Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will examine the safety and efficacy of the addition of sitagliptin (MK-0431) compared to placebo in patients with type 2 diabetes mellitus with inadequate glycemic control who are taking pioglitazone and metformin.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg tablet orally once daily for 26 weeks.
DRUGComparator: Placebo
Placebo to sitagliptin 100 mg tablet orally once daily for 26 weeks.
DRUGPioglitazone
Participants taking 30 mg or more pioglitazone oral tablet(s) daily at screening in combination with metformin will enter a 4-week dose-stable period followed by a 2-week single-blind run-in and a 26-week treatment period. Participants taking 4 mg or more rosiglitazone oral tablet(s) daily at screening in combination with metformin were to be switched to a corresponding dose of pioglitazone prior to starting a 4-week dose-stable period. Participants who are taking less than 30 mg/day or no pioglitazone at screening will be titrated to a stable dose of at least 30 mg pioglitazone once daily over a maximum of 4 weeks followed by a dose-stable period of 10 weeks, a 2-week single-blind placebo run-in, and a 26-week treatment period. Total treatment with pioglitazone will be up to 42 weeks.
DRUGMetformin
Participants taking 1500 mg or more metformin oral tablet(s) and at least 30 mg pioglitazone or 4 mg rosiglitazone daily at screening will enter a 4-week dose-stable period followed by a 2-week single-blind placebo run-in, and a 26-week treatment period. Participants who are taking less than 1500 mg/day metformin at screening will be titrated to a stable dose of at least 1500 mg metformin once daily over a maximum of 4 weeks followed by a dose-stable period of 10 weeks, a 2-week single-blind placebo run-in, and a 26-week treatment period. Total treatment with metformin will be up to 42 weeks.
DRUGGlipizide
Participants not meeting specific glycemic controls during the 26-week treatment period will use glipizide oral tablets as rescue therapy. In countries where glipizide is not available, participants will receive a sulfonylurea marketed in that country.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
* has type 2 diabetes and is at least 18 years of age and no older than 78 years of age * is male or is a female who is unlikely to conceive children * is on stable doses of a peroxisome proliferator-activated receptor gamma agonist and metformin OR metformin and a sulfonylurea agent
Exclusion criteria
* has type 1 diabetes * has taken a dipeptidyl peptidase (DPP-4) inhibitor or a glucagon-like peptide-1 (GLP-1) analogue * is on a weight loss program that is not in the maintenance phase or has started a weight loss medication within 8 weeks of screening * has had surgery within 30 days of screening or has major surgery planned during the study * is on or is likely to require treatment with corticosteroids for more than 2 weeks * has a history of active liver disease, including hepatitis B or C, cirrhosis, or gallbladder disease * is human immunodeficiency virus (HIV) positive * has congestive heart failure, or has had new or worsening symptoms of coronary heart disease within 3 months prior to screening * has had acute coronary syndrome, coronary artery intervention, or stroke within 3 months of screening * has severe active peripheral vascular disease * has a history of cancer or blood disorder * is pregnant or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (A1C) at Week 26 | Baseline and Week 26 | Change from baseline reflects the Week 26 value minus the baseline value. A1C represents the percentage of glycosylated hemoglobin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-Hour Post-Meal Glucose (PMG) at Week 26 | Baseline and Week 26 | Change from baseline reflects the Week 26 value minus the baseline value. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Baseline and Week 26 | Change from baseline reflects the Week 26 value minus the baseline value. |
Participant flow
Pre-assignment details
Lab abnormalities (the reason for discontinuation cited below) included creatinine, creatinine clearance, and estimated glomerular filtration rate.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin 100 mg once daily | 157 |
| Placebo Placebo to sitagliptin once daily | 156 |
| Total | 313 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Contradiction to study medication | 0 | 2 |
| Overall Study | Excluded medication | 2 | 2 |
| Overall Study | Lab abnormalities | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Physician Decision | 0 | 3 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Sitagliptin | Total | Placebo |
|---|---|---|---|
| 2-hour post-meal glucose (PMG) | 275.5 mg/dL STANDARD_DEVIATION 66.4 | 270.8 mg/dL STANDARD_DEVIATION 64.5 | 266.0 mg/dL STANDARD_DEVIATION 62.4 |
| Age, Continuous | 55.7 years STANDARD_DEVIATION 8.7 | 56.1 years STANDARD_DEVIATION 9 | 56.4 years STANDARD_DEVIATION 9.4 |
| Fasting plasma glucose (FPG) | 179.3 mg/dL STANDARD_DEVIATION 44.3 | 176.5 mg/dL STANDARD_DEVIATION 41.7 | 173.6 mg/dL STANDARD_DEVIATION 38.9 |
| Hemoglobin A1c (A1C) | 8.8 Percent of gylcosylated hemoglobin STANDARD_DEVIATION 1 | 8.7 Percent of gylcosylated hemoglobin STANDARD_DEVIATION 1 | 8.7 Percent of gylcosylated hemoglobin STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 60 Participants | 118 Participants | 58 Participants |
| Sex: Female, Male Male | 97 Participants | 195 Participants | 98 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 157 | 20 / 156 |
| serious Total, serious adverse events | 3 / 157 | 6 / 156 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (A1C) at Week 26
Change from baseline reflects the Week 26 value minus the baseline value. A1C represents the percentage of glycosylated hemoglobin.
Time frame: Baseline and Week 26
Population: Full analysis set excluded participants without baseline or post-baseline data. Full analysis set with last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Hemoglobin A1c (A1C) at Week 26 | -1.15 Percent of glycosylated hemoglobin | 95% Confidence Interval 0.93 |
| Placebo | Change From Baseline in Hemoglobin A1c (A1C) at Week 26 | -0.40 Percent of glycosylated hemoglobin | 95% Confidence Interval 1 |
Secondary
Change From Baseline in 2-Hour Post-Meal Glucose (PMG) at Week 26
Change from baseline reflects the Week 26 value minus the baseline value.
Time frame: Baseline and Week 26
Population: Full analysis set excluded participants without baseline or post-baseline data. Full analysis set with last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in 2-Hour Post-Meal Glucose (PMG) at Week 26 | -54.4 mg/dL | 95% Confidence Interval 64.4 |
| Placebo | Change From Baseline in 2-Hour Post-Meal Glucose (PMG) at Week 26 | -14.7 mg/dL | 95% Confidence Interval 59.6 |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
Change from baseline reflects the Week 26 value minus the baseline value.
Time frame: Baseline and Week 26
Population: Full analysis set excluded participants without baseline or post-baseline data. Full analysis set with last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -20.3 mg/dL | 95% Confidence Interval 49.5 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -2.8 mg/dL | 95% Confidence Interval 41.6 |