Effect of SCH 497079 on Metabolic Parameters and Influence of Race/Ethnic Origin on Therapeutic Response (Study P05338)(COMPLETED)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of SCH 497079 on metabolic parameters and to determine the influence of race/ethnic origin on therapeutic response.

Detailed Description
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This study includes two parts, each part includes three consecutive 28-day treatment periods. Part 1 (to be conducted in the United States): each participant will receive the following treatments for 28 days in each of three treatment periods in an order determined by a random code: SCH 497079, or matching placebo, or metformin. Part 2 (to be conducted in India): this part of the study will be conducted after completion of Part 1 and an analysis indicates a clinically significant decrease in blood glucose in participants with type 2 diabetes mellitus (T2DM) compared to placebo. The same procedures conducted in Part 1 will be conducted in Part 2.

Official Title
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A Randomized, Placebo-controlled, Three-Way Crossover Study to Evaluate the Effect of SCH 497079 on Metabolic Parameters and to Determine the Influence of Race/Ethnic Origin on Therapeutic Response

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: SCH 497079
* Drug: Placebo
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: >=18 years of age to 65 years of age, of either sex, and having a body mass index (BMI) between 27 and 35, inclusive (USA participants) Clinical laboratory tests (complete blood count, blood chemistry, and urinalysis) within normal limits (excluding glucose and other changes usually associated with diabetes eg, dyslipidemia) Type 2 diabetes mellitus Exclusion Criteria: Female participants who are premenopausal or are not surgically sterilized. Participants who are pregnant, intend to become pregnant (within 3 months of ending the study), or are breast-feeding. Participants who have received insulin therapy within 6 months, prior to Day 1/Period 1 or who require thiazide diuretics, beta-blockers and cyclic hormone therapy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment sequence 1: SCH 497079 → Placebo → Metformin<br>Participants received SCH 497079 daily for 4 weeks followed by placebo daily for 4 weeks followed by metformin daily for 4 weeks. | Drug: SCH 497079<br>* SCH 497079 100 mg capsule, administered orally, once daily for 4 weeks<br>Drug: Placebo<br>* Placebo capsules matching SCH 497079, administered orally, once daily for 4 weeks<br>Drug: Metformin<br>* Metformin extended release 750 mg, 2 tablets administered orally, once daily for 4 weeks (1500 mg total daily dose)<br>|
| Experimental: Treatment sequence 2: Placebo → Metformin → SCH 497079<br>Participants received placebo daily for 4 weeks followed by metformin daily for 4 weeks followed by SCH 497079 daily for 4 weeks. | Drug: SCH 497079<br>* SCH 497079 100 mg capsule, administered orally, once daily for 4 weeks<br>Drug: Placebo<br>* Placebo capsules matching SCH 497079, administered orally, once daily for 4 weeks<br>Drug: Metformin<br>* Metformin extended release 750 mg, 2 tablets administered orally, once daily for 4 weeks (1500 mg total daily dose)<br>|
| Experimental: Treatment sequence 3: Metformin → SCH 497079 → Placebo<br>Participants received metformin daily for 4 weeks followed by SCH 497079 daily for 4 weeks followed by placebo daily for 4 weeks. | Drug: SCH 497079<br>* SCH 497079 100 mg capsule, administered orally, once daily for 4 weeks<br>Drug: Placebo<br>* Placebo capsules matching SCH 497079, administered orally, once daily for 4 weeks<br>Drug: Metformin<br>* Metformin extended release 750 mg, 2 tablets administered orally, once daily for 4 weeks (1500 mg total daily dose)<br>|
| Experimental: Treatment sequence 4: SCH 497079 → Metformin → Placebo<br>Participants received SCH 497079 daily for 4 weeks followed by metformin daily for 4 weeks followed by placebo daily for 4 weeks. | Drug: SCH 497079<br>* SCH 497079 100 mg capsule, administered orally, once daily for 4 weeks<br>Drug: Placebo<br>* Placebo capsules matching SCH 497079, administered orally, once daily for 4 weeks<br>Drug: Metformin<br>* Metformin extended release 750 mg, 2 tablets administered orally, once daily for 4 weeks (1500 mg total daily dose)<br>|
| Experimental: Treatment sequence 5: Placebo → SCH 49709 → Metformin<br>Participants received placebo daily for 4 weeks followed by SCH 497079 daily for 4 weeks followed by metformin daily for 4 weeks. | Drug: SCH 497079<br>* SCH 497079 100 mg capsule, administered orally, once daily for 4 weeks<br>Drug: Placebo<br>* Placebo capsules matching SCH 497079, administered orally, once daily for 4 weeks<br>Drug: Metformin<br>* Metformin extended release 750 mg, 2 tablets administered orally, once daily for 4 weeks (1500 mg total daily dose)<br>|
| Experimental: Treatment sequence 6: Metformin → Placebo → SCH 497079<br>Participants received metformin daily for 4 weeks followed by placebo daily for 4 weeks followed by SCH 497079 daily for 4 weeks. | Drug: SCH 497079<br>* SCH 497079 100 mg capsule, administered orally, once daily for 4 weeks<br>Drug: Placebo<br>* Placebo capsules matching SCH 497079, administered orally, once daily for 4 weeks<br>Drug: Metformin<br>* Metformin extended release 750 mg, 2 tablets administered orally, once daily for 4 weeks (1500 mg total daily dose)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic: Change From Baseline in Mean 24-hour Plasma Glucose (AUC/Duration) at Week 4 (Part 1 - United States) | Change from baseline in 24-hour plasma glucose on the last day of treatment. On the day of the glucose collections (and the day prior to), standardized meals breakfast, lunch, dinner, and snack) were provided and consumed over 15 minutes. AUC/duration is presented as mg/dL and was calculated by dividing AUC (mg/dL*hr) by the duration in hours. Model-based least squares mean: ANOVA extracting the effects due to treatment, sequence, period and participant. | Pre-dose (-30 minutes), pre-standard breakfast (0 hour), 0.5, .75, 1, 2, 3, 4, 4.5, 4.75, 5, 6, 7, 8, 9, 9.5, 9.75, 10, 11, 12, 13, 14, 15, 16, and 24 hours after the beginning of the standardized breakfast on Day -1 and Day 28 | 
| Pharmacodynamic: Change From Baseline in 24-hour Plasma Glucose (AUC/Duration) at Week 4 (Part 2 - India) | Change from baseline in 24-hour plasma glucose on the last day of treatment. On the day of the glucose collections (and the day prior to), standardized meals (breakfast, lunch, dinner, and snack) were provided and consumed over 15 minutes. AUC/duration is presented as mg/dL and was calculated by dividing AUC (mg/dL*hr) by the duration in hours. Model-based least squares mean: ANOVA extracting the effects due to treatment, sequence, period and participant. | Pre-dose (-30 mnutes), pre-standard breakfast (0 hour), 0.5, .75, 1, 2, 3, 4, 4.5, 4.75, 5, 6, 7, 8, 9, 9.5, 9.75, 10, 11, 12, 13, 14, 15, 16, and 24 hours after the beginning of the standardized breakfast on Day -1 and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced at Least One Adverse Event (Part 1 - United States) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. | Up to 14 days after last dose of study drug (up to 98 days) | 
| Number of Participants Who Experienced at Least One Adverse Event (Part 2 - India) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which does not necessarily have a causal relationship with the treatment. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. | Up to 14 days after last dose of study drug (up to 98 days) | 
| Pharmacodynamic: Change From Baseline in 12-hour Postprandial Plasma Glucose (AUC/Duration) at Week 4 (Part 1 - United States) | The postprandial period is defined as the sum of 4 hours after breakfast, 4 hours after lunch and 4 hours after dinner for a total of 12 hours. AUC/duration is presented as mg/dL and was calculated by dividing AUC (mg/dL*hr) by the duration in hours. Model-based least squares mean: ANOVA extracting the effects due to treatment, sequence, period and participant. | Pre-dose (-30 minutes), pre-standard breakfast (0 hour), 0.5, .75, 1, 2, 3, 4, 4.5, 4.75, 5, 6, 7, 8, 9, 9.5, 9.75, 10, 11, 12, 13, 14, 15, 16, and 24 hours after the beginning of the standardized breakfast on Day -1 and Day 28 | 
| Pharmacodynamic: Change From Baseline in 12-hour Postprandial Plasma Glucose (AUC/Duration) at Week 4 (Part 2 - India) | The postprandial period is defined as the sum of 4 hours after breakfast, 4 hours after lunch and 4 hours after dinner for a total of 12 hours. AUC/duration is presented as mg/dL and was calculated by dividing AUC (mg/dL*hr) by the duration in hours. Model-based least squares mean: ANOVA extracting the effects due to treatment, sequence, period and participant. | Pre-dose (-30 minutes), pre-standard breakfast (0 hour), 0.5, .75, 1, 2, 3, 4, 4.5, 4.75, 5, 6, 7, 8, 9, 9.5, 9.75, 10, 11, 12, 13, 14, 15, 16, and 24 hours after the beginning of the standardized breakfast on Day -1 and Day 28 | 
| Pharmacodynamic: Change From Baseline in Plasma Glucose During the 12-hour Post Absorptive State (AUC/Duration) at Week 4 (Part 1 - United States) | The post absorptive state is defined as the remaining part of day and night that is not the postprandial period. The postprandial period is defined as the sum of 4 hours after breakfast, 4 hours after lunch and 4 hours after dinner for a total of 12 hours. AUC/duration is presented as mg/dL and was calculated by dividing AUC (mg/dL*hr) by the duration in hours. Model-based least squares mean: ANOVA extracting the effects due to treatment, sequence, period and participant. | Baseline and Week 4 | 
| Pharmacodynamic: Change From Baseline in Plasma Glucose During the 12-hour Post Absorptive State (AUC/Duration) at Week 4 (Part 2 - India) | The post absorptive state is defined as the remaining part of day and night that is not the postprandial period. The postprandial period is defined as the sum of 4 hours after breakfast, 4 hours after lunch and 4 hours after dinner for a total of 12 hours. AUC/duration is presented as mg/dL and was calculated by dividing AUC (mg/dL*hr) by the duration in hours. Model-based least squares mean: ANOVA extracting the effects due to treatment, sequence, period and participant. | Baseline and Week 4 | 
| Pharmacokinetic: Mean Plasma Glucose (Over 24 Hours) at Week 4 (Part 1 - United States) | Blood samples for SCH 497079 pharmacokinetics will be collected at pre-dose/0-hour on Day 1 (Period 1 only) and pre-dose Day 14 and pre-dose/0-hour and at 0.5, 1, 2, 6, 12, and 24 hours post study drug administration (not breakfast) on Day 28 of the placebo and SCH 497079 periods only. In addition to these time points, a sample for metformin level will also be collected pre-dose on Day 1, Day 14, and Day 28 of the metformin administration period only. | Pre-dose (0 hour), 0.5, 1, 2, 6, 12, and 24 hours after administration of study drug | 
| Pharmacokinetic: Mean Plasma Glucose (Over 24 Hours) at Week 4 (Part 2 - India) | Blood samples for SCH 497079 pharmacokinetics will be collected at pre-dose/0-hour on Day 1 (Period 1 only) and pre-dose Day 14 and pre-dose/0-hour and at 0.5, 1, 2, 6, 12, and 24 hours post study drug administration (not breakfast) on Day 28 of the placebo and SCH 497079 periods only. In addition to these time points, a sample for metformin level will also be collected pre-dose on Day 1, Day 14, and Day 28 of the metformin administration period only. | Pre-dose (0 hour), 0.5, 1, 2, 6, 12, and 24 hours after administration of study drug | 
| Pharmacokinetic: Mean Maximum Observed Plasma Concentration (Cmax) (Part 1 - United States) | Blood samples for SCH 497079 pharmacokinetics will be collected at pre-dose/0-hour on Day 1 (Period 1 only) and pre-dose Day 14 and pre-dose/0-hour and at 0.5, 1, 2, 6, 12, and 24 hours post study drug administration (not breakfast) on Day 28 of the placebo and SCH 497079 periods only. In addition to these time points, a sample for metformin level will also be collected pre-dose on Day 1, Day 14, and Day 28 of the metformin administration period only. | Pre-dose (0 hour), 0.5, 1, 2, 6, 12, and 24 hours after administration of study drug | 
| Pharmacokinetic: Mean Plasma Cmax (Part 2 - India) | Blood samples for SCH 497079 pharmacokinetics will be collected at pre-dose/0-hour on Day 1 (Period 1 only) and pre-dose Day 14 and pre-dose/0-hour and at 0.5, 1, 2, 6, 12, and 24 hours post study drug administration (not breakfast) on Day 28 of the placebo and SCH 497079 periods only. In addition to these time points, a sample for metformin level will also be collected pre-dose on Day 1, Day 14, and Day 28 of the metformin administration period only. | Pre-dose (0 hour), 0.5, 1, 2, 6, 12, and 24 hours after administration of study drug | 
| Pharmacokinetic: Mean Time to Maximum Observed Plasma Concentration (Tmax) (Part 1 - United States) | Blood samples for SCH 497079 pharmacokinetics will be collected at pre-dose/0-hour on Day 1 (Period 1 only) and pre-dose Day 14 and pre-dose/0-hour and at 0.5, 1, 2, 6, 12, and 24 hours post study drug administration (not breakfast) on Day 28 of the placebo and SCH 497079 periods only. In addition to these time points, a sample for metformin level will also be collected pre-dose on Day 1, Day 14, and Day 28 of the metformin administration period only. | Pre-dose (0 hour), 0.5, 1, 2, 6, 12, and 24 hours after administration of study drug | 
| Pharmacokinetic: Mean Plasma Tmax (Part 2 - India) | Blood samples for SCH 497079 pharmacokinetics will be collected at pre-dose/0-hour on Day 1 (Period 1 only) and pre-dose Day 14 and pre-dose/0-hour and at 0.5, 1, 2, 6, 12, and 24 hours post study drug administration (not breakfast) on Day 28 of the placebo and SCH 497079 periods only. In addition to these time points, a sample for metformin level will also be collected pre-dose on Day 1, Day 14, and Day 28 of the metformin administration period only. | Pre-dose (0 hour), 0.5, 1, 2, 6, 12, and 24 hours after administration of study drug |