Claudication of Vascular Endothelial Growth Factor 121 in Patients With Disabling Intermittent Disease : A Phase II Randomized , Double-Blind , Controlled Study of Adenoviral Delivery Regional Angiogenesis With Vascular Endothelial Growth Factor in Peripheral Arterial

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 (4×109 PU) AdVEGF121, high-dose (4×1010 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 (&Dgr;PWT) 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 &Dgr;PWT, 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 VEGF121 as a treatment strategy in patients with unilateral PAD.

[1]  Photocoagulation therapy for diabetic eye disease. Early Treatment Diabetic Retinopathy Study Research Group. , 1985, JAMA.

[2]  P. Carmeliet,et al.  Conditional switching of VEGF provides new insights into adult neovascularization and pro‐angiogenic therapy , 2002, The EMBO journal.

[3]  I. Kovesdi,et al.  Increased revascularization efficacy after administration of an adenovirus encoding VEGF121 , 2004, Gene Therapy.

[4]  R O Bonow,et al.  Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary. , 2000, Circulation.

[5]  J. Bergelson,et al.  The Murine CAR Homolog Is a Receptor for Coxsackie B Viruses and Adenoviruses , 1998, Journal of Virology.

[6]  J. A. Herd,et al.  Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. , 1998, Journal of vascular surgery.

[7]  J. Isner,et al.  Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. , 1999, The Journal of clinical investigation.

[8]  L. Philipson,et al.  HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Kligfield,et al.  Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. , 1999, Annals of surgery.

[10]  S. Rajagopalan,et al.  Phase I study of direct administration of a replication deficient adenovirus vector containing the vascular endothelial growth factor cDNA (CI-1023) to patients with claudication. , 2002, The American journal of cardiology.

[11]  S. Rajagopalan,et al.  Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial. , 2003, American heart journal.

[12]  R. Lederman,et al.  Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial , 2002, The Lancet.

[13]  M. Post,et al.  Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. , 1999, Circulation.

[14]  Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. , 1991, Ophthalmology.

[15]  Hanns Lochmüller,et al.  Strategies for muscle-specific targeting of adenoviral gene transfer vectors , 2002, Neuromuscular Disorders.

[16]  R. Crystal,et al.  Salvage angiogenesis induced by adenovirus-mediated gene transfer of vascular endothelial growth factor protects against ischemic vascular occlusion. , 1998, Journal of vascular surgery.

[17]  E. Lakatta,et al.  Adenovirus-mediated VEGF(121) gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia. , 2000, Circulation.

[18]  J. Skinner,et al.  Progressive vs single-stage treadmill tests for evaluation of claudication. , 1991, Medicine and science in sports and exercise.

[19]  C. Diehm,et al.  European multicenter study on propionyl-L-carnitine in intermittent claudication. , 1999, Journal of the American College of Cardiology.

[20]  D. Dawson,et al.  Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. , 1998, Circulation.

[21]  Hanns Lochmüller,et al.  The spread of transgene expression at the site of gene construct injection , 2001, Muscle & nerve.

[22]  K. Alitalo,et al.  Gene transfer as a tool to induce therapeutic vascular growth , 2003, Nature Medicine.

[23]  Brian H Annex,et al.  The VIVA Trial Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003 .

[24]  R. Hajjar,et al.  Decreased Efficiency of Adenovirus-Mediated Gene Transfer in Aging Cardiomyocytes , 2003, Circulation.

[25]  S. Rajagopalan,et al.  Adenoviral-mediated gene transfer of vascular endothelial growth factor in critical limb ischemia: safety results from a phase I trial , 2003, Vascular medicine.

[26]  Peter Carmeliet,et al.  VEGF gene therapy: stimulating angiogenesis or angioma-genesis? , 2000, Nature Medicine.