A Study to Assess the Safety and Efficacy of Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus (T2DM) and Inadequate Glycemic Control (MK-3102-011)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety and efficacy of omarigliptin (MK-3102), dosed once-weekly in participants with T2DM who have inadequate glycemic control on diet and exercise. The primary hypothesis is that after 24 weeks, treatment with omarigliptin compared with placebo provides greater reduction in hemoglobin A1c (A1C).

Official Title
-----------------
A Multicenter, Phase III, Randomized, Placebo-Controlled Trial to Assess the Safety and Efficacy of MK-3102 Monotherapy in Subjects With Type 2 Diabetes Mellitus and Inadequate Glycemic Control

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Omarigliptin
* Drug: Placebo to Omarigliptin
* Drug: Metformin
* Drug: Placebo to metformin
* Drug: Glimepiride


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Has type 2 diabetes mellitus Participants in India must be ≤65 years of age Meets one of the following criteria: currently not on an antihyperglycemic agent (AHA) for >= 12 weeks and has an A1C of >=7% and <=10% or on stable AHA monotherapy or low-dose combination therapy for > 12 weeks and has an A1C of >=6.5% and <=9% Participant is one of the following: male, female who is not of reproductive potential, female of reproductive potential who agrees to remain abstinent 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: a thiazolidinedione (TZD) within 4 months of study participation, a glucagon-like peptide-1 (GLP-1) receptor mimetic or agonist or dipeptidyl peptidase IV (DPP-4) inhibitor within 6 months of study participation, insulin or sodium-glucose cotransporter inhibitor within 12 weeks of study participation, omarigliptin at any time prior to study participation History of hypersensitivity to DPP-4 inhibitor History of intolerance, hypersensitivity or any contraindication to metformin and/or glimepiride or other sulfonylurea Is on a weight loss program and not in the maintenance phase or has started 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 corticosteroids (inhaled, nasal and topical corticosteroids are permitted) Is currently being treated for hyperthyroidism or is on thyroid hormone 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 steatosis) including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease 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: acute coronary syndrome, coronary artery intervention, 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 Hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) 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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 25 mg capsule administered orally once a week for 24 weeks (Phase A) followed by omarigliptin 25 mg administered orally once a week plus placebo to metformin daily (Phase B). Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B. | Drug: Omarigliptin<br>* Omarigliptin 25 mg capsule administered orally once a week.<br>Drug: Metformin<br>* If necessary, participants may have glycemic rescue therapy initiated with open-label metformin during Phase A of the study. Participants in the placebo treatment group who were not rescued with open-label metformin during Phase A will receive blinded metformin (starting at 500 mg orally twice daily with up-titration to 1000 mg orally twice daily) in Phase B. Participants in the omarigliptin treatment group who were rescued with open-label metformin in Phase A will continue open-label metformin during Phase B of the study.<br>* Other names: Glycoran®;Drug: Placebo to metformin<br>* During Phase B of the study, participants in the omarigliptin treatment group who did not initiate glycemic rescue therapy during Phase A will receive placebo to metformin for 30 weeks (Phase B of the study).<br>Drug: Glimepiride<br>* If necessary during Phase B of the study, participants will initiate open-label glimepiride as glycemic rescue therapy<br>* Other names: Armaryl®;|
| Placebo Comparator: Placebo to Omarigliptin<br>Placebo to omarigliptin administered orally once a week for 24 weeks (Phase A) followed by placebo to omarigliptin administered orally once a week plus metformin daily for an additional 30 weeks (Phase B). Open-label metformin was to be initiated for participants meeting protocol-specified glycemic criteria during Phase A, but was otherwise prohibited. Open-label glimepiride daily may be initiated as glycemic rescue therapy during Phase B. | Drug: Placebo to Omarigliptin<br>* Placebo to omarigliptin capsule administered orally once a week<br>Drug: Metformin<br>* If necessary, participants may have glycemic rescue therapy initiated with open-label metformin during Phase A of the study. Participants in the placebo treatment group who were not rescued with open-label metformin during Phase A will receive blinded metformin (starting at 500 mg orally twice daily with up-titration to 1000 mg orally twice daily) in Phase B. Participants in the omarigliptin treatment group who were rescued with open-label metformin in Phase A will continue open-label metformin during Phase B of the study.<br>* Other names: Glycoran®;Drug: Glimepiride<br>* If necessary during Phase B of the study, participants will initiate open-label glimepiride as glycemic rescue therapy<br>* Other names: Armaryl®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (A1C) at Week 24 (Phase A, FAS Population) | A1C (%) is used to report average blood glucose levels over prolonged periods of time. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis). | Baseline and Week 24 | 
| Percentage of Participants Who Experienced at Least One Adverse Event in Phase A (Excluding Data After Glycemic Rescue, Safety Population) | An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Up to 27 weeks | 
| Percentage of Participants Who Discontinued From the Study Drug Due to an Adverse Event in Phase A (Excluding Data After Glycemic Rescue, Safety Population) | An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Up to 24 weeks | 
| Percentage of Participants Who Experienced at Least One Adverse Event (Phase A + Phase B, Excluding Data After Glycemic Rescue, Safety Population) | An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Up to 57 weeks | 
| Percentage of Participants Who Discontinued From the Study Drug Due to an Adverse Event (Phase A + Phase B, Excluding Data After Glycemic Rescue, Safety Population) | An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of preexisting conditions. This analysis may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Up to 57 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve an A1C Goal of <7% (53 mmol/Mol) at Week 24 (Phase A, FAS Population) | A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). The percentage of participants who achieved A1C values <7.0% (53 mmol/mol) in the FAS population at Week 24. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis). | Week 24 | 
| Percentage of Participants Who Achieve an A1C Goal of <6.5% (48 mmol/Mol) at Week 24 (Phase A, FAS Population) | A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). The percentage of participants who achieved A1C values <6.5% (48 mmol/mol) in the FAS population at Week 24. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis). | Week 24 | 
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Phase A, FAS Population) | Blood glucose was measured on a fasting basis (collected after an 10-hour fast). FPG is expressed as mg/dL. This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis). | Baseline and Week 24 | 
| Change From Baseline in 2-hour Post Meal Glucose (PMG) at Week 24 (Phase A, FAS Population) | Blood glucose was measured 2 hours after a meal (2-hour PMG). 2-hour PMG is expressed as mg/dL. This change from baseline in 2-hour PMG reflects the Week 24 2-hour PMG minus the Week 0 2-hour PMG. Because it was discovered that in another omarigliptin study (MK-3102-028, NCT01814748) subjects had taken metformin (prohibited per protocol, and taken without investigator knowledge), after unblinding of Phase A of this study, an analysis of metformin levels was performed on stored Week 18 blood samples. Of the subjects not rescued with metformin prior to Week 18, 10% in the omarigliptin group and 20% in the placebo group had levels showing that they were taking metformin (prohibited per protocol). The use of prohibited metformin disproportionately by the placebo group may have resulted in a smaller than expected treatment effect for efficacy outcome measures (see post-hoc analysis). | Baseline and Week 24 | 
| Change From Baseline in A1C at Week 54 (Phase A + Phase B, FAS Population) | A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Thus, this change from baseline reflects the Week 54 A1C minus the Week 0 A1C. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Baseline and Week 54 | 
| Percentage of Participants Who Achieve an A1C Goal of <7% (53 mmol/Mol) at Week 54 (Phase A + Phase B, FAS Population) | The percentage of participants who achieved A1C values <7.0% (53 mmol/mol) in the FAS population at Week 54. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Week 54 | 
| Percentage of Participants Who Achieve an A1C Goal of <6.5% at Week 54 (Phase A + Phase B, FAS Population) | A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). The percentage of participants who achieved A1C values <6.5% (48 mmol/mol) in the FAS population at Week 54. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Week 54 | 
| Change From Baseline in FPG at Week 54 (Phase A + Phase B, FAS Population) | Blood glucose was measured on a fasting basis (collected after an 10-hour fast). FPG is expressed as mg/dL. This change from baseline reflects the FPG level at Week 54 minus the FPG level at Week 0. The results of the study at Week 54 may have been confounded by use of prohibited metformin (see results above for description of the use of prohibited metformin). | Baseline and Week 54 |