Peripheral Arterial Disease
Conditions
Keywords
Lower leg claudication, Poor circulation of the leg muscles, Cramping or discomfort in the lower legs, Lower leg pain, PAD (Peripheral arterial disease)
Brief summary
The goal of this study is to evaluate whether supervised treadmill exercise combined with ranolazine 1000 mg twice daily provides an incremental benefit in absolute walking distance over supervised exercise alone in patients with stable claudication. Investigators also seek to determine if the administration of ranolazine provides a sustained benefit after the completion of a supervised exercise regimen. Lastly, investigators wish to determine whether both exercise and ranolazine improves peak oxygen consumption and anaerobic threshold in patients with stable claudication.
Detailed description
The treatment groups are: A. Group A will be randomized to a 12 week supervised exercise program and ranolazine, (Ranexa) 1000 mg orally, twice daily, by mouth. B. Group B will be randomized to a 12 week supervised exercise program and placebo. After the 12 week supervised exercise program, all participants will undergo a second randomization to ranolazine or placebo for an additional 12 weeks, during which independent walking will be encouraged. Both groups will participate in a two week lead-in period after each randomization of the trial, allowing for the stabilization of their medications and dosing of ranolazine. Medications such as cilostazol, calcium channel blockers and nitrates will be discontinued during the lead-in period, unless their use is for management for high blood pressure. Anti-platelet (blood thinner) medications will be continued throughout the trial.
Interventions
DRUGRanolazine
Ranolazine, 1000 mg, capsule, twice daily, by mouth.
DRUGPlacebo
twice daily
Sponsors
Corewell Health East
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females greater than 40 years of age. * Documented peripheral arterial disease * Stable lower extremity intermittent claudication (Rutherford class 1-3) for 3 months.
Exclusion criteria
* Critical limb ischemia (Rutherford class 4-6). * Percutaneous or surgical lower extremity revascularization within last 12 months. * Myocardial infarction within the last 6 months. * cardiac surgery within the last 6 months. * Unstable angina * Stable chronic angina * New York Heart Association Class II-IV heart failure * Left ventricular ejection fraction less than or equal to 35% * Venous thromboembolism within the last 6 months. * Uncontrolled high blood pressure, defined as systolic blood pressure greater than or equal to 180 mmHg or diastolic blood pressure greater than or equal to 110 mmHg. * Allergy to ranolazine. * corrected QT interval (QTc) greater than or equal to 440 ms in males or 460 ms in females. * Pregnant or nursing females. * Chronic dialysis therapy. * Significant liver impairment (defined as transaminases greater than or equal to 3 times the upper limit of normal) within the last 6 months. * Concomitant use of Cytochrome P450-3A (CYP3A) inhibitors * Concomitant use of CYP3A inducers * QTc prolonging agents * Orthopedic or neurologic disorders that prevent treadmill walking. * Current participation in a structured exercise program.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Increase in Absolute Walking Distance Following Phase 1 | 12 weeks | Change in absolute walking distance in meters from baseline to 12 week follow-up treadmill test, as a percentage from baseline treadmill test |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Increase in Absolute Walking Distance Following Phase 2 | 24 weeks | Change in absolute walking distance in meters from baseline to 24 week follow-up treadmill test, as a percentage from baseline treadmill test |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1-Ranolazine, Phase 2-Ranolazine This group will participate in the Phase 1 -12 week supervised exercise program and will additionally receive ranolazine 1000 mg orally, twice daily, by mouth. In Phase 2, the group will exercise independently and also receive ranolazine 1000 mg orally twice daily by mouth.
Ranolazine: Ranolazine, 1000 mg, capsule, twice daily, by mouth. | 3 |
| Phase 1 -Ranolazine, Phase 2 -Placebo This group will participate in the Phase 1 -12 week supervised exercise program and will additionally receive ranolazine 1000 mg orally, twice daily, by mouth. In Phase 2, the group will exercise independently and will receive a sugar pill in place of the study drug.
Ranolazine: Ranolazine, 1000 mg, capsule, twice daily, by mouth.
Placebo: twice daily | 6 |
| Phase 1 -Placebo, Phase 2 -Ranolazine This group will participate in the Phase 1 -12 week supervised exercise regimen and will receive a sugar pill in place of the study drug. In Phase 2, the group will exercise independently and also receive ranolazine 1000 mg orally twice daily by mouth.
Ranolazine: Ranolazine, 1000 mg, capsule, twice daily, by mouth.
Placebo: twice daily | 6 |
| Phase 1 -Placebo, Phase 2 -Placebo This group will participate in the Phase 1 -12 week supervised exercise regimen and will receive a sugar pill in place of the study drug. In Phase 2, the group will exercise independently and will receive a sugar pill in place of the study drug.
Placebo: twice daily | 8 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1 | Adverse Event | 1 | 0 | 0 | 0 |
| Phase 1 | Physician Decision | 4 | 0 | 1 | 2 |
| Phase 1 | Withdrawal by Subject | 0 | 2 | 4 | 0 |
| Phase 2 | Withdrawal by Subject | 1 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase 1 -Ranolazine, Phase 2 -Placebo | Phase 1 -Placebo, Phase 2 -Ranolazine | Phase 1-Ranolazine, Phase 2-Ranolazine | Phase 1 -Placebo, Phase 2 -Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 5 Participants | 2 Participants | 4 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 8 Participants |
| Age, Continuous | 69.7 years STANDARD_DEVIATION 6.9 | 77.0 years STANDARD_DEVIATION 10.5 | 69.0 years STANDARD_DEVIATION 3.6 | 65.8 years STANDARD_DEVIATION 14.9 | 70.1 years STANDARD_DEVIATION 11.3 |
| Region of Enrollment United States | 6 Participants | 6 Participants | 3 Participants | 8 Participants | 23 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 3 Participants | 8 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 5 | 0 / 4 | 0 / 8 |
| other Total, other adverse events | 0 / 3 | 0 / 5 | 0 / 4 | 0 / 8 |
| serious Total, serious adverse events | 1 / 3 | 0 / 5 | 0 / 4 | 0 / 8 |
Outcome results
Primary
Percentage Increase in Absolute Walking Distance Following Phase 1
Change in absolute walking distance in meters from baseline to 12 week follow-up treadmill test, as a percentage from baseline treadmill test
Time frame: 12 weeks
Population: Missing data for 12 week test in 1 subject in Ranolazine/Ranolazine group, 1 subject in Ranolazine/placebo group, and 3 subjects in placebo/placebo group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1-Ranolazine, Phase 2-Ranolazine | Percentage Increase in Absolute Walking Distance Following Phase 1 | 112 percentage of baseline |
| Phase 1 -Ranolazine, Phase 2 -Placebo | Percentage Increase in Absolute Walking Distance Following Phase 1 | 108 percentage of baseline |
| Phase 1 -Placebo, Phase 2 -Ranolazine | Percentage Increase in Absolute Walking Distance Following Phase 1 | 145 percentage of baseline |
| Phase 1 -Placebo, Phase 2 -Placebo | Percentage Increase in Absolute Walking Distance Following Phase 1 | 155 percentage of baseline |
Secondary
Percentage Increase in Absolute Walking Distance Following Phase 2
Change in absolute walking distance in meters from baseline to 24 week follow-up treadmill test, as a percentage from baseline treadmill test
Time frame: 24 weeks
Population: Missing data from one subject 24 week treadmill test in placebo/placebo group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1-Ranolazine, Phase 2-Ranolazine | Percentage Increase in Absolute Walking Distance Following Phase 2 | 98 percentage of baeline |
| Phase 1 -Ranolazine, Phase 2 -Placebo | Percentage Increase in Absolute Walking Distance Following Phase 2 | 120 percentage of baeline |
| Phase 1 -Placebo, Phase 2 -Ranolazine | Percentage Increase in Absolute Walking Distance Following Phase 2 | 181 percentage of baeline |
| Phase 1 -Placebo, Phase 2 -Placebo | Percentage Increase in Absolute Walking Distance Following Phase 2 | 145 percentage of baeline |