Type 2 Diabetes Mellitus
Conditions
Brief summary
A study to compare safety and efficacy of sitagliptin and placebo therapy when added to stable sulfonylurea alone or in combination with metformin in participants with type 2 diabetes mellitus (T2DM). The primary hypothesis of this study is that after 24 weeks, the addition of sitagliptin compared with placebo provides greater reduction in hemoglobin A1C (HbA1C) in T2DM participants on sulfonylurea alone or in combination with metformin.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg oral tablet once daily for 24 weeks
DRUGPlacebo
Matching placebo to sitagliptin oral tablet once daily for 24 weeks
DRUGGliclazide
Participants will continue ongoing open-label therapy with gliclazide (dosed according to the China drug label) throughout the study.
DRUGGlimepiride
Participants will continue ongoing open-label therapy with glimepiride (dosed according to the China drug label) throughout the study.
DRUGMetformin
Participants will continue ongoing open-label therapy with metformin (at least 1500 mg daily) throughout the study.
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
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
* has T2DM * is currently on a stable regimen of gliclazide or glimepiride, either alone or in combination with metformin for ≥ 10 weeks * has a Visit 1/Screening HbA1C between 7.5% and 11.0% * is a male, or a female who is highly unlikely to conceive during the study and for 14 days after the last dose of study medication
Exclusion criteria
* has a history of type 1 diabetes mellitus or a history of ketoacidosis * has been treated with any antihyperglycemic therapies other than a sulfonylurea (alone or with metformin) within the prior 12 weeks or has ever been treated with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 mimetic or analogue * has a history of intolerance or hypersensitivity, or has any contraindication to sitagliptin, gliclazide/glimepiride, or metformin * is on a weight loss program and not in the maintenance phase, or has started a weight loss medication or has undergone bariatric surgery within 12 months * has undergone a surgical procedure within 4 weeks or has planned major surgery during the study * has a medical history of active liver disease * has had new or worsening signs or symptoms of coronary heart disease within the past 3 months, or has acute coronary syndrome, coronary artery intervention, or stroke or transient ischemic neurological disorder * has a diagnosis of congestive heart failure with New York Heart Association Class III - IV cardiac status * has a systolic blood pressure ≥ 160 mmHg or a diastolic blood pressure ≥ 90 mmHg * has human immunodeficiency virus (HIV) * has severe peripheral vascular disease * is currently being treated for hyperthyroidism or is on thyroid hormone therapy and has not been on a stable dose for at least 6 weeks * has a history of malignancy ≤ 5 years before the study, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer * has a clinically important hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) * is pregnant or breast feeding, or is expecting to conceive or donate eggs during the study, including 14 days after the last dose of study medication * is a user of recreational or illicit drugs or has had a recent history of drug abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | Baseline and Week 24 | A1C was measured as a percent. This change from baseline reflects the A1C percent at Week 24 minus the A1C percent at Week 0. |
| Number of Participants Who Experienced an Adverse Event | Up to 26 weeks | An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of pre-existing conditions. |
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | Up to 24 weeks | An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of pre-existing conditions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | Baseline and Week 24 | A1C was measured as a percent. This change from baseline reflects the A1C percent at Week 24 minus the A1C percent at Week 0. |
| Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and a Sulfonylurea in Combination With Metformin | Baseline and Week 24 | This change from baseline reflects the 2-hr PMG level at Week 24 minus the 2-hr PMG level at Week 0. |
| Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | Baseline and Week 24 | This change from baseline reflects the 2-hr PMG level at Week 24 minus the 2-hr PMG level at Week 0. |
| Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin | Baseline and Week 24 | This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0. |
| Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | Baseline and Week 24 | This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0. |
| Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | Baseline and Week 24 | This change from baseline reflects the 2-hr PMG level at Week 24 minus the 2-hr PMG level at Week 0. |
| Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | Baseline and Week 24 | This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0. |
| Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin | Baseline and Week 24 | A1C was measured as a percent. This change from baseline reflects the A1C percent at Week 24 minus the A1C percent at Week 0. |
Participant flow
Recruitment details
All participants randomized population.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin 100 mg once daily for 24 weeks. Participants continued pre-study gliclazide or glimepiride with or without metformin for ≥10 weeks before and throughout the study. | 249 |
| Placebo Matching placebo once daily for 24 weeks. Participants continued pre-study gliclazide or glimepiride with or without metformin for ≥10 weeks before and throughout the study. | 249 |
| Total | 498 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other Protocol Specified Criteria | 5 | 14 |
| Overall Study | Protocol Violation | 1 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 15 |
Baseline characteristics
| Characteristic | Sitagliptin | Total | Placebo |
|---|---|---|---|
| 2-hour post meal glucose (2-hr PMG) | 296.5 mg/dL STANDARD_DEVIATION 68 | 293.4 mg/dL STANDARD_DEVIATION 70.2 | 290.2 mg/dL STANDARD_DEVIATION 72.4 |
| Age, Continuous | 57.5 Years STANDARD_DEVIATION 9.5 | 57.0 Years STANDARD_DEVIATION 9.4 | 56.5 Years STANDARD_DEVIATION 9.3 |
| Fasting plasma glucose (FPG) | 181.5 mg/dL STANDARD_DEVIATION 40.9 | 180.6 mg/dL STANDARD_DEVIATION 40.8 | 179.8 mg/dL STANDARD_DEVIATION 40.7 |
| Hemoglobin A1c (A1C) | 8.61 Percent of glycosylated hemoglobin (A1C) STANDARD_DEVIATION 1.06 | 8.55 Percent of glycosylated hemoglobin (A1C) STANDARD_DEVIATION 0.99 | 8.48 Percent of glycosylated hemoglobin (A1C) STANDARD_DEVIATION 0.91 |
| Sex: Female, Male Female | 132 Participants | 249 Participants | 117 Participants |
| Sex: Female, Male Male | 117 Participants | 249 Participants | 132 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 54 / 248 | 40 / 249 |
| serious Total, serious adverse events | 7 / 248 | 7 / 249 |
Outcome results
Primary
Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin
A1C was measured as a percent. This change from baseline reflects the A1C percent at Week 24 minus the A1C percent at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set consists of all participants who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | -0.88 Percent of glycosylated hemoglobin (A1C) |
| Placebo | Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | -0.27 Percent of glycosylated hemoglobin (A1C) |
p-value: <0.00195% CI: [-0.77, -0.44]ANCOVA
Primary
Number of Participants Who Discontinued Study Drug Due to an Adverse Event
An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: Up to 24 weeks
Population: All participants as treated population defined as all randomized participants who received at least one dose of study medication. Participants are included in the treatment group corresponding to the study treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | 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 | 7 Participants |
Primary
Number of Participants Who Experienced an Adverse Event
An adverse event is any untoward medical occurrence in a participant administered study drug which does not necessarily have a causal relationship with the treatment. Adverse events may include the onset of new illness and the exacerbation of pre-existing conditions.
Time frame: Up to 26 weeks
Population: All participants as treated population defined as all randomized participants who received at least one dose of study medication. Participants are included in the treatment group corresponding to the study treatment actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants Who Experienced an Adverse Event | 106 Participants |
| Placebo | Number of Participants Who Experienced an Adverse Event | 98 Participants |
Secondary
Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and a Sulfonylurea in Combination With Metformin
This change from baseline reflects the 2-hr PMG level at Week 24 minus the 2-hr PMG level at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set (on metformin) consists of all participants on metformin who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and a Sulfonylurea in Combination With Metformin | -33.4 mg/dL |
| Placebo | Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and a Sulfonylurea in Combination With Metformin | -6.2 mg/dL |
p-value: <0.00195% CI: [-41.2, -13.2]Robust regression
Secondary
Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone
This change from baseline reflects the 2-hr PMG level at Week 24 minus the 2-hr PMG level at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set (not on metformin) consists of all participants not on metformin who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | -49.5 mg/dL |
| Placebo | Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | -11.9 mg/dL |
p-value: <0.00195% CI: [-56.9, -18.4]ANCOVA
Secondary
Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin
This change from baseline reflects the 2-hr PMG level at Week 24 minus the 2-hr PMG level at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set consists of all participants who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | -40.7 mg/dL |
| Placebo | Change From Baseline in 2-hr PMG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | -7.7 mg/dL |
p-value: <0.00195% CI: [-45.4, -20.4]ANCOVA
Secondary
Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone
A1C was measured as a percent. This change from baseline reflects the A1C percent at Week 24 minus the A1C percent at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set (not on metformin) consists of all participants not on metformin who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | -0.85 Percent of glycosylated hemoglobin (A1C) |
| Placebo | Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | -0.05 Percent of glycosylated hemoglobin (A1C) |
p-value: <0.00195% CI: [-1.07, -0.53]ANCOVA
Secondary
Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin
A1C was measured as a percent. This change from baseline reflects the A1C percent at Week 24 minus the A1C percent at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set (on metformin) consists of all participants on metformin who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin | -0.86 Percent of glycosylated hemoglobin (A1C) |
| Placebo | Change From Baseline in A1C Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin | -0.45 Percent of glycosylated hemoglobin (A1C) |
p-value: <0.00195% CI: [-0.63, -0.2]ANCOVA
Secondary
Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone
This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set (not on metformin) consists of all participants not on metformin who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | -26.3 mg/dL |
| Placebo | Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone | -9.3 mg/dL |
p-value: <0.00195% CI: [-26.9, -7.1]Robust Regression
Secondary
Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin
This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set consists of all participants who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | -24.4 mg/dL | 95% Confidence Interval -29.1 |
| Placebo | Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea Alone or in Combination With Metformin | -7.7 mg/dL | — |
p-value: <0.00195% CI: [-23.3, -10.2]Robust regression
Secondary
Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin
This change from baseline reflects the FPG level at Week 24 minus the FPG level at Week 0.
Time frame: Baseline and Week 24
Population: Full analysis set (on metformin) consists of all participants on metformin who received at least one dose of study drug, have a baseline measurement, and have at least one post-randomization measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin | -22.2 mg/dL |
| Placebo | Change From Baseline in FPG Levels at Week 24 in Participants Receiving Sitagliptin and Sulfonylurea in Combination With Metformin | -5.7 mg/dL |
p-value: <0.00195% CI: [-25.3, -7.8]Robust Regression