Study of the Electrocardiographic Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects

Exclusion Criteria

• •1. Subject has a 12 lead safety ECG result at Screening or Check in of Period 1 with evidence of any of the following abnormalities:
• •* QTc using Fridericia correction (QTcF) \>450 milliseconds (ms) for men and \>470 ms for women
• •* PR interval \>220 ms
• •* QRS duration \>110 ms
• •* Second- or third-degree atrioventricular block
• •* Complete left or right bundle branch block or incomplete right bundle branch block
• •* Heart rate \<40 or \>90 beats per minute
• •* Pathological Q-waves (defined as Q wave \>40 ms)
• •* Ventricular pre-excitation
• •2. Subject has more than 12 to 20 ectopic beats during the 3 hour Holter ECG at Screening.
• •3. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsades de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome.
• •4. Subject has a history or current evidence of any clinically significant (as determined by the investigator) cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy (excluding nonmelanoma skin cancer). The investigator may allow exceptions to these criteria (e.g., stable mild joint disease \[that will not interfere with or influence the leg raises/exercises required by the protocol, in the opinion of the investigator\], cholecystectomy, childhood asthma) following discussion with the medical monitor.
• •5. Subject has a history of thoracic surgery.
• •6. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).
• •7. Subject has a skin condition likely to compromise ECG electrode placement.
• •8. Subject is a female with breast implants.
• •9. Subject's laboratory test results at Screening or Check in of Period 1 are outside the reference ranges provided by the clinical laboratory and considered clinically significant (as determined and documented by the investigator or designee).
• •10. Subject's laboratory test results at Screening or Check in of Period 1 indicate hypokalemia, hypocalcemia, or hypomagnesemia according to lower limits of the reference ranges provided by the clinical laboratory.
• •11. Subject's laboratory test results at Screening or Check in of Period 1 are \>2 × the upper limit of normal (ULN) for alanine aminotransferase or aspartate aminotransferase, \>1.5 × ULN for bilirubin, or \>1.5 × ULN for creatinine.
• •12. Subject has a positive test result at Screening for human immunodeficiency virus antibody, hepatitis C antibodies, or hepatitis B surface antigen.
• •13. Subject has a mean systolic blood pressure \<90 or \>140 mmHg or a mean diastolic blood pressure \<50 or \>90 mmHg at either Screening or Check in of Period 1. Blood pressure will be measured in triplicate after the subject has been resting in a supine position for a minimum of 5 minutes.
• •14. Subject has a known hypersensitivity to ranolazine, dofetilide, verapamil, or quinidine or related compounds.
• •15. Subject has consumed alcohol, xanthine containing products (e.g., tea, coffee, chocolate, cola), caffeine, grapefruit, or grapefruit juice within 48 hours before dosing or anticipates an inability to abstain from these products throughout the duration of the study.
• •16. Subject has used nicotine containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks before Screening (self reported).
• •17. Subject is unable to tolerate a controlled, quiet study conduct environment, including avoidance of music, television, movies, games, and activities that may cause excitement, emotional tension, or arousal during the prespecified time points (e.g., before and during ECG extraction windows).
• •18. Subject is unwilling to comply with study rules, including the study specific diet, attempting to void at specified times (e.g., before ECG extraction windows), remaining quiet, awake, undistracted, motionless, and supine during specified times, and avoiding vigorous exercise as directed.
• •19. Subject has a history of consuming more than 14 units of alcoholic beverages per week within 6 months before Screening, has a history of alcoholism or drug/chemical/substance abuse within 2 years before Screening (Note: 1 unit = 12 ounces of beer, 4 ounces of wine or 1 ounce of spirits/hard liquor), or has a positive test result for alcohol or drugs of abuse (amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates) at Screening or Check in of each period.
• •20. Subject has used any prescription or nonprescription drugs within 14 days or 5 half lives (whichever is longer), or complementary and alternative medicines within 28 days before the first dose of study drug (excluding oral contraceptives, hormone replacement therapy, aspirin, ibuprofen, and acetaminophen).
• •21. Subject is currently participating in another clinical study of an investigational drug or has been treated with any investigational drug within 30 days or 5 half lives (whichever is longer) of the compound.
• •22. Subject has had any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood or blood products within 60 days, or donated plasma within 7 days before Check in of Period 1.
• •23. Subject has any other condition that precludes his or her participation in the study (as determined by the investigator).