Regional Angiogenesis With Vascular Endothelial Growth Factor
Regional Angiogenesis With Vascular Endothelial Growth Factor
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 (AdGVVEGF121.10) 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
10 particle units), high dose (4
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 GVVEGF 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.
Angiogenesis involves capillary sprouting by proliferation and migration of fully differentiated endothelial cells. Although ischemia from vascular occlusion upregulates expression of angiogenic growth factors, patients with disabling angina or claudication indicate that such natural compensatory processes are not always sufficient. Therapeutic angiogenesis is a strategy by which the growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) delivered as recombinant protein or gene transfer approaches promote neovascularization with the ostensible purpose of improving blood flow to an end organ. Current gene transfer strategies using plasmid and adenoviral vectors produce transient transfection for a duration of 2 to 3 weeks only, which is suitable for the time frame required for angiogenesis. Therapeutic angiogenesis in atherosclerotic peripheral artery disease (PAD) attempts to improve lower-extremity perfusion with protein or gene transfer. Small open-label phase 1 angiogenesis trials (with plasmid and adenoviral strategies) have demonstrated the feasibility and safety of such an approach in patients with symptomatic PAD. Because these trials used no placebo control subjects, they are not inherently suited for meaningful efficacy assessment. These early investigations have also suggested that therapeutic approaches in PAD that use regional administration of angiogenic molecules may be effective, while minimizing the potential adverse effects of systemic exposure. Although data from well-performed large scale trials of recombinant protein in both coronary artery disease and PAD have been reported, the clinical efficacy and safety of a regional angiogenic approach with a gene transfer strategy in a large cohort of patients with PAD remains untested.
The current study will use AdGVVEGF121.10 (Bio-bypass), which is a recombinant adenovirus (Ad) vector based on Ad 5 genome deleted for all of E1a, most of E1b, and E3 sequences, rendering it replication deficient. The deleted sequences have been replaced by the gene encoding for human complementary DNA VEGF isoform 121. Animal studies have shown that AdGVVEGF121.10 can induce angiogenesis in healthy and ischemic organs. In the Regional Angiogenesis with Vascular Endothelial Growth Factor (RAVE) trial, we hypothesized that intramuscular injection of AdGVVEGF121.10 would improve ischemic limb symptoms in patients with symptomatic unilateral claudication caused by infrainguinal PAD.
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 (AdGVVEGF121.10) 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
10 particle units), high dose (4
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 GVVEGF 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.
Angiogenesis involves capillary sprouting by proliferation and migration of fully differentiated endothelial cells. Although ischemia from vascular occlusion upregulates expression of angiogenic growth factors, patients with disabling angina or claudication indicate that such natural compensatory processes are not always sufficient. Therapeutic angiogenesis is a strategy by which the growth factors such as vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) delivered as recombinant protein or gene transfer approaches promote neovascularization with the ostensible purpose of improving blood flow to an end organ. Current gene transfer strategies using plasmid and adenoviral vectors produce transient transfection for a duration of 2 to 3 weeks only, which is suitable for the time frame required for angiogenesis. Therapeutic angiogenesis in atherosclerotic peripheral artery disease (PAD) attempts to improve lower-extremity perfusion with protein or gene transfer. Small open-label phase 1 angiogenesis trials (with plasmid and adenoviral strategies) have demonstrated the feasibility and safety of such an approach in patients with symptomatic PAD. Because these trials used no placebo control subjects, they are not inherently suited for meaningful efficacy assessment. These early investigations have also suggested that therapeutic approaches in PAD that use regional administration of angiogenic molecules may be effective, while minimizing the potential adverse effects of systemic exposure. Although data from well-performed large scale trials of recombinant protein in both coronary artery disease and PAD have been reported, the clinical efficacy and safety of a regional angiogenic approach with a gene transfer strategy in a large cohort of patients with PAD remains untested.
The current study will use AdGVVEGF121.10 (Bio-bypass), which is a recombinant adenovirus (Ad) vector based on Ad 5 genome deleted for all of E1a, most of E1b, and E3 sequences, rendering it replication deficient. The deleted sequences have been replaced by the gene encoding for human complementary DNA VEGF isoform 121. Animal studies have shown that AdGVVEGF121.10 can induce angiogenesis in healthy and ischemic organs. In the Regional Angiogenesis with Vascular Endothelial Growth Factor (RAVE) trial, we hypothesized that intramuscular injection of AdGVVEGF121.10 would improve ischemic limb symptoms in patients with symptomatic unilateral claudication caused by infrainguinal PAD.