Ranolazine When Added to Glimepiride in Subjects With Type 2 Diabetes Mellitus

• Postprandial serum glucose [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
• Fasting serum glucose [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the effect of ranolazine when added to glimepiride on glycemic control in subjects with type 2 diabetes mellitus who are inadequately controlled despite current treatment with stable sulfonylurea or metformin therapy in addition to diet and exercise.

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the effect of ranolazine when added to glimepiride on glycemic control in subjects with type 2 diabetes mellitus (T2DM) who are inadequately controlled despite current treatment with stable sulfonylurea or metformin therapy in addition to diet and exercise. The study has been designed to determine the effect of ranolazine on glycemic control and to characterize the relationship between HbA1c reduction and other glycemic parameters in subjects with T2DM.

• Drug: Ranolazine
  Subjects will receive one tablet of ranolazine 500 mg twice daily followed by two tablets of ranolazine 500 mg twice daily, in addition to glimepiride, for the duration of the study.
  Other Name: Ranexa
• Drug: Placebo
  Subjects will receive one tablet of matching placebo twice daily followed by two tablets of matching placebo twice daily, in addition to glimepiride, for the duration of the study.

• Experimental: Ranolazine
  Intervention: Drug: Ranolazine
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Written informed consent
• Males and females, 18 to 75 years old, inclusive
• Documented history of T2DM

• Receiving one of the following sulfonylurea (SU) or metformin therapies in addition to diet and exercise for at least 90 days prior to Screening:

  • glimepiride at a daily dose of ≥ 2 mg and ≤ 4 mg
  • glimepiride at a daily dose of ≥ 1 mg and ≤ 2 mg for subjects with severe renal impairment (eGFR < 30 mL/min/1.73m2 by the MDRD method)
  • glipizide, glyburide, or glibenclamide (or equivalent) at a daily dose of ≥ 7.5 mg
  • gliclazide at a daily dose of > 160 mg (or > 60 mg for the MR formulation)
  • metformin at a daily dose of ≥ 1500 mg
• Body mass index (BMI) 27 kg/m2 to 45 kg/m2, inclusive, at Screening
• HbA1c 7% to 10%, inclusive, at Screening and at the end of Period 1 (Day 14 + 2 days)
• FSG ≥ 130 mg/dL (7.2 mmol/L) and ≤ 240 mg/dL (13.3 mmol/L) at Screening and at the end of Period 1 (Day 14 +2 days)
• C-peptide > 1 ng/mL at Screening

Exclusion Criteria:

• History of type 1 diabetes mellitus
• History of acute or chronic ketoacidosis, ketosis-prone diabetes, or hyperosmolar hyperglycemic coma
• History of a severe episode of hypoglycemia (eg, requiring assistance of another person or active intervention of any kind) < 3 months prior to Screening
• Any clinically significant cardiovascular or cerebrovascular event (eg, MI, ACS, recent 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 a systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg at Screening and at Period 2 Day 1
• 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)
• Hemoglobin < 12 g/dL for males or < 11g/dL for females at Screening
• History of bariatric surgery at any time in the past or any other surgery < 2 months before Screening; or any planned surgery that in the opinion of the investigator might have an effect on glucose homeostasis
• 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
• 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
• Treatment with strong or moderate CYP3A inhibitors within 14 days prior to Period 2 Day 1
• Treatment with CYP3A inducers or P-gp inducers within 14 days prior to Period 2 Day 1
• Treatment with CYP3A4 substrates with a narrow therapeutic range (eg, cyclosporine, tacrolimus, or sirolimus) within 14 days prior to Period 2 Day 1
• Treatment with simvastatin at a dose of > 20 mg daily within 14 days prior to Period 2 Day 1
• Use of OHAs other than SU agents or metformin, including but not limited to dipeptidyl peptidase-4 inhibitors (eg, saxagliptin and sitagliptin) and glucagon-like peptide-mimetics (eg, exenatide) < 3 months prior to Screening. Use of thiazolidinediones (TZDs) (eg, rosiglitazone or pioglitazone) < 6 months prior to Screening
• Weight loss medication or anti-obesity medication (prescription or non prescription) < 3 months prior to Screening
• Treatment with niacin > 200 mg daily; if receiving > 200 mg daily, should be on stable doses for ≥ 3 months prior to Screening
• Expected or current treatment with systemic corticosteroids (oral or injectable) for > 14 days from Screening through the end of Period 2. 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 Period 2 Day 1