A Multicenter, Randomized, Active-Controlled, Open-label Clinical Trial to Evaluate the Safety and Efficacy of Glimepiride, Gliclazide, Repaglinide or Acarbose as a Third OAHA on Top of Sitagliptin+Metformin Combination Therapy in Chinese Patients With Type 2 Diabetes Mellitus
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 5,570
- Primary Endpoint
- Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2)
Study Overview
Brief Summary
To assess the effect of adding acarbose or repaglinide or gliclazide to sitagliptin plus metformin, compared to adding glimepiride, on glycemic improvements in Type 2 Diabetes Mellitus (T2DM) participants who require the addition of a third oral anti-hyperglycemic agent (OAHA) according to China Guideline for Type 2 Diabetes. The three co-primary hypotheses are that after 24 weeks of treatment in phase 2, the mean change from baseline in hemoglobin A1c (A1c) in participants receiving either (1)acarbose or (2)repaglinide or (3)gliclazide added to sitagliptin and metformin combination is non-inferior to that of participants receiving glimepiride added to sitagliptin and metformin combination. The study would be declared successful if at least one of the three primary hypotheses was met.
Detailed Description
Participants coming on study will be stabilized to a standardized metformin dose: this may take about 10 weeks, and then combination therapy with metformin + sitagliptin will begin during Phase 1 (Week 0 through Week 20). If a participant has already been on a stabilized metformin dose, they will start immediately on combination therapy with metformin + sitagliptin for 20 weeks (Phase 1).
In Phase 2, participants who have failed to achieve adequate glycemic control (A1c ≥ 7% and ≤ 10% at Week 16 and fasting finger stick glucose ≥130 mg/dL and ≤280 mg/dL at Week 20) will be randomized to receive add-on therapy with glimepiride, repaglinide, acarbose, or gliclazide for 24 weeks (Week 20 through Week 44).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Has Type 2 Diabetes Mellitus;
- •Agrees to use an effective method of contraception or must not otherwise be at risk of becoming pregnant (female participants).
Exclusion Criteria
- •Has a history of type 1 diabetes mellitus or a history of ketoacidosis;
- •Has been treated with insulin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a Glucagon-like peptide-1 (GLP-1) mimetic or analogue before;
- •Is on a weight loss program (not in maintenance phase), has started a weight loss medication, or has undergone bariatric surgery within 12 months;
- •Has undergone a surgical procedure within 4 weeks;
- •Has had new or worsening signs or symptoms of coronary heart disease or congestive heart failure within past 3 months, or has acute coronary syndrome, coronary artery intervention, or stroke or transient ischemic neurological disorder;
- •Has a medical history of active liver disease, including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease;
- •Has poorly controlled hypertension;
- •Has severe peripheral vascular disease;
- •Has human immunodeficiency virus (HIV);
- •Has had a clinically important hematological disorder;
- •Routinely consumes >2 alcoholic drinks per day or >14 alcoholic drinks per week, or engages in binge drinking;
- •Has a history of intolerance or hypersensitivity or any contraindication to study medications (including sitagliptin, metformin, glimepiride, repaglinide, acarbose or gliclazide) based upon the Chinese label;
- •Is on or likely to require treatment with ≥2 consecutive weeks or repeated courses of pharmacologic doses of corticosteroids (other than inhaled, nasal, or topical corticosteroids);
- •Is pregnant or breast feeding or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study drug (female participants).
Arms & Interventions
Metformin + Sitagliptin + Glimepiride
During Phase 2, participants receive up to 6 mg glimepiride daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Metformin (Drug)
Metformin + Sitagliptin + Glimepiride
During Phase 2, participants receive up to 6 mg glimepiride daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Sitagliptin (Drug)
Metformin + Sitagliptin + Glimepiride
During Phase 2, participants receive up to 6 mg glimepiride daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Glimepiride (Drug)
Metformin + Sitagliptin + Repaglinide
During Phase 2, participants receive up to 16 mg repaglinide daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Metformin (Drug)
Metformin + Sitagliptin + Repaglinide
During Phase 2, participants receive up to 16 mg repaglinide daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Sitagliptin (Drug)
Metformin + Sitagliptin + Repaglinide
During Phase 2, participants receive up to 16 mg repaglinide daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Repaglinide (Drug)
Metformin + Sitagliptin + Acarbose
During Phase 2, participants receive 50-100 mg acarbose three times daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Metformin (Drug)
Metformin + Sitagliptin + Acarbose
During Phase 2, participants receive 50-100 mg acarbose three times daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Sitagliptin (Drug)
Metformin + Sitagliptin + Acarbose
During Phase 2, participants receive 50-100 mg acarbose three times daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Acarbose (Drug)
Metformin + Sitagliptin + Gliclazide
During Phase 2, participants receive 30-120 mg gliclazide daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Metformin (Drug)
Metformin + Sitagliptin + Gliclazide
During Phase 2, participants receive 30-120 mg gliclazide daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Sitagliptin (Drug)
Metformin + Sitagliptin + Gliclazide
During Phase 2, participants receive 30-120 mg gliclazide daily as an add-on to metformin + sitagliptin combination therapy for 24 weeks (Week 20 through Week 44).
Intervention: Gliclazide (Drug)
Outcomes
Primary Outcomes
Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2)
Time Frame: Phase 2 Baseline (Week 20) and Week 44
HbA1c is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Change from baseline reflects the Week 44 A1C minus baseline A1C. Baseline is defined as Visit 6/Week 20. If this measurement was unavailable, the Week 16 value was used. Change from baseline was based on the constrained longitudinal data analysis (cLDA) model including all available measurements from baseline through the last visit. The terms in the cLDA model include treatment, time in weeks (categorical), regions, and treatment-by-time interaction.
Secondary Outcomes
- Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2)(Phase 2 Baseline (Week 20), Week 44)
- Percentage of Participants With Hypoglycemia Events (Phase 2)(From Week 20 through Week 44)
- Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2)(From Week 20 through Week 44)
- Percentage of Participants With a GI AE of Vomiting (Phase 2)(From Week 20 through Week 44)
- Percentage of Participants With a GI AE of Diarrhea (Phase 2)(From Week 20 through Week 44)
- Percentage of Participants With a GI AE of Abdominal Pain (Phase 2)(From Week 20 through Week 44)