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

• Sponsor: Food and Drug Administration (FDA) (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT01873950
• Collaborator: Spaulding Clinical Research LLC (Other)
• Enrollment: 22
• Arms: 5
• Duration (Months): 19

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug-induced Surface ECG Changes	Drug: Ranolazine; Drug: Dofetilide; Drug: Verapamil; Drug: Quinidine sulfate; Drug: Placebo	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Placebo-Controlled Single-Dose, Five Period Crossover Study of the Electrocardiographic Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranolazine 1500mg Ranolazine	Drug: Ranolazine
Experimental: Dofetilide 500mcg Dofetilide	Drug: Dofetilide
Experimental: Verapamil HCl 120 mg Verapamil	Drug: Verapamil
Experimental: Quinidine sulfate 400mg Quinidine sulfate	Drug: Quinidine sulfate
Placebo Comparator: Placebo Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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)

3. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

1. Subject has more than 12 to 20 ectopic beats during the 3 hour Holter ECG at Screening.

2. 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.

3. 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.

4. Subject has a history of thoracic surgery.

5. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).

6. Subject has a skin condition likely to compromise ECG electrode placement.

7. Subject is a female with breast implants.

8. 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).

9. 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.

10. 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.

11. Subject has a positive test result at Screening for human immunodeficiency virus antibody, hepatitis C antibodies, or hepatitis B surface antigen.

12. 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.

13. Subject has a known hypersensitivity to ranolazine, dofetilide, verapamil, or quinidine or related compounds.

14. 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.

15. Subject has used nicotine containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks before Screening (self reported).

16. 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).

17. 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.

18. 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.

19. 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).

20. 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.

21. 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.

22. Subject has any other condition that precludes his or her participation in the study (as determined by the investigator).

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Food and Drug Administration (FDA)
• Spaulding Clinical Research LLC

Investigators

• Principal Investigator: Carlos Sanabria, MD, Spaulding Clinical Research LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Food and Drug Administration (FDA)
• ClinicalTrials.gov Identifier: NCT01873950
• Other Study ID Numbers: 13-011D; SCR-002
• First Posted: Jun 10, 2013
• Last Update Posted: Mar 8, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Quinidine; Quinidine gluconate; Verapamil; Dofetilide; Ranolazine

Study Results

Participant Flow

Pre-assignment Detail	52 healthy volunteers were assessed for eligibility. 24 subjects were excluded because they did not meet the inclusion criteria. 22 of 28 subjects who met the inclusion criteria were randomized and allocated to receive crossed-over intervention. Williams Latin square design balanced for first-order carryover effects was used for randomization.

Arm/Group Title	Ranolazine 1500 mg	Dofetilide 500 mcg	Verapamil HCl 120 mg	Quinidine Sulfate 400 mg	Placebo
Arm/Group Description	Single oral dose of Ranolazine 1500mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Single oral dose of Dofetilide 500mcg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Single oral dose of Verapamil HCl 120 mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Single oral dose of Quinidine sulfate 400mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Single oral dose of Placebo (comparison group). Each subject received each drug only once in a randomized sequence (10 sequences in total).
Period Title: Period 1
STARTED	5	4	5	4	4
COMPLETED	5	4	5	4	4
NOT COMPLETED	0	0	0	0	0
Period Title: Period 1
STARTED	5	4	4	4	5
COMPLETED	5	4	4	4	5
NOT COMPLETED	0	0	0	0	0
Period Title: Period 1
STARTED	4	4	5	5	4
COMPLETED	4	4	5	5	4
NOT COMPLETED	0	0	0	0	0
Period Title: Period 1
STARTED	4	5	4	4	5
COMPLETED	4	5	4	4	5
NOT COMPLETED	0	0	0	0	0
Period Title: Period 1
STARTED	4	5	4	4	4
COMPLETED	4	5	4	3	4
NOT COMPLETED	0	0	0	1	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	Participants who were randomized to receive either ranolazine, dofetilide, verapamil, quinidine or placebo.
Overall Participants	22
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.9 (5.5)
Sex: Female, Male (Count of Participants)
Female	11 50%
Male	11 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.5%
Not Hispanic or Latino	21 95.5%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 18.2%
White	17 77.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (participants) [Number]
White / Not Hispanic or Latino	16 72.7%
White / Hispanic or Latino	1 4.5%
African American / Not Hispanic or Latino	4 18.2%
Asian / Not Hispanic or Latino	1 4.5%
Region of Enrollment (participants) [Number]
United States	22 100%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	23.1 (2.6)
Systolic blood pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	107.1 (8.5)
Diastolic blood pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	59.7 (7.2)
Heart rate (beats per minute (bpm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [beats per minute (bpm)]	56.8 (6.4)
PR interval (ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ms]	162.1 (21.6)
QRS duration (ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ms]	97.4 (6.7)
J-Tpeakc (heart rate corrected J-Tpeak interval) (ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ms]	225.6 (19.8)
Tpeak-Tend interval (ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ms]	73.1 (6.4)
QTc (Fridericia's heart rate corrected QT interval) (ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ms]	395.9 (17.1)
Spatial QRS-T angle (degrees) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [degrees]	34.5 (9.9)
Ventricular gradient (mV*ms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mV*ms]	111.4 (29.5)

Outcome Measures

1. Primary Outcome

Title	Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc
Description	Compute maximum mean placebo, and baseline-adjusted change for: PR (ms), QRS (ms), J-Tpeak (ms), Tpeak-Tend (ms) and QTc (ms)
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Dofetilide 500mcg	Verapamil HCl 120 mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	22	22	21
Change in PR interval	6.5	2.3	32.1	5.1
Change in QRS duration	2.7	1.1	2.6	2.1
Change in J-Tpeakc	3.3	39.5	-2.4	29.1
Change in Tpeak-Tend	8.8	40.0	4.8	49.8
Change in QTc	12.6	79.3	5.2	78.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 1500mg, Dofetilide 500mcg, Verapamil HCl 120 mg, Quinidine Sulfate 400mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	For each ECG biomarker and treatment, the null hypothesis is that there is no difference in the biomarker change from baseline between the treatment and placebo.
	Method	Mixed Models Analysis
	Comments	For each ECG biomarker and treatment, the placebo-corrected change from baseline was computed using linear mixed effect model.

2. Primary Outcome

Title	Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle
Description	Compute maximum mean placebo, and baseline-adjusted change for: spatial QRS-T angle (degrees)
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Dofetilide 500mcg	Verapamil HCl 120 mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	22	22	21
Least Squares Mean (95% Confidence Interval) [degrees]	-2.2	-4.9	-2.4	3.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 1500mg, Dofetilide 500mcg, Verapamil HCl 120 mg, Quinidine Sulfate 400mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	For each ECG biomarker and treatment, the null hypothesis is that there is no difference in the biomarker change from baseline between the treatment and placebo.
	Method	Mixed Models Analysis
	Comments	For each ECG biomarker and treatment, the placebo-corrected change from baseline was computed using linear mixed effect model.

3. Primary Outcome

Title	Placebo, and Baseline-adjusted Changes in Ventricular Gradient
Description	Compute maximum mean placebo, and baseline-adjusted change for: ventricular gradient (mV*ms).
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Dofetilide 500mcg	Verapamil HCl 120 mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	22	22	21
Least Squares Mean (95% Confidence Interval) [mV*ms]	2.5	4.8	4.2	6.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranolazine 1500mg, Dofetilide 500mcg, Verapamil HCl 120 mg, Quinidine Sulfate 400mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	For each ECG biomarker and treatment, the null hypothesis is that there is no difference in the biomarker change from baseline between the treatment and placebo.
	Method	Mixed Models Analysis
	Comments	For each ECG biomarker and treatment, the placebo-corrected change from baseline was computed using linear mixed effect model.

4. Secondary Outcome

Title	Change in Relationship (Ratio) Between Heart Rate and QT
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Dofetilide 500mcg	Verapamil HCl 120 mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	22	22	21
Mean (95% Confidence Interval) [ratio]	0.01	0.06	0.02	0.11

5. Secondary Outcome

Title	Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms)
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dofetilide 500mcg	Verapamil HCl 120 mg
Arm/Group Description	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg
Measure Participants	22	22
Change in PR	-0.5	28.7
Change in QTc	73.6	3.9
Change in QRS	0.2	0.3
Change in J-Tpeakc	39.1	-0.7
Change in Tpeak-Tend	34.4	3.6

6. Secondary Outcome

Title	Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms)
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	21
Change in PR	4.2	3.0
Change in QTc	12.0	78.9
Change in QRS	0.8	0.4
Change in J-Tpeakc	0.7	26.1
Change in Tpeak-Tend	10.0	51.2

7. Secondary Outcome

Title	Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms)
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dofetilide 500mcg	Verapamil HCl 120 mg
Arm/Group Description	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg
Measure Participants	22	22
Mean (95% Confidence Interval) [degrees per ng/ml]	-3.9	0.4

8. Secondary Outcome

Title	Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms)
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	21
Mean (95% Confidence Interval) [degrees per mcg/ml]	-1.0	2.7

9. Secondary Outcome

Title	Change in Ventricular Gradient Using Exposure/Response (Dofetilide and Verapamil Arms)
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dofetilide 500mcg	Verapamil HCl 120 mg
Arm/Group Description	Single oral dose of Dofetilide 500mcg	Single oral dose of Verapamil HCl 120 mg
Measure Participants	22	22
Mean (95% Confidence Interval) [mV.ns per ng/ml]	4.0	1.2

10. Secondary Outcome

Title	Change in Ventricular Gradient Using Exposure/Response (Ranolazine and Quinidine Arms)
Description	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.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ranolazine 1500mg	Quinidine Sulfate 400mg
Arm/Group Description	Single oral dose of Ranolazine 1500mg	Single oral dose of Quinidine sulfate 400mg
Measure Participants	22	21
Mean (95% Confidence Interval) [mV.ns per mcg/ml]	-0.7	1.6

Adverse Events

Time Frame	From May 2013 to July 2013
Arm/Group Title	Ranolazine 1500mg		Dofetilide 500mcg		Verapamil HCl 120 mg		Quinidine Sulfate 400mg		Placebo
Arm/Group Description	Single oral dose of Ranolazine 1500mg		Single oral dose of Dofetilide 500mcg		Single oral dose of Verapamil HCl 120 mg		Single oral dose of Quinidine sulfate 400mg		Single oral dose of Placebo (comparison group)
All Cause Mortality
	Ranolazine 1500mg		Dofetilide 500mcg		Verapamil HCl 120 mg		Quinidine Sulfate 400mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ranolazine 1500mg		Dofetilide 500mcg		Verapamil HCl 120 mg		Quinidine Sulfate 400mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/22 (0%)		0/22 (0%)		0/21 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Ranolazine 1500mg		Dofetilide 500mcg		Verapamil HCl 120 mg		Quinidine Sulfate 400mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/22 (18.2%)		6/22 (27.3%)		6/22 (27.3%)		12/21 (57.1%)		3/22 (13.6%)
Cardiac disorders
Palpitations	0/22 (0%)	0	1/22 (4.5%)	1	0/22 (0%)	0	0/21 (0%)	0	1/22 (4.5%)	1
Gastrointestinal disorders
Nausea	2/22 (9.1%)	2	2/22 (9.1%)	2	2/22 (9.1%)	2	5/21 (23.8%)	5	0/22 (0%)	0
Nervous system disorders
Dizziness	3/22 (13.6%)	4	2/22 (9.1%)	2	4/22 (18.2%)	4	8/21 (38.1%)	8	1/22 (4.5%)	1
Headache	1/22 (4.5%)	1	1/22 (4.5%)	1	0/22 (0%)	0	2/21 (9.5%)	2	1/22 (4.5%)	1
Psychiatric disorders
Anxiety	1/22 (4.5%)	1	0/22 (0%)	0	0/22 (0%)	0	2/21 (9.5%)	2	1/22 (4.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.