Type 2 Diabetes Mellitus
Conditions
Brief summary
This trial is designed to evaluate, in adult participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control on sub-maximal metformin mono-therapy (1000 mg/day), the effect of up-titration of metformin plus the addition of sitagliptin compared to up-titration of metformin alone on glycemic control. The primary hypothesis of this study is that up-titration of metformin to 2000 mg/day (1000 mg/twice a day) plus the addition of sitagliptin 100 mg/day provides greater reduction in hemoglobin A1C (A1C) compared to metformin up-titration alone. Another primary objective of this study is to evaluate the safety and tolerability of this treatment.
Interventions
DRUGSitagliptin
Oral tablet, 100 mg, once daily at approximately the same time each day
DRUGPlacebo
Oral tablet, once daily at approximately the same time each day
DRUGMetformin IR
All participants will take Met-IR as background medication. Initially, they will take 1 x 500 mg tablet Met-IR b.i.d. (1000 mg/day). After randomization, all participants will be titrated to 2 x 500 mg tablets of Met-IR b.i.d. (2000 mg/day).
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants with T2DM in accordance with American Diabetes Association (ADA) guidelines * Meet one of the following criteria: 1. Be on stable Met-IR monotherapy 1000 mg/day for ≥8 weeks with a Screening A1C ≥7.5% and ≤11.0%. OR 2. Be on stable Met-XR monotherapy 1000 mg/day for ≥8 weeks with a Screening A1C ≥7.5% and ≤11.0%. OR 3. Not on any anti-hyperglycemic agent (AHA) for ≥8 weeks (≥12 weeks if previously taking thiazolidinediones) with a Screening A1C ≥8.5% and ≤12.0%. OR 4. Be on stable monotherapy with a sulfonylurea, a glinide, or an α-glucosidase inhibitor for ≥8 weeks with a Screening A1C ≥7.5% and ≤11.0%. * A body mass index (BMI) ≥18.0 kg/m2. * Is a male or a female not of reproductive potential (defined as one who is postmenopausal or has had a hysterectomy and/or bilateral oophorectomy, or had bilateral tubal ligation or occlusion at least 6 weeks prior to Screening visit). If participant is a female of reproductive potential, must agree to remain abstinent from heterosexual activity or agrees to use (or have her partner use) acceptable contraception to prevent pregnancy while receiving blinded study drug and for 14 days after the last dose of blinded study drug
Exclusion criteria
* Has a history of type 1 diabetes mellitus or a history of ketoacidosis or has a history of secondary causes of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and post-organ transplant). * A known hypersensitivity or intolerance to any DPP-4 inhibitor. A known hypersensitivity or intolerance to metformin, including participants who were previously unable to tolerate metformin at a dose \>1000 mg/day or who have evidence of intolerance to the dose of metformin they are currently taking. * Has been treated with any of the following agents within 8 weeks (12 weeks for thiazolidinediones) of study participation: 1. Insulin of any type (except for short-term use \[i.e., ≤7 days\] during concomitant illness or other stress) 2. DPP-4 inhibitor 3. Pioglitazone or rosiglitazone (thiazolidinediones) 4. Glucagon-like peptide-1 receptor (GLP-1R) agonists 5. Sodium glucose co-transporter 2 (SGLT2) inhibitors 6. Bromocriptine (Cycloset™) 7. Colesevelam (Welchol™) 8. Any other AHA with the exception of protocol-approved agents * Intends to initiate weight loss medication during the study period * Has undergone bariatric surgery within 12 months of Screening visit * Has started a weight loss medication or a medication associated with weight changes within the prior 12 weeks * A history of myocardial infarction, unstable angina, arterial revascularization, stroke, transient ischemic attack, NYHA functional class III-IV heart failure, or severe peripheral vascular disease (e.g., claudication with minimal activity, a nonhealing ischemic ulcer, or disease which is likely to require surgery or angioplasty) within 3 months of study participation * A history of malignancy ≤5 years prior to study participation (i.e., the diagnosis occurred, or any evidence of residual or recurrent disease occurred, within the past 5 years), except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer. Note: A patient with any history of melanoma, leukemia, lymphoma, or renal cell carcinoma is excluded. * Has human immunodeficiency virus (HIV) 1. with AIDS related complications, or 2. has not been on a stable anti-retroviral regimen for \>6 months, or 3. has progressive disease, or 4. using agents associated with glucose intolerance such as nucleoside reverse transcriptase inhibitors (NRTIs) such as azidothymidine (AZT), didanosine (ddI), and stavudine (d4T). * Is on or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids. * Has undergone a major surgical procedure within 12 weeks prior to signing the informed consent form (ICF) or has major surgery planned during the trial. * Currently participating, or has participated, in a study in which the participant received an investigational compound or used an investigational device within the prior 12 weeks of signing informed consent or is not willing to refrain from participating in another study. * Is pregnant or breast-feeding, has a positive urine pregnancy test, or is planning to conceive or donate eggs during the study, including 14 days following the last dose of blinded investigational product. * A recent history of alcohol or drug abuse (within 3 years) or is a user of recreational or illicit drugs at the time of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C at Week 20 | Baseline and Week 20 | Hemoglobin A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The change from baseline represents the Week 20 A1C value minus the Week 0 (baseline) A1C value. |
| Percentage of Participants Who Experienced at Least One Adverse Event (AE) | Up to 22 weeks | An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
| Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event | Up to 20 weeks | An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hemoglobin A1C <7% at Week 20 | Week 20 | Hemoglobin A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. |
| Percentage of Participants Receiving Glycemic Rescue Therapy | Up to 20 weeks | Participants who met pre-specified criteria for glycemic rescue received appropriate rescue therapy. The choice of anti-hyperglycemic rescue agent, dose, and regimen was directed by the investigator, as clinically appropriate. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20 | Baseline and Week 20 | Plasma glucose was measured on a fasting basis and is expressed as mg/dL. Blood was drawn predose on Day 1 and after 20 weeks of treatment to determine change in FPG levels. The change from baseline represents the Week 20 FPG value minus the Week 0 (baseline) FPG value. |
| Percentage of Participants With Hemoglobin A1C ≥8.5% at Baseline That Attained A1C Goal of <7% at Week 20 | Baseline and Week 20 | Hemoglobin A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Participants received sitagliptin 100 mg once daily for 20 weeks. They also received Met-IR, which was titrated from a baseline dose of 1000 mg/day (500 mg/b.i.d.) up to 2000 mg/day (1000 mg/b.i.d.) by Day 15. Participants also received glycemic rescue therapy as needed. | 229 |
| Placebo Participants received placebo matching sitagliptin once daily for 20 weeks. They also received Met-IR, which was titrated from baseline dose of 1000 mg/day (500 mg/b.i.d.) up to 2000 mg/day (1000 mg/b.i.d.) by Day 15. Participants also received glycemic rescue therapy as needed. | 229 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 2 | 6 |
Baseline characteristics
| Characteristic | Total | Placebo | Sitagliptin |
|---|---|---|---|
| Age, Continuous | 55.5 Years STANDARD_DEVIATION 10.4 | 55.3 Years STANDARD_DEVIATION 10.4 | 55.6 Years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 298 Participants | 151 Participants | 147 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 148 Participants | 70 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 12 Participants | 8 Participants | 4 Participants |
| Fasting Plasma Glucose | 183.0 mg/dL STANDARD_DEVIATION 43.2 | 184.4 mg/dL STANDARD_DEVIATION 44.7 | 181.7 mg/dL STANDARD_DEVIATION 41.6 |
| Hemoglobin A1C (%) | 8.7 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.9 | 8.7 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1 | 8.6 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 50 Participants | 27 Participants | 23 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 7 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 70 Participants | 39 Participants | 31 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 322 Participants | 155 Participants | 167 Participants |
| Sex: Female, Male Female | 275 Participants | 136 Participants | 139 Participants |
| Sex: Female, Male Male | 183 Participants | 93 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 229 | 0 / 229 |
| other Total, other adverse events | 18 / 229 | 11 / 229 |
| serious Total, serious adverse events | 3 / 229 | 4 / 229 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C at Week 20
Hemoglobin A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The change from baseline represents the Week 20 A1C value minus the Week 0 (baseline) A1C value.
Time frame: Baseline and Week 20
Population: All randomized participants who received at least 1 dose of study medication and had at least 1 observation for the analysis endpoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in Hemoglobin A1C at Week 20 | -1.10 A1C (%) |
| Placebo | Change From Baseline in Hemoglobin A1C at Week 20 | -0.69 A1C (%) |
p-value: <0.00195% CI: [-0.59, -0.23]Longitudinal Data Analysis
Primary
Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event
An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time frame: Up to 20 weeks
Population: All randomized participants who received at least 1 dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event | 0.9 Percentage of participants |
| Placebo | Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event | 0.0 Percentage of participants |
Primary
Percentage of Participants Who Experienced at Least One Adverse Event (AE)
An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Time frame: Up to 22 weeks
Population: All randomized participants who received at least 1 dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 44.1 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 45.9 Percentage of participants |
95% CI: [-10.8, 7.4]Miettinen and Nurminen method
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20
Plasma glucose was measured on a fasting basis and is expressed as mg/dL. Blood was drawn predose on Day 1 and after 20 weeks of treatment to determine change in FPG levels. The change from baseline represents the Week 20 FPG value minus the Week 0 (baseline) FPG value.
Time frame: Baseline and Week 20
Population: All randomized participants who received at least 1 dose of study treatment and had at least 1 observation for the analysis endpoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20 | -29.3 mg/dL |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 20 | -16.9 mg/dL |
p-value: 0.00295% CI: [-20.2, -4.6]Longitudinal Data Analysis
Secondary
Percentage of Participants Receiving Glycemic Rescue Therapy
Participants who met pre-specified criteria for glycemic rescue received appropriate rescue therapy. The choice of anti-hyperglycemic rescue agent, dose, and regimen was directed by the investigator, as clinically appropriate.
Time frame: Up to 20 weeks
Population: All randomized participants who received at least 1 dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants Receiving Glycemic Rescue Therapy | 1.3 Percentage of participants |
| Placebo | Percentage of Participants Receiving Glycemic Rescue Therapy | 3.1 Percentage of participants |
Secondary
Percentage of Participants With Hemoglobin A1C <7% at Week 20
Hemoglobin A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100.
Time frame: Week 20
Population: All randomized participants who received at least 1 dose of study treatment and had at least 1 observation for the analysis endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants With Hemoglobin A1C <7% at Week 20 | 28.8 Percentage of participants |
| Placebo | Percentage of Participants With Hemoglobin A1C <7% at Week 20 | 16.6 Percentage of participants |
p-value: 0.00295% CI: [1.2, 2.5]Miettinen and Nurminen method
Secondary
Percentage of Participants With Hemoglobin A1C ≥8.5% at Baseline That Attained A1C Goal of <7% at Week 20
Hemoglobin A1C is a blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100.
Time frame: Baseline and Week 20
Population: The subgroup of randomized participants who had a baseline hemoglobin A1C ≥8.5%, received at least 1 dose of study medication, and had at least 1 observation for the analysis endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants With Hemoglobin A1C ≥8.5% at Baseline That Attained A1C Goal of <7% at Week 20 | 15.6 Percentage of participants |
| Placebo | Percentage of Participants With Hemoglobin A1C ≥8.5% at Baseline That Attained A1C Goal of <7% at Week 20 | 5.7 Percentage of participants |