Clinical trial NCT01703208: A Study to Assess Cardiovascular Outcomes Following Treatment With Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus (MK-3102-018)
Official title: A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Assess Cardiovascular Outcomes Following Treatment With MK-3102 in Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2012-10-10
Enrollment: 4202
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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:

  1. 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
  2. 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
  3. 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

Primary outcomes:
measure: Number of Participants With MACE-plus (Confirmed Cardiovascular [CV]-Related Death, Nonfatal Myocardial Infarction [MI], Nonfatal Stroke, or Hospitalization Due to Unstable Angina)
timeFrame: Up to 156 weeks
measure: Number of Participants With an Event of MACE (Confirmed CV-Related Death, Fatal and Nonfatal MI, and Fatal and Nonfatal Stroke)
timeFrame: Up to 179 weeks
measure: 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)
timeFrame: Up to 179 weeks
measure: Change From Baseline in Hemoglobin A1C (A1C) at Week 18
timeFrame: Baseline and Week 18
measure: Change From Baseline in A1C at Week 18 in a Sub-Study of Participants Taking Insulin (With or Without Metformin)
timeFrame: Baseline and Week 18
measure: 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
timeFrame: Up to Week 18
measure: 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
timeFrame: Up to Week 18
Secondary outcomes:
measure: Number of Participants With an Event of CV-Related Death
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event Per 100 Person-Years of CV-Related Death
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event of First MI (Fatal and Non-fatal)
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event Per 100 Person-Years of First MI (Fatal and Non-fatal)
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event of Stroke (Fatal and Non-fatal)
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event Per 100 Person-Years of First Stroke (Fatal and Non-fatal)
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event of All-Cause Death
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event Per 100 Person-Years of the Event of All-Cause Death
timeFrame: Up to 179 weeks
measure: Change From Baseline in A1C at Week 142
timeFrame: Baseline and Week 142
measure: Percentage of Participants Achieving a Target A1C <7.0 % (53 mmol/Mol) at 4 Months
timeFrame: 4 months
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at 4 Months
timeFrame: Baseline and 4 months
measure: Time to Initiation of Long-Term Insulin Therapy in Participants Not Receiving Insulin at Baseline
timeFrame: Up to 179 weeks
measure: Percentage of Participants Who Experienced at Least One Adverse Event
timeFrame: Up to 234 weeks
measure: Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event
timeFrame: Up to 212 weeks
measure: Change From Baseline in FPG at Week 18 in a Sub-Study of Participants Taking Insulin
timeFrame: Baseline and Week 18
measure: Percentage of Participants Achieving a Target A1C <7.0 % (53 mmol/Mol) at Week 18 in a Sub-Study of Participants Taking Insulin
timeFrame: 18 weeks
Other outcomes:
measure: Number of Participants With an Event of First Hospitalization for Heart Failure (Exploratory)
timeFrame: Up to 179 weeks
measure: Number of Participants With an Event Per 100 Person-years of the Event of the First Hospitalization for Heart Failure (Exploratory)
timeFrame: Up to 179 weeks
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Gantz I, Chen M, Suryawanshi S, Ntabadde C, Shah S, O'Neill EA, Engel SS, Kaufman KD, Lai E. A randomized, placebo-controlled study of the cardiovascular safety of the once-weekly DPP-4 inhibitor omarigliptin in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2017 Sep 11;16(1):112. doi: 10.1186/s12933-017-0593-8.