Study Of GW823093 In Japanese Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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To investigate the preliminary pharmacokinetics, pharmacodynamics, safety and tolerability of GW823093 at doses of 15mg and 30mg given once daily for 7 days in Japanese Type 2 diabetes mellitus (T2DM) patients.

Official Title
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PK/PD Study of GW823093 in Japanese Subjects With T2DM: A Single-blind, Placebo Controlled, Randomized, Multi-dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GW823093C Administered Orally for 7 Days in Japanese Subjects With Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: GW823093 15mg
* Drug: GW823093 placebo capsule
* Drug: GW823093 30mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: T2DM diagnosed at least 3 months prior to Screening and fasting plasma glucose (FPG) level <280mg/dL at the Screening visit. Concurrent T2DM therapy: Must be diet controlled - OR - not taking more than 2 oral anti-diabetic agents, and willing to withdraw from these treatments 2 weeks prior to the first dosing. Exclusion criteria: Must not have any other major illness other than diabetes

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received two capsules of matching placebo orally once daily in the morning with 150 milliliter (mL) of water at least 15 minutes prior to breakfast for 7 Days. | Drug: GW823093 placebo capsule<br>* Matching placebo of GW823093 capsule or 15mg capsule<br>|
| Experimental: GW823093C 15 mg<br>Participants received one 15 milligrams (mg) of GW823093C capsule and one placebo capsule orally once daily in the morning with 150 mL of water at least 15 minutes prior to breakfast for 7 Days. | Drug: GW823093 15mg<br>* White opaque capsule containing 15mg of GW823093 as free base<br>* Other names: GW823093;Drug: GW823093 placebo capsule<br>* Matching placebo of GW823093 capsule or 15mg capsule<br>|
| Experimental: GW823093C 30 mg<br>Participants received 30 mg (2x15 mg) of GW823093C capsules orally once daily in the morning with 150 mL of water at least 15 minutes prior to breakfast for 7 Days. | Drug: GW823093 30mg<br>* White opaque capsule containing 15mg of GW823093 as free base<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standard Pharmacokinetic (PK) Parameter: Maximum Observed Plasma Drug Concentration (Cmax) | PK parameters were calculated using data at the actual time of blood collection. Cmax was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hours [hr]), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Time at Which Cmax Was Observed (Tmax) | PK parameters were calculated using data at the actual time of blood collection. Tmax was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Half Life of Terminal Elimination Phase (t1/2) | PK parameters were calculated using data at the actual time of blood collection. T1/2 was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Area Under the Plasma Drug Concentration Versus Time Curve Extrapolated to Infinity (AUC[0-inf]), AUC From 0 to the Last Measurable Concentration (AUC[0-t]) | PK parameters were calculated using data at the actual time of blood collection. AUC[0-inf] and AUC[0-t] was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Percentage of AUC(0-inf) Obtained by Extrapolation (%AUCex) | PK parameters were calculated using data at the actual time of blood collection. %AUCex was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Constant Rate of Elimination (lambda_z) | PK parameters were calculated using data at the actual time of blood collection. Lambda_z was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Total Clearance (CL/F) | PK parameters were calculated using data at the actual time of blood collection. CL/F was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: Apparent Volume of Distribution (Vz/F) | PK parameters were calculated using data at the actual time of blood collection. Vz/F was determined from plasma concentration-time data, using standard model independent methods. | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Standard PK Parameter: R[Cmax], Extent of Accumulation (Ro), Steady State Accumulation Ratio (Rs) | PK parameters were calculated using data at the actual time of blood collection. R[Cmax], Ro and Rs were determined from plasma concentration-time data, using standard model independent methods. R[Cmax] = Cmax (Day 7)/Cmax (Day 1), Ro = AUC(0-tau) (Day 7)/ AUC(0-tau) (Day 1) and Rs = AUC(0-tau) (Day 7)/ AUC(0-inf) (Day 1). | Day 1 (at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 hr), Day 2 (0 hr) and Day 7 (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) | 
| Percent Dipeptidyl-peptidase IV (DPP-IV) Inhibition by Dose (Day 7) | For analysis of DPP-IV activity, approximately 2 mL of whole blood was collected into a vacuum tube containing ethylenediamine tetraacetic acid (EDTA2K) and centrifuged at approximately 4 degree Celsius, at approximately 2500 revolution per minute (rpm) for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. DPP-IV inhibition was estimated by using the percent change from pre-dose of DPP-IV activity. DPP-IV inhibition was done at pre-dose, 0.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr and 24 hr. | Day 7 | 
| DPP-IV Activity Weighted Mean AUCs at Baseline (Day -1) and Day 7 | For analysis of DPP-IV activity, approximately 2 mL of whole blood was collected into a vacuum tube containing EDTA2K and centrifuged at approximately 4 degree Celsius, at approximately 2500 rpm for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. Double-delta represented active treatment within participant change from Baseline summarized across participants, subtracted from placebo within participant change from Baseline summarized across participants. AUC with respect to these time interval was calculated using linear trapezoidal rule by sum of the areas between each chronological pair of assessments (using observed times). Weighted mean was then determined by dividing AUC by observed length of collection interval (time of last assessment - time of first assessment in hr). Double-delta analysis has been presented in analysis. Unit of measure: Nano mole per minute per milliliter (nmol/min/mL). | Baseline (Day -1) and Day 7 | 
| Active Glucagon-like Peptide-1 (GLP-1) Weighted Mean AUCs at Baseline (Day -1) and Day 7 | For the analysis of active GLP-1 concentrations, approximately 3 mL of whole blood was collected into a vacuum tube containing DPP-IV inhibitor, and then centrifuged in a refrigerated centrifuge at approximately 4 degree Celsius, at approximately 2500 rpm for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. Double-delta represented the active treatment within participant change from Baseline summarized across participants, subtracted from placebo within participant change from Baseline summarized across participants. AUC with respect to these time interval was calculated using linear trapezoidal rule by sum of the areas between each chronological pair of assessments (using observed times). Weighted mean was then determined by dividing AUC by observed length of collection interval (time of last assessment - time of first assessment in hr). Double-delta analysis for weighted mean AUCs has been presented in the statistical analysis section. | Baseline (Day -1) and Day 7 | 
| Insulin Weighted Mean AUCs at Baseline (Day -1) and Day 7 | For the analysis of plasma insulin, approximately 2 mL of whole blood was collected into a vacuum tube containing EDTA2Na, and then centrifuged in a refrigerated centrifuge at approximately 4 degree Celsius, at approximately 2500 rpm for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. Double-delta represented the active treatment within participant change from Baseline summarized across participants, subtracted from placebo within participant change from Baseline summarized across participants. AUC with respect to these time interval was calculated using linear trapezoidal rule by sum of the areas between each chronological pair of assessments (using observed times). Weighted mean was then determined by dividing AUC by observed length of collection interval (time of last assessment - time of first assessment in hr). Double-delta analysis for weighted mean AUCs has been presented in the statistical analysis section. | Baseline (Day -1) and Day 7 | 
| Glucagon Weighted Mean AUCs at Baseline (Day -1) and Day 7 | For the analysis of plasma glucagons concentrations, approximately 2 mL of whole blood was collected into a vacuum tube containing aprotinin, and then centrifuged in a refrigerated centrifuge at approximately 4 degree Celsius, at approximately 2500 rpm for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. Double-delta represented the active treatment within participant change from Baseline summarized across participants, subtracted from placebo within participant change from Baseline summarized across participants. AUC with respect to these time interval was calculated using linear trapezoidal rule by sum of the areas between each chronological pair of assessments (using observed times). Weighted mean was then determined by dividing AUC by observed length of collection interval (time of last assessment - time of first assessment in hr). Double-delta analysis for weighted mean AUCs has been presented in the statistical analysis section. | Baseline (Day -1) and Day 7 | 
| C-peptide Weighted Mean AUCs at Baseline (Day -1) and Day 7 | For the analysis of plasma C-peptide concentrations, approximately 2 mL of whole blood was collected into a vacuum tube containing EDTA2Na, and then centrifuged in a refrigerated centrifuge at approximately 4 degree Celsius, at approximately 2500 rpm for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. Double-delta represented the active treatment within participant change from Baseline summarized across participants, subtracted from placebo within participant change from Baseline summarized across participants. AUC with respect to these time interval was calculated using linear trapezoidal rule by sum of the areas between each chronological pair of assessments (using observed times). Weighted mean was then determined by dividing AUC by observed length of collection interval (time of last assessment - time of first assessment in hr). Double-delta analysis for weighted mean AUCs has been presented in the statistical analysis section. | Baseline (Day -1) and Day 7 | 
| Glucose Weighted Mean AUCs at Baseline (Day -1) and Day 7 | For the analysis of plasma glucose concentrations, approximately 2 mL of whole blood was collected into a vacuum tube containing sodium fluoride, and then centrifuged in a refrigerated centrifuge at approximately 4 degree Celsius, at approximately 2500 rpm for 15 minutes. Samples were stored in a freezer at -70 degree Celsius or lower. Double-delta represented the active treatment within participant change from Baseline summarized across participants, subtracted from placebo within participant change from Baseline summarized across participants. AUC with respect to these time interval was calculated using linear trapezoidal rule by sum of the areas between each chronological pair of assessments (using observed times). Weighted mean was then determined by dividing AUC by observed length of collection interval (time of last assessment - time of first assessment in hr). Double-delta analysis for weighted mean AUCs has been presented in the statistical analysis section. | Baseline (Day -1) and Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE is defined as any untoward medical occurrence in a 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. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is serious corresponding to those listed in above definition. | Up to post-study screen (Follow-up [7 days after the last dose of study medication]) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacodynamics, Diabetes, pharmacokinetics