A Study of the Safety and Efficacy of Glimepiride, Gliclazide, Repaglinide or Acarbose When Added to Sitagliptin + Metformin Combination Therapy in Chinese Participants With Diabetes (MK-0431-313)

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Metformin
* Drug: Sitagliptin
* Drug: Acarbose
* Drug: Repaglinide
* Drug: Glimepiride
* Drug: Gliclazide


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin + Sitagliptin + Glimepiride<br>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). | Drug: Metformin<br>* Metformin, 500 mg or 850 mg oral tablets, twice or three times a day (BID or TID) for a total dose of at least 1500 mg daily; administered with food.<br>* Other names: Glycoran®;Drug: Sitagliptin<br>* Sitagliptin, 100 mg oral tablet, once daily (QD); administered with or without food<br>* Other names: Ristaben®;Drug: Glimepiride<br>* Glimepiride, 1 mg and/or 2 mg oral tablets, QD (up to 6 mg daily); administered before the first main meal of the day<br>* Other names: Glimy;|
| Experimental: Metformin + Sitagliptin + Repaglinide<br>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). | Drug: Metformin<br>* Metformin, 500 mg or 850 mg oral tablets, twice or three times a day (BID or TID) for a total dose of at least 1500 mg daily; administered with food.<br>* Other names: Glycoran®;Drug: Sitagliptin<br>* Sitagliptin, 100 mg oral tablet, once daily (QD); administered with or without food<br>* Other names: Ristaben®;Drug: Repaglinide<br>* Repaglinide, 0.5 mg and/or 1 mg oral tablets, TID (up to 16 mg daily); administered within 30 minutes of each meal.<br>* Other names: Fulaidi™;|
| Experimental: Metformin + Sitagliptin + Acarbose<br>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). | Drug: Metformin<br>* Metformin, 500 mg or 850 mg oral tablets, twice or three times a day (BID or TID) for a total dose of at least 1500 mg daily; administered with food.<br>* Other names: Glycoran®;Drug: Sitagliptin<br>* Sitagliptin, 100 mg oral tablet, once daily (QD); administered with or without food<br>* Other names: Ristaben®;Drug: Acarbose<br>* Acarbose, 50 mg oral tablets, TID (150 mg total daily dose); administered with the first bite of each main meal.<br>* Other names: Glucobay™;|
| Experimental: Metformin + Sitagliptin + Gliclazide<br>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). | Drug: Metformin<br>* Metformin, 500 mg or 850 mg oral tablets, twice or three times a day (BID or TID) for a total dose of at least 1500 mg daily; administered with food.<br>* Other names: Glycoran®;Drug: Sitagliptin<br>* Sitagliptin, 100 mg oral tablet, once daily (QD); administered with or without food<br>* Other names: Ristaben®;Drug: Gliclazide<br>* Gliclazide, 30 mg oral tablets, QD or BID (30 mg to 120 mg total daily dose); administered with meal.<br>* Other names: Diamicron MR™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2) | 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. | Phase 2 Baseline (Week 20) and Week 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2) | Change from baseline in body weight in Phase 2 was reported. Change from baseline reflects the Week 44 body weight minus baseline body weight. Baseline is defined as Visit 6/Week 20. If this measurement was unavailable, the Week 16 value was used. | Phase 2 Baseline (Week 20), Week 44 | 
| Percentage of Participants With Hypoglycemia Events (Phase 2) | Hypoglycemia events represent epidsodes symptomatic of hypoglycemia (e.g., weakness, dizziness, shakiness, increased sweating, palpitations, or confusion) and/or finger stick glucose values of ≤70 mg/dL (3.9 mmol/L). The percentage of participants with hypoglycemia events was reported. | From Week 20 through Week 44 | 
| Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2) | The percentage of participants with a GI AE of nausea was reported. | From Week 20 through Week 44 | 
| Percentage of Participants With a GI AE of Vomiting (Phase 2) | The percentage of participants with a GI AE of vomiting was reported. | From Week 20 through Week 44 | 
| Percentage of Participants With a GI AE of Diarrhea (Phase 2) | The percentage of participants with a GI AE of diarrhea was reported. | From Week 20 through Week 44 | 
| Percentage of Participants With a GI AE of Abdominal Pain (Phase 2) | The percentage of participants with a GI AE of abdominal pain was reported. | From Week 20 through Week 44 |