CiPA Phase 1 ECG Biomarker Validation Study
Condition: Drug-induced QT Prolongation; Pharmacokinetics; Pharmacodynamics
MeSH terms: Long QT Syndrome
Intervention: Ranolazine; Verapamil; Lopinavir / Ritonavir; Chloroquine; Placebo; Dofetilide and Diltiazem
Intervention description: Ranolazine 1500 mg orally two times per day for 2.5 days; Verapamil 120 mg immediate release (IR) morning and afternoon doses on Days 1 and 2, 240 mg extended release (ER) evening dose on Days 1 and 2, and 120 mg IR morning dose on Day 3 (all oral doses); Lopinavir / Ritonavir 800 mg / 200 mg orally two times per day for 2.5 days; Chloroquine 1000 mg on Day 1, 500 mg on Day 2, 1000 mg on Day 3 (all oral doses); Placebo (administered orally); In one period subjects receive Dofetilide 0.125 mg on Day 1, 0.375 mg on Day 3.
In a second period (randomized cross-over) subject receive Diltiazem 120 mg IR morning dose on Day 8, 240 mg ER evening dose on Days 8 and 9, and 120 mg IR on Day 10 with coadministration of 0.25 mg dofetilide on Day 10.
Intervention MeSH terms: Ritonavir; Lopinavir; Chloroquine; Verapamil; Dofetilide; Diltiazem; Ranolazine
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This clinical study consists of 2 parts:
50 subjects in Part 1 will be randomized to receive one of four drugs (ranolazine, verapamil, lopinavir / ritonavir, chloroquine) or placebo over 3 days.
10 subjects in Part 2 will be randomized to receive one of two treatment sequences (1. dofetilide or 2. diltiazem combined with dofetilide) over 3 days, then after washout, the subjects will receive the other treatment sequence over 3 days. Thus, Part 2 will have a cross-over component.
A maximum of 14 additional replacement subjects may be enrolled.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 60.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study will assess whether exposure response analysis of the electrocardiographic QTc and
      J-Tpeakc intervals in Phase 1 clinical pharmacology studies can be used to confirm that drugs
      that predominantly block the potassium channel encoded by the human ether-à-go-go-related
      gene (hERG) with approximately equipotent late sodium and/or calcium block ("balanced ion
      channel" drugs) do not cause J-Tpeakc prolongation and that drugs that predominantly block
      hERG without late sodium or L-type calcium current block ("predominant hERG" drugs) cause QTc
      prolongation.
    

Eligibility criteria:

        Inclusion criteria:

          1. Subject signs an institutional review board (IRB) approved written informed consent
             and privacy language as per national regulations (e.g., Health Insurance Portability
             and Accountability Act [HIPAA] authorization) before any study related procedures are
             performed.

          2. Subject is a healthy man or woman, 18 to 50 years of age, inclusive, who weighs at
             least 50 kg (110 pounds) and has a body mass index of 18 to 30 kg/m2, inclusive, at
             Screening.

          3. Subject has normal medical history findings, clinical laboratory results, vital sign
             measurements, 12 lead 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 will 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).

          5. Female subjects must not be pregnant or lactating before enrollment in the study.

          6. 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.

          7. Subject is highly likely (as determined by the investigator) to comply with the
             protocol defined procedures and to complete the study.

        Exclusion criteria:

          1. Subject has a safety 12 lead ECG result at Screening or Check in with evidence of any
             of the following abnormalities:

               -  QTc using Fridericia correction (QTcF) >430 msec

               -  PR interval >220 msec or <120 msec

               -  QRS duration >110 msec

               -  Second- or third-degree atrioventricular block

               -  Complete left or right bundle branch block or incomplete right bundle branch
                  block

               -  Heart rate <50 or >90 beats per minute

               -  Pathological Q-waves (defined as Q wave >40 msec)

               -  Ventricular pre-excitation

          2. Subject has more than 12 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, torsade 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.,
             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 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 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 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 I or
             II antibody, hepatitis C virus antibodies, or hepatitis B surface antigen.

         13. Subject has a mean systolic blood pressure <100 or >140 mmHg or a mean diastolic blood
             pressure <50 or >90 mmHg at either Screening or Check in. 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 any of the study drugs 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 at Screening or Check in.

         20. Subject has used any prescription or nonprescription drugs (including aspirin or
             nonsteroidal anti inflammatory drugs [NSAIDs] and excluding oral contraceptives and
             acetaminophen) 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.

         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.

         23. Subject has any other condition that precludes his or her participation in the study
             (as determined by the investigator).

         24. Subject is unwilling to have genetic analysis performed or a blood sample collected
             for isolating peripheral blood mononuclear cells (PBMCs).