Abstract 19419: A Phase IIa Randomized Double-Blind, Placebo Controlled Study to Evaluate Plasmid Stromal Cell-Derived Factor-1 for Treatment of Critical Limb Ischemia - The STOP-CLI Trial

Abstract

Background: Stromal cell-derived factor-1 (SDF-1) promotes tissue repair by increasing cell survival, endogenous stem cell recruitment and vasculogenesis. Preclinical studies demonstrated that non-viral DNA plasmid encoding human SDF-1 (pSDF-1) is safe and increased vessel density in animal models of hindlimb ischemia versus placebo. Additionally, clinical studies have demonstrated safety of pSDF-1 and evidence of neovascularization at the microvascular level. A Phase IIa multi-center double blind randomized placebo-controlled dose escalation study (STOP-CLI) was initiated to evaluate the safety and efficacy of pSDF-1 administered via direct intramuscular injection in patients with critical limb ischemia (CLI). Methods: Forty eight CLI (Rutherford 4 or 5) patients who were poor candidates for surgical revascularization on stable medical therapy with ankle systolic pressure ≤70 mmHg or toe systolic pressure ≤50 mmHg were enrolled into 4 cohorts (n=12 each). Within each cohort, subjects were randomized 3:1 to receive a single set of direct intramuscular injections (8 or 16) to the ischemic limb of escalating doses of 1 mg/ml pSDF-1 (4, 8, 8 or 16mg) or placebo and were followed for 12 months post-dosing. Efficacy endpoints include: quality of life via SF-36, visual analog scale (VAS), Rutherford class, time to first/number of amputations, wound healing, and survival. Results: Enrollment was completed in July 2013. At baseline, patients were, 58.6±13.7 years, 88% male, and had an equal number of Rutherford 4 and 5 (n=24 each). To date, 482 follow up months have been completed with 36 Serious Adverse Events reported, none drug-related. Interim 12 month efficacy results show patients who received 8 injections (8 x 1 mg) totaling 8 mg pSDF-1 improved in rest pain (VAS -3.3±2.5 cm vs. -0.8±2.4 cm; 8 x 1 mg injections vs. placebo, p=0.12) and demonstrate improvements in SF-36 Overall Physical (22.4 ± 27 vs. -2.6 ± 29.7, p=0.22) and Mental (21.0 ± 12.7 vs. 0.26 ± 28.2, p=0.16) Health. Final 12 month data will be available in September 2014. Conclusions: STOP-CLI tests the hypothesis that delivery of pSDF-1 is safe and will improve the clinical status of patients with CLI. The interim results of STOP-CLI demonstrate safety and bioactivity of pSDF-1 for treatment of CLI.