Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to examine the insulin-sparing effect of sitagliptin 100 mg once-daily compared with placebo over 24 weeks in participants with type 2 diabetes mellitus who have inadequate glycemic control on insulin alone or in combination with metformin. The primary hypothesis of this study is that after 24 weeks, sitagliptin reduces the dose of insulin relative to placebo.
Interventions
DRUGSitagliptin
Sitagliptin 100 mg tablet once daily for 24 weeks
DRUGComparator: Placebo
Placebo to sitagliptin once daily for 24 weeks
BIOLOGICALInsulin Glargine
Participants on insulin glargine or another insulin regimen for at least 10 weeks prior to screening will continue or switch to open-label insulin glargine once-daily in the evening for the duration of the study.
DRUGMetformin
Participants on metformin oral tablet(s) at a dose of at least 1500 mg/day for at least 10 weeks prior to screening will continue receiving metformin at their current dose for the duration of the study.
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 80 Years
Healthy volunteers
No
Inclusion criteria
* has type 2 diabetes mellitus * has one of the following criteria: * diagnosed with diabetes after age 40 years and insulin therapy was initiated at least 3 years following diagnosis * if diagnosed with diabetes under age 40 years or insulin started earlier than 3 years after diagnosis, has a fasting C-peptide greater than 0.7 ng/mL * must be at least 18 years of age and less than or equal to 80 years of age (for participants in India: must be at least 18 years of age and less than or equal to 65 years of age) * on a stable regimen of insulin for at least 10 weeks with or without metformin (at least 1500 mg/day) and/or sulfonylurea for at least 10 weeks * is highly unlikely to become pregnant (not of reproductive potential or agrees to remain abstinent or use (or have their partner use) an acceptable method of birth control during the study and for 14 days after the last dose of study medication
Exclusion criteria
* has been treated with a dipeptidyl peptidase IV (DPP-4) inhibitor, a thiazolidinedione (TZD), or a glucagon-like peptide-1 (GLP-1) mimetic or analogue, within the past 12 weeks * currently on treatment with daily use (one or more injections per day) of a pre-prandial short-acting or rapid-acting insulin alone or as part of a basal/bolus insulin regimen * has symptomatic hyperglycemia that requires immediate initiation, adjustment, or addition of antihyperglycemic therapy * has a history of 2 or more episodes of hypoglycemia resulting in seizure, coma, or loss of consciousness, - or - has had recurrent (≥3 times per week) episodes of hypoglycemia over the past 8 weeks * has a history of ketoacidosis * is not appropriate for or does not agree to target a fasting glucose of 72-100 mg/dL \[4.0-5.6 mmol/L\] * is on or likely to require treatment with corticosteroids * has undergone a surgical procedure within 4 weeks or has planned major surgery during the study * 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 active liver disease (other than non-alcoholic hepatic steatosis) * has had new or worsening signs or symptoms of coronary heart disease or congestive heart failure within the past 3 months, or has any of the following disorders within the past 3 months: * acute coronary syndrome * coronary artery intervention * stroke or transient ischemic neurological disorder * has a systolic blood pressure greater than 160 mm Hg or a diastolic blood pressure greater than 90 mm Hg * has human immunodeficiency virus (HIV) * has severe peripheral vascular disease * has a clinically important hematological disorder * has a history of malignancy that is less than 5 years from study start, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer * has a positive urine pregnancy test * is pregnant or breast-feeding, or is expecting to conceive or donate eggs during the study * 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 Daily Insulin Dose at Week 24 | Baseline and Week 24 | Change in daily insulin dose following 24 weeks of therapy (i.e., daily insulin dose at Week 24 minus daily insulin dose at baseline) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Baseline and Week 24 | A1C is measured as the percentage of glycosylated hemoglobin. Change in A1C following 24 weeks of therapy (i.e., A1C at Week 24 minus A1C at baseline) |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline and Week 24 | Change in FPG (before breakfast) following 24 weeks of therapy (i.e., FPG at Week 24 minus FPG at baseline) |
| Percent of Participants Achieving Fasting Glucose Target at Any Time During the Study | Up to 24 weeks | The fasting glucose target was defined as 3 consecutive days with a fingerstick glucose of 72 to 100 mg/dL (4.0 - 5.6 mmol/L). |
| Time to Achieve the Fasting Glucose Target | Up to 24 weeks | Fasting glucose target 3 consecutive days with a fingerstick glucose of 72 to 100 mg/dL (4.0 - 5.6 mmol/L). This analysis was the Kaplan-Meier estimated 50th percentile of time (days) to first attainment of target. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin 100 mg administered orally once daily for 24 weeks. | 329 |
| Placebo Placebo to sitagliptin administered orally once daily for 24 weeks. | 329 |
| Total | 658 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 |
| Overall Study | Creatinine and eGFR, excluded medication | 8 | 4 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lack of Efficacy | 0 | 2 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Non-compliance with study drug | 3 | 0 |
| Overall Study | Physician Decision | 2 | 5 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Screen failure | 1 | 1 |
| Overall Study | Withdrawal by Subject | 7 | 2 |
Baseline characteristics
| Characteristic | Sitagliptin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 8.9 | 58.3 Years STANDARD_DEVIATION 9.7 | 58.8 Years STANDARD_DEVIATION 9.3 |
| Sex: Female, Male Female | 178 Participants | 165 Participants | 343 Participants |
| Sex: Female, Male Male | 151 Participants | 164 Participants | 315 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 121 / 329 | 168 / 329 |
| serious Total, serious adverse events | 13 / 329 | 12 / 329 |
Outcome results
Primary
Change From Baseline in Daily Insulin Dose at Week 24
Change in daily insulin dose following 24 weeks of therapy (i.e., daily insulin dose at Week 24 minus daily insulin dose at baseline)
Time frame: Baseline and Week 24
Population: Full Analysis Set (FAS) population included all randomized participants who took at least one dose of study medication and had at least one measurement either at baseline or post-randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Daily Insulin Dose at Week 24 | 19.0 International Units (IU) | 95% Confidence Interval 19.6 |
| Placebo | Change From Baseline in Daily Insulin Dose at Week 24 | 23.8 International Units (IU) | 95% Confidence Interval 24 |
p-value: 0.00995% CI: [-8.3, -1.2]Longitudinal data analysis
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Change in FPG (before breakfast) following 24 weeks of therapy (i.e., FPG at Week 24 minus FPG at baseline)
Time frame: Baseline and Week 24
Population: FAS population included all randomized participants who took at least one dose of study medication and had at least one measurement either at baseline or post-randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -55.5 mg/dL | 95% Confidence Interval 52 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -44.8 mg/dL | 95% Confidence Interval 62.4 |
Secondary
Change From Baseline in Hemoglobin A1c (A1C) at Week 24
A1C is measured as the percentage of glycosylated hemoglobin. Change in A1C following 24 weeks of therapy (i.e., A1C at Week 24 minus A1C at baseline)
Time frame: Baseline and Week 24
Population: FAS population included all randomized participants who took at least one dose of study medication and had at least one measurement either at baseline or post-randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | -1.31 Percent of total hemoglobin | 95% Confidence Interval 0.98 |
| Placebo | Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | -0.87 Percent of total hemoglobin | 95% Confidence Interval 1.1 |
Secondary
Percent of Participants Achieving Fasting Glucose Target at Any Time During the Study
The fasting glucose target was defined as 3 consecutive days with a fingerstick glucose of 72 to 100 mg/dL (4.0 - 5.6 mmol/L).
Time frame: Up to 24 weeks
Population: FAS population included all randomized participants who took at least one dose of study medication, and had at least one post-randomization glycemic goal assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percent of Participants Achieving Fasting Glucose Target at Any Time During the Study | 77.4 Percentage of participants |
| Placebo | Percent of Participants Achieving Fasting Glucose Target at Any Time During the Study | 74.1 Percentage of participants |
Secondary
Time to Achieve the Fasting Glucose Target
Fasting glucose target 3 consecutive days with a fingerstick glucose of 72 to 100 mg/dL (4.0 - 5.6 mmol/L). This analysis was the Kaplan-Meier estimated 50th percentile of time (days) to first attainment of target.
Time frame: Up to 24 weeks
Population: FAS population included all randomized participants who took at least one dose of study medication and had at least one post-randomization glycemic goal assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sitagliptin | Time to Achieve the Fasting Glucose Target | 78 Days to first attainment of target |
| Placebo | Time to Achieve the Fasting Glucose Target | 90 Days to first attainment of target |