A Study to Evaluate the Safety, Tolerability, and Efficacy of the Addition of Omarigliptin (MK-3102) to Participants With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin Therapy (MK-3102-024)

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and efficacy of omarigliptin compared to placebo in participants with inadequate glycemic control on metformin monotherapy. The primary hypothesis is that after 24 weeks, the addition of treatment with omarigliptin provides greater reduction in hemoglobin A1c (A1C) than placebo.

Detailed Description
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Participants received blinded omarigliptin or matching placebo to omarigliptin for 104 weeks. During the first 24 weeks (Phase A) they did not receive any other blinded study medication. In Phase B (subsequent 80 weeks), participants who did not initiate glycemic rescue in Phase A received additional blinded study medication: participants in the omarigliptin group received placebo to glimepiride and participants in the placebo group received glimepiride.

Official Title
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A Multicenter, Randomized, Double-Blind Study to Evaluate the Safety, Tolerability, and Efficacy of the Addition of MK-3102 to Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin Therapy

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Omarigliptin
* Drug: Matching placebo to omarigliptin
* Drug: Glimepiride
* Drug: Matching placebo to glimepiride
* Drug: Insulin glargine
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has type 2 diabetes mellitus Currently on a stable dose of metformin monotherapy (>=1500 mg per day) for at least 12 weeks prior to study participation Male, or female who is not of reproductive potential or if of reproductive potential agrees to abstain from heterosexual activity or use (or have their partner use) acceptable contraception to prevent pregnancy during the study and for 21 days after the last dose of study drug Exclusion Criteria: History of type 1 diabetes mellitus or a history of ketoacidosis Has been treated with any antihyperglycemic agent (AHA) other than the protocol-required metformin within 12 weeks prior to study participation or with omarigliptin at any time prior to signing informed consent History of hypersensitivity to a dipeptidyl peptidase IV (DPP-4) inhibitor History of intolerance, hypersensitivity, or any other contraindication to metformin, glimepiride, or insulin glargine Is on a weight loss program and is not in the maintenance phase or has been on a weight loss medication in the past 6 months or has undergone bariatric surgery within 12 months prior to study participation Has undergone a surgical procedure within 4 weeks of study participation or has planned major surgery during the study Is on or likely to require treatment for >=2 consecutive weeks or repeated courses of corticosteroids (inhaled, nasal and topical corticosteroids are permitted) Currently being treated for hyperthyroidism or is on thyroid hormone replacement therapy and has not been on a stable dose for at least 6 weeks Is expecting to undergo hormonal therapy in preparation to donate eggs during the period of the trial, including 21 days after the last dose of blinded study medication History of active liver disease (other than non-alcoholic steatosis) including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease Human immunodeficiency virus (HIV) New or worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months, or myocardial infarction, unstable angina, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke, or transient ischemic attacks in the past 3 months Poorly controlled hypertension History of malignancy <=5 years prior to study participation, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer Hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) Positive urine pregnancy test Pregnant or breastfeeding, or is expecting to conceive during the study including 21 days following the last dose of blinded study drug User of recreational or illicit drugs or has had a recent history of drug abuse Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking Has donated blood products or has had phlebotomy of >300 mL within 8 weeks of study participation, or intends to donate blood products within the projected duration of the trial or has received, or is anticipated to receive, blood products within 12 weeks of study participation or within the projected duration of the trial

Ages Eligible for Study
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Minimum Age: 18 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 (Phase A) → Omarigliptin (Phase B)<br>Phase A: Omarigliptin 25 mg capsule administered orally once weekly for 24 weeks. Phase B: Omarigliptin 25 mg capsule administered orally once weekly and matching placebo to glimepiride tablet/capsule administered orally once daily for 80 weeks. Participants will continue pre-study metformin throughout the duration of the study. If necessary, rescue therapy may be initiated (open-label glimepiride during Phase A and insulin glargine during Phase B). | Drug: Omarigliptin<br>* Omarigliptin 25 mg capsule administered orally once weekly (preferably on the same day of each week)<br>* Other names: MK-3102;Drug: Matching placebo to glimepiride<br>* Matching placebo to glimepiride tablet/capsule administered orally once daily and up-titrated to a mock maximum dose of 6 mg daily. Participants rescued with open-label glimepiride during Phase A will not receive glimepiride or matching placebo to glimepiride during Phase B.<br>Drug: Insulin glargine<br>* During Phase B of the study, participants who received a maximum up-titration of open-label glimepiride or blinded glimepiride/matching placebo to glimepiride, may be rescued with open-label insulin glargine.<br>* Other names: Lantus;Drug: Metformin<br>* Participants continue stable pre-study dose of metformin tablet(s) administered orally (>= 1500 mg daily) throughout the study.<br>* Other names: Glycoran®;|
| Placebo Comparator: Placebo to omarigliptin (Phase A) → Glimepiride (Phase B)<br>Phase A: matching placebo to omarigliptin orally once a week for 24 weeks. Phase B: Matching placebo to omarigliptin capsule administered orally once weekly and glimepiride 1 or 2 mg tablet/capsule administered orally once daily (titrated up to 6 mg daily) for 80 weeks. Participants will continue pre-study metformin throughout the duration of the study. If necessary, rescue therapy may be initiated (open-label glimepiride during Phase A and insulin glargine during Phase B). | Drug: Matching placebo to omarigliptin<br>* Matching placebo to omarigliptin capsule administered orally once weekly (preferably on the same day of each week)<br>Drug: Glimepiride<br>* Glimepiride 1 or 2 mg tablet/capsule administered orally once daily and up-titrated to a maximum dose of 6 mg daily. Participants rescued with open-label glimepiride during Phase A will not receive glimepiride or matching placebo to glimepiride during Phase B.<br>* Other names: Amaryl®;Drug: Insulin glargine<br>* During Phase B of the study, participants who received a maximum up-titration of open-label glimepiride or blinded glimepiride/matching placebo to glimepiride, may be rescued with open-label insulin glargine.<br>* Other names: Lantus;Drug: Metformin<br>* Participants continue stable pre-study dose of metformin tablet(s) administered orally (>= 1500 mg daily) throughout the study.<br>* Other names: Glycoran®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (A1C) at Week 24 (Phase A) | A1C is measured as a percent. Change from baseline in A1C at Week 24 was analyzed using a constrained longitudinal data analysis (cLDA) method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 24 | 
| Percentage of Participants Who Experienced at Least One Adverse Event (Phase A+B) | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Presented data exclude data after glycemic rescue. | Up to 107 weeks | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (Phase A+B) | An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Presented data exclude data after glycemic rescue. | Up to 104 weeks | 
| Percentage of Participants Who Experienced an Adverse Event Which Were Included Under the System Order Class of Investigations (Phase A+B) | The following laboratory parameters were included: blood chemistry, hematology, electrocardiograms, lipids, body weight, and vital signs. | Up to 104 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 2-hour Post-meal Glucose (PMG) at Week 24 (Phase A) | Change from baseline in 2-hour PMG at Week 24 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 24 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Phase A) | Change from baseline in FPG at Week 24 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 24 | 
| Change From Baseline in A1C at Week 104 (Phase A+B) | A1C is measured as a percent. Change from baseline in A1C at Week 104 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 104 | 
| Change From Baseline in FPG at Week 104 (Phase A+B) | Change from baseline in FPG at Week 104 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 104 | 
| Percentage of Participants Attaining A1C Glycemic Goals of <7.0% After 24 Weeks of Treatment (Phase A) | Percentage of participants attaining A1C glycemic goals of <7.0% (53 mmol/mol) after 24 weeks of treatment estimated using standard multiple imputation techniques. | 24 weeks | 
| Percentage of Participants Attaining A1C Glycemic Goals of <6.5% After 24 Weeks of Treatment (Phase A) | Percentage of participants attaining A1C glycemic goals of <6.5% (48 mmol/mol) after 24 weeks of treatment estimated using standard multiple imputation techniques. | 24 weeks | 
| Percentage of Participants Attaining A1C Glycemic Goals of <7% After 104 Weeks of Treatment (Phase A+B) | Percentage of participants attaining A1C glycemic goals of <7.0% (53 mmol/mol) after 104 weeks of treatment estimated using standard multiple imputation techniques. | 104 weeks | 
| Percentage of Participants Attaining A1C Glycemic Goals of <6.5% After 104 Weeks of Treatment (Phase A+B) | Percentage of participants attaining A1C glycemic goals of <6.5% (48 mmol/mol) after 104 weeks of treatment estimated using standard multiple imputation techniques. | 104 weeks | 
| Change From Baseline in PMG Total Area Under the Plasma Concentration Time Curve (AUC) at Week 24 (Phase A) | Change from baseline in PMG total AUC at Week 24 based on a cLDA model including terms for treatment, time, and the interaction of time by treatment. Plasma glucose levels were measured before the meal (0 minutes), and at 60 and 120 minutes after the meal. | Baseline and Week 24 | 
| Change From Baseline in Fasting Insulin at Week 24 (Phase A) | Change from baseline in fasting insulin at Week 24 based on a cLDA model including terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 24 | 
| Change From Baseline in Fasting Insulin at Week 104 (Phase A+B) | Change from baseline in fasting insulin at Week 104 based on a cLDA model including terms for treatment, time, and the interaction of time by treatment. | Baseline and Week 104 | 
| Kaplan-Meier Estimate of Cumulative Incidence of Participants Requiring Glycemic Rescue Therapy by 24 Weeks (Phase A) | Participants who did not meet progressively stricter glycemic criteria in Phase A had rescue initiated with open-label glimepiride. | Up to 24 weeks | 
| Kaplan-Meier Estimate of Cumulative Incidence of Participants Requiring Glycemic Rescue Therapy by 104 Weeks (Phase A+B) | Participants who did not meet progressively stricter glycemic criteria in Phase A had rescue initiated with open-label glimepiride. If during Phase B participants on open-label glimepiride or blinded glimepiride/glimepiride matching placebo needed rescue after maximum up-titration, then insulin glargine was initiated and the dose of open-label glimepiride or blinded glimepiride/glimepiride-matching placebo was discontinued. | Up to 104 weeks | 
| Percentage of Participants Requiring Glycemic Rescue Therapy at or Before Week 24 (Phase A) | Data presented are a cumulative incidence of participants with glycemic rescue by Week 24. | Up to 24 weeks | 
| Percentage of Participants Requiring Glycemic Rescue Therapy at or Before Week 104 (Phase A+B) | Data presented are a cumulative incidence of participants with glycemic rescue by Week 104. | Up to 104 weeks |