Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial.

OBJECTIVES

We have previously reported the results of a dose-finding phase II trial showing that HGF angiogenic gene therapy can increase TcPO2 compared with placebo in patients with critical limb ischemia (CLI). The purpose of this randomized placebo controlled multi-center trial was to further assess the safety and clinical efficacy of a modified HGF gene delivery technique in patients with CLI and no revascularization options.

METHODS

Patients with lower extremity ischemic tissue loss (Rutherford 5 and 6) received three sets of eight intramuscular injections every 2 weeks of HGF plasmid under duplex ultrasound guidance. Injection locations were individualized for each patient based on arteriographically defined vascular anatomy. Primary safety end point was incidence of adverse events (AE) or serious adverse events (SAE). Clinical end points included change from baseline in toe brachial index (TBI), rest pain assessment by a 10 cm visual analogue scale (VAS) as well as wound healing, amputation, and survival at 3 and 6 months.

RESULTS

Randomization ratio was 3:1 HGF (n = 21) vs placebo (n = 6). Mean age was 76 ± 2 years, with 56% male and 59% diabetic. There was no difference in demographics between groups. There was no difference in AEs or SAEs, which consisted mostly of transient injection site discomfort, worsening of CLI, and intercurrent illnesses. Change in TBI significantly improved from baseline at 6 months in the HGF-treated group compared with placebo (0.05 ± 0.05 vs -0.17 ± 0.04; P = .047). Change in VAS from baseline at 6 months was also significantly improved in the HGF-treated group compared with placebo (-1.9 ± 1.3 vs +0.06 ± 0.2; P = .04). Complete ulcer healing at 12 months occurred in 31% of the HGF group and 0% of the placebo (P = .28) There was no difference in major amputation of the treated limb (HGF 29% vs placebo 33%) or mortality at 12 months (HGF 19% vs placebo 17%) between groups.

CONCLUSION

HGF gene therapy using a patient vascular anatomy specific delivery technique appears safe, maintained limb perfusion, and decreased rest pain in patients with CLI compared with placebo. A larger study to assess the efficacy of this therapy on more clinically relevant end points is warranted.