Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus
Brief summary
This study will evaluate whether the addition of Sitagliptin treatment provides a greater decrease in A1C levels compared to placebo in participants with inadequate glycemic control on sulfonylurea and metformin combination therapy.
Interventions
DRUGSitagliptin phosphate
Phase A (Weeks 0-24): Sitagliptin 100 mg once a day for 24 weeks; Phase B (Weeks 24-54): Sitagliptin 100 mg once a day for 30 weeks
Phase B (Weeks 24-54): placebo to pioglitazone 30 mg once a day for 30 weeks
Phase A (Weeks 0-24): placebo to Sitagliptin 100 mg once a day for 24 weeks; Phase B (Weeks 24-54): placebo to Sitagliptin once a day for 30 weeks
Phase B (Weeks 24-54): pioglitazone 30 mg once a day for 30 weeks
DRUGGlimepiride or gliclazide
Phase A (Weeks 0-24): stable dose, as prescribed by investigator, of glimepiride or gliclazide; Phase B (Weeks 24-54): stable dose, as prescribed by investigator, of glimepiride or gliclazide
DRUGMetformin
Phase A (Weeks 0-24): stable dose, as prescribed by investigator, of metformin; Phase B (Weeks 24- 54): stable dose, as prescribed by investigator, of metformin
DRUGPioglitazone rescue therapy
Phase A (Weeks 0-24): participants not meeting specific glycemic goals will receive pioglitazone (open label) at a dose determined by the investigator. These participants will not initiate Phase B (Weeks 24-54) double blind pioglitazone.
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
* Type 2 diabetes mellitus * Hemoglobin A1C of ≥7.5% and ≤10.5% * Currently taking a stable dose of metformin (at least 1500 mg/day) and either glimepiride (at least 2 mg/day) or gliclazide (at least 50% of maximum registered dose) for at least 10 weeks prior to study start * Male, or a female who is highly unlikely to conceive
Exclusion criteria
* Type 1 diabetes mellitus or ketoacidosis * Taking a dipeptidyl peptidase-4 (DPP-4) inhibitor (such as sitagliptin) or a glucagon-like peptide-1 (GLP-1) mimetic (such as exenatide or liraglutide) or required insulin therapy within 12 weeks prior to study start * On a weight loss program not in the maintenance phase or on a weight loss medication * History of liver disease, heart failure, heart disease, stroke, high blood pressure, blood disorders, or cancer * HIV positive * Pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (%) at Week 24 | Baseline and Week 24 | Change from baseline reflects the Week 24 value minus the baseline value. A1C represents the percentage of glycosylated hemoglobin. |
| Number of Participants With One or More Adverse Events (AEs) - Week 0 to Week 54 | Week 0 to Week 54 | — |
| Number of Participants Discontinuing Study Drug Due to An Adverse Event | Week 0 to Week 54 | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Post-Meal Glucose at Week 24 | Baseline and Week 24 | Change from baseline reflects the Week 24 value minus the baseline value. Two-hour post-meal glucose was measured following a standard meal. |
| Change From Baseline in Fasting Plasma Glucose at Week 24 | Baseline to Week 24 | Change from baseline reflects the Week 24 value minus the baseline value. |
Participant flow
Pre-assignment details
762 participants were screened, 335 participants were excluded, and 427 participants were randomized. There was a single-blind run-in prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Phase A (Weeks 0-24): Sitagliptin 100 mg; Phase B (Weeks 24-54): Sitagliptin 100 mg + Placebo to Pioglitazone | 210 |
| Placebo/Pioglitazone Phase A (Weeks 0-24): Placebo to Sitagliptin 100 mg; Phase B (Weeks 24-54): Placebo to Sitagliptin 100 mg + Pioglitazone 30 mg | 212 |
| Total | 422 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 9 |
| Overall Study | Lack of Efficacy | 5 | 4 |
| Overall Study | Lost to Follow-up | 6 | 5 |
| Overall Study | other | 19 | 9 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 19 |
Baseline characteristics
| Characteristic | Sitagliptin | Total | Placebo/Pioglitazone |
|---|---|---|---|
| 2-Hour Post-Meal Glucose | 240.3 mg/dL STANDARD_DEVIATION 60.6 | 241.8 mg/dL STANDARD_DEVIATION 64.8 | 243.3 mg/dL STANDARD_DEVIATION 68.8 |
| Age, Continuous | 54.4 years STANDARD_DEVIATION 9.6 | 54.9 years STANDARD_DEVIATION 9.9 | 55.4 years STANDARD_DEVIATION 10.2 |
| Fasting Plasma Glucose | 164.8 mg/dL STANDARD_DEVIATION 40.8 | 164.9 mg/dL STANDARD_DEVIATION 42.4 | 165.0 mg/dL STANDARD_DEVIATION 43.9 |
| Hemoglobin A1C | 8.4 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.8 | 8.4 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.8 | 8.4 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 115 Participants | 229 Participants | 114 Participants |
| Sex: Female, Male Male | 95 Participants | 193 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 | 49 / 210 | 44 / 212 |
| serious Total, serious adverse events | 6 / 210 | 9 / 212 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C (%) at Week 24
Change from baseline reflects the Week 24 value minus the baseline value. A1C represents the percentage of glycosylated hemoglobin.
Time frame: Baseline and Week 24
Population: The Full Analysis Set Population received at least one dose of study treatment and had baseline data and at least one post-baseline treatment endpoint observation for the analysis endpoint. Missing data were imputed using last observation carried forward (LOCF). Five participants were excluded from analyses due to one site's non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Hemoglobin A1C (%) at Week 24 | -0.84 Percentage of glycosylated hemoglobin | 95% Confidence Interval 0.82 |
| Placebo/Pioglitazone | Change From Baseline in Hemoglobin A1C (%) at Week 24 | -0.16 Percentage of glycosylated hemoglobin | 95% Confidence Interval 0.84 |
Comparison: Pairwise comparison - Sitagliptin vs. Placebo, using the difference in the Least Squares Means.p-value: <0.00195% CI: [-0.87, -0.5]ANCOVA
Primary
Number of Participants Discontinuing Study Drug Due to An Adverse Event
Time frame: Week 0 to Week 54
Population: The All Patients as Treated Population took at least 1 dose of study drug. Participants received glycemic rescue medication if they met specific glycemic goals up to Week 24. Participants discontinued due to adverse events are reported regardless of rescue medication. Five participants were excluded from analyses due to 1 site's non-compliance.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants Discontinuing Study Drug Due to An Adverse Event | 3 participants |
| Placebo/Pioglitazone | Number of Participants Discontinuing Study Drug Due to An Adverse Event | 9 participants |
Primary
Number of Participants With One or More Adverse Events (AEs) - Week 0 to Week 54
Time frame: Week 0 to Week 54
Population: The All Patients as Treated Population took at least one dose of study drug. Participants received glycemic rescue medication if they met specific glycemic goals up to Week 24. Adverse events include those that occurred prior to a receiving rescue medication. Five participants were excluded from analyses due to 1 site's non-compliance.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants With One or More Adverse Events (AEs) - Week 0 to Week 54 | 120 participants |
| Placebo/Pioglitazone | Number of Participants With One or More Adverse Events (AEs) - Week 0 to Week 54 | 122 participants |
Secondary
Change From Baseline in 2-hour Post-Meal Glucose at Week 24
Change from baseline reflects the Week 24 value minus the baseline value. Two-hour post-meal glucose was measured following a standard meal.
Time frame: Baseline and Week 24
Population: The Full Analysis Set Population received at least one dose of study treatment and had baseline data and at least one post-baseline treatment endpoint observation for the analysis endpoint. Missing data were imputed using last observation carried forward (LOCF). Five participants were excluded from analyses due to one site's non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in 2-hour Post-Meal Glucose at Week 24 | -36.8 mg/dL | 95% Confidence Interval 60.8 |
| Placebo/Pioglitazone | Change From Baseline in 2-hour Post-Meal Glucose at Week 24 | -3.3 mg/dL | 95% Confidence Interval 67.8 |
Comparison: Pairwise comparison - Sitagliptin vs. Placebo, difference in the Least Squares Means.p-value: <0.00195% CI: [-45.3, -21.7]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose at Week 24
Change from baseline reflects the Week 24 value minus the baseline value.
Time frame: Baseline to Week 24
Population: The Full Analysis Set Population received at least one dose of study treatment and had baseline data and at least one post-baseline treatment endpoint observation for the analysis endpoint. Missing data were imputed using last observation carried forward (LOCF). Five participants were excluded from analyses due to one site's non-compliance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in Fasting Plasma Glucose at Week 24 | -13.2 mg/dL |
| Placebo/Pioglitazone | Change From Baseline in Fasting Plasma Glucose at Week 24 | 5.3 mg/dL |
Comparison: Pairwise comparison - Sitagliptin vs. Placebo, using the difference in the Least Squares Means.p-value: <0.00195% CI: [-26.4, -10.7]ANCOVA