Key papers ✓ 1✗ 3~ 2? 2

• ✗ Negative human RCTWound Repair Regen · 2021

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

  Humans148 peopleRandomizedPlacebo-controlledDouble-blind

  Phase IIb double-blind, randomized, placebo-controlled multicentre trial (HEAL LL-37) of topical LL-37 (0.5 or 1.6 mg/mL) plus compression

  Phase IIb trial in 148 patients with hard-to-heal venous leg ulcers: topical LL-37 plus compression did not improve healing vs placebo overall; a post hoc subgroup with large wounds did better. Well tolerated.

  Key resultNo significant improvement in healing with LL-37 vs placebo in the full population; a post hoc analysis showed significant improvement in several healing parameters in patients with wounds of at least 10 cm2.

  Study details

  Studied

  Patients with hard-to-heal venous leg ulcers (mean age 67.6 years, median ulcer duration 20.3 months)

  Compared with

  Placebo

  Main outcome

  Ulcer healing

  Sample

  148 patients in three arms

  Authors' conclusion

  The trial did not detect significant healing differences overall; a subgroup with large ulcers suggested possible benefit and warrants a further adequately powered study. LL-37 was well tolerated.

  Limitations

  Primary result negative; subgroup finding was post hoc.

  DOI 10.1111/wrr.12977PubMed 34687253Free full text
• ~ Mixed human RCTWound Repair Regen · 2014

  Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial.

  Humans34 peopleRandomizedPlacebo-controlledDouble-blind3-week run-in, 4-week treatment, 4-week follow-up

  First-in-man randomized, double-blind, placebo-controlled dose-response trial after an open-label placebo run-in

  First-in-human trial in 34 venous leg ulcer patients: the two lower LL-37 doses healed faster than placebo (significant for the lowest dose), but the highest dose showed no difference; no safety concerns.

  Key resultHealing rate constants for 0.5 and 1.6 mg/mL LL-37 were about six- and threefold higher than placebo (p = 0.003 and p = 0.088); mean ulcer area fell 68% (0.5 mg/mL) and 50% (1.6 mg/mL).

  Study details

  Studied

  Patients with hard-to-heal venous leg ulcers

  Compared with

  Placebo

  Main outcome

  Safety and healing rate

  Sample

  34 participants with venous leg ulcers

  Authors' conclusion

  Topical LL-37 was safe and well tolerated, with a marked effect on healing predictors at the two lower doses, warranting further investigation. No difference from placebo at 3.2 mg/mL.

  Limitations

  Small first-in-man trial; the 1.6 mg/mL rate difference was not significant (p = 0.088).

  DOI 10.1111/wrr.12211PubMed 25041740
• ~ Mixed human RCTArch Dermatol Res · 2023

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

  Humanssize not reportedRandomizedPlacebo-controlledDouble-blind4 weeks (twice weekly application)

  Randomized, double-blind, placebo-controlled trial of LL-37 cream

  Double-blind trial in mildly infected diabetic foot ulcers: LL-37 cream improved granulation (healing) index vs placebo at days 7-28 but did not reduce inflammatory cytokines or bacterial colonization.

  Key resultGranulation index increased more with LL-37 on days 7, 14, 21 and 28 (p = 0.031, 0.009, 0.006 and 0.037).

  Study details

  Studied

  Patients with diabetic foot ulcer with mild infection (Jakarta)

  Compared with

  Placebo cream

  Main outcome

  Wound healing (granulation index), IL-1α, TNF-α, aerobic bacterial colonization

  Authors' conclusion

  LL-37 cream enhanced the healing rate of diabetic foot ulcers with mild infection but did not reduce IL-1α, TNF-α or aerobic bacterial colonization.

  Limitations

  Sample size not given in the abstract; cytokine and bacterial differences were not significant.

  DOI 10.1007/s00403-023-02657-8PubMed 37480520Free full text
  Fig. 2 Fig. 1
• ✗ Negative case reportJ Cutan Pathol · 2018

  Dermatologic toxicity from novel therapy using antimicrobial peptide LL-37 in melanoma: A detailed examination of the clinicopathologic features.

  HumansSingle case reportNo control group8 weekly injections; lesions resolved within 2 months of stopping

  Case report

  A melanoma patient in a phase 1 trial of LL-37 injected into tumors developed multiple wart-like and keratoacanthoma-like skin lesions about 45 days in; they resolved within 2 months of stopping.

  Study details

  Studied

  63-year-old woman with stage IIIC melanoma receiving intra-tumoral LL-37 injections

  Main outcome

  Dermatologic toxicity

  Authors' conclusion

  LL-37 injections were followed by verrucous, keratoacanthoma-like skin lesions that resolved after stopping therapy; the authors highlight adverse dermatological effects of LL-37 therapy.

  Limitations

  Single case.

  DOI 10.1111/cup.13262PubMed 29665030
• ✓ Positive animalMil Med Res · 2020

  Chitosan hydrogel encapsulated with LL-37 peptide promotes deep tissue injury healing in a mouse model.

  Humans + animalsMouse groups of n = 6Randomized21 days

  In vitro tests and randomized mouse study of LL-37 in chitosan hydrogel

  In a mouse pressure-ulcer model, LL-37 in a chitosan hydrogel shrank wounds faster and increased new blood vessel formation compared with controls.

  Key resultUlcer area was significantly lower with LL-37/CS hydrogel than all other groups on days 11, 13 and 15 (84.24% ± 0.25%, 56.22% ± 3.91%, 48.12% ± 0.28%).

  Study details

  Studied

  Cultured fibroblasts and macrophages, plus male C57BL/6 mice with magnet-induced pressure ulcers

  Compared with

  Naked LL-37, hydrogel alone, no intervention

  Main outcome

  Pressure ulcer area, histology, angiogenesis markers

  Authors' conclusion

  Chitosan hydrogel encapsulating LL-37 is biocompatible and could promote healing of pressure ulcers, in mice.

  Limitations

  Mouse model; the unit for the reported percentages is not defined in the abstract.

  DOI 10.1186/s40779-020-00249-5PubMed 32321591Free full text
  Fig. 3
• ✗ Negative in vitroCancers (Basel) · 2023

  LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages.

  Humans + animals

  Immunohistochemistry plus in vivo and in vitro experiments

  LL-37 levels in human melanoma rose with tumor stage, and LL-37 stimulated melanoma cells and macrophages to make pro-invasion, pro-angiogenic factors in cell and mouse experiments, a possible safety concern.

  Study details

  Studied

  Melanoma tissue from patients (immunohistochemistry), B16F10 mouse melanoma, A375 human melanoma cells and M2 macrophages

  Main outcome

  LL-37 expression vs T stage; pro-angiogenic and invasion factor expression

  Authors' conclusion

  LL-37 expression correlated positively with melanoma T stage and stimulated tumor cells and macrophages to induce pro-angiogenic factors, suggesting LL-37 might promote melanoma invasion. A safety signal for LL-37, not a treatment study.

  Limitations

  Mostly preclinical; correlation in tissue.

  DOI 10.3390/cancers15061678PubMed 36980564Free full text
  Figure 6
• ? Inconclusive reviewFront Immunol · 2013

  The Human Cathelicidin Antimicrobial Peptide LL-37 as a Potential Treatment for Polymicrobial Infected Wounds.

  No new data

  Narrative review

  A 2013 review argues LL-37 has anti-biofilm, antibacterial and wound-healing properties that may suit topical treatment of polymicrobial infected wounds, but presents it as a potential, not proven, therapy.

  Study details

  Studied

  Infected diabetic and other chronic wounds (reviewed literature)

  Main outcome

  Mechanisms and therapeutic potential of LL-37 in wounds

  Authors' conclusion

  LL-37 or its derivatives could be a platform for new strategies against biofilm-mediated wound infections.

  Limitations

  Review with no new data; both deficient and excessive LL-37 levels are discussed as harmful.

  DOI 10.3389/fimmu.2013.00143PubMed 23840194Free full text
  Figure 6
• ? Inconclusive reviewWorld J Microbiol Biotechnol · 2023

  Antibiofilm properties of cathelicidin LL-37: an in-depth review.

  No new data

  Narrative review of antibiofilm effects of LL-37

  A 2023 review finds LL-37 prevents biofilm formation by many bacterial species in laboratory studies, but notes many open questions about in vivo efficacy and safety.

  Study details

  Studied

  Biofilm-forming bacteria in laboratory studies (reviewed literature)

  Main outcome

  Antibiofilm mechanisms

  Authors' conclusion

  LL-37 may open opportunities to prevent and treat biofilm-mediated infections, but efficacy and safety in vivo remain to be answered.

  Limitations

  Review with no new data; mostly in vitro evidence.

  DOI 10.1007/s11274-023-03545-zPubMed 36781570

Reported side effects

• reportedWart-like / keratoacanthoma-like skin lesions after injection into tumors [ref]

Topical LL-37 on leg ulcers was well tolerated in trials of up to 148 patients; there are no human safety data for injected LL-37 outside a melanoma trial.

5 registered human trials (0 active)

✓ positive · ✗ negative · ~ mixed · ? inconclusive, judged on each paper's own main outcome. Grades: A strong human evidence → D little or none. Papers and verdicts are drawn from PubMed, Europe PMC and Russian journals (CyberLeninka); not medical advice.