Ranolazine Monotherapy in Subjects With Type 2 Diabetes Mellitus

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ranolazine Monotherapy in Subjects With Type 2 Diabetes Mellitus

This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study to determine the effect of ranolazine when given as monotherapy on glycemic control in subjects with type 2 diabetes mellitus (T2DM) who were inadequately controlled with diet and exercise alone and who are treatment naive to antihyperglycemic therapy or have not received antihyperglycemic therapy in the 90 days (or thiazolidinediones [TZDs] for at least 24 weeks) prior to screening, and to characterize the relationship between HbA1c reduction and other glycemic parameters in subjects with T2DM.

Inclusion Criteria:

• Written informed consent
• Males and females, 18 to 75 years old, inclusive
• Documented history of T2DM
• Treatment naïve to antihyperglycemic therapy or having received no prior treatment with antihyperglycemic therapy for at least 90 days (TZDs for at least 24 weeks) prior to screening
• Body mass index (BMI) 25 kg/m2 to 45 kg/m2 inclusive at screening
• HbA1c 7% - 10%, inclusive at screening and at the end of the Qualifying Period (Day 14 +2 days)
• Fasting serum glucose (FSG) of ≥ 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 (Day 14 +2 days). A one-time central laboratory re-test of FSG is allowed in subjects with an initial central laboratory FSG ≥ 125 mg/dL (6.9 mmol/L) and < 130 mg/dL (7.2 mmol/L) who are otherwise eligible as determined by the investigator.
• Fasting serum C-peptide ≥ 0.8 ng/mL at screening
• Able and willing to comply with all study procedures during the course of the study
• Females of child-bearing potential must have a negative pregnancy test at screening and must agree to use highly effective contraception methods from screening throughout the duration of the Treatment Period and for 14 days following the last dose of study drug
• At least 80% compliant with dosing during the Qualifying Period

Exclusion Criteria:

• History of or current diagnosis of type 1 diabetes mellitus
• History of diabetic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma
• History of a severe episode of hypoglycemia (≥ 1 episode within 3 months prior to screening or ≥ 2 episodes within 6 months prior to screening), defined as hypoglycemia requiring 3rd party assistance to actively administer carbohydrate, glucagon, or other resuscitative actions due to severe impairment in consciousness or behavior
• Clinically significant complications of diabetes that, in the judgment of the investigator, would make the subject unsuitable to participate in this study
• History of any clinically significant cardiovascular or cerebrovascular event (eg, myocardial infarction [MI], acute coronary syndrome [ACS], recent coronary revascularization [including coronary artery bypass graft procedures or percutaneous coronary intervention], transient ischemic attack or ischemic stroke) ≤ 3 months prior to screening
• Inadequately controlled or unstable hypertension as defined by systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg at screening and randomization
• Prolonged QTc interval > 500 msec by ECG at screening, a personal or family history of QTc prolongation, congenital long QT syndrome, or subjects who are receiving drugs that prolong the QTc interval, such as Class Ia or Class III antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, ziprasidone)
• History of bariatric surgery at any time in the past or any other surgery < 2 months before screening, or planning to undergo surgery during the study. Subjects with a planned minor surgery may be enrolled upon approval by the Medical Monitor.
• Any other hospitalization in the 14 days prior to screening or planned hospitalization at any time during the study
• Significant weight change (± 5%) < 2 months prior to screening or on a weight-loss program and is not in the maintenance phase at screening
• Severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) by the Modification of Diet in Renal Disease (MDRD) equation < 30 mL/min/1.73 m2 at screening or undergoing any type of dialysis at screening or planning to undergo any type of dialysis during the course of the study.
• History of liver cirrhosis (Child-Pugh Class A, B or C)
• Active liver disease and/or significant abnormal liver function defined as aspartate aminotransferase (AST) > 3x upper limit of the normal range (ULN) and/or alanine aminotransferase (ALT) > 3x ULN and/or serum total bilirubin > 2.0 mg/dL
• History of cancer (except non-melanomic skin cancers or cervical in situ) within 5 years prior to screening
• History of alcohol or other drug abuse < 12 months prior to screening
• Any other clinically significant existing medical or psychiatric condition, including clinically significant laboratory abnormalities, or one requiring further evaluation that, in the opinion of the investigator, could interfere with conduct of the study or interpretation of the data
• Prior treatment with open-label ranolazine or known hypersensitivity or intolerance to ranolazine or any of its excipients
• Treatment with strong or moderate cytochrome (CYP)3A 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 CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, sirolimus) within 14 days prior to randomization
• Treatment with simvastatin at a daily dose > 20 mg or lovastatin at a daily dose > 40 mg, within 14 days prior to randomization
• Weight-loss medication or anti-obesity medication (prescription or nonprescription) < 3 months prior to screening
• Treatment with niacin > 200 mg daily; if receiving ≤ 200 mg daily, should be on stable doses for ≥ 90 days prior to screening and for the duration of the study
• Expected or current treatment with systemic corticosteroids (oral or injectable) for > 14 days from screening through the end of the Treatment Period. Topical or inhaled corticosteroid formulations are permitted at any time during the study
• If receiving thyroid replacement therapy, should be on stable doses for at least 6 weeks prior to randomization
• Hemoglobin < 12 g/dL for males; or < 11 g/dL for females, at screening
• Participation in another clinical study involving an investigational drug or device < 30 days prior to screening; participation in another clinical study involving an antihyperglycemic therapy < 90 days prior to screening
• Donation of blood < 2 months prior to screening; plans to donate blood while participating in the study
• Females who are pregnant or breastfeeding
• Other condition(s) that, in the opinion of the investigator, would compromise the safety of the subject, would prevent compliance with the study protocol (including the ability to comply with Mixed Meal Tolerance Test [MMTT]), or would compromise the quality of the clinical study