Chronic Stable Angina
Conditions
Brief summary
The primary objective is to assess whether the increased angina threshold on ranolazine and subsequent higher training intensity will result in improved exercise tolerance and oxygen consumption; and greater than that observed with exercise training on placebo. The study team anticipates the chronic exercise improvements with ranolazine will be incrementally higher than the acute effects provided by ranolazine alone and demonstrated in previous trials. Key secondary objectives include the acute ranolazine and chronic exercise plus ranolazine effects on total daily energy expenditure (TDEE) and angina-related quality of life.
Interventions
DRUGRanolazine
Comparison of Ranolazine 1000mg twice per day versus placebo twice per day
BEHAVIORALAerobic Exercise
Aerobic exercise 3 times per week, 45 minutes per session at an intensity of 10-20 beats per minute below the angina threshold (heart rate at which angina symptoms began on the stress test)
DRUGPlacebo
Comparison of placebo twice per day vs. Ranolazine 1000mg twice per day
Sponsors
Gilead Sciences
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Documented CAD diagnosis * Stable angina ≥ 3 months
Exclusion criteria
* Class III or IV heart failure * Myocardial Infarction or coronary revascularization procedure within 2 months * QT interval \> 500ms or prescribed medication known to prolong the QTc interval * Contraindicated Medications * Metformin dose \> 1700mg/day * Class Ia, Ic and III anti-arrhythmics * CYP3A inhibitors * Simvastatin \>20mg/day * Severe renal disease (\< 30ml/min creatinine clearance) * Currently on dialysis * Lack of transportation to the exercise and testing facilities * Implanted pacemaker that is not rate responsive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak Oxygen Consumption (VO2 Max) | Baseline, Week 2 and Week 14 | This test involves exercising on a treadmill or bike to maximal exertion, during which the subject's breathing and oxygen consumption are measured. Under a set study protocol, treadmill or bike workload will increase every minute until the participant either chooses to end the test or the study personnel choose to end the test for safety purposes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Treatment Satisfaction as Measured by the Seattle Angina Questionnaire | Baseline, Week 2 and Week 14 | The Treatment Satisfaction scale is one of five scales of the Seattle Angina Questionnaire. The possible range of scores is 0 to 100, with higher scores indicating better quality of life. |
| Change in Total Daily Energy Expenditure | Week 1, Week 4 and Week 14 | Total daily physical activity is measured via Actigraph GT3X accelerometers. Accelerometers will be worn for 7 days pre-drug, post-drug/pre-exercise (week 4) and again in the final month of the exercise intervention (week 13) |
Countries
United States
Participant flow
Recruitment details
Thirty-eight subjects were recruited for this study. One dropped out before randomization.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Plus Exercise Placebo pill twice per day plus aerobic exercise three times per week, 45 minutes per session at an intensity of 10-20 beats per minute below the angina threshold.
Aerobic Exercise: Aerobic exercise 3 times per week, 45 minutes per session at an intensity of 10-20 beats per minute below the angina threshold (heart rate at which angina symptoms began on the stress test)
Placebo: Comparison of placebo twice per day vs. Ranolazine 1000mg twice per day | 19 |
| Ranolazine Plus Exercise Ranolazine 1000mg pill twice per day plus aerobic exercise three times per week, 45 minutes per session at an intensity of 10-20 beats per minute below the angina threshold.
Ranolazine: Comparison of Ranolazine 1000mg twice per day versus placebo twice per day
Aerobic Exercise: Aerobic exercise 3 times per week, 45 minutes per session at an intensity of 10-20 beats per minute below the angina threshold (heart rate at which angina symptoms began on the stress test) | 18 |
| Total | 37 |
Baseline characteristics
| Characteristic | Placebo Plus Exercise | Total | Ranolazine Plus Exercise |
|---|---|---|---|
| Age, Continuous | 69.2 years STANDARD_DEVIATION 8.3 | 68.4 years STANDARD_DEVIATION 9.6 | 67.4 years STANDARD_DEVIATION 11.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 26 Participants | 13 Participants |
| Region of Enrollment United States | 19 Participants | 37 Participants | 18 Participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Male | 13 Participants | 24 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 0 / 18 | 1 / 19 |
| serious Total, serious adverse events | 0 / 18 | 0 / 19 |
Outcome results
Primary
Change in Peak Oxygen Consumption (VO2 Max)
This test involves exercising on a treadmill or bike to maximal exertion, during which the subject's breathing and oxygen consumption are measured. Under a set study protocol, treadmill or bike workload will increase every minute until the participant either chooses to end the test or the study personnel choose to end the test for safety purposes.
Time frame: Baseline, Week 2 and Week 14
Population: Subjects who completed the study were included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Plus Exercise | Change in Peak Oxygen Consumption (VO2 Max) | Change at 2 weeks | 0.03 ml/kg/min | Standard Deviation 1.2 |
| Placebo Plus Exercise | Change in Peak Oxygen Consumption (VO2 Max) | Change at 14 weeks | 0.9 ml/kg/min | Standard Deviation 1.5 |
| Ranolazine Plus Exercise | Change in Peak Oxygen Consumption (VO2 Max) | Change at 2 weeks | 0.38 ml/kg/min | Standard Deviation 1.9 |
| Ranolazine Plus Exercise | Change in Peak Oxygen Consumption (VO2 Max) | Change at 14 weeks | 2.1 ml/kg/min | Standard Deviation 3.4 |
Comparison: 2-0 weeksp-value: >0.05t-test, 2 sided
Comparison: 0-14 weeksp-value: 0.03t-test, 2 sided
Comparison: 2-0 weeksp-value: >0.05t-test, 2 sided
Comparison: 14-0 weeksp-value: 0.005t-test, 2 sided
Secondary
Change in Total Daily Energy Expenditure
Total daily physical activity is measured via Actigraph GT3X accelerometers. Accelerometers will be worn for 7 days pre-drug, post-drug/pre-exercise (week 4) and again in the final month of the exercise intervention (week 13)
Time frame: Week 1, Week 4 and Week 14
Population: Subjects who completed the study were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Plus Exercise | Change in Total Daily Energy Expenditure | 2-0 weeks | 2.0 kj/hr | Standard Deviation 39.3 |
| Placebo Plus Exercise | Change in Total Daily Energy Expenditure | 14-0 weeks | 22.2 kj/hr | Standard Deviation 54.2 |
| Ranolazine Plus Exercise | Change in Total Daily Energy Expenditure | 2-0 weeks | -7.6 kj/hr | Standard Deviation 29.3 |
| Ranolazine Plus Exercise | Change in Total Daily Energy Expenditure | 14-0 weeks | 24.3 kj/hr | Standard Deviation 29.9 |
Comparison: 2-0 weeksp-value: >0.05t-test, 2 sided
Comparison: 0-14 weeksp-value: 0.13t-test, 2 sided
Comparison: 2-0 weeksp-value: >0.05t-test, 2 sided
Comparison: 14-0 weeksp-value: 0.013t-test, 2 sided
Secondary
Change in Treatment Satisfaction as Measured by the Seattle Angina Questionnaire
The Treatment Satisfaction scale is one of five scales of the Seattle Angina Questionnaire. The possible range of scores is 0 to 100, with higher scores indicating better quality of life.
Time frame: Baseline, Week 2 and Week 14
Population: Subjects who completed the study were included in the analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Plus Exercise | Change in Treatment Satisfaction as Measured by the Seattle Angina Questionnaire | 2-0 Weeks | 0.8 units on a scale | Standard Deviation 9.1 |
| Placebo Plus Exercise | Change in Treatment Satisfaction as Measured by the Seattle Angina Questionnaire | 14-0 weeks | 3.1 units on a scale | Standard Deviation 13.3 |
| Ranolazine Plus Exercise | Change in Treatment Satisfaction as Measured by the Seattle Angina Questionnaire | 2-0 Weeks | 5.3 units on a scale | Standard Deviation 8 |
| Ranolazine Plus Exercise | Change in Treatment Satisfaction as Measured by the Seattle Angina Questionnaire | 14-0 weeks | -1.0 units on a scale | Standard Deviation 13 |
Comparison: 2-0 weeksp-value: >0.05t-test, 2 sided
Comparison: 14-0 weeksp-value: >0.05t-test, 2 sided
Comparison: 2-0 weeksp-value: 0.03t-test, 2 sided
Comparison: 14-0 weeksp-value: >0.05t-test, 2 sided