Study of the Electrocardiographic Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects
Condition: Drug-induced Surface ECG Changes
Intervention: Ranolazine; Dofetilide; Verapamil; Quinidine sulfate; Placebo
Intervention MeSH terms: Quinidine; Quinidine gluconate; Verapamil; Dofetilide; Ranolazine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 35 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study seeks to compare 4 known QT prolonging drugs versus placebo to determine their
      effects on electrophysiological and other clinical parameters. The underlying purpose is to
      determine if depolarization and repolarization effects caused by drugs with differing ionic
      channel mechanisms can be distinguished from one another, and to gauge the sensitivity and
      specificity of novel signal analyses for detection of depolarization and repolarization
      changes. Secondarily, to evaluate the exposure response relationship and drug induced effects
      on the heart rate biomarker relationship.
    

Eligibility criteria:

        Inclusion Criteria: Subjects who meet all of the following inclusion criteria will be
        eligible to participate in the study:

          1. Subject signs an IRB approved written informed consent and privacy language as per
             national regulations (e.g., Health Insurance Portability and Accountability Act
             [HIPAA] authorization for sites in the United States) before any study related
             procedures are performed.

          2. Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at
             least 50 kg (110 pounds) and has a body mass index of 18 to 27 kg/m2, inclusive, at
             Screening.

          3. Subject has normal medical history findings, clinical laboratory results, vital sign
             measurements, 12 lead electrocardiogram (ECG) results, and physical examination
             findings at Screening or, if abnormal, the abnormality is not considered clinically
             significant (as determined and documented by the investigator or designee).

          4. Female subjects must be at least 2 years postmenopausal, surgically sterile or
             practicing 2 highly effective methods of birth control (as determined by the
             investigator or designee; one of the methods must be a barrier technique), and not
             pregnant or lactating before enrollment in the study.

          5. Male or female subjects must agree to practice 2 highly effective methods of birth
             control (as determined by the investigator or designee; one of the methods must be a
             barrier technique) from Screening until 30 days after the last dose of study drug.

          6. Subject is highly likely (as determined by the investigator) to comply with the
             protocol defined procedures and to complete the study.

        Exclusion Criteria:

          -  Subjects who meet any of the following exclusion criteria will not be eligible to
             participate in the study:

               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).