Myocardial Ischemia, Myocardial Perfusion Imaging
Conditions
Keywords
SPECT MPI
Brief summary
This study enrolled participants with documented exercise-induced myocardial ischemia in order to evaluate whether ranolazine, when taken prior to exercise, can improve blood flow to the heart (myocardial perfusion), as assessed by exercise-induced myocardial perfusion defect size (PDS) and total perfusion deficit (TPD), using gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). This was a 2-period crossover study. The last dose of each period must have been taken 3-4 hours prior to conduct of the exercise SPECT MPI. After the research exercise SPECT MPI was performed at the end of Period 1, participants discontinued the treatment they were randomized to for that period and began the other treatment in Period 2.
Interventions
DRUGRanolazine
* One 500 mg tablet in the evening on Day 1 of the period * One 500 mg tablet, twice daily on Days 2-3 of the period * Two 500 mg tablets (1000 mg total), twice daily from Day 4 to the end of the period (Day 15 ± 2 days)
Placebo to match ranolazine administered in the same form and frequency as the active drug.
PROCEDURESPECT MPI
Gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) to confirm the presence of reversible exercise-induced left ventricular perfusion defect size (PDS) performed within 12 weeks prior to baseline or at the baseline visit, and at the end-of-period 1 and end-of-period 2 visits.
BEHAVIORALExercise
Treadmill stress test
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Exercise SPECT MPI study (stress and rest) showing at least 10% reversible myocardial ischemia (as confirmed by the core nuclear laboratory using Corridor4DM imaging software) performed not more than 12 weeks prior to screening, OR * Exercise SPECT MPI study (stress and rest) conducted during screening (after consultation with the Medical Monitor and after informed consent was obtained) showing at least 10% reversible myocardial ischemia (as confirmed by the core nuclear laboratory) * Stable antianginal medical therapy (excluding short-acting nitroglycerin) Key
Exclusion criteria
* Left bundle branch block * Automated implantable defibrillator and/or pacemaker (selected subjects with permanent pacemakers who had an intact sinus mechanism may have been included following consultation with the Medical Monitor) * Intervening coronary revascularization between the time of qualifying exercise SPECT MPI study and randomization * Acute myocardial infarction (MI) within 60 days prior to screening or at any time after the qualifying exercise SPECT MPI study, or MI undergoing staged intervention during a subject's participation in the trial * Unstable angina within 30 days prior to screening, or at any time after the qualifying exercise SPECT MPI study * Coronary artery bypass graft surgery within 60 days prior to screening or at any time after the qualifying exercise SPECT MPI study, or percutaneous coronary intervention within 30 days prior to screening or at any time after the qualifying exercise SPECT MPI study * Anticipated coronary revascularization during the trial period * Cerebrovascular attack or transient ischemic attack within 90 days prior to screening * History of serious arrhythmias * Current atrial fibrillation or atrial flutter * QTc interval \> 500 milliseconds * Diagnosed as having New York Heart Association Class III or IV heart failure * Inability to exercise or exercise limitation due to other comorbidities that may have interfered with ability to perform required exercise SPECT MPI study * Body mass index greater than or equal to 38 kg/m\^2 (may have been up to 40 kg/m\^2 after consultation with the Medical Monitor) * Any absolute contraindications to exercise stress testing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exercise-induced Perfusion Defect Size (PDS) Following Ranolazine and Placebo Treatment | Up to 33 days | PDS is the amount (percent) of the myocardium with decreased blood flow. A lower percentage means more of the myocardium is receiving blood flow. Measurements were obtained by gated single photon emission computed tomography (SPECT) imaging following exercise at the end of the ranolazine and placebo treatment periods. |
| Exercise-induced Total Perfusion Deficit (TPD) Following Ranolazine and Placebo Treatment | Up to 33 days | TPD is a score that measures the overall impact of a region of decreased myocardial blood flow, incorporating both the amount and severity of the decreased flow. TPD is measured on a scale of 0-100, with higher scores being worse and lower scores being better. Measurements were obtained by SPECT imaging following exercise at the end of the ranolazine and placebo treatment periods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | Up to 33 days | Perfusion defect severity was assessed for each participant as the percentage of the 17 myocardium segments with a relative perfusion defect score of 3 or 4 on a 0-4 scale. Segment scores are: 0 = normal perfusion; 1 = mild reduction in counts-not definitely abnormal; 2 = moderate reduction in counts-definitely abnormal; 3 = severe reduction in counts; 4 = absent uptake (lower scores correspond to less severity and higher scores correspond to increased severity). A lower percentage means fewer segments have severely reduced blood flow. Measurements were obtained by SPECT imaging following exercise at baseline and at the end of Periods 1 and 2. |
| Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | Up to 33 days | Exercise-induced reversible PDS was derived as the exercise PDS at baseline and at the end of Periods 1 and 2 minus the resting PDS at baseline. A lower percentage means more of the myocardium is receiving blood flow. Measurements were obtained by SPECT imaging at baseline both at rest and following exercise and following exercise at the end of Periods 1 and 2. |
| Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | Up to 33 days | Exercise-induced reversible TPD was derived as the exercise TPD at baseline and at the end of Periods 1 and 2 minus the resting TPD at baseline. TPD is measured on a scale of 0-100, with higher scores being worse and lower scores being better. Measurements were obtained by SPECT imaging at baseline both at rest and following exercise and following exercise at the end of Periods 1 and 2. |
Countries
Canada, Czechia, Finland, Israel, Italy, Singapore, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled in a total of 27 study sites in the United States, Canada, Czech Republic, and Israel. The first participant was screened on 29 September 2010. The last participant observation was on 27 September 2012.
Pre-assignment details
Number screened: 222; randomized and treated (RAT; Safety Analysis Set): 81 Efficacy Analysis Set: 61 RAT participants with data for both end-of-period (EOP) scans, completed ≥ 7 consecutive days treatment in each period, took the morning dose before each EOP scan, and had baseline perfusion defect size ≥ 5% as measured by QPS imaging software.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Baseline characteristics were analyzed as a single group (Safety Analysis Set). All participants were assigned to complete the same treatment periods in the same manner.
Ranolazine Treatment Period: Participants received ranolazine 1 × 500 mg tablet administered once in the evening on Day 1, 1 × 500 mg tablet twice daily on Days 2-3, and 2 × 500 tablets twice daily from Day 4 to the end of the period (Day 15 ± 2 days), followed by an exercise SPECT MPI study.
Placebo Treatment Period: Participants received placebo to match ranolazine from Day 1 to the end of the period (Day 15 ± 2 days), followed by an exercise SPECT MPI study. | 81 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 2 | 0 |
| Period 1 | Consent Withdrawal | 0 | 1 |
| Period 1 | Significant Dosing Noncompliance | 0 | 1 |
| Period 2 | Adverse Event | 0 | 2 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 66 years STANDARD_DEVIATION 9 |
| Age, Customized 18 to 39 years | 0 participants |
| Age, Customized 40 to 64 years | 29 participants |
| Age, Customized 65 to 74 years | 39 participants |
| Age, Customized ≥ 75 years | 13 participants |
| Body mass index | 29.6 kg/m^2 STANDARD_DEVIATION 3.8 |
| Race/Ethnicity, Customized African-American | 5 participants |
| Race/Ethnicity, Customized Hispanic Or Latino | 9 participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino | 62 participants |
| Race/Ethnicity, Customized Not Reported | 5 participants |
| Race/Ethnicity, Customized Other | 4 participants |
| Race/Ethnicity, Customized Unknown | 5 participants |
| Race/Ethnicity, Customized White | 72 participants |
| Region of Enrollment Canada | 27 participants |
| Region of Enrollment Czech Republic | 2 participants |
| Region of Enrollment Israel | 14 participants |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 75 Participants |
| Weight | 88.6 kg STANDARD_DEVIATION 14.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 25 / 80 | 7 / 79 | 28 / 80 |
| serious Total, serious adverse events | 2 / 80 | 0 / 79 | 2 / 80 |
Outcome results
Primary
Exercise-induced Perfusion Defect Size (PDS) Following Ranolazine and Placebo Treatment
PDS is the amount (percent) of the myocardium with decreased blood flow. A lower percentage means more of the myocardium is receiving blood flow. Measurements were obtained by gated single photon emission computed tomography (SPECT) imaging following exercise at the end of the ranolazine and placebo treatment periods.
Time frame: Up to 33 days
Population: Efficacy Analysis Set: 61 randomized and treated participants with data for both end-of-period (EOP) scans, completed ≥ 7 consecutive days treatment in each period, took the morning dose before each EOP scan, and had baseline perfusion defect size ≥ 5% as measured by QPS imaging software
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Exercise-induced Perfusion Defect Size (PDS) Following Ranolazine and Placebo Treatment | 21.54 percentage of myocardium | Standard Error 1.51 |
| Placebo | Exercise-induced Perfusion Defect Size (PDS) Following Ranolazine and Placebo Treatment | 20.87 percentage of myocardium | Standard Error 1.51 |
p-value: 0.2995% CI: [-0.6, 1.9]Mixed Models Analysis
Primary
Exercise-induced Total Perfusion Deficit (TPD) Following Ranolazine and Placebo Treatment
TPD is a score that measures the overall impact of a region of decreased myocardial blood flow, incorporating both the amount and severity of the decreased flow. TPD is measured on a scale of 0-100, with higher scores being worse and lower scores being better. Measurements were obtained by SPECT imaging following exercise at the end of the ranolazine and placebo treatment periods.
Time frame: Up to 33 days
Population: Efficacy Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Exercise-induced Total Perfusion Deficit (TPD) Following Ranolazine and Placebo Treatment | 17.23 units on a scale | Standard Error 1.26 |
| Placebo | Exercise-induced Total Perfusion Deficit (TPD) Following Ranolazine and Placebo Treatment | 16.57 units on a scale | Standard Error 1.26 |
p-value: 0.2295% CI: [-0.4, 1.7]Mixed Models Analysis
Secondary
Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2
Exercise-induced reversible PDS was derived as the exercise PDS at baseline and at the end of Periods 1 and 2 minus the resting PDS at baseline. A lower percentage means more of the myocardium is receiving blood flow. Measurements were obtained by SPECT imaging at baseline both at rest and following exercise and following exercise at the end of Periods 1 and 2.
Time frame: Up to 33 days
Population: Efficacy Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | Baseline exercise minus baseline resting | 12.5 percentage of myocardium | Standard Error 1.1 |
| Ranolazine | Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | End of Period 1 exercise minus baseline resting | 12.7 percentage of myocardium | Standard Error 1.2 |
| Ranolazine | Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | End of Period 2 exercise minus baseline resting | 12.4 percentage of myocardium | Standard Error 1 |
| Placebo | Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | Baseline exercise minus baseline resting | 13.5 percentage of myocardium | Standard Error 1.3 |
| Placebo | Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | End of Period 1 exercise minus baseline resting | 14.1 percentage of myocardium | Standard Error 1.4 |
| Placebo | Exercise-induced Reversible Perfusion Defect Size (PDS) at Baseline, End of Period 1, and End of Period 2 | End of Period 2 exercise minus baseline resting | 15.2 percentage of myocardium | Standard Error 1.4 |
Secondary
Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2
Exercise-induced reversible TPD was derived as the exercise TPD at baseline and at the end of Periods 1 and 2 minus the resting TPD at baseline. TPD is measured on a scale of 0-100, with higher scores being worse and lower scores being better. Measurements were obtained by SPECT imaging at baseline both at rest and following exercise and following exercise at the end of Periods 1 and 2.
Time frame: Up to 33 days
Population: Efficacy Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | Baseline exercise minus baseline resting | 10.5 units on a scale | Standard Error 0.9 |
| Ranolazine | Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | End of Period 1 exercise minus baseline resting | 10.5 units on a scale | Standard Error 0.9 |
| Ranolazine | Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | End of Period 2 exercise minus baseline resting | 10.1 units on a scale | Standard Error 0.8 |
| Placebo | Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | Baseline exercise minus baseline resting | 10.5 units on a scale | Standard Error 1 |
| Placebo | Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | End of Period 1 exercise minus baseline resting | 10.7 units on a scale | Standard Error 1 |
| Placebo | Exercise-induced Reversible Total Perfusion Deficit (TPD) at Baseline, End of Period 1, and End of Period 2 | End of Period 2 exercise minus baseline resting | 11.6 units on a scale | Standard Error 1.1 |
Secondary
Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2
Perfusion defect severity was assessed for each participant as the percentage of the 17 myocardium segments with a relative perfusion defect score of 3 or 4 on a 0-4 scale. Segment scores are: 0 = normal perfusion; 1 = mild reduction in counts-not definitely abnormal; 2 = moderate reduction in counts-definitely abnormal; 3 = severe reduction in counts; 4 = absent uptake (lower scores correspond to less severity and higher scores correspond to increased severity). A lower percentage means fewer segments have severely reduced blood flow. Measurements were obtained by SPECT imaging following exercise at baseline and at the end of Periods 1 and 2.
Time frame: Up to 33 days
Population: Efficacy Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranolazine | Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | Baseline | 11.4 percentage of segments | Standard Error 2 |
| Ranolazine | Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | End of Period 1 | 11.6 percentage of segments | Standard Error 1.9 |
| Ranolazine | Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | End of Period 2 | 10.4 percentage of segments | Standard Error 1.9 |
| Placebo | Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | Baseline | 8.5 percentage of segments | Standard Error 2 |
| Placebo | Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | End of Period 1 | 10.2 percentage of segments | Standard Error 2.1 |
| Placebo | Perfusion Defect Severity at Baseline, End of Period 1, and End of Period 2 | End of Period 2 | 9.5 percentage of segments | Standard Error 2 |