A Randomized, Double-Blind, Placebo-Controlled Phase II Study of Hepatocyte Growth Factor in the Treatment of Critical Limb Ischemia

Abstract

NL003 is a plasmid engineered to simultaneously express two isoforms of hepatocyte growth factor. This phase II study was performed to assess the clinical safety and efficacy of intramuscular injection of NL003 in critical limb ischemia (CLI) patients for 6 months. Two hundred patients (Rutherford scale 4-5) were randomly assigned: placebo (n = 50), low-dose NL003 (n = 50), middle-dose NL003 (n = 50), or high-dose NL003 (n = 50). The drug was administered in the affected limb of 197 patients on days 0, 14, and 28. No significant differences in the incidence of adverse events (AEs) or serious AEs were found among the groups. At 6 months, pain severity was significantly reduced in all NL003 groups, but not in the placebo group (p < 0.05). The proportion of patients with complete ulcer healing in the high-dose group was significantly higher than that of the placebo group (p = 0.0095). There were no statistically significant differences in transcutaneous oxygen pressure (TcPO 2 ), ankle-brachial index (ABI), or toe-brachial index (TBI) value among the four groups throughout the study period. These results provide the first effective evidence of significant improvements in total healing of ulcers in treated legs, complete pain relief without analgesics, and safety for NL003 in patients with Rutherford stage 4-5.

Influence of Human Platelet Lysate on Extracellular Matrix Deposition and Cellular Characteristics in Adipose-Derived Stem Cell Sheets

“…HGF production is important for ASC potency by mediating the proangiogenic, prosurvival, and repair promotion activities of ASCs (Cai et al, 2007). A recent clinical trial also demonstrated the effectiveness of topical HGF injection in promoting healing of ischemic ulcers in lower limbs (Gu et al, 2019). Moreover, IL-6 released by ASCs can also stimulate angiogenesis and enhanced recovery after ischemia-reperfusion injury (Pu et al, 2017), suggesting IL-6 up-regulation in HPL-cultured ASC sheets may also contribute to angiogenesis.…”

Comprehensive Assessment of Current Management Strategies for Patients With Diabetes and Chronic Limb-Threatening Ischemia

“…A more recent phase II trial evaluated 197 patients with CLTI (36% with diabetes) who received low-, middle-, or high-dose intramuscular injections of NL003, a plasmid designed to express two isoforms of HGF 723 and HGF 728 simultaneously ( 159 ). Patients were randomized equally into one of three treatment groups or placebo.…”

Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia

“…[ 17 ] HGF angiogenic gene therapy is a case of particular interest since it showed promissory results in phase II and III of clinical trials. [ 18 ] Powell et al. reported that HGF‐gene therapy was able to increase transcutaneous oxygen pressure when compared with placebo‐treated patients of CLTI.…”