Intact fish skin graft for deep diabetic foot ulcers: results from the KEREFISH randomized controlled trial.

BackgroundDiabetic foot ulcers are chronic, difficult to heal, and potentially life-threatening. Few medical devices have been studied in diabetic ulcers penetrating to bone or tendon.MethodsWe conducted an international, open-label randomized controlled trial, randomly assigning patients with diabetic ulcers penetrating to bone, joint, or tendon 1:1 to intact fish skin graft or standard wound care, with assigned treatment applied through 14 weeks. The primary end point was the proportion of ulcers healed at 16 weeks, defined as reepithelization as identified by the investigator, and confirmed 14 days later. A blinded adjudication committee confirmed healing at both time points. Healing was also assessed at 20 and 24 weeks.ResultsBetween July 2020 and November 2022, 255 patients were randomly assigned to intact fish skin graft (n=129) or standard of care (n=126). Healing was achieved in 44% of patients at 16 weeks with intact fish skin graft compared with 26% for standard of care (P<0.001, unadjusted), with additional healing at 20 weeks (46% vs. 32%) and 24 weeks (55% vs. 38%). Mean (SD) time to healing was 17.3 (0.69) weeks (95% confidence interval [CI], 15.5 to 18.7) for the intact fish skin graft group and 19.4 (0.66) weeks (95% CI, 18.1 to 20.7) for the standard of care group. In a Cox regression, intact fish skin graft was associated with faster time to healing (hazard ratio, 1.59; 95% CI, 1.07 to 2.36). Primary wound infections were the most common adverse event, occurring in 39 (30.2%) of patients in the intact fish skin graft group and 31 (24.6%) of patients in the standard of care group.ConclusionsAmong patients with deep diabetic foot ulcers, treatment with intact fish skin graft was superior to standard of care in proportion of wounds healed at 16 weeks and was associated with faster time to healing. (Funded by European Commission Fast Track to Innovation Horizon 2020, and Kerecis Ltd. ClinicalTrials.gov NCT04257370.)

In the Original Article, “Intact Fish Skin Graft to Treat Deep Diabetic Foot Ulcers”, originally published October 4, 2024 (DOI: https://doi.org/10.1056/EVIDoa2400171), in the Results section of the , where it said, “Primary wound infections were the most common adverse event, occurring in 39 (30.2%) of patients in the intact fish skin graft group and 31 (24.6%) of patients in the standard of care group” should have read “Primary wound infections were the most common adverse event, occurring in 39 (30.2%) of patients in the intact fish skin graft group and 37 (29.3%) of patients in the standard of care group”.

Omega-3-rich fish skin grafts have been shown to accelerate wound healing in full-thickness wounds. The goal of this study was to compare the fish skin graft with standard of care (SOC) using collagen alginate dressing in the management of treatment-resistant diabetic foot ulcers (DFUs), defined as superficial ulcers not involving tendon capsule or bone. Patients with DFUs who were first treated with SOC (offloading, appropriate debridement, and moist wound care) for a 2-week screening period were then randomized to either receiving SOC alone or SOC plus fish skin graft applied weekly for up to 12 weeks. The primary endpoint was the percentage of wounds closed at 12 weeks. Forty-nine patients were included in the final analysis. At 12 weeks, 16 of 24 patients' DFUs (67%) in the fish skin arm were completely closed, compared with 8 of 25 patients' DFUs (32%) in the SOC arm (P value = .0152 [N = 49]; significant at P < .047). At 6 weeks, the percentage area reduction was 41.2% in the SOC arm and 72.8% in the fish skin arm. The application of fish skin graft to previously nonresponsive DFUs resulted in significantly more fully healed wounds at 12 weeks than SOC alone. The study findings support the use of fish skin graft for chronic DFUs that do not heal with comprehensive SOC treatment.

Diabetic foot ulcers (DFUs) are at risk for detrimental complications even with current, standard of care (SOC) treatments. The primary objective of this randomised controlled trial was to compare a unique resorbable glass microfiber matrix (Mirragen; Advanced Wound Matrix [BBGFM]; ETS Wound Care, Rolla, Missouri) compared with a standard of care group (SOC, collagen alginate dressing) at 12 weeks. Both groups received standard diabetic foot care including glucose monitoring, weekly debridements when needed and an offloading device. The primary endpoint was proportion of full‐thickness, non‐infected, non‐ischaemic wounds healed at 12 weeks, with secondary endpoints including percent area reduction (PAR) and changes in Semmes‐Weinstein monofilament testing. The result illustrated in the intent‐to‐treat analysis at 12 weeks showed that 70% (14/20) of the BBGFM‐treated DFUs healed compared with 25% (5/20) treated with SOC alone (adjusted P = .006). Mean PAR at 12 weeks was 79% in the BBGFM group compared with 37% in the SOC group (adjusted P = .027). Mean change in neuropathic score between baseline and up to 12 weeks of treatment was 2.0 in the BBGFM group compared with −0.6 in the SOC group where positive improvement in scores are better (adjusted P = .008). The mean number of BBGFM applications was 6.0. In conclusion, adding BBGFM to SOC significantly improved wound healing with no adverse events related to treatment compared with SOC alone.

Preclinical and phase 1/2 studies with esmolol hydrochloride suggest its potential role in treatment of diabetic foot ulcers (DFUs). To study the efficacy of topical esmolol for healing of uninfected DFUs. A randomized, double-blind, multicenter, phase 3 clinical trial was conducted from December 26, 2018, to August 19, 2020, at 27 referral centers across India. Participants included adults with DFUs. Participants were randomized after a run-in phase (1 week) to receive esmolol, 14%, gel with standard of care (SoC), SoC only, or vehicle with SoC (3:3:1 proportion) for 12 weeks (treatment phase) and followed up subsequently until week 24. The primary outcome was the proportion of wound closure within the 12-week treatment phase in the esmolol with SoC and SoC only groups. Analysis was conducted using an intention-to-treat safety evaluable population, full analysis set or efficacy-evaluable population, and per-protocol population comparing the esmolol plus SoC and SoC only treatment groups. In the study, 176 participants (122 men [69.3%]; mean [SD] age, 56.4 [9.0] years; mean [SD] hemoglobin A1c level, 8.6% [1.6%]) with DFUs classified as University of Texas Diabetic Wound Classification system grade IA and IC (mean [SD] ulcer area, 4.7 [2.9] cm2) were randomized to the 3 groups. A total of 140 participants were analyzed for efficacy. The proportion of participants in the esmolol with SoC group who achieved target ulcer closure within 12 weeks was 41 of 68 (60.3%) compared with 30 of 72 (41.7%) participants in the SoC only group (odds ratio [OR], 2.13; 95% CI, 1.08-4.17; P = .03). A total of 120 participants completed the end of study visit which were analyzed. Target ulcer closure by the end of the study (week 24) was achieved in 44 of 57 (77.2%) participants in the esmolol with SoC group and 35 of 63 (55.6%) participants in the SoC only group (OR, 2.71; 95% CI, 1.22-5.99; P = .01). The median time for ulcer closure was 85 days for the esmolol with SoC group and was not estimable for SoC only group. Significant benefits of Esmolol with SoC were seen in patients with factors that impede the healing of DFU. Treatment-emergent adverse events were noted in 18.8% of the participants, but most (87.3%) of these events were not attributable to the study drug. In this multicenter, randomized, double-blind clinical trial, the addition of esmolol to SoC was shown to significantly improve the healing of DFUs. With these results, topical esmolol may be an appropriate addition to SoC for treating DFUs. ClinicalTrials.gov Identifier: NCT03998436; Clinical Trial Registry, India CRI Number: CTRI/2018/11/016295.

Background:Allogeneic grafts derived from amnion/chorion are known to be efficacious in healing chronic diabetic foot ulcerations (DFUs). The goal of this study was to compare aseptically processed dehydrated human amnion and chorion allograft (dHACA) versus standard of care (SOC) in facilitating wound closure in nonhealing DFUs.Methods:Patients with DFUs treated with SOC (off-loading, appropriate debridement, and moist wound care) after a 2-week screening period were randomized to either SOC or wound-size-specific dHACA (AmnioBand, Musculoskeletal Transplant Foundation, Edison, N.J.) applied weekly for up to 12 weeks plus SOC. Primary endpoint was the percentage of wounds healed at 6 weeks between groups.Results:At 6 weeks, 70% (14/20) of the dHACA-treated DFUs healed compared with 15% (3/20) treated with SOC alone. Furthermore, at 12 weeks, 85% (17/20) of the DFUs in the dHACA group healed compared with 25% (5/20) in the SOC group, with a corresponding mean time to heal of 36 and 70 days, respectively. At 12 weeks, the mean number of grafts used per healed wound for the dHACA group was 3.8 (median 3.0), and mean cost of the tissue to heal a DFU was $1400. The mean wastage at 12 weeks was 40%. One adverse event and 1 serious adverse event occurred in the dHACA group; neither was graft related. Three adverse events and 1 serious adverse event occurred in the SOC group.Conclusion:Aseptically processed dHACA heals diabetic foot wounds significantly faster than SOC at 6 and 12 weeks with minimal graft wastage.

The Effects of Romiplostim or Standard of Care (SOC) on Splenectomy and Treatment Failure of Patients Who Had Immune Thrombocytopenia (ITP) for Less Than or Equal to One Year.

Epoetin Alfa Once Weekly Improves Anemia in HIV/Hepatitis C Virus-Coinfected Patients Treated With Interferon/Ribavirin: A Randomized Controlled Trial

Randomized double-blind study on safety and tolerability of TP-102 phage cocktail in patients with infected and non-infected diabetic foot ulcers.

The choice of the debridement method is very important for the healing of diabetic foot ulcers (DFUs), but the relative effectiveness of different debridement methods in the healing of DFUs remains unclear. This study conducted a network meta-analysis of the relative healing effectiveness of different debridement methods in patients with DFUs. We performed a literature search in PubMed, Embase, and Cochrane Library from database inception up to 30 June 2023 for screening randomized controlled trials on the healing effectiveness of debridement in DFUs. Outcome measures included ulcer healing rate and ulcer area reduction rate. The Cochrane Risk Bias Tool, version 2.0, was used to assess the risk of bias in the included trials. R software was used for performing statistical analysis and GraphPad Prism was used for image plotting. A total of 19 randomized controlled trials were included, and 900 patients with DFUs were assessed in this analysis. The proteolytic fraction from the latex of Vasconcellea cundinamarcensis (P1G10) in enzymatic debridement showed the best ulcer healing rate (SURCA = 0.919) when compared with the standard of care (SOC) group, with a mean difference (MD) and 95% confidence interval (CI) of 1.40 (0.57, 2.36). Kiwifruit extract demonstrated the best effect on the ulcer area reduction rate (SURCA = 0.931), when compared with that in the SOC group, with an MD and 95% CI of 0.47 (0.27, 0.66). Enzymatic debridement was superior to other debridement methods in terms of ulcer healing rate and ulcer area reduction rate in patients with DFUs. However, as the quality of the included trials is low, enzymatic debridement can be used as a candidate debridement method in addition to sharp-based debridement in clinical practice. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023441715.

Background and objectives The persistent nature of diabetic foot ulcers (DFUs) is mainly attributable to compromised wound healing mechanisms, which are aggravated due to poor blood flow, neuropathy, and infection. Growth factors have become essential agents in the treatment of DFUs, serving as primary mediators that enhance wound healing through the stimulation of cell proliferation, migration, and angiogenesis. This prospective open-label, randomised, comparative, multi-centre, investigator-initiated study compared the safety and effectiveness of adjuvant therapy with topical application of autologous growth factor concentrate (AGFC) using the Healrex® therapy kit (Wockhardt, India) versus standard of care (SoC) in DFUs. Methods Fifty-two adult men and women with DFU (Grades I or II as per Maggitt-Wagner classification) were randomised to the Healrex® (n = 26) or SoC (n = 26) group. AGFC concentrate was prepared using the Healrex® therapy kit, and application was from baseline to day 70 (visit 2 to visit 16). Wound assessment and size estimation post debridement were done from screening, i.e., day -03 to -01 day to 70 days (visit 1 to visit 16). The primary outcome was complete response defined as the proportion of patients having healthy granulation tissue covering ≥75% of the ulcer surface at the test of cure (ToC) or visit 17, whereas secondary outcomes were the percentage of patients with complete wound closure at ToC/visit 17, mean percentage reduction of ulcer size at ToC/visit 17 and time to appearance of healthy granulation tissues. Safety was measured in the form of treatment-emergent adverse events (TEAEs) reported, deviations in the desirable range of parameters determined using laboratory tests (haematology, serum biochemistry, urine examination), and electrocardiogram (ECG) done from baseline to ToC. Two patients were lost to follow-up, and one from the Healrex® arm was withdrawn from the study, resulting in a final efficacy analysis on 49 participants (24 in the Healrex® group and 25 in the SoC group) in the per-protocol (PP) dataset. Safety analysis was conducted on the intention-to-treat (ITT) dataset, which included all 52 participants. Results Complete response was observed in all 24 patients (n = 24 (100.0%)) with Healrex® compared to only n = 21 (84.0%) with SoC (p = 0.042). Complete wound closure was observed in 11 patients (n = 24 (45.8%)) treated with Healrex® compared to 13 patients (n = 13 (52.0%)) with SoC. The time required for wound closure was similar (p = 0.669) in the two groups. A greater reduction in the ulcer area was observed with Healrex® as against SoC (p < 0.0001). The time for the emergence of healthy granulation tissue was comparable between the two groups (p = 0.342). Ten patients with Healrex® reported mild adverse events (headache, fever, and cold) and none with SoC. Conclusion AGFC application using the Healrex® therapy kit as an adjuvant to standard wound care provides better outcomes compared to SoC alone in the management of DFUs.

ABSTRACTA novel advanced synthetic bioactive glass matrix was studied in patients with non‐healing diabetic foot ulcers (DFUs). Bioactive glasses can be constructed to be biocompatible, with water‐soluble materials in multiple geometries including fibre scaffolds that mimic the 3D architecture of a fibrin clot. In this trial, chronic, Wagner Grade 1 DFUs were randomised to receive borate‐based bioactive glass Fibre Matrix (BBGFM) plus standard of care (SOC) therapy for 12 weeks or SOC alone. The primary study endpoint was the proportion of subjects that obtained complete wound closure at 12 weeks. Secondary endpoints included time to achieve complete wound closure at 12 weeks. In the modified intent‐to‐treat (mITT) analysis, 48% (32/67) treated with BBGFM plus SOC healed at 12 weeks compared to 24% (16/66) with SOC alone (p = 0.007). In the per protocol (PP) population, 73% (32/44) of subjects treated with BBGFM plus SOC healed versus 42% (16/38) in the SOC group (p = 0.007). Based on the success of this trial, BBGFM demonstrates faster healing of DFUs compared to SOC and should be considered in the treatment armamentarium for Wagner Grade 1 DFUs. Future trials should investigate the use of BBGFM for healing deeper chronic DFUs, other wound aetiologies, or complex surgical wounds.

Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population. Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC). The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04). In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population. This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

Purpose: Inadequate response to wound management is defined as a reduction in the wound area of <40-50% following four weeks of standard of care (SOC) and should be managed with a skin substitute product. We set out to evaluate a novel outcome-based model focusing on the management of hard-to-heal venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs) using SOC treatment or intact fish skin grafts (FSGs) in a regional hospital. Methods: We built an outcome-based model applying surrogate markers and endpoints of wound healing for VLU and DFU to determine the healing trajectory with SOC treatment. We could predict if VLU and DFU would heal by weeks 20 and 24, respectively, after four weeks of evaluating the initial wound area reduction. 51 patients were recruited (26 VLUs and 25 DFUs) and 42 wounds were randomized. 17 wounds deemed unlikely to heal by week 8 received management with FSG as per the Swiss Society for Dermatology and Venereology (SGDV) and the Swiss Association for Woundcare (SAfW) guidelines for the use of skin replacement products, and 26 wounds continued SOC for weeks 5-8. Results/Discussion: 12 wounds managed with FSG beat the modeled SOC healing predictions, with the majority healed >50% sooner and as early as <10% of the time than was predicted. Of these 17, five wounds failed to achieve the required size reduction in Week 4-8 (over 25% improvement in wound area vs. SOC). The FSG were assigned to treatment-resistant VLU and DFUs and were still able to heal these wounds most of the time and even changed the wound's healing trajectory that increased in size in the initial four weeks. Conclusion: This pilot study showed that management with FSG results in faster healing wounds than SOC predicted, while SOC-treated wounds mostly followed model predictions.

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