Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial

Abstract

Many patients with venous leg ulcers do not reach complete healing with compression treatment alone, which is current standard care. This clinical trial HEAL LL-37 was a phase IIb double-blind, randomized, placebo-controlled study, with the aim to evaluate the efficacy and safety of a new drug LL-37 for topical administration, in combination with compression therapy, in 148 patients suffering from hard-to-heal venous leg ulcers. The study had three arms, consisting of two groups treated with LL-37 at concentrations of 0.5 or 1.6 mg/mL, and a placebo cohort. Patients had a mean age of 67.6 years, a median ulcer duration of 20.3 months, and a mean wound size at the time of randomization of 11.6 cm² . Efficacy analysis performed on the full study population did not identify any significant improvement in healing in patients treated with LL-37 as compared with the placebo. In contrast, a post hoc analysis revealed statistically significant improvement with LL-37 treatment in several interrelated healing parameters in the subgroup of patients with large target wounds (a wound area of at least 10 cm² at randomization), which is a known negative prognostic factor for healing. The study drug was well tolerated and safe in both dose strengths. In summary, this clinical trial did not detect any significant differences in healing of venous lower leg ulcers in the entire study cohort comparing patients treated with LL-37 versus placebo. A subgroup analysis provided an interesting observation that LL-37 could offer a treatment benefit in patients with large ulcers, exigently warranting a further study adequately powered to statistically assess the treatment outcome in this patient group.

Keywords: LL-37; phase II clinical trial; venous leg ulcers; wound healing.

FIGURE 1

Schematic presentation of the study design. The trial comprised a 3‐week, open‐label, run‐in phase on placebo, followed by a 13‐week randomized double‐blind treatment phase with twice weekly applications of LL‐37 (0.5 or 1.6 mg/mL) or placebo, and a 4‐months follow‐up period

FIGURE 2

Flow of participants through the trial

FIGURE 3

Safety analysis. (A,B) Percentage of patients in safety analysis set with any sign of inflammation on the target ulcer (A) or skin irritation adjacent to the target ulcer (B). Visits 1–6 were performed during run‐in period and visits 7–32 were performed during the treatment period. (C) Number of study patients in safety analysis set reporting any AEs as well as selected categories of AEs. (C) Total number of AEs by severity