Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial.
BACKGROUND
Patients with intermittent claudication caused by infrainguinal atherosclerosis have limited pharmacologic options "Therapeutic angiogenesis" is a novel treatment approach that seeks to improve perfusion of ischemic limbs by the induction of collateral vessel formation. This trial is a phase 2 randomized double-blind placebo-controlled proof of concept trial that will use an intramuscular adenoviral gene transfer approach of vascular endothelial growth factor, 121 isoform (Ad(GV)VEGF(121.10)) to patients with severe IC caused by infrainguinal disease.


METHODS
This is a phase 2, double-blind, randomized, placebo-controlled, dose-finding, multicenter study. Patients with severe intermittent claudication caused by infrainguinal atherosclerosis predominantly involving the superficial femoral artery confirmed with imaging studies that meet inclusion criteria will be stratified on the basis of the presence or absence of diabetes mellitus and randomized in a 1:1:1 fashion to low dose (4 x 10(9) particle units), high dose (4 x 10(10) particle units), or placebo arms (35-36 patients per group). Subjects are required to have exercise-limiting IC in the index extremity during 2 qualifying exercise treadmill tests, with peak walking times between 1 and 10 minutes. A single dose of Ad(GV)VEGF(121.10) will be administered as 20 intramuscular injections throughout the area of the lower limb requiring collateralization.


RESULTS
The primary efficacy parameter for the Regional Angiogenesis With Vascular Endothelial Growth Factor (RAVE) trial is the change in peak walking time at 12 weeks compared with baseline. The sample size is expected to provide an 80% power to detect a difference of 1.5 minutes between any of the 2 treatment groups and the placebo group. Secondary efficacy parameters include claudication onset time, hemodynamic effects of therapy assessed with ankle-brachial index, assessment of physical impairment, and health-related quality of life as measured with the Walking Impairment Questionnaire and SF-36 Health Survey. All randomized patients will also be evaluated for safety.
Rajagopalan
Sanjay
S
Department of Internal Medicine, Section of Vascular Medicine, Division of Cardiology, University of Michigan Health System, Ann Arbor 48109-0273, USA. srajagop@umich.edu
Mohler
Emile
E
Lederman
Robert J
RJ
Saucedo
Jorge
J
Mendelsohn
Farrell O
FO
Olin
Jeffrey
J
Blebea
John
J
Goldman
Corey
C
Trachtenberg
Jeffrey D
JD
Pressler
Milton
M
Rasmussen
Henrik
H
Annex
Brian H
BH
Hirsch
Alan T
AT
D000256:Adenoviridae; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D016228:Endothelial Growth Factors / Q000235:genetics / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000627:therapeutic use*; D007383:Intermittent Claudication / Q000235:genetics / Q000628:therapy*; D008222:Lymphokines / Q000235:genetics / Q000627:therapeutic use*; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000235:genetics*; D018579:Patient Selection; D012107:Research Design; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors