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

Phase 1

Completed

• Conditions: Drug-induced Surface ECG Changes
• Interventions: Drug: Placebo; Drug: Ranolazine; Drug: Dofetilide; Drug: Verapamil; Drug: Quinidine sulfate

• Registration Number: NCT01873950
• Lead Sponsor: Food and Drug Administration (FDA)

Brief 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.

Detailed Description

This will be a randomized, double blind, 5 way crossover research study in healthy male and female subjects, 18 to 35 years of age, to compare 4 known QT prolonging drugs versus placebo to determine their effects on electrophysiological and other clinical parameters. To maintain the study blind, subjects will be blindfolded during study drug administration. The cardiologists at the central ECG laboratory (Spaulding Clinical Research, LLC) will be blinded to treatment, time, and study day/subject identifiers.

Subjects who meet all of the following inclusion criteria will be eligible to participate in the study:

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 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 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.

Study Timeline

• Study Start: 2013-05
• Study First Submitted: 2013-05-22
• Study First Submitted QC: 2013-06-05
• Study First Posted: 2013-06-10
• Primary Completion: 2013-07
• Study Completion: 2014-12
• Results First Submitted: 2015-03-16
• Results First Submitted QC: 2015-05-05
• Results First Posted: 2015-05-21
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-06
• Last Update Posted: 2018-03-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo
Ranolazine 1500mg	Ranolazine	Ranolazine
Dofetilide 500mcg	Dofetilide	Dofetilide
Verapamil HCl 120 mg	Verapamil	Verapamil
Quinidine sulfate 400mg	Quinidine sulfate	Quinidine sulfate

Primary Outcome Measures

Name	Time	Method
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc	24 hours	Compute maximum mean placebo, and baseline-adjusted change for: PR (ms), QRS (ms), J-Tpeak (ms), Tpeak-Tend (ms) and QTc (ms)
Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle	24 hours	Compute maximum mean placebo, and baseline-adjusted change for: spatial QRS-T angle (degrees)
Placebo, and Baseline-adjusted Changes in Ventricular Gradient	24 hours	Compute maximum mean placebo, and baseline-adjusted change for: ventricular gradient (mV\*ms).

Secondary Outcome Measures

Name	Time	Method
Change in Relationship (Ratio) Between Heart Rate and QT	24 hours	Different post-dose time-points employ different techniques for altering heart rate (leg raises and postural maneuvers). Using the measurements from all the time-points of postural maneuvers, the QT/RR relationship was modeled as a linear relationship between the square root of RR in seconds and QT in seconds and computed on a by subject, treatment and time-point basis. The change in the QT and heart rate relationship was assessed as the difference (mean and 95% CI) between the slopes from the models for each drug vs. placebo.
Change in Ventricular Gradient Using Exposure/Response (Dofetilide and Verapamil Arms)	24 hours	The exposure response analysis will be performed for each treatment and will use a linear or nonlinear model (as determined by visual inspection) to quantify the relationship between exposure and Baseline and placebo adjusted change from Baseline for each ECG parameter (same as for primary analysis).; The magnitude of change (mean and 95% CI) in ventricular gradient for the observed mean Cmax for each drug may be calculated.
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms)	24 hours	The exposure response analysis will be performed for each treatment and will use a linear or nonlinear model (as determined by visual inspection) to quantify the relationship between exposure and Baseline and placebo adjusted change from Baseline for each ECG parameter (same as for primary analysis).; The magnitude of change (mean and 95% CI) in QTc for the observed mean Cmax for each drug may be calculated.
Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms)	24 hours	The exposure response analysis will be performed for each treatment and will use a linear or nonlinear model (as determined by visual inspection) to quantify the relationship between exposure and Baseline and placebo adjusted change from Baseline for each ECG parameter (same as for primary analysis).; The magnitude of change (mean and 95% CI) in spatial QRS-T angle for the observed mean Cmax for each drug may be calculated.
Change in Ventricular Gradient Using Exposure/Response (Ranolazine and Quinidine Arms)	24 hours	The exposure response analysis will be performed for each treatment and will use a linear or nonlinear model (as determined by visual inspection) to quantify the relationship between exposure and Baseline and placebo adjusted change from Baseline for each ECG parameter (same as for primary analysis).; The magnitude of change (mean and 95% CI) in ventricular gradient for the observed mean Cmax for each drug may be calculated.
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms)	24 hours	The exposure response analysis will be performed for each treatment and will use a linear or nonlinear model (as determined by visual inspection) to quantify the relationship between exposure and Baseline and placebo adjusted change from Baseline for each ECG parameter (same as for primary analysis).; The magnitude of change (mean and 95% CI) in QTc for the observed mean Cmax for each drug may be calculated.
Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms)	24 hours	The exposure response analysis will be performed for each treatment and will use a linear or nonlinear model (as determined by visual inspection) to quantify the relationship between exposure and Baseline and placebo adjusted change from Baseline for each ECG parameter (same as for primary analysis).; The magnitude of change (mean and 95% CI) in spatial QRS-T angle for the observed mean Cmax for each drug may be calculated.