Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease - A phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication

Background -"Therapeutic angiogenesis" seeks to improve perfusion by the growth of new blood vessels. The Regional Angiogenesis with Vascular Endothelial growth factor ( RAVE) trial is the first major randomized study of adenoviral vascular endothelial growth factor ( VEGF) gene transfer for the treatment of peripheral artery disease ( PAD). Methods and Results - This phase 2, double-blind, placebo-controlled study was designed to test the efficacy and safety of intramuscular delivery of AdVEGF121, a replication-deficient adenovirus encoding the 121-amino-acid isoform of vascular endothelial growth factor, to the lower extremities of subjects with unilateral PAD. In all, 105 subjects with unilateral exercise-limiting intermittent claudication during 2 qualifying treadmill tests, with peak walking time (PWT) between 1 to 10 minutes, were stratified on the basis of diabetic status and randomized to low-dose (4 x 10(9) PU) AdVEGF121, high-dose (4 x 10(10) PU) AdVEGF121, or placebo, administered as 20 intramuscular injections to the index leg in a single session. The primary efficacy end point, change in PWT (DeltaPWT) at 12 weeks, did not differ between the placebo (1.8 +/- 3.2 minutes), low-dose (1.6 +/- 1.9 minutes), and high-dose (1.5 +/- 3.1 minutes) groups. Secondary measures, including DeltaPWT, ankle-brachial index, claudication onset time, and quality-of-life measures (SF-36 and Walking Impairment Questionnaire), were also similar among groups at 12 and 26 weeks. AdVEGF121 administration was associated with increased peripheral edema. Conclusions - A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF(121) as a treatment strategy in patients with unilateral PAD.