Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. — VialBase Research

Summary

This is a randomized, double-blind, placebo-controlled human trial of LL-37 cream applied topically to diabetic foot ulcers (DFU) with mild infection, conducted in Jakarta from January 2020 to June 2021 and registered as NCT04098562. The rationale was that wound healing in DFU features a prolonged inflammation phase and defective granulation tissue formation, and that LL-37 has antimicrobial properties while also inducing angiogenesis and keratinocyte migration and proliferation. Subjects applied either LL-37 cream or placebo cream twice a week for 4 weeks, with wounds measured on days 7, 14, 21 and 28 and analyzed with ImageJ; LL-37, IL-1α and TNF-α levels in wound fluid were measured by ELISA and aerobic bacterial colonization was counted from cultured isolates. Baseline LL-37 levels in the ulcers were equally low across arms — 1.07 (0.37-4.96) ng/mg protein in the LL-37 group versus 1.11 (0.24-2.09) ng/mg protein in placebo. The increase in granulation index was consistently greater in the LL-37 group at every measured timepoint, reaching statistical significance on days 7, 14, 21 and 28 (p = 0.031, 0.009, 0.006 and 0.037 respectively). The trial’s other endpoints did not follow: IL-1α and TNF-α levels increased in both groups on days 14 and 21 with no significant between-group difference (p > 0.05), and while the decrease in aerobic bacterial colonization was numerically greater in the LL-37 group on days 7, 14 and 21, it was greater in the placebo group on day 28 and none of those comparisons were significant. The authors’ own conclusion is that LL-37 cream enhanced the healing rate of mildly infected DFU but did not decrease IL-1α, TNF-α, or aerobic bacterial colonization.

Key Findings

• Genuine randomized, double-blind, placebo-controlled human trial (NCT04098562), conducted January 2020 to June 2021 in Jakarta
• Intervention was topical LL-37 cream, applied to the ulcer twice a week for 4 weeks — not an injected or systemic peptide
• Baseline wound LL-37 was equally low in both arms: 1.07 (0.37-4.96) ng/mg protein (LL-37) vs. 1.11 (0.24-2.09) ng/mg protein (placebo)
• Granulation index increase was consistently greater with LL-37 cream at days 7, 14, 21 and 28 (p = 0.031, 0.009, 0.006, 0.037)
• Negative on the inflammatory and microbiological endpoints: IL-1α and TNF-α rose in both groups at days 14 and 21 (p > 0.05), and the reduction in aerobic bacterial colonization was not significant — greater with LL-37 on days 7, 14 and 21 but greater with placebo on day 28 (p > 0.05)

Relevance to LL-37

Of the available literature on LL-37, this is the single genuine randomized double-blind human trial, which makes it the most clinically meaningful data point — and also the one most often misrepresented. Two boundaries matter. First, the route was topical cream applied directly to the wound, so it provides no evidence about injected or systemic LL-37, which is how the compound is typically sold in the research-peptide market. Second, the trial was positive on only one endpoint: granulation index improved significantly at all four timepoints, but LL-37 cream did not significantly reduce IL-1α or TNF-α (both actually rose in both arms) and did not significantly reduce aerobic bacterial colonization, despite LL-37’s well-documented in vitro antimicrobial activity. That dissociation — a wound-healing signal without a demonstrated in vivo anti-inflammatory or antibacterial effect — is the honest read, and it directly undercuts marketing that extrapolates LL-37’s laboratory antimicrobial potency into a clinical infection-fighting claim.

Citation

Miranda E, Bramono K, Yunir E, et al. Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. Archives of dermatological research. 2023;315(9):2623-2633. doi:10.1007/s00403-023-02657-8.

See Also

• Parent compound: LL-37