A Study of the Safety and Efficacy of Omarigliptin (MK-3102) in ≥18 and <45 Year-Old Participants With Type 2 Diabetes Mellitus and Inadequate Glycemic Control (MK-3102-028)

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of MK-3102 in ≥18 and <45 Year-Old Subjects With Type 2 Diabetes Mellitus and Inadequate Glycemic Control

This study will examine the safety and efficacy of once-weekly omarigliptin in participants 18 to <45 years of age with Type 2 diabetes mellitus and inadequate glycemic control. The study hypothesis is that treatment with omarigliptin compared with placebo provides greater reduction in hemoglobin A1c (A1C) in participants after 24 weeks.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Omarigliptin; Drug: Metformin; Drug: Placebo to omarigliptin

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 44 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has type 2 diabetes mellitus
• Currently not on an antihyperglycemic agent (AHA) for at least the past 12 weeks and has not been treated with omarigliptin at any time prior to study participation

• Participant is one of the following:

  1. Male
  2. Female who is not of reproductive potential
  3. Female of reproductive potential who agrees to remain abstinent from heterosexual activity or use (or have her partner use) 2 acceptable 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
• History of hypersensitivity to dipeptidyl-peptidase-4 (DPP-4) inhibitor
• Currently participating in or has participated in a clinical trial in the past 12 weeks
• Is on a weight loss program and not in the maintenance phase; 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 ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids
• Is currently being treated for hyperthyroidism or is on thyroid 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 study, including 21 days following the last dose of study drug
• 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
• Has human immunodeficiency virus (HIV)

• Has had new or worsening coronary heart disease or congestive heart failure within the past 3 months, or has any of the following disorders within the past 3 months:

  1. Acute coronary syndrome
  2. Coronary artery intervention
  3. Stroke or transient ischemic neurological disorder
• Has poorly controlled hypertension
• History of malignancy ≤5 years prior to study participation, except for basal cell or squamous cell skin cancer or in situ cervical cancer
• Has a hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
• Has a positive urine pregnancy test
• Pregnant or breastfeeding, or is expecting to conceive during the study, including 21 days following the last dose of 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 a phlebotomy (>300 mL) within 8 weeks of study participation, or intends to donate blood products during the study or has received, or is anticipated to receive, blood products within 12 weeks of study participation or during the study
• Has a clinically significant electrocardiogram abnormality

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Omarigliptin 25 mg; Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.	Drug: Omarigliptin; Omarigliptin 25 mg capsule administered orally once weekly; Other Names: MK-3102; Drug: Metformin; Open-label metformin (dosed daily according to the country-specific product label) was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.; Other Names: Fortamet®; Glucophage®; Glucophage® XR; Glumetza®; Riomet®; Metgluco®; Glycoran®
Placebo Comparator: Placebo; Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.	Drug: Metformin; Open-label metformin (dosed daily according to the country-specific product label) was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.; Other Names: Fortamet®; Glucophage®; Glucophage® XR; Glumetza®; Riomet®; Metgluco®; Glycoran®; Drug: Placebo to omarigliptin; Matching placebo to omarigliptin 25 mg capsule administered orally once weekly

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in A1C at Week 24	A1C (%) is used to report average blood glucose levels over prolonged periods of time. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.	Baseline and Week 24
Percentage of Participants Who Experienced at Least One Adverse Event (AE)	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. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the all participants as treated (APaT) population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).	Up to Week 27
Percentage of Participants Who Discontinued Study Drug Due to an AE	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. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in 2-hr PMG at Week 24	Blood glucose was measured 120 minutes from start of meal. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.	Baseline and Week 24
Change in Baseline in FPG at Week 24	Blood glucose was measured on a fasting basis. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.	Baseline and Week 24
Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24	Percentage of participants was estimated using standard multiple imputation techniques (constrained longitudinal data analysis [cLDA] model). Within-group confidence intervals (CIs) were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.	Week 24
Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24	Percentage of participants was estimated using standard multiple imputation techniques (cLDA). Within-group CIs were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.	Week 24
Percentage of Participants Who Required Glycemic Rescue by Week 24	Participants exceeding pre-specified glycemic thresholds after starting the double-blind treatment period may have received rescue therapy (per protocol) with open-label metformin initiated by the investigator. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).	Up to Week 24

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Gantz I, Sokolova L, Jain L, Iredale C, O'Neill EA, Wei Z, Lam R, Suryawanshi S, Kaufman KD, Engel SS, Lai E. Use of Prohibited Medication, a Potentially Overlooked Confounder in Clinical Trials: Omarigliptin (Once-weekly DPP-4 Inhibitor) Monotherapy Trial in 18- to 45-year-olds. Clin Ther. 2017 Oct;39(10):2024-2037. doi: 10.1016/j.clinthera.2017.08.009. Epub 2017 Sep 18.

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2013
• Primary Completion (Actual): September 14, 2015
• Study Completion (Actual): September 14, 2015

Study Registration Dates

• First Submitted: March 18, 2013
• First Submitted That Met QC Criteria: March 18, 2013
• First Posted (Estimate): March 20, 2013

Study Record Updates

• Last Update Posted (Actual): September 10, 2018
• Last Update Submitted That Met QC Criteria: August 9, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Metformin; Diabetes Mellitus, Type 2; Pharmacologic Actions; Therapeutic Uses; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hypoglycemic Agents
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 3102-028; 2012-004303-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf