Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will assess the efficacy and safety of initial treatment with sitagliptin and metformin in patients with type 2 diabetes mellitus in China. The primary hypothesis is that after 24 weeks, initial co-administration treatment with sitagliptin and metformin provided greater reduction in hemoglobin A1C (A1C) compared to initial treatment with sitagliptin alone and with metformin alone.
Interventions
Sitagliptin 50 mg tablet twice a day, prior to the morning and evening meal, for 24 weeks.
DRUGMetformin 500 mg
Metformin 500 mg tablet twice daily, prior to the morning and evening meal, for 24 weeks.
Sitagliptin 100 mg once daily for 24 weeks.
DRUGPlacebo
Matching placebo tablets to sitagliptin or metformin for 24 weeks.
DRUGMetformin 850 mg
Metformin 850 mg tablet twice daily, prior to the morning and evening meal, for 24 weeks.
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 mellitus * is male, a female who cannot have children, or a female who agrees to use birth control during the study * is not on an antihyperglycemic agent (AHA) (hemoglobin A1c \[A1C\] 7.5-11.0%) or on oral single AHA (A1C 7.0-10.5%) or low-dose AHA combination therapy (A1C 7.0-10.0%)
Exclusion criteria
* Patient has type 1 diabetes mellitus or ketoacidosis * Patient is taking a dipeptidyl peptidase-4 (DPP-4) inhibitor (such as sitagliptin) * Patient is on a weight loss program not in the maintenance phase or on a weight loss medication * Patient has a history of liver disease, heart failure, heart disease, stroke, high blood pressure, blood disorders, or cancer * Patient is HIV positive * Patient is pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | Baseline and Week 24 | A1C is measured as percent. Thus, this change from baseline reflects the Week 24 A1C percent minus the Week 0 A1C percent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | Baseline and Week 24 | Change from baseline in 2-h PMG at Week 24 is defined as Week 24 2-h PMG minus Week 0 2-h PMG. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline and Week 24 | Change from baseline in FPG at Week 24 is defined as Week 24 FPG minus Week 0 FPG. |
Participant flow
Pre-assignment details
In total, 744 participants were randomized to treatment. Of these 744 participants, 1 participant, assigned to the placebo group, did not receive study medication. This participant was not included in the safety analyses.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin 50 mg + Metformin 500 mg Sitagliptin 50 mg twice daily + metformin 500 mg twice daily | 122 |
| Sitagliptin 50 mg + Metformin 850 mg Sitagliptin 50 mg twice daily + metformin 850 mg twice daily | 125 |
| Metformin 500 mg Metformin 500 mg twice daily | 126 |
| Metformin 850 Metformin 850 mg twice daily | 124 |
| Sitagliptin 100 mg Sitagliptin 100 mg once daily | 120 |
| Placebo Matching placebo to sitagliptin and/or metformin. Population includes 1 participant who did not receive any study medication. | 127 |
| Total | 744 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 6 | 3 | 2 | 3 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 1 | 1 | 2 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other protocol specified criteria | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 3 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 8 | 14 | 10 | 11 | 17 |
Baseline characteristics
| Characteristic | Sitagliptin 50 mg + Metformin 500 mg | Total | Placebo | Sitagliptin 100 mg | Metformin 850 | Metformin 500 mg | Sitagliptin 50 mg + Metformin 850 mg |
|---|---|---|---|---|---|---|---|
| 2-hour post meal glucose (2-h PMG) | 292.7 mg/dL STANDARD_DEVIATION 81.2 | 299.0 mg/dL STANDARD_DEVIATION 76.2 | 308.3 mg/dL STANDARD_DEVIATION 83.6 | 297.7 mg/dL STANDARD_DEVIATION 74.7 | 298.8 mg/dL STANDARD_DEVIATION 74.6 | 303.2 mg/dL STANDARD_DEVIATION 74.1 | 292.9 mg/dL STANDARD_DEVIATION 68.4 |
| Age, Continuous | 52.6 Years STANDARD_DEVIATION 11.3 | 52.7 Years STANDARD_DEVIATION 10 | 53.6 Years STANDARD_DEVIATION 9.7 | 51.7 Years STANDARD_DEVIATION 10.2 | 53.0 Years STANDARD_DEVIATION 10.3 | 52.6 Years STANDARD_DEVIATION 9.5 | 52.4 Years STANDARD_DEVIATION 9.3 |
| Fasting plasma glucose (FPG) | 175.6 mg/dL STANDARD_DEVIATION 40.6 | 182.3 mg/dL STANDARD_DEVIATION 45 | 185.8 mg/dL STANDARD_DEVIATION 47.3 | 182.5 mg/dL STANDARD_DEVIATION 44 | 183.5 mg/dL STANDARD_DEVIATION 47.7 | 184.6 mg/dL STANDARD_DEVIATION 46.8 | 181.9 mg/dL STANDARD_DEVIATION 43 |
| Hemoglobin A1c (A1C) | 8.46 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.97 | 8.70 Percent of glycosylated hemoglobin STANDARD_DEVIATION 1.04 | 8.97 Percent of glycosylated hemoglobin STANDARD_DEVIATION 1.05 | 8.74 Percent of glycosylated hemoglobin STANDARD_DEVIATION 1.14 | 8.67 Percent of glycosylated hemoglobin STANDARD_DEVIATION 1.08 | 8.69 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.99 | 8.66 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.95 |
| Sex: Female, Male Female | 37 Participants | 287 Participants | 40 Participants | 46 Participants | 49 Participants | 57 Participants | 58 Participants |
| Sex: Female, Male Male | 85 Participants | 457 Participants | 87 Participants | 74 Participants | 75 Participants | 69 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 122 | 14 / 125 | 8 / 126 | 13 / 124 | 6 / 120 | 4 / 126 |
| serious Total, serious adverse events | 0 / 122 | 0 / 125 | 1 / 126 | 1 / 124 | 3 / 120 | 1 / 126 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C (A1C) at Week 24
A1C is measured as percent. Thus, this change from baseline reflects the Week 24 A1C percent minus the Week 0 A1C percent.
Time frame: Baseline and Week 24
Population: Full Analysis Set, all randomized participants except those who: failed to take at least 1 dose of study treatment, lacked all post-randomization data for the A1C subsequent to at least 1 dose of study treatment, or lacked baseline data for the A1C. Last observation carried forward (missing data approach).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 50 mg + Metformin 500 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.67 Percent of glycosylated hemoglobin |
| Sitagliptin 50 mg + Metformin 850 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.83 Percent of glycosylated hemoglobin |
| Metformin 500 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.29 Percent of glycosylated hemoglobin |
| Metformin 850 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.56 Percent of glycosylated hemoglobin |
| Sitagliptin 100 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -0.99 Percent of glycosylated hemoglobin |
| Placebo | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -0.59 Percent of glycosylated hemoglobin |
p-value: 0.08795% CI: [-0.58, 0.04]ANCOVA
p-value: <0.00195% CI: [-1.15, -0.52]ANCOVA
p-value: 0.01495% CI: [-0.69, -0.08]ANCOVA
p-value: <0.00195% CI: [-0.99, -0.37]ANCOVA
p-value: <0.00195% CI: [-1.55, -0.93]ANCOVA
p-value: <0.00195% CI: [-1.28, -0.66]ANCOVA
p-value: <0.00195% CI: [-1.39, -0.78]ANCOVA
p-value: <0.00195% CI: [-1.01, -0.39]ANCOVA
p-value: 0.01195% CI: [-0.71, -0.09]ANCOVA
p-value: 0.00895% CI: [-0.62, -0.09]Regression, Robust
p-value: <0.00195% CI: [-1.13, -0.6]Regression, Robust
p-value: 0.00795% CI: [-0.63, -0.1]Regression, Robust
p-value: <0.00195% CI: [-0.88, -0.35]Regression, Robust
p-value: <0.00195% CI: [-1.52, -0.99]Regression, Robust
p-value: <0.00195% CI: [-1.16, -0.63]Regression, Robust
p-value: <0.00195% CI: [-1.26, -0.74]Regression, Robust
p-value: <0.00195% CI: [-0.9, -0.37]Regression, Robust
p-value: 0.00495% CI: [-0.65, -0.12]Regression, Robust
Secondary
Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24
Change from baseline in 2-h PMG at Week 24 is defined as Week 24 2-h PMG minus Week 0 2-h PMG.
Time frame: Baseline and Week 24
Population: Full Analysis Set, all randomized participants except those who: failed to take at least 1 dose of study treatment, lacked all post-randomization data for 2-h PMG subsequent to at least 1 dose of study treatment, or lacked baseline data for 2-h PMG. Last observation carried forward (missing data approach).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 50 mg + Metformin 500 mg | Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | -97.05 mg/dL |
| Sitagliptin 50 mg + Metformin 850 mg | Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | -109.46 mg/dL |
| Metformin 500 mg | Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | -65.67 mg/dL |
| Metformin 850 mg | Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | -90.93 mg/dL |
| Sitagliptin 100 mg | Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | -48.11 mg/dL |
| Placebo | Change From Baseline in 2-hour Post Meal Glucose (2-h PMG) at Week 24 | -21.88 mg/dL |
p-value: 0.01795% CI: [-33.75, -3.29]ANCOVA
p-value: <0.00195% CI: [-76.61, -46.07]ANCOVA
p-value: <0.00195% CI: [-46.49, -16.28]ANCOVA
p-value: <0.00195% CI: [-64.21, -33.67]ANCOVA
p-value: <0.00195% CI: [-102.87, -72.27]ANCOVA
p-value: <0.00195% CI: [-84.41, -53.7]ANCOVA
p-value: <0.00195% CI: [-90.47, -59.87]ANCOVA
p-value: <0.00195% CI: [-58.99, -28.58]ANCOVA
p-value: <0.00195% CI: [-41.62, -10.84]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Change from baseline in FPG at Week 24 is defined as Week 24 FPG minus Week 0 FPG.
Time frame: Baseline and Week 24
Population: Full Analysis Set, all randomized participants except those who: failed to take at least 1 dose of study treatment, lacked all post-randomization data for FPG subsequent to at least 1 dose of study treatment, or lacked baseline data for FPG. Last observation carried forward (missing data approach).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 50 mg + Metformin 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -39.38 mg/dL |
| Sitagliptin 50 mg + Metformin 850 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -47.74 mg/dL |
| Metformin 500 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -33.66 mg/dL |
| Metformin 850 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -39.63 mg/dL |
| Sitagliptin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -21.86 mg/dL |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -11.93 mg/dL |
p-value: 0.06995% CI: [-16.86, 0.64]ANCOVA
p-value: <0.00195% CI: [-34.72, -17.04]ANCOVA
p-value: 0.19895% CI: [-14.44, 3]ANCOVA
p-value: <0.00195% CI: [-26.33, -8.72]ANCOVA
p-value: <0.00195% CI: [-44.56, -27.06]ANCOVA
p-value: <0.00195% CI: [-36.4, -19]ANCOVA
p-value: <0.00195% CI: [-36.18, -18.73]ANCOVA
p-value: <0.00195% CI: [-30.42, -13.04]ANCOVA
p-value: 0.02795% CI: [-18.72, -1.14]ANCOVA