A Study of Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus With Chronic Kidney Disease or Kidney Failure on Dialysis (MK-3102-019)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of omarigliptin in participants with type 2 diabetes mellitus and moderate or severe chronic renal insufficiency or end stage renal disease on dialysis with inadequate glycemic control. The primary hypothesis of the study is that omarigliptin compared to placebo produces greater reduction in glycosylated hemoglobin (A1C) after 24 weeks.

Official Title
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A Phase III, Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of MK-3102 Versus Placebo in Subjects With Type 2 Diabetes Mellitus With Moderate or Severe Chronic Kidney Disease or Kidney Failure on Dialysis Who Have Inadequate Glycemic Control.

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Omarigliptin
* Drug: Placebo to omarigliptin
* Drug: Glipizide
* Drug: Placebo to glipizide
* Biological: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus and be at least 30 years of age Moderate or severe chronic renal insufficiency or end stage renal disease on dialysis Meet one of the following criteria: is currently not on an antihyperglycemic agent (AHA) and has A1C >=7% and <=10% at screening is currently on a single oral AHA or low-dose dual oral combination AHA and has A1C >=6.5% and <=9% at screening is currently on a stable insulin regimen (>= 15 U/day) for >= 10 weeks, with no oral AHA, and has A1C >=7.5% and <=10% and FPG >130 mg/dL at screening (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 28 days after the last dose of study drug Exclusion Criteria: History of type 1 diabetes mellitus or a history of ketoacidosis Treated with any incretin mimetic or thiazolidinedione (TZD) within 12 weeks prior to screening or with omarigliptin at any time prior to study participation History of hypersensitivity to a dipeptidyl peptidase IV (DPP-4) inhibitor History of intolerance or hypersensitivity to glipizide or insulin glargine or any contraindication to glipizide or insulin glargine 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 Undergone a surgical procedure within 4 weeks prior to screening or has planned major surgery during the trial On or likely to require treatment for >=2 consecutive weeks or repeated courses of corticosteroids (note: inhaled, nasal or topical corticosteroids are permitted) Currently being treated for hyperthyroidism or is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks If on dialysis, does not regularly adhere to dialysis schedule Diagnosis of congestive heart failure with New York Heart Association (NYHA) Class IV 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) 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 Poorly controlled hypertension Severe active peripheral vascular disease 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) Positive pregnancy test Pregnant or breast-feeding, or is expecting to conceive or donate eggs during the trial, including 28 days following the last dose of study drug User of recreational or illicit drugs or has had a recent history of drug abuse or routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking

Ages Eligible for Study
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Minimum Age: 30 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 12.5 mg or 25 mg capsule orally once a week for 24 weeks. Phase B: omarigliptin 12.5 mg or 25 mg capsule orally once a week for 30 weeks. Participants who are not on background insulin therapy or who did not receive open-label glipizide or insulin as rescue therapy during Phase A of the study (Week 1 through Week 24) will receive matching placebo to glipizide daily in a blinded manner during Phase B of the study (Week 24 through Week 54). | Drug: Omarigliptin<br>* Participants with moderate renal insufficiency will receive one omarigliptin 25 mg capsule orally once a week; participants with severe renal insufficiency or end stage renal disease will receive one omarigliptin 12.5 mg capsule orally once a week<br>* Other names: MK-3102;Drug: Glipizide<br>* Phase A: Participants may receive open-label glipizide as rescue therapy up to Week 24 of the study. Phase B: Participants who received placebo to omarigliptin during Phase A and are not on background insulin therapy or who did not receive open-label glipizide or insulin as rescue therapy during Phase A of the study Week 1 through Week 24) will receive glipizide capsule(s) 2.5 daily up to a maximum of 20 mg daily (based on glycemic control) in a blinded manner during Phase B of the study (Week 24 through Week 54).<br>* Other names: Glucotrol XL;Drug: Placebo to glipizide<br>* Matching placebo to glipizide daily<br>Biological: Insulin<br>* Participants on insulin therapy at screening will continue insulin therapy during the study. Insulin glargine therapy may be administered as rescue therapy as determined by the investigator.<br>|
| Active Comparator: Placebo to omarigliptin (Phase A) → Glipizide (Phase B)<br>Phase A: matching placebo to omarigliptin orally once a week for 24 weeks. Phase B: matching placebo to omarigliptin orally once a week for 30 weeks. Participants who are not on background insulin therapy or who did not receive open-label glipizide or insulin as rescue therapy during Phase A of the study (Week 1 through Week 24) will receive glipizide 2.5 daily up to a maximum of 20 mg daily (based on glycemic control) in a blinded manner during Phase B of the study (Week 24 through Week 54). | Drug: Placebo to omarigliptin<br>* Matching placebo to omarigliptin capsule administered orally once a week<br>Drug: Glipizide<br>* Phase A: Participants may receive open-label glipizide as rescue therapy up to Week 24 of the study. Phase B: Participants who received placebo to omarigliptin during Phase A and are not on background insulin therapy or who did not receive open-label glipizide or insulin as rescue therapy during Phase A of the study Week 1 through Week 24) will receive glipizide capsule(s) 2.5 daily up to a maximum of 20 mg daily (based on glycemic control) in a blinded manner during Phase B of the study (Week 24 through Week 54).<br>* Other names: Glucotrol XL;Drug: Placebo to glipizide<br>* Matching placebo to glipizide daily<br>Biological: Insulin<br>* Participants on insulin therapy at screening will continue insulin therapy during the study. Insulin glargine therapy may be administered as rescue therapy as determined by the investigator.<br>|

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 | A1C is measured as a percent. Change from baseline in A1C at Week 24 was analyzed using constrained longitudinal data analysis (cLDA) method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, renal insufficiency stratum, baseline treatment with insulin stratum, time, the interaction of time by treatment, the interaction of time by renal insufficiency stratum, and the interaction of time by baseline treatment with insulin stratum. | Baseline and Week 24 | 
| Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period) | 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 28 weeks (including 28 days following the last dose of study therapy for participants who discontinued study drug) | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (Phase A: 24-week Placebo Controlled Period) | 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 24 weeks | 
| Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period + Phase B: 30-week Active Controlled Period) | 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 58 weeks (including 28 days following the last dose of study therapy) | 
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (Phase A: 24-week Placebo Controlled Period + Phase B: 30-week Active Controlled Period) | 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 54 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | 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, renal insufficiency stratum, baseline treatment with insulin stratum, time, the interaction of time by treatment, the interaction of time by renal insufficiency stratum, and the interaction of time by baseline treatment with insulin stratum. | Baseline and Week 24 | 
| Change From Baseline in A1C at Week 54 | A1C is measured as a percent. Change from baseline in A1C at Week 54 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, renal insufficiency stratum, baseline treatment with insulin stratum, time, the interaction of time by treatment, the interaction of time by renal insufficiency stratum, and the interaction of time by baseline treatment with insulin stratum. | Baseline and Week 54 | 
| Change From Baseline in FPG at Week 54 | Change from baseline in FPG at Week 54 was analyzed using cLDA method with a restriction of the same baseline mean across treatment groups. The cLDA model included terms for treatment, renal insufficiency stratum, baseline treatment with insulin stratum, time, the interaction of time by treatment, the interaction of time by renal insufficiency stratum, and the interaction of time by baseline treatment with insulin stratum. | Baseline and Week 54 | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 | Based on an cLDA model including terms for treatment, renal status stratum, treatment on insulin at screening stratum, time, the interaction of time by treatment, the interaction of time by renal status stratum, and the interaction of time by treatment on insulin at screening stratum, with the constraint that the mean baseline is the same for all treatment groups. Excluding data after glycemic rescue or initiation of dialysis as well as participants classified with end stage renal disease (ESRD) on dialysis. | Baseline and Week 24 | 
| Change From Baseline in eGFR at Week 54 | Based on an cLDA model including terms for treatment, renal status stratum, treatment on insulin at screening stratum, time, the interaction of time by treatment, the interaction of time by renal status stratum, and the interaction of time by treatment on insulin at screening stratum, with the constraint that the mean baseline is the same for all treatment groups. Excluding data after glycemic rescue or initiation of dialysis as well as participants classified with ESRD on dialysis. | Baseline and Week 54 |