Type 2 Diabetes Mellitus
Conditions
Brief summary
A study to compare safety and efficacy of sitagliptin and placebo therapy when added to stable insulin 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 insulin alone or in combination with metformin.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg once daily for 24 weeks
DRUGPlacebo
Matching placebo once daily for 24 weeks
BIOLOGICALInsulin
Participants can be on on pre-mixed (mixture of rapid- and long-acting insulin) or intermediate- or long-acting insulin at a dose of at least 12 U/day.
DRUGMetformin
At randomization, participants will be stratified according to their use of metformin (on or not on). All participants receiving metformin will be required to be on a daily dose of metformin at least 1500 mg per day.
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 pre-mixed, intermediate-acting, or long-acting insulin at a dose of at least 12 U/day, either alone or in combination with metformin \>=1500 mg/day 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 been treated with any antihyperglycemic therapies other than a protocol-required insulin (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 * is currently on treatment with daily use (one or more injections per day) of pre-prandial short-acting or rapid-acting insulin * has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, or has had recurrent episodes of hypoglycemia over the past 8 weeks * has a history of intolerance or hypersensitivity, or has any contraindication to sitagliptin, insulin, 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 Hemoglobin A1C (HbA1C) Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin | Baseline and Week 24 | — |
| Number of Participants With One or More Adverse Events | Up to Week 26 | An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
| Number of Participants Discontinuing Study Medication Due to an AE | Up to Week 24 | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in HbA1C Levels at Week 24 in Participants Receiving Insulin in Combination With Metformin | Baseline and Week 24 |
| Change From Baseline in 2-Hour Post Meal Glucose Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin | Baseline and Week 24 |
Participant flow
Recruitment details
This study was performed with research participants at 28 study centers in China.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Participants treated with sitagliptin 100 mg, once daily, for 24 weeks. All participants will be under treatment with a stable dose of insulin with or without metformin for ≥10 weeks before and throughout the study. All participants will receive placebo during the Placebo Run-in period. | 234 |
| Placebo Participants treated with placebo to sitagliptin 100 mg, once daily, for 24 weeks. All participants will be under treatment with a stable dose of insulin with or without metformin for ≥10 weeks before and throughout the study. All participants will receive placebo during the Placebo Run-in period. | 233 |
| Total | 467 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other Protocol Specified Criteria | 2 | 4 |
| Overall Study | Protocol Violation | 4 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 5 |
Baseline characteristics
| Characteristic | Sitagliptin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.6 Years STANDARD_DEVIATION 8.4 | 56.7 Years STANDARD_DEVIATION 9.1 | 57.6 Years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 104 Participants | 117 Participants | 221 Participants |
| Sex: Female, Male Male | 130 Participants | 116 Participants | 246 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 83 / 234 | 68 / 233 |
| serious Total, serious adverse events | 4 / 234 | 9 / 233 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C (HbA1C) Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin
Time frame: Baseline and Week 24
Population: The Full Analysis Set (FAS) consisted of all randomized participants receiving insulin alone or in combination with metformin, took at least one dose of study treatment, had at least one observation for the analysis endpoint subsequent to the first dose of study treatment, and had baseline data for the analysis endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in Hemoglobin A1C (HbA1C) Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin | -0.67 A1C % |
| Placebo | Change From Baseline in Hemoglobin A1C (HbA1C) Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin | -0.32 A1C % |
p-value: <0.00195% CI: [-0.5, -0.19]Robust Regression
Primary
Number of Participants Discontinuing Study Medication Due to an AE
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to Week 24
Population: The APaT population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants Discontinuing Study Medication Due to an AE | 4 Participants |
| Placebo | Number of Participants Discontinuing Study Medication Due to an AE | 2 Participants |
Primary
Number of Participants With One or More Adverse Events
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to Week 26
Population: The All Patients as Treated (APaT) population consisted of all randomized participants who received at least one dose of study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received for the analysis of safety data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants With One or More Adverse Events | 126 Participants |
| Placebo | Number of Participants With One or More Adverse Events | 116 Participants |
Secondary
Change From Baseline in 2-Hour Post Meal Glucose Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin
Time frame: Baseline and Week 24
Population: The FAS consisted of all randomized participants receiving insulin alone or in combination with metformin, took at least one dose of study treatment, had at least one observation for the analysis endpoint subsequent to the first dose of study treatment, and had baseline data for the analysis endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in 2-Hour Post Meal Glucose Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin | -47.9 mg/dL |
| Placebo | Change From Baseline in 2-Hour Post Meal Glucose Levels at Week 24 in Participants Receiving Insulin Alone or in Combination With Metformin | -21.3 mg/dL |
p-value: <0.00195% CI: [-38.4, -14.7]ANCOVA
Secondary
Change From Baseline in HbA1C Levels at Week 24 in Participants Receiving Insulin in Combination With Metformin
Time frame: Baseline and Week 24
Population: The FAS consisted of all randomized participants receiving insulin in combination with metformin, took at least one dose of study treatment, had at least one observation for the analysis endpoint subsequent to the first dose of study treatment, and had baseline data for the analysis endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in HbA1C Levels at Week 24 in Participants Receiving Insulin in Combination With Metformin | -0.72 A1C % |
| Placebo | Change From Baseline in HbA1C Levels at Week 24 in Participants Receiving Insulin in Combination With Metformin | -0.34 A1C % |
p-value: 0.00295% CI: [-0.61, -0.14]Robust Regression