Type 2 Diabetes Mellitus
Conditions
Brief summary
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.
Interventions
DRUGOmarigliptin
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
Matching placebo to omarigliptin capsule administered orally once a week
DRUGGlipizide
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).
Matching placebo to glipizide daily
BIOLOGICALInsulin
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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: 1. is currently not on an antihyperglycemic agent (AHA) and has A1C \>=7% and \<=10% at screening 2. is currently on a single oral AHA or low-dose dual oral combination AHA and has A1C \>=6.5% and \<=9% at screening 3. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Up to 54 weeks | 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. |
| Change From Baseline in Glycosylated Hemoglobin (A1C) at Week 24 | Baseline and 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. |
| Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period) | Up to 28 weeks (including 28 days following the last dose of study therapy for participants who discontinued study drug) | 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. |
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (Phase A: 24-week Placebo Controlled Period) | Up to 24 weeks | 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. |
| Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period + Phase B: 30-week Active Controlled Period) | Up to 58 weeks (including 28 days following the last dose of study therapy) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline and 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. |
| Change From Baseline in A1C at Week 54 | Baseline and 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. |
| Change From Baseline in FPG at Week 54 | Baseline and 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. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 | Baseline and 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. |
| Change From Baseline in eGFR at Week 54 | Baseline and 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Omarigliptin (Phase A) Phase A: omarigliptin 12.5 mg or 25 mg capsule orally once a week for 24 weeks. | 107 |
| Placebo to Omarigliptin (Phase A) Phase A: matching placebo to omarigliptin orally once a week for 24 weeks. | 106 |
| Total | 213 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase A | Adverse Event | 2 | 1 |
| Phase A | Death | 1 | 1 |
| Phase A | Kidney [transplant] | 0 | 1 |
| Phase A | Lack of Efficacy | 1 | 0 |
| Phase A | Lost to Follow-up | 1 | 2 |
| Phase A | Protocol Violation | 1 | 0 |
| Phase A | Withdrawal by Subject | 3 | 4 |
| Phase B | Adverse Event | 6 | 3 |
| Phase B | Death | 0 | 1 |
| Phase B | Hyperglycemia Discontinuation Criteria | 0 | 1 |
| Phase B | Lack of Efficacy | 0 | 1 |
| Phase B | Lost to Follow-up | 0 | 1 |
| Phase B | Physician Decision | 1 | 1 |
| Phase B | Protocol Violation | 1 | 1 |
| Phase B | Withdrawal by Subject | 6 | 2 |
Baseline characteristics
| Characteristic | Omarigliptin (Phase A) | Placebo to Omarigliptin (Phase A) | Total |
|---|---|---|---|
| Age, Continuous | 65.9 Years STANDARD_DEVIATION 9.4 | 64.5 Years STANDARD_DEVIATION 9.7 | 65.2 Years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 39 Participants | 43 Participants | 82 Participants |
| Sex: Female, Male Male | 68 Participants | 63 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 24 / 106 | 25 / 106 | 44 / 106 | 52 / 106 |
| serious Total, serious adverse events | 10 / 106 | 13 / 106 | 22 / 106 | 22 / 106 |
Outcome results
Primary
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.
Time frame: Baseline and Week 24
Population: Full analysis set (FAS) population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement in Phase A for the analysis endpoint subsequent to at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin (Phase A) | Change From Baseline in Glycosylated Hemoglobin (A1C) at Week 24 | -0.77 Percent |
| Placebo to Omarigliptin (Phase A) | Change From Baseline in Glycosylated Hemoglobin (A1C) at Week 24 | -0.44 Percent |
p-value: 0.03595% CI: [-0.63, -0.02]ANCOVA
Primary
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.
Time frame: Up to 24 weeks
Population: APaT population consists of all randomized participants who took at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin (Phase A) | Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (Phase A: 24-week Placebo Controlled Period) | 2.8 Percentage of participants |
| Placebo to Omarigliptin (Phase A) | Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event (Phase A: 24-week Placebo Controlled Period) | 0.9 Percentage of participants |
95% CI: [-2.6, 7.2]
Primary
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.
Time frame: Up to 54 weeks
Population: APaT population consists of all randomized participants who took at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin (Phase A) | 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) | 6.6 Percentage of participants |
| Placebo to Omarigliptin (Phase A) | 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) | 3.8 Percentage of participants |
95% CI: [-3.6, 9.8]
Primary
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.
Time frame: Up to 28 weeks (including 28 days following the last dose of study therapy for participants who discontinued study drug)
Population: All-Participants-as-Treated (APaT) population consists of all randomized participants who took at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin (Phase A) | Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period) | 66.0 Percentage of participants |
| Placebo to Omarigliptin (Phase A) | Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period) | 69.8 Percentage of participants |
95% CI: [-16.3, 8.8]
Primary
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.
Time frame: Up to 58 weeks (including 28 days following the last dose of study therapy)
Population: APaT population consists of all randomized participants who took at least 1 dose of trial treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin (Phase A) | Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period + Phase B: 30-week Active Controlled Period) | 77.4 Percentage of participants |
| Placebo to Omarigliptin (Phase A) | Percentage of Participants Who Experienced at Least One Adverse Event (Phase A: 24-week Placebo Controlled Period + Phase B: 30-week Active Controlled Period) | 78.3 Percentage of participants |
95% CI: [-12.2, 10.3]
Secondary
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.
Time frame: Baseline and Week 54
Population: FAS population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement for the analysis endpoint subsequent to at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin (Phase A) | Change From Baseline in A1C at Week 54 | -0.79 Percent |
| Placebo to Omarigliptin (Phase A) | Change From Baseline in A1C at Week 54 | -0.83 Percent |
Secondary
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.
Time frame: Baseline and Week 54
Population: APaT population consists of all randomized participants who took at least 1 dose of trial treatment. Excludes all participants on dialysis and data after initiation of dialysis. Phase B includes 1 omarigliptin participant in the severe renal impairment stratum (not on dialysis) who was misclassified in the ESRD stratum on dialysis during Phase A.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin (Phase A) | Change From Baseline in eGFR at Week 54 | -2.0 mL/min/1.73 m^2 |
| Placebo to Omarigliptin (Phase A) | Change From Baseline in eGFR at Week 54 | -2.3 mL/min/1.73 m^2 |
Secondary
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.
Time frame: Baseline and Week 24
Population: APaT population consists of all randomized participants who took at least 1 dose of trial treatment. Excludes participants on dialysis and data after initiation of dialysis. One omarigliptin participant with severe renal impairment was misclassified as ESRD on dialysis in Phase A and was excluded from the Phase A analysis (corrected in Phase B).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin (Phase A) | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 | -0.5 mL/min/1.73 m^2 |
| Placebo to Omarigliptin (Phase A) | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 | -0.0 mL/min/1.73 m^2 |
p-value: 0.7295% CI: [-2.7, 1.9]cLDA
Secondary
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.
Time frame: Baseline and Week 24
Population: FAS population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement in Phase A for the analysis endpoint subsequent to at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin (Phase A) | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -24.6 mg/dL |
| Placebo to Omarigliptin (Phase A) | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -20.7 mg/dL |
p-value: 0.5495% CI: [-16.5, 8.7]ANCOVA
Secondary
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.
Time frame: Baseline and Week 54
Population: FAS population included all randomized participants who received at least 1 dose of study medication and had a baseline measurement or a post-randomization measurement for the analysis endpoint subsequent to at least 1 dose of study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin (Phase A) | Change From Baseline in FPG at Week 54 | -19.3 mg/dL |
| Placebo to Omarigliptin (Phase A) | Change From Baseline in FPG at Week 54 | -16.4 mg/dL |