Type 2 Diabetes Mellitus
Conditions
Brief summary
This study will evaluate the effect of the addition of metformin once daily (q.d.) or twice daily (b.i.d.) to sitagliptin monotherapy in Japanese participants with Type 2 diabetes mellitus (T2DM) who have inadequate glycemic control with diet/exercise therapy and sitagliptin monotherapy. The primary hypotheses are that the addition of metformin 250 mg b.i.d. or metformin 500 mg q.d. is superior to the addition of placebo on the change from baseline in hemoglobin A1c (HbA1c) at 24 weeks and that the addition of metformin 500 mg q.d. is non-inferior to the addition of metformin 250 mg b.i.d. on the change from baseline in HbA1c at 24 weeks.
Interventions
DRUGSitagliptin
Sitagliptin, orally, 50 or 100 mg tablet (continuation of the pre-study dose)
DRUGMetformin
Metformin, orally, 500 mg daily (single dose; two 250 mg tablets) for 24 weeks
DRUGPlacebo
Placebo to match metformin 250 mg tablets, orally, 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
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 Diabetes Mellitus (T2DM) * Currently being treated with diet/exercise and on stable dose of sitagliptin for ≥ 4 weeks, on any additional oral hypoglycemic agent (AHA) in the prior 8 weeks, and HbA1c ≥ 6.0% and ≤ 9.0%; or * Currently being treated with diet/exercise and on stable dose of sitagliptin for ≥ 10 weeks, not on any additional oral AHA in the prior 8 weeks, and HbA1c ≥ 6.5% and \< 10.0%
Exclusion criteria
* Type 1 diabetes mellitus, * Secondary diabetes mellitus, or * Gestational diabetes mellitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) | Baseline and Week 24 | Based on a constrained longitudinal data analysis (cLDA) model with terms for treatment, other prior antihyperglycemic agent (AHA) therapy status other than sitagliptin (yes/no), study drug regimen (just before meal/after meal), sitagliptin dosage (50 mg/100 mg), time and the interaction of time by treatment, time by other prior AHA therapy status, time by study drug regimen, time by sitagliptin dosage and study drug regimen by sitagliptin dosage, with a constraint that the mean baseline is the same for all treatment groups. |
| Percentage of Participants Who Experienced at Least One Adverse Event | Up to 26 weeks | — |
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Up to 24 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) | Baseline and Week 24 | Based on a cLDA model with terms for treatment, other prior AHA therapy status other than sitagliptin (yes/no), study drug regimen (just before meal/after meal), sitagliptin dosage (50 mg/100 mg), time and the interaction of time by treatment, time by other prior AHA therapy status, time by study drug regimen, time by sitagliptin dosage and study drug regimen by sitagliptin dosage, with a constraint that the mean baseline is the same for all treatment groups. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin 500 mg q.d. Participants received sitagliptin daily at pre-study dose, 2 metformin 250 mg tablets in the morning and 1 matching placebo tablet in the evening. | 138 |
| Metformin 250 mg b.i.d. Participants received sitagliptin daily at pre-study dose, 1 metformin 250 mg tablet and 1 matching placebo tablet in the morning and 1 metformin 250 mg tablet in the evening. | 133 |
| Placebo Participants received sitagliptin daily at pre-study dose, 2 matching placebo tablets in the morning and 1 matching placebo tablet in the evening. | 66 |
| Total | 337 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 1 |
| Overall Study | Lack of Efficacy | 3 | 2 | 5 |
| Overall Study | Other | 1 | 1 | 0 |
| Overall Study | Participant moved or relocated | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 2 |
Baseline characteristics
| Characteristic | Metformin 500 mg q.d. | Metformin 250 mg b.i.d. | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 59.46 Years STANDARD_DEVIATION 9.61 | 59.65 Years STANDARD_DEVIATION 9.22 | 60.05 Years STANDARD_DEVIATION 9.3 | 59.65 Years STANDARD_DEVIATION 9.37 |
| Fasting plasma glucose (FPG) | 158.58 mg/dL STANDARD_DEVIATION 32.45 | 148.98 mg/dL STANDARD_DEVIATION 26.27 | 154.27 mg/dL STANDARD_DEVIATION 27.51 | 153.95 mg/dL STANDARD_DEVIATION 29.42 |
| Hemoglobin A1c (HbA1c) | 7.60 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.83 | 7.40 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.68 | 7.53 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.77 | 7.51 Percent of glycosylated hemoglobin STANDARD_DEVIATION 0.76 |
| Sex: Female, Male Female | 52 Participants | 46 Participants | 28 Participants | 126 Participants |
| Sex: Female, Male Male | 86 Participants | 87 Participants | 38 Participants | 211 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 29 / 138 | 35 / 133 | 8 / 66 |
| serious Total, serious adverse events | 4 / 138 | 2 / 133 | 0 / 66 |
Outcome results
Primary
Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c)
Based on a constrained longitudinal data analysis (cLDA) model with terms for treatment, other prior antihyperglycemic agent (AHA) therapy status other than sitagliptin (yes/no), study drug regimen (just before meal/after meal), sitagliptin dosage (50 mg/100 mg), time and the interaction of time by treatment, time by other prior AHA therapy status, time by study drug regimen, time by sitagliptin dosage and study drug regimen by sitagliptin dosage, with a constraint that the mean baseline is the same for all treatment groups.
Time frame: Baseline and Week 24
Population: Per-protocol population defined as all randomized participants who had at least one measurement (baseline or post-randomization), with participants and/or selected data excluded due to protocol violations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Metformin 500 mg q.d. | Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) | -0.434 Percent of glycosylated hemoglobin |
| Metformin 250 mg b.i.d. | Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) | -0.587 Percent of glycosylated hemoglobin |
| Placebo | Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) | 0.091 Percent of glycosylated hemoglobin |
p-value: <0.00195% CI: [-0.868, -0.489]cLDA
p-value: <0.00195% CI: [-0.713, -0.337]cLDA
95% CI: [0, 0.306]
Primary
Number of Participants Who Discontinued Study Drug Due to an Adverse Event
Time frame: Up to 24 weeks
Population: All participants as treated defined as all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin 500 mg q.d. | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 2 Participants |
| Metformin 250 mg b.i.d. | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 3 Participants |
| Placebo | Number of Participants Who Discontinued Study Drug Due to an Adverse Event | 1 Participants |
Primary
Percentage of Participants Who Experienced at Least One Adverse Event
Time frame: Up to 26 weeks
Population: All participants as treated defined as all randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin 500 mg q.d. | Percentage of Participants Who Experienced at Least One Adverse Event | 65.9 Percentage of participants |
| Metformin 250 mg b.i.d. | Percentage of Participants Who Experienced at Least One Adverse Event | 67.7 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Adverse Event | 60.6 Percentage of participants |
Secondary
Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG)
Based on a cLDA model with terms for treatment, other prior AHA therapy status other than sitagliptin (yes/no), study drug regimen (just before meal/after meal), sitagliptin dosage (50 mg/100 mg), time and the interaction of time by treatment, time by other prior AHA therapy status, time by study drug regimen, time by sitagliptin dosage and study drug regimen by sitagliptin dosage, with a constraint that the mean baseline is the same for all treatment groups.
Time frame: Baseline and Week 24
Population: Per-protocol population defined as all randomized participants who had at least one measurement (baseline or post-randomization), with participants and/or selected data excluded due to protocol violations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Metformin 500 mg q.d. | Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) | -9.02 mg/dL |
| Metformin 250 mg b.i.d. | Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) | -11.27 mg/dL |
| Placebo | Change From Baseline to Week 24 in Fasting Plasma Glucose (FPG) | 7.32 mg/dL |
p-value: <0.00195% CI: [-23.62, -9.06]cLDA
95% CI: [-3.63, 8.14]
p-value: <0.00195% CI: [-25.94, -11.24]cLDA