A Phase 3 Study of Ranolazine in Subjects With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone

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 subjects
with type 2 diabetes mellitus (T2DM) who are inadequately controlled despite current
treatment with stable 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.

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 7% to 10%, inclusive, at Screening and at the end of Period 1

- C-peptide ≥ 0.8 ng/mL at Screening

- 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

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

- 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)

- 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) > 3x upper limit of the normal range (ULN) and/or alanine
aminotransferase (ALT) > 3x 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 the start of Period 2

- Treatment with strong or moderate cytochrome P450 3A (CYP3A) inhibitors or
P-glycoprotein (P-gp) 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 simvastatin or lovastatin at a dose > 20 mg or > 40 mg daily,
respectively, within 14 days prior to Period 2 Day 1