pUDK-HGF Gene Therapy to Relieve CLI Rest Pain and Ulcers: A Phase II, Double-Blind, Randomized Placebo-Controlled Trial

Background: Critical limb ischemia (CLI) has become a global problem. Less invasive therapy is needed. Hepatocyte growth factor (HGF) is one of the most potent angiogenic protein and the plasmid encoding human hepatocyte growth factor (HGF) is considered to be the most promising gene therapy for CLI.MethodsWe conducted a randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of intramuscular injection of plasmid pUDK-HGF expressing HGF. Pain-at-rest patients and ulcer patients were enrolled as two cohorts and randomized to receive intramuscular injection of placebo or pUDK-HGF. Efficacy assessments included pain scale, ulcer size, TBI, ABI, and TcPO 2 over 180 day. Safety analysis was based on the occurrence of adverse events. ResultsIn the pain-at-rest cohort, the proportion of patients with complete pain relief after receiving pUDK-HGF injections was significantly higher than that of the placebo group on day 180 (p = 0.0148). More responders with >50% pain reduction were also observed in the pUDK-HGF groups than in the placebo groups (p = 0.0168). In the ulcer cohort of patients, pUDK-HGF treatment tended to be superior to the placebo in the percentage of patients with both complete ulcer healing and >50% ulcer healing. No significant differences in the incidence of adverse events or serious adverse events were observed among the groups. ConclusionIntramuscular injection of pUDK-HGF is safe and can significantly reduce pain-at-rest and possibly promotes ulcer healing in CLI patients. The mid dose pUDK-HGF (6 mg) was the most efficacious, and is an appropriate dose for phase III clinical trial. Clinical Trial RegistrationChina Food and Drug Administration number: 2013L00637, Data: 2013/03/15. China Clinical Trial Registry URL: http://www. chinadrugtrials.org.cn. Unique Identifier: 20130378)