK1292263 (Part B)

  Outcome measure was added with caveat "as data permits". The data for T1/2 was not 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, at pre-dose (post-breakfast), 1, 2, 4 (pre-lunch), 6 and 10 (immediately post-dinner, pre-dose for BID regimen).

• Mean Accumulation Ratio by AUC (0-10), AUC (0-24) and Cmax for GSK1292263 (Part B)

  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).

  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.

• Change From Baseline in Mean Fasted Glucose Value (Part A)

  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.

  Baseline and at pre-breakfast on Day 1 and 24 h post-dose.

• Change From Baseline in Mean Fasted Insulin Value (Part A)

  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.

  Baseline and at pre-breakfast on Day 1 and 24 hours post-dose.

• Change From Baseline in Mean Fasted Glucose Value (Part B)

  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.

  Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.

• Change From Baseline in Mean Fasted Insulin Value (Part B)

  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.

  Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.

• Mean Post Meal Glucose Value (Part B)

  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.

  At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.

• Mean Post Meal Insulin Value (Part B)

  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.

  At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.

• Change From Baseline in Weighted Mean for Glucose Value (Part B)

  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.

  Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.

• Change From Baseline in Weighted Mean for Insulin Value (Part B)

  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.

  Baseline and at pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose.

• Number of Participants With Relationship Between GSK1292263 Drug Exposures and Pharmacodynamic Parameters (Part B)

  Data was not collected for this outcome measure.

  At pre-breakfast on Days -1 and 14, and then at 0.5, 1, 1.5, 2 and 3 hours post dose

Study Arms (4)

Part A

OTHER

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

Part B - PLA

PLACEBO COMPARATOR

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

Part B - Active

ACTIVE COMPARATOR

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

Part B - Sitagliptin

ACTIVE COMPARATOR

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

Interventions

GSK1292263 DRUG

Tablet

Part A; Part B - Active

GSK1292263 matching placebo DRUG

Tablet

Part B - PLA

Sitagliptin DRUG

Tablet

Part B - Sitagliptin

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Chula Vista, California, 91910, United States

Location

GSK Investigational Site

Miami, Florida, 33169, United States

Location

Related Publications (1)

• 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.

  PMID: 24699248 DERIVED

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate; Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2010
• First Posted: May 24, 2010
• Study Start: November 23, 2009
• Primary Completion: April 12, 2010
• Study Completion: April 12, 2010
• Last Updated: October 16, 2017
• Results First Posted: October 16, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will share

Locations

US (2)