A Study to Assess Cardiovascular Outcomes Following Treatment With Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus (MK-3102-018)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the cardiovascular (CV) safety profile of omarigliptin in participants with type 2 diabetes mellitus (T2DM). The primary hypothesis is that treatment with omarigliptin 25 mg once weekly is non-inferior to treatment with placebo and active comparators across the omarigliptin program with regard to the risk of developing a confirmed event in the primary CV composite endpoint.

Detailed Description
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The trial was amended to extend the length of the trial in order to meet FDA requirements for the post-approval assessment of cardiovascular (CV) safety. The trial now contains 2 time intervals: Period 1 and Period 2. Period 1 refers to the time interval up to this recent protocol amendment and Period 2, the time interval from this protocol amendment until the end of the study. Participants in Period 1 will be re-consented and continue into Period 2. If required, additional participants will be enrolled in Period 2. Stage 1 refers to the prefiling United States Food and Drug Administration (US FDA) requirement to rule out a 80% increased CV risk. Stage 2 refers to the US FDA post-marketing requirement to rule out a 30% increased CV risk. The Stage 1 assessment of CV risk occurred during Period 1 and was based on a meta-analysis of major adverse CV events (MACE) and unstable angina across the omarigliptin Phase 2/Phase 3 program. The Stage 2 assessment will be based on MACE in P018 alone including CV events from both Period 1 and Period 2.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Assess Cardiovascular Outcomes Following Treatment With MK-3102 in Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Omarigliptin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with type 2 diabetes mellitus Is on one of the following diabetes treatment regimens that is stable for at least 12 weeks (except for pioglitazone for at least 16 weeks) and is within the associated A1C range for that treatment regimen: A1C >= 6.5% and <= 10.0% (>=48 mmol/mol and <=86 mmol/mol) on: (a) diet or exercise alone (not on antihyperglycemic agent [AHA] for >= 12 weeks) OR (b) monotherapy with metformin (MF), pioglitazone (PIO) or an alpha-glucosidase inhibitor (AGI) or a sodium-glucose cotransporter inhibitor (SGLT2i) OR (c) dual combination therapy with MF, PIO, AGI or SGLT2i OR A1C >= 7.0% and <=10.0% (>=53 mmol/mol and <=86 mmol/mol) on (a) monotherapy with a sulfonylurea or meglitinide OR (b) dual combination therapy with a sulfonylurea or a meglitinide and MF, PIO, AGI, or SGLT2i OR A1C >=7.0% and <=10.0% (>=53 mmol/mol and <=86 mmol/mol) on one of the following insulin regimens (with or without metformin): (a) basal insulin (e.g.; insulin glargine, insulin detemir, NPH insulin, degludec) OR (b) prandial insulin (e.g. regular, aspart, lispro, glulisine) OR (c) basal/prandial insulin regimen consisting of multiple dose insulin injections of basal and prandial insulin or the use of pre-mixed insulin (e.g., Novolog 70/30®, Novolin 70/30®, Humalog 75/25®, or Humulin 70/30® Pre-existing vascular disease (coronary artery disease, ischemic cerebrovascular disease, atherosclerotic peripheral artery disease) (1) Male; (2) female not of reproductive potential; or (3) female of reproductive potential who agrees to remain abstinent or use alone or in conjunction with their partner 2 methods of 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 Treated with rosiglitazone, a dipeptidyl peptidase-IV (DPP-4) inhibitor, or a glucagon-like peptide-1 (GLP-1) receptor agonist within 12 weeks prior to study participation or previously treated with omarigliptin 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 Medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease Human immunodeficiency virus (HIV) as assessed by medical history New or worsening coronary heart disease, congestive heart failure, myocardial infarction, unstable angina, coronary artery intervention, stroke, or transient ischemic neurological disorder within the past 3 months 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 Clinically important hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) Pregnant or breast feeding, or is expecting to conceive or donate eggs during the trial, including 21 days following the last dose of study drug

Ages Eligible for Study
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Minimum Age: 40 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<br>Omarigliptin (MK-3102) 25 mg capsule or tablet administered orally once weekly | Drug: Omarigliptin<br>* Omarigliptin (MK-3102) 25 mg capsule or tablet administered orally once weekly<br>|
| Placebo Comparator: Placebo<br>Matching placebo to omarigliptin capsule or tablet administered orally once weekly | Drug: Placebo<br>* Matching placebo to omarigliptin capsule or tablet administered orally once weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced at Least One Adverse Event in a Sub-study of Participants Taking Insulin Excluding Data After Background Antihyperglycemic Agent (AHA) Change | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to Week 18 | 
| Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event in a Sub-Study of Participants Taking Insulin Excluding Data After Background AHA Change | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to Week 18 | 
| Change From Baseline in Hemoglobin A1C (A1C) at Week 18 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 18 A1C minus the Week 0 A1C. | Baseline and Week 18 | 
| Change From Baseline in A1C at Week 18 in a Sub-Study of Participants Taking Insulin (With or Without Metformin) | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 18 A1C minus the Week 0 A1C. | Baseline and Week 18 | 
| Number of Participants With MACE-plus (Confirmed Cardiovascular [CV]-Related Death, Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, or Hospitalization Due to Unstable Angina) | Participants with confirmed MACE-plus events (confirmed cardiovascular, CV-related death, nonfatal myocardial infarction [MI], nonfatal stroke, or hospitalization due to unstable angina). In the MK-3102-018 study, MACE plus events had a data cut-off date of April 15, 2015. | Up to 156 weeks | 
| Number of Participants With an Event of MACE (Confirmed CV-Related Death, Fatal and Nonfatal MI, and Fatal and Nonfatal Stroke) | Participants with an Event of MACE (confirmed cardiovascular, CV-related death, fatal and nonfatal myocardial infarction [MI], and fatal and nonfatal stroke). | Up to 179 weeks | 
| Number of Participants With an Event Per 100 Person-Years for First Event of MACE (Confirmed CV-Related Death, Fatal and Nonfatal MI, and Fatal and Nonfatal Stroke) | Participants with an event of MACE (confirmed cardiovascular, CV-related death, fatal and nonfatal myocardial infarction [MI], and fatal and nonfatal stroke). Person-years were calculated as the sum of all participants' follow-up time to first event. | Up to 179 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Event of CV-Related Death | Participants with adjudicated and confirmed AEs of cardiovascular-related death. | Up to 179 weeks | 
| Number of Participants With an Event Per 100 Person-Years of CV-Related Death | Participants with adjudicated and confirmed AEs of cardiovascular-related death. Person-years were calculated as the sum of all participants' follow-up time to event. | Up to 179 weeks | 
| Number of Participants With an Event of First MI (Fatal and Non-fatal) | Participants with adjudicated and confirmed AEs of fatal and non-fatal MI. | Up to 179 weeks | 
| Number of Participants With an Event Per 100 Person-Years of First MI (Fatal and Non-fatal) | Participants with adjudicated and confirmed AEs of fatal and non-fatal MI. Person-years were calculated as the sum of all participants' follow-up time to first event. | Up to 179 weeks | 
| Number of Participants With an Event of Stroke (Fatal and Non-fatal) | Participants with adjudicated and confirmed AEs fatal and non-fatal stroke. | Up to 179 weeks | 
| Number of Participants With an Event Per 100 Person-Years of First Stroke (Fatal and Non-fatal) | Participants with adjudicated and confirmed AEs fatal and non-fatal stroke. Person-years were calculated as the sum of all participants' follow-up time to event. | Up to 179 weeks | 
| Number of Participants With an Event of All-Cause Death | All-cause death was death from any cause. | Up to 179 weeks | 
| Number of Participants With an Event Per 100 Person-Years of the Event of All-Cause Death | All-cause death was death for any cause. Person-years were calculated as the sum of all participants' follow-up time to event. | Up to 179 weeks | 
| Change From Baseline in A1C at Week 142 | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 142 A1C minus the Week 0 A1C. | Baseline and Week 142 | 
| Percentage of Participants Achieving a Target A1C <7.0 % (53 mmol/Mol) at 4 Months | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). | 4 months | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at 4 Months | This change from baseline reflects the Month 4 FPG minus the Week 0 FPG. | Baseline and 4 months | 
| Time to Initiation of Long-Term Insulin Therapy in Participants Not Receiving Insulin at Baseline | Long-term insulin therapy was defined as a continuous period of insulin use of more than 3 months. | Up to 179 weeks | 
| Percentage of Participants Who Experienced at Least One Adverse Event | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to 234 weeks | 
| Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to 212 weeks | 
| Change From Baseline in FPG at Week 18 in a Sub-Study of Participants Taking Insulin | This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. | Baseline and Week 18 | 
| Percentage of Participants Achieving a Target A1C <7.0 % (53 mmol/Mol) at Week 18 in a Sub-Study of Participants Taking Insulin | A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Analysis was performed with multiple data imputation. | 18 weeks |