A Dose-Range Finding Study in Participants With Type 2 Diabetes (MK-3102-006)

Study Overview
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Brief Summary
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The purpose of this study is to assess the hypothesis that treatment with study medication (omarigliptin; MK-3102) provides greater reduction in A1C Hemoglobin (a marker of diabetic severity) compared with placebo, after 12 weeks of treatment. The study will evaluate 5 different doses of omarigliptin to identify which dose is the most effective in the treatment of type 2 diabetes.

Detailed Description
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MK-3102-006-Ext 1 added a 66-week extension to the base study (MK-3102 P006) to assess the long-term safety and tolerability of omarigliptin. To be eligible for the extension, participants must complete the double-blind base study, must have had at least a 75% compliance with study drug during the base study and can not meet any of the criteria for discontinuation. Participants randomized to placebo in the base study will be switched in a blinded manner to pioglitazone 30 mg once daily, in the extension study prior to implementation of amendment P006-13. Once amendment P006-13 has been IRB/IEC approved and blinded metformin drug supply is available at the site, participants will be switched from pioglitazone to metformin, starting at 500 mg once daily and titrated up to 1000 mg twice daily. Participants with a contraindication to metformin will be discontinued from the study. Participants randomized to 0.25 mg, 1 mg, 3 mg, and 10 mg of omarigliptin in the base study will be switched to omarigliptin 25 mg; those randomized to 25 mg of omarigliptin in the base study will continue on the same dose in the extension study. After the clinical dose of omarigliptin selected for further development has been identified based upon the results of the base study, all participants randomized to omarigliptin will be switched to the identified clinical dose.

Official Title
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A Phase IIb, Randomized, Placebo-Controlled, Dose-Range Finding Clinical Trial to Study the Safety and Efficacy of MK-3102 in Patients With Type 2 Diabetes Mellitus and Inadequate Glycemic Control

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Omarigliptin
* Drug: Placebo to omarigliptin
* Drug: Pioglitazone
* Drug: Metformin
* Drug: Placebo to metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The prospective participant must meet, at least, all of the criteria below (among others determined by the study staff) to be eligible for study participation. The participant: Has type 2 diabetes mellitus and is between 18 and 70 years of age; for Japan, 20 to 70 years of age; Has a body mass index (BMI) > 20 kg/m^2 and < 43 kg/m^2; for Japan: BMI >18 kg/m^2 and <43 kg/m^2; Is currently not on an antihyperglycemic agent (AHA) medication (off for ≥ 14 weeks) or is on oral AHA therapy but has inadequate glycemic control; Is a male, or a female who is highly unlikely to conceive. Exclusion Criteria: If the prospective participant meets any of the criteria below (among others determined by the study staff) they will NOT be eligible for study participation. The participant: Has a history of type 1 diabetes mellitus or a history of ketoacidosis; Is on a weight loss program or has started a weight loss medication within the prior 8 weeks; Has required insulin therapy within 14 weeks prior to signing informed consent; Has a medical history of active liver disease (other than nonalcoholic hepatic steatosis), including chronic active hepatitis B or C, cirrhosis, or symptomatic gallbladder disease; Has congestive heart failure or has new or worsening signs or symptoms of coronary heart disease; Had any of the following disorders within the past 3 months: acute coronary syndrome, coronary artery intervention, stroke or transient ischemic neurological disorder; Has a history of malignancy or clinically important hematological disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Omarigliptin 0.25 mg (Base)<br>Omarigliptin 0.25 mg administered once weekly for 12 weeks (Base) | Drug: Omarigliptin<br>* Omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For omarigliptin 3 mg, participants received two omarigliptin 1.5 mg capsules.<br>|
| Experimental: Omarigliptin 1 mg (Base)<br>Omarigliptin 1 mg administered once weekly for 12 weeks (Base) | Drug: Omarigliptin<br>* Omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For omarigliptin 3 mg, participants received two omarigliptin 1.5 mg capsules.<br>|
| Experimental: Omarigliptin 3 mg (Base)<br>Omarigliptin 3 mg administered once weekly for 12 weeks (Base) | Drug: Omarigliptin<br>* Omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For omarigliptin 3 mg, participants received two omarigliptin 1.5 mg capsules.<br>|
| Experimental: Omarigliptin 10 mg (Base)<br>Omarigliptin 10 mg administered once weekly for 12 weeks (Base) | Drug: Omarigliptin<br>* Omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For omarigliptin 3 mg, participants received two omarigliptin 1.5 mg capsules.<br>|
| Experimental: Omarigliptin 25 mg (Base)<br>Omarigliptin 25 mg administered once weekly for 12 weeks (Base) | Drug: Omarigliptin<br>* Omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For omarigliptin 3 mg, participants received two omarigliptin 1.5 mg capsules.<br>|
| Placebo Comparator: Placebo (Base)<br>Matching placebo to omarigliptin administered once weekly for 12 weeks (Base) | Drug: Placebo to omarigliptin<br>* Matching placebo to omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For matching placebo to omarigliptin 3 mg, participants received two matching placebo to omarigliptin 1.5 mg capsules.<br>|
| Experimental: Pooled omarigliptin (Extension)<br>Participants who received omarigliptin during the base study, received omarigliptin 25 mg once weekly and placebo to metformin once daily for 66 weeks (Extension). | Drug: Omarigliptin<br>* Omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For omarigliptin 3 mg, participants received two omarigliptin 1.5 mg capsules.<br>Drug: Placebo to metformin<br>* Matching placebo to metformin oral tablet administered once daily<br>|
| Active Comparator: Placebo/Metformin<br>Participants who received matching placebo to omarigliptin during the base period, received pioglitazone administered once daily and matching placebo to omarigliptin once weekly for 66 weeks (extension period). Note: A protocol amendment removed pioglitazone during the extension period. Participants discontinued pioglitazone and switched to blinded metformin. Participants who were previously rescued with open-label metformin during the base period continued in the extension period on open-label metformin. | Drug: Placebo to omarigliptin<br>* Matching placebo to omarigliptin 0.25, 1, 1.5, 10 or 25 mg oral capsule administered once weekly. For matching placebo to omarigliptin 3 mg, participants received two matching placebo to omarigliptin 1.5 mg capsules.<br>Drug: Pioglitazone<br>* Pioglitazone 15 mg oral tablet or capsule administered once daily<br>Drug: Metformin<br>* Metformin 500 mg oral tablet administered once or twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Plasma A1C Levels at Week 12 | A1C levels were measured as a percent. Change from baseline was calculated by subtracting the baseline level from the Week 12 level. | Baseline (Week 0) and Week 12 | 
| Percentage of Participants Who Experienced at Least One Adverse Event During the Base Period | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of the Sponsor's product, is also an adverse event. Data presented below excludes data after the initiation of glycemic rescue. | Up to 16 weeks (including 28 days following the last dose of study drug) | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event During the 12-week Base Period | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which is temporally associated with the use of the Sponsor's product, is also an adverse event. Data presented below excludes data after the initiation of glycemic rescue. | Up to 12 weeks | 
| Percentage of Participants Who Experienced at Least One Adverse Event During the 66-week Extension Period | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product, is also an adverse event. Data presented below excludes data after the initiation of glycemic rescue. | Up to 70 Weeks (Weeks 12 to 78 plus 4-week follow-up period) | 
| Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event During the 66-week Extension Period | An adverse event is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the Sponsor's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the Sponsor's product, is also an adverse event. Data presented below excludes data after the initiation of glycemic rescue. | Up to 66 weeks (Weeks 12 to 78) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 2 Hour-post-meal Glucose (2h-PMG) Levels at Week 12 | Change from baseline was calculated by subtracting the baseline level from the Week 12 level. | Baseline (Week 0) and Week 12 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) Levels at Week 12 | Change from baseline was calculated by subtracting the baseline level from the Week 12 level. | Baseline (Week 0) and Week 12 | 
| Mean Plasma A1C Level at Baseline of the Extension Period | A1C levels were measured as a percent at baseline (Week 0) for participants who entered the extension period. | Baseline (Week 0) | 
| Change From Baseline in Plasma A1C Levels at Week 78 | A1C levels were measured as a percent. Change from baseline was calculated by subtracting the baseline level from the Week 78 level. | Baseline (Week 0) and Week 78 | 
| Mean 2h-PMG Level at Baseline of the Extension Period | Plasma 2h-PMG levels were measured at baseline (Week 0) for participants who entered the extension period. | Baseline (Week 0) | 
| Change From Baseline in 2h-PMG at Week 78 | Change from baseline was calculated by subtracting the baseline level from the Week 78 level. | Baseline (Week 0) and Week 78 | 
| Mean FPG Level at Baseline of the Extension Period | Plasma FPG levels were measured at baseline (Week 0) for particiapnts who entered the extension period. | Baseline (Week 0) | 
| Change From Baseline in FPG Levels at Week 78 | Change from baseline was calculated by subtracting the baseline level from the Week 78 level. | Baseline (Week 0) and Week 78 |