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. 2024 Jul 27:75:102750.
doi: 10.1016/j.eclinm.2024.102750. eCollection 2024 Sep.

Once daily Bromelain-based enzymatic debridement of venous leg ulcers versus gel vehicle (placebo) and non-surgical standard of care: a three-arm multicenter, double blinded, randomized controlled study

Yaron Shoham  1 , Robert J Snyder  2 , Yael Katz Levy  2 , Keren David Zarbiv  2 , Ety Klinger  2 , Miri Kramer  2 , Cyaandi R Dove  3 , Ram Avrahami  4 , Alex Reyzelman  5 , Felix Sigal  6 , Gregory Tovmassian  7 , Eyal Shapira  8 , Moti Harats  9 , Francisco Perez-Clavijo  10 , John C Lantis  11 , Shawn M Cazzell  12 , Yadwinder S Dhillon  13 , Cherison A Cuffy  14 , Dana Egozi  15 , Dean Vayser  16 , Adam J Singer  17 , Richard C Galperin  18 , Jason R Hanft  19 , Cindy Martinez  20 , Avshalom Shalom  21 , Laurence Toutous-Trellu  22 , Lior Rosenberg  1
Affiliations

Once daily Bromelain-based enzymatic debridement of venous leg ulcers versus gel vehicle (placebo) and non-surgical standard of care: a three-arm multicenter, double blinded, randomized controlled study

Yaron Shoham et al. EClinicalMedicine. .

Abstract

Background: Debridement is considered the first step in treatment of chronic wounds, however, current enzymatic and autolytic debridement agents are slow or ineffective. Previous studies have shown positive initial results with EscharEx® (EX-02 formulation), a Bromelain-based enzymatic debridement agent in development for chronic wounds. The main objective of this study was to assess its efficacy in debriding venous leg ulcers (VLU), compared to gel vehicle (GV) as a placebo control and to non-surgical standard of care (NSSOC).

Methods: A prospective, randomized, multicenter, placebo-controlled trial in patients with VLU from 20 medical centers and clinics in the United States, Switzerland and Israel was undertaken. Patients were treated with daily topical applications of either EX-02, GV, or NSSOC (in a 3:3:2 ratio), until reaching complete debridement or up to 8 daily treatments (within 2 weeks), and then followed-up for up to 14 weeks. The primary efficacy endpoint was the incidence of complete debridement. This study is registered with ClinicalTrials.gov (NCT03588130) and EudraCT (number 2020-004861-38).

Findings: A total of 196 patients were enrolled, and 119 randomized (between November 12th, 2019, and February 15th, 2022); 46 to the EX-02 arm, 43 to the GV arm, and 30 to the NSSOC arm. Eight patients dropped out of the study (2 in EX-02, 2 in GV, 4 in NSSOC). The incidence of complete debridement within 8 daily treatments was 63% (29/46 patients) in the EX-02 arm as compared to 30.2% (13/43 patients) in the GV arm (p = 0.004) and 13.3% (4/30 patients) in the NSSOC arm (p < 0.001). Sixty-five patients reported wound related adverse events throughout the study; 24 (52.2%), 27 (62.8%) and 14 (46.7%) patients in the EX-02, GV and NSSOC arms (p = NS). No deaths occurred during the study.

Interpretation: EX-02 lead to a significantly higher incidence of complete debridement as compared to GV and NSSOC, without significant safety issues. Additional studies are needed to explore the benefits of EX-02 in VLU and other chronic wound etiologies.

Funding: MediWound Ltd.

Keywords: Chronic wounds; Enzymatic debridement; EscharEx; RCT; VLU; Venous leg ulcer.

PubMed Disclaimer

Conflict of interest statement

YS is a consultant for MediWound Ltd and Vericel Corp. LR, JCL and CD are consultants for MediWound Ltd. RJS, EK, KDZ, MK and YKL are MedWound's Chief Medical Officer, Chief R&D Officer, Director of Clinical Affairs, Medical Director and Director of Clinical Development. AR served as an advisory board member for MediWound Ltd. AR and LTT report receiving study funding. The other authors report no competing interests beyond funding to their institutions for the current project.

Figures

Fig. 1
Fig. 1
Patient flow diagram.
Fig. 2
Fig. 2
Kaplan–Meier estimates for time to complete debridement for EscharEx (EX-02), Gel Vehicle (GV) and Non-Surgical Standard of Care (NSSOC) arms. The medians depicted by the gray lines (and 95% CI) were 9 (5–15) days for EX-02, 59 (30–85) days for GV, and 63 (21–93) days for NSSOC.
Fig. 3
Fig. 3
Serial photographs of a VLU (pre-existing for 32 weeks, wound area 8 cm2) in a 59-year-old woman (BMI = 35) treated with EX-02 during the study: A) Baseline; B) After 1st application of EX-02; C) After 2nd application of EX-02 (complete debridement); D) Wound closure confirmation 53 days after 1st application.
Fig. 4
Fig. 4
Treatment emergent adverse events throughout the study (reported in >4% of patients in any of the study arms).
Supplementary material Figure S1
Supplementary material Figure S1
Study periods diagram.
Supplementary material Figure S2
Supplementary material Figure S2
Flow chart describing the method for EX-02 (EscharEx)/GV (Gel Vehicle) application during the study.
See this image and copyright information in PMC

References

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