A Study of the Safety and Efficacy of Sitagliptin Addition During Metformin Up-titration (MK-0431-848)
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Sitagliptin; Placebo; Metformin IR
Intervention description: Oral tablet, 100 mg, once daily at approximately the same time each day; Oral tablet, once daily at approximately the same time each day; 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).
Intervention MeSH terms: Metformin; Sitagliptin Phosphate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 458.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.