A Phase 3 Study of Ranolazine in Subjects With Type 2 Diabetes Who Are Inadequately Controlled on Metformin Alone

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the effect of ranolazine when added to metformin on glycemic control in adults with type 2 diabetes mellitus (T2DM) who are inadequately controlled despite current treatment with stable metformin therapy in addition to diet and exercise.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Ranolazine When Added to Metformin in Subjects With Type 2 Diabetes Mellitus

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ranolazine
* Drug: Placebo to match ranolazine
* Drug: Metformin
* Drug: Placebo to match metformin
* Behavioral: Diet
* Behavioral: Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented history of T2DM Metformin therapy at a stable total daily dose ≥ 1500 mg and ≤ 2550 mg in addition to diet and exercise for ≥ 8 weeks prior to Screening Body mass index (BMI) 25 to 45 kg/m^2, inclusive, at Screening HbA1c within specified ranges at Screening and at the end of the Qualifying Period based on current metformin dose C-peptide ≥ 0.8 ng/mL at Screening Fasting serum glucose (FSG) ≥ 130 mg/dL (7.2 mmol/L) and ≤ 240 mg/dL (13.3 mmol/L) at Screening and at the end of the Qualifying Period Exclusion Criteria: Type 1 diabetes mellitus History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma History of severe hypoglycemia Any clinically significant cardiovascular or cerebrovascular event ≤ 3 months prior to Screening History of congestive heart failure Corrected QT interval (QTc) > 500 msec by ECG at Screening, a personal or family history of QTc prolongation, congenital long QT syndrome, or individuals who are receiving drugs that prolong the QTc interval, such as Class Ia or Class III antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, ziprasidone) Serum creatinine concentration ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females at Screening Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) > 3 x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) > 3 x ULN and/or serum total bilirubin > 2.0 mg/dL Use of any non-insulin antihyperglycemic therapy (other than metformin) for more than 14 days (consecutive or not) during the 12 weeks (24 weeks for thiazolidinediones) prior to Screening and/or use of any antihyperglycemic therapy other than metformin, at any dose, at any time during the 4 weeks prior to randomization Treatment with chronic insulin within 24 weeks prior to Screening (except for one temporary period of daily insulin injections no longer than 7 days) Treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or P-glycoprotein (P-gp) inhibitors within 14 days prior to randomization Treatment with CYP3A inducers or P-gp inducers within 14 days prior to randomization Treatment with simvastatin or lovastatin at a dose > 20 mg or > 40 mg daily, respectively, within 14 days prior to randomization

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranolazine+metformin<br>Qualifying Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening). Treatment Period: Participants will receive ranolazine 500 mg + metformin 500 mg + placebo to match metformin twice daily on Days 1 through 7, followed by ranolazine 1000 mg + metformin 500 mg + placebo to match metformin twice daily from Day 8 through Week 24. Participants are required to maintain their diet and exercise regimen. | Drug: Ranolazine<br>* Ranolazine tablet(s) administered orally<br>* Other names: Ranexa®;Drug: Metformin<br>* Metformin tablet(s) administered orally once daily<br>Drug: Placebo to match metformin<br>* Placebo to match metformin for the duration of the study<br>Behavioral: Diet<br>* Participants are instructed to continue the diet regimen prescribed by their physician.<br>Behavioral: Exercise<br>* Participants are instructed to continue the exercise regimen prescribed by their physician.<br>|
| Placebo Comparator: Placebo+metformin<br>Qualifying Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily for either 2 or 8 weeks (dependent on metformin dose and HbA1c level at Screening). Treatment Period: Participants will receive metformin 1000 mg + placebo to match ranolazine twice daily through Week 24. Participants are required to maintain their diet and exercise regimen. | Drug: Placebo to match ranolazine<br>* Placebo to match ranolazine for the duration of the study<br>Drug: Metformin<br>* Metformin tablet(s) administered orally once daily<br>Behavioral: Diet<br>* Participants are instructed to continue the diet regimen prescribed by their physician.<br>Behavioral: Exercise<br>* Participants are instructed to continue the exercise regimen prescribed by their physician.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | The average (mean) change from baseline in HbA1c at Week 24 was analyzed. | Baseline; Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Serum Glucose at Week 24 | The average (mean) change from baseline in fasting serum glucose at Week 24 was analyzed. | Baseline; Week 24 | 
| Change From Baseline in 2-hour Postprandial Serum Glucose at Week 24 | The average (mean) change from baseline in 2-hour postprandial serum glucose at Week 24 was analyzed. Mixed Meal Tolerance Test (MMTT) Full Analysis Set: randomized participants who received at least one dose of study treatment with a baseline and at least one postbaseline measurement of serum glucose at T=120 minutes during the MMTT, administered under fasting conditions, excluding participants with major eligibility protocol violations; analyzed based on the randomized treatment regardless of actual treatment received. | Baseline; Week 24 |