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Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease - RAVE
Description:
The goal of the Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease (RAVE) trial was to evaluate whether treatment with adenovirus encoding vascular endothelial growth factor (AdVEGF121) increased peak walking time in patients with intermittent claudication (IC) due to infra-inguinal atherosclerosis.
Hypothesis:
Treatment with AdVEGF121 will increase peak walking time on exercise tolerance test (ETT) over placebo in patients with IC due to infra-inguinal atherosclerosis.
Study Design
Study Design:
Patients Screened: 229
Patients Enrolled: 105
Mean Follow Up: One year
Mean Patient Age: Mean 66 years
Patient Populations:
IC due to infra-inguinal atherosclerosis; IC had to be in the same lower limb during two qualifying treadmill tests with PWT between 1-10 minutes; and age 40-80 years
Exclusions:
Renal failure (serum creatinine >2.5 mg/dl); prior or suspected malignancy or retinopathy; and angina, acute coronary syndrome, chronic heart failure, percutaneous coronary intervention, or coronary artery bypass grafting within three months
Primary Endpoints:
Safety and change in PWT at 12 weeks
Secondary Endpoints:
Ankle brachial index (ABI), PWT at 26 and 52 weeks, claudication onset time, and quality of life measures at 12, 26, and 52 weeks
Drug/Procedures Used:
Patients were randomized to low-dose AdVEGF121 (4 x 109 pu, n=32), high-dose AdVEGF121 (4 x 1010 pu, n=40), or placebo (n=30), administered as 20 intramuscular injections to the index leg. Patients underwent treadmill tests at baseline, 12 weeks, 26 weeks, and 52 weeks.
Principal Findings:
There was no difference in the primary end point of change in peak walking time (PWT) at 12 weeks between the placebo (1.80 minutes), low-dose (1.60 minutes), and high-dose arm (1.50 minutes; p=NS). Change in claudication onset time also did not differ between the arms at either 12 weeks (1.8 minutes vs. 1.2 minutes vs. 1.0 minutes; p=NS) or 26 weeks (3.1 minutes vs. 1.2 minutes vs. 1.7 minutes for placebo, low-, and high-dose arms, respectively, p=NS).
Major safety end points were similar in the three arms, with the exception of a dose-dependent increase with AdVEGF121 in peripheral edema, which occurred in 9% of placebo patients, 19% of low-dose, and 31% of high-dose patients.
Interpretation:
Among patients with intermittent claudication due to infra-inguinal atherosclerosis, treatment with AdVEGF121 was not associated with a difference in the primary end point of change in PWT at 12 weeks. RAVE is the first large, randomized, placebo-controlled trial to examine VEGF therapy in patients with peripheral artery disease.
With the exception of peripheral edema, there were no major safety concerns reported with AdVEGF121. However, there was no efficacy benefit associated with angiogenesis therapy in peripheral artery disease.
There are several potential aspects that can differ with gene therapy treatment, including the delivery system or the specific gene. Patients enrolled in the trial were relatively low-risk, and all had patency as part of the enrollment criteria. It is possible that treatment in higher risk patients would result in a benefit not seen in these lower risk patients, potentially due to collateral formation.
References:
Rajagopalan S, et al. Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial Disease. Circulation. 2003;108:r87-r92.
Presented at Late-Breaking Clinical Trials, ACC 2003.
Keywords: Exercise Tolerance, Intermittent Claudication, Walking, Genetic Therapy, Atherosclerosis, Vascular Endothelial Growth Factor A, Injections, Intramuscular, Peripheral Arterial Disease, Edema, Lower Extremity, Exercise Test
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