Trial Outcomes & Findings for Study of the Electrocardiographic Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects (NCT NCT01873950)

Last Updated: 2018-03-08

Results Overview

Compute maximum mean placebo, and baseline-adjusted change for: PR (ms), QRS (ms), J-Tpeak (ms), Tpeak-Tend (ms) and QTc (ms)

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

22 participants

Primary outcome timeframe

24 hours

Results posted on

2018-03-08

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Ranolazine 1500 mg Single oral dose of Ranolazine 1500mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Dofetilide 500 mcg Single oral dose of Dofetilide 500mcg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Quinidine Sulfate 400 mg Single oral dose of Quinidine sulfate 400mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Placebo Single oral dose of Placebo (comparison group). Each subject received each drug only once in a randomized sequence (10 sequences in total).
Period 1 STARTED	5	4	5	4	4
Period 1 COMPLETED	5	4	5	4	4
Period 1 NOT COMPLETED	0	0	0	0	0
Period 2 STARTED	5	4	4	4	5
Period 2 COMPLETED	5	4	4	4	5
Period 2 NOT COMPLETED	0	0	0	0	0
Period 3 STARTED	4	4	5	5	4
Period 3 COMPLETED	4	4	5	5	4
Period 3 NOT COMPLETED	0	0	0	0	0
Period 4 STARTED	4	5	4	4	5
Period 4 COMPLETED	4	5	4	4	5
Period 4 NOT COMPLETED	0	0	0	0	0
Period 5 STARTED	4	5	4	4	4
Period 5 COMPLETED	4	5	4	3	4
Period 5 NOT COMPLETED	0	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Ranolazine 1500 mg Single oral dose of Ranolazine 1500mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Dofetilide 500 mcg Single oral dose of Dofetilide 500mcg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Quinidine Sulfate 400 mg Single oral dose of Quinidine sulfate 400mg. Each subject received each drug only once in a randomized sequence (10 sequences in total).	Placebo Single oral dose of Placebo (comparison group). Each subject received each drug only once in a randomized sequence (10 sequences in total).
Period 5 Withdrawal by Subject	0	0	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Study Participants n=22 Participants Participants who were randomized to receive either ranolazine, dofetilide, verapamil, quinidine or placebo.
Age, Continuous	26.9 years STANDARD_DEVIATION 5.5 • n=93 Participants
Sex: Female, Male Female	11 Participants n=93 Participants
Sex: Female, Male Male	11 Participants n=93 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants n=93 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	1 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	4 Participants n=93 Participants
Race (NIH/OMB) White	17 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Race/Ethnicity, Customized White / Not Hispanic or Latino	16 participants n=93 Participants
Race/Ethnicity, Customized White / Hispanic or Latino	1 participants n=93 Participants
Race/Ethnicity, Customized African American / Not Hispanic or Latino	4 participants n=93 Participants
Race/Ethnicity, Customized Asian / Not Hispanic or Latino	1 participants n=93 Participants
Region of Enrollment United States	22 participants n=93 Participants
Body mass index	23.1 kg/m^2 STANDARD_DEVIATION 2.6 • n=93 Participants
Systolic blood pressure	107.1 mm Hg STANDARD_DEVIATION 8.5 • n=93 Participants
Diastolic blood pressure	59.7 mm Hg STANDARD_DEVIATION 7.2 • n=93 Participants
Heart rate	56.8 beats per minute (bpm) STANDARD_DEVIATION 6.4 • n=93 Participants
PR interval	162.1 ms STANDARD_DEVIATION 21.6 • n=93 Participants
QRS duration	97.4 ms STANDARD_DEVIATION 6.7 • n=93 Participants
J-Tpeakc (heart rate corrected J-Tpeak interval)	225.6 ms STANDARD_DEVIATION 19.8 • n=93 Participants
Tpeak-Tend interval	73.1 ms STANDARD_DEVIATION 6.4 • n=93 Participants
QTc (Fridericia's heart rate corrected QT interval)	395.9 ms STANDARD_DEVIATION 17.1 • n=93 Participants
Spatial QRS-T angle	34.5 degrees STANDARD_DEVIATION 9.9 • n=93 Participants
Ventricular gradient	111.4 mV*ms STANDARD_DEVIATION 29.5 • n=93 Participants

PRIMARY outcome

Timeframe: 24 hours

Compute maximum mean placebo, and baseline-adjusted change for: PR (ms), QRS (ms), J-Tpeak (ms), Tpeak-Tend (ms) and QTc (ms)

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg n=22 Participants Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg n=21 Participants Single oral dose of Quinidine sulfate 400mg
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Change in QTc	12.6 ms Interval 5.5 to 19.6	79.3 ms Interval 72.2 to 86.3	5.2 ms Interval -1.8 to 12.2	78.1 ms Interval 70.9 to 85.2
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Change in QRS duration	2.7 ms Interval 0.5 to 4.9	1.1 ms Interval -1.1 to 3.3	2.6 ms Interval 0.4 to 4.8	2.1 ms Interval -0.2 to 4.3
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Change in J-Tpeakc	3.3 ms Interval -3.4 to 9.9	39.5 ms Interval 32.8 to 46.2	-2.4 ms Interval -9.0 to 4.3	29.1 ms Interval 22.4 to 35.9
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Change in Tpeak-Tend	8.8 ms Interval 1.9 to 15.8	40.0 ms Interval 33.0 to 46.9	4.8 ms Interval -2.2 to 11.7	49.8 ms Interval 42.8 to 56.8
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Change in PR interval	6.5 ms Interval 1.1 to 11.8	2.3 ms Interval -3.0 to 7.6	32.1 ms Interval 26.7 to 37.4	5.1 ms Interval -0.3 to 10.5

PRIMARY outcome

Timeframe: 24 hours

Compute maximum mean placebo, and baseline-adjusted change for: spatial QRS-T angle (degrees)

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg n=22 Participants Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg n=21 Participants Single oral dose of Quinidine sulfate 400mg
Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle	-2.2 degrees Interval -4.6 to 0.1	-4.9 degrees Interval -7.2 to -2.6	-2.4 degrees Interval -4.4 to 0.3	3.9 degrees Interval 1.6 to 6.3

PRIMARY outcome

Timeframe: 24 hours

Compute maximum mean placebo, and baseline-adjusted change for: ventricular gradient (mV\*ms).

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg n=22 Participants Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg n=21 Participants Single oral dose of Quinidine sulfate 400mg
Placebo, and Baseline-adjusted Changes in Ventricular Gradient	2.5 mV*ms Interval -1.8 to 6.8	4.8 mV*ms Interval 0.5 to 9.1	4.2 mV*ms Interval -0.1 to 8.5	6.0 mV*ms Interval 1.6 to 10.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg n=22 Participants Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg n=21 Participants Single oral dose of Quinidine sulfate 400mg
Change in Relationship (Ratio) Between Heart Rate and QT	0.01 ratio Interval -0.02 to 0.05	0.06 ratio Interval 0.02 to 0.09	0.02 ratio Interval -0.01 to 0.06	0.11 ratio Interval 0.07 to 0.14

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg Single oral dose of Quinidine sulfate 400mg
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) Change in PR	-0.5 ms per ng/ml Interval -3.2 to 2.2	28.7 ms per ng/ml Interval 22.9 to 34.5	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) Change in Tpeak-Tend	34.4 ms per ng/ml Interval 26.9 to 42.0	3.6 ms per ng/ml Interval 1.9 to 5.4	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) Change in QTc	73.6 ms per ng/ml Interval 65.8 to 81.5	3.9 ms per ng/ml Interval -0.7 to 8.5	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) Change in QRS	0.2 ms per ng/ml Interval -1.7 to 2.1	0.3 ms per ng/ml Interval -1.8 to 2.4	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) Change in J-Tpeakc	39.1 ms per ng/ml Interval 31.6 to 46.6	-0.7 ms per ng/ml Interval -4.5 to 3.0	—	—

SECONDARY outcome

Timeframe: 24 hours

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=21 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg Single oral dose of Quinidine sulfate 400mg
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) Change in Tpeak-Tend	10.0 ms per mcg/ml Interval 7.3 to 12.7	51.2 ms per mcg/ml Interval 34.6 to 67.8	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) Change in PR	4.2 ms per mcg/ml Interval 0.8 to 7.6	3.0 ms per mcg/ml Interval -0.8 to 6.8	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) Change in QTc	12.0 ms per mcg/ml Interval 7.3 to 16.7	78.9 ms per mcg/ml Interval 68.2 to 89.7	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) Change in QRS	0.8 ms per mcg/ml Interval -0.9 to 2.6	0.4 ms per mcg/ml Interval -1.8 to 2.6	—	—
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) Change in J-Tpeakc	0.7 ms per mcg/ml Interval -3.3 to 4.7	26.1 ms per mcg/ml Interval 13.5 to 38.7	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg Single oral dose of Quinidine sulfate 400mg
Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms)	-3.9 degrees per ng/ml Interval -5.4 to -2.4	0.4 degrees per ng/ml Interval -1.0 to 1.9	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=21 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg Single oral dose of Quinidine sulfate 400mg
Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms)	-1.0 degrees per mcg/ml Interval -2.62 to 0.67	2.7 degrees per mcg/ml Interval -0.3 to 5.8	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ranolazine 1500mg n=22 Participants Single oral dose of Ranolazine 1500mg	Dofetilide 500mcg n=22 Participants Single oral dose of Dofetilide 500mcg	Verapamil HCl 120 mg Single oral dose of Verapamil HCl 120 mg	Quinidine Sulfate 400mg Single oral dose of Quinidine sulfate 400mg
Change in Ventricular Gradient Using Exposure/Response (Dofetilide and Verapamil Arms)	4.0 mV.ns per ng/ml Interval 0.6 to 7.5	1.2 mV.ns per ng/ml Interval -1.5 to 3.4	—	—

SECONDARY outcome

Timeframe: 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.