A Study of the Safety and Efficacy of Sitagliptin Addition During Metformin Up-titration (MK-0431-848)

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Sitagliptin During Metformin Up-titration Compared With Metformin Up-titration Alone in Subjects With Type 2 Diabetes Mellitus

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.

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.