Drug-induced Surface ECG Changes
Conditions
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.
Interventions
Sponsors
Spaulding Clinical Research LLC
Food and Drug Administration (FDA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 35 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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 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 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 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 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. |
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive either ranolazine, dofetilide, verapamil, quinidine or placebo. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 5 | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 26.9 years STANDARD_DEVIATION 5.5 |
| Body mass index | 23.1 kg/m^2 STANDARD_DEVIATION 2.6 |
| Diastolic blood pressure | 59.7 mm Hg STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Heart rate | 56.8 beats per minute (bpm) STANDARD_DEVIATION 6.4 |
| J-Tpeakc (heart rate corrected J-Tpeak interval) | 225.6 ms STANDARD_DEVIATION 19.8 |
| PR interval | 162.1 ms STANDARD_DEVIATION 21.6 |
| QRS duration | 97.4 ms STANDARD_DEVIATION 6.7 |
| QTc (Fridericia's heart rate corrected QT interval) | 395.9 ms STANDARD_DEVIATION 17.1 |
| Race/Ethnicity, Customized African American / Not Hispanic or Latino | 4 participants |
| Race/Ethnicity, Customized Asian / Not Hispanic or Latino | 1 participants |
| Race/Ethnicity, Customized White / Hispanic or Latino | 1 participants |
| Race/Ethnicity, Customized White / Not Hispanic or Latino | 16 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 11 Participants |
| Spatial QRS-T angle | 34.5 degrees STANDARD_DEVIATION 9.9 |
| Systolic blood pressure | 107.1 mm Hg STANDARD_DEVIATION 8.5 |
| Tpeak-Tend interval | 73.1 ms STANDARD_DEVIATION 6.4 |
| Ventricular gradient | 111.4 mV*ms STANDARD_DEVIATION 29.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 22 | 6 / 22 | 6 / 22 | 12 / 21 | 3 / 22 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 22 | 0 / 21 | 0 / 22 |
Outcome results
Primary
Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc
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
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in Tpeak-Tend | 8.8 ms |
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QRS duration | 2.7 ms |
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QTc | 12.6 ms |
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in J-Tpeakc | 3.3 ms |
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in PR interval | 6.5 ms |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in J-Tpeakc | 39.5 ms |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in Tpeak-Tend | 40.0 ms |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QTc | 79.3 ms |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QRS duration | 1.1 ms |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in PR interval | 2.3 ms |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in J-Tpeakc | -2.4 ms |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in PR interval | 32.1 ms |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QRS duration | 2.6 ms |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in Tpeak-Tend | 4.8 ms |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QTc | 5.2 ms |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in Tpeak-Tend | 49.8 ms |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QRS duration | 2.1 ms |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in PR interval | 5.1 ms |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in J-Tpeakc | 29.1 ms |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc | Change in QTc | 78.1 ms |
p-value: <0.05Mixed Models Analysis
Primary
Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle
Compute maximum mean placebo, and baseline-adjusted change for: spatial QRS-T angle (degrees)
Time frame: 24 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle | -2.2 degrees |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle | -4.9 degrees |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle | -2.4 degrees |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle | 3.9 degrees |
p-value: <0.05Mixed Models Analysis
Primary
Placebo, and Baseline-adjusted Changes in Ventricular Gradient
Compute maximum mean placebo, and baseline-adjusted change for: ventricular gradient (mV\*ms).
Time frame: 24 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ranolazine 1500mg | Placebo, and Baseline-adjusted Changes in Ventricular Gradient | 2.5 mV*ms |
| Dofetilide 500mcg | Placebo, and Baseline-adjusted Changes in Ventricular Gradient | 4.8 mV*ms |
| Verapamil HCl 120 mg | Placebo, and Baseline-adjusted Changes in Ventricular Gradient | 4.2 mV*ms |
| Quinidine Sulfate 400mg | Placebo, and Baseline-adjusted Changes in Ventricular Gradient | 6.0 mV*ms |
p-value: <0.05Mixed Models Analysis
Secondary
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms)
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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) | Change in Tpeak-Tend | 3.6 ms per ng/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) | Change in PR | 28.7 ms per ng/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) | Change in QTc | 3.9 ms per ng/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) | Change in QRS | 0.3 ms per ng/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms) | Change in J-Tpeakc | -0.7 ms per ng/ml |
Secondary
Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms)
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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Ranolazine 1500mg | 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 |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) | Change in Tpeak-Tend | 51.2 ms per mcg/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) | Change in PR | 3.0 ms per mcg/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) | Change in QTc | 78.9 ms per mcg/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) | Change in QRS | 0.4 ms per mcg/ml |
| Dofetilide 500mcg | Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms) | Change in J-Tpeakc | 26.1 ms per mcg/ml |
Secondary
Change in Relationship (Ratio) Between Heart Rate and QT
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ranolazine 1500mg | Change in Relationship (Ratio) Between Heart Rate and QT | 0.01 ratio |
| Dofetilide 500mcg | Change in Relationship (Ratio) Between Heart Rate and QT | 0.06 ratio |
| Verapamil HCl 120 mg | Change in Relationship (Ratio) Between Heart Rate and QT | 0.02 ratio |
| Quinidine Sulfate 400mg | Change in Relationship (Ratio) Between Heart Rate and QT | 0.11 ratio |
Secondary
Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms)
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ranolazine 1500mg | Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms) | -3.9 degrees per ng/ml |
| Dofetilide 500mcg | Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms) | 0.4 degrees per ng/ml |
Secondary
Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms)
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ranolazine 1500mg | Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms) | -1.0 degrees per mcg/ml |
| Dofetilide 500mcg | Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms) | 2.7 degrees per mcg/ml |
Secondary
Change in Ventricular Gradient Using Exposure/Response (Dofetilide and Verapamil Arms)
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ranolazine 1500mg | Change in Ventricular Gradient Using Exposure/Response (Dofetilide and Verapamil Arms) | 4.0 mV.ns per ng/ml |
| Dofetilide 500mcg | Change in Ventricular Gradient Using Exposure/Response (Dofetilide and Verapamil Arms) | 1.2 mV.ns per ng/ml |
Secondary
Change in Ventricular Gradient Using Exposure/Response (Ranolazine and Quinidine Arms)
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ranolazine 1500mg | Change in Ventricular Gradient Using Exposure/Response (Ranolazine and Quinidine Arms) | -0.7 mV.ns per mcg/ml |
| Dofetilide 500mcg | Change in Ventricular Gradient Using Exposure/Response (Ranolazine and Quinidine Arms) | 1.6 mV.ns per mcg/ml |