SDF-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD): Randomized, double-blind, placebo-controlled clinical trial.

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 - a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe-brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients' mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204.