Evaluating the Effect of Omega-3–rich Fish Skin in the Treatment of Chronic, Nonresponsive Diabetic Foot Ulcers: Penultimate Analysis of a Multicenter, Prospective, Randomized Controlled Trial

In 2021, Lullove et al¹ published a planned interim report on the effect of omega-3–rich fish skin graft (FSG; Kerecis Omega3 [Kerecis]) in the management of chronic nonresponsive diabetic foot ulcers (DFUs). The anticipated completion date for patient enrollment and data acquisition was December 2021. As with many other trials, however, the timeline of this trial was significantly disrupted by COVID-19.² Clinical researchers have experienced unprecedented challenges, including quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, and other considerations resulting from site personnel or trial participants becoming infected with COVID-19.²

Therefore, the authors of the current study conducted a previously unscheduled penultimate (or unscheduled interim) analysis to follow up on the results presented by Lullove et al¹ in 2021. The premise remains that the faster the closure of a DFU, the less likely it is that the patient will progress to a minor or major amputation.³ The authors of the current study continue to evaluate whether or not earlier wound closure affects the amputation rate. Several xenografts have been evaluated for use in the closure of DFUs. Intact FSGs have been shown to accelerate acute wound healing in full-thickness wounds compared with porcine graft⁴ and human amniotic membrane.⁵ The FSG is made from the skin of wild-caught Atlantic cod originating from a North Atlantic Icelandic fishery. There is no known risk of disease transmission between cold-water fish and humans, and the graft requires only mild processing, thus preserving its 3-dimensional structure and chemical composition, including omega-3 polyunsaturated fatty acids.^6,7

This prospective, single-blind, multicenter, parallel-group, randomized controlled trial is designed to assess the efficacy of the FSG in the management of resistant DFUs that do not involve tendon or bone compared with the standard of care (SOC) using a collagen alginate dressing. This is a further evaluation of the previously reported prospective randomized controlled trial. It is important to note that this is not a second trial; rather, it is a larger analysis of the ongoing prospective trial.

As previously reported, the patients in study arm 1 received SOC treatment plus application of FSG secured with surgical adhesive strips and covered with a nonadherent dressing.¹ The FSG was reapplied, and the dressing was changed by the site investigator once weekly. Patients in study arm 2 received SOC treatment only, consisting of wound care and a covering collagen alginate dressing (Fibracol Plus Collagen Wound Dressing with Alginate; 3M) followed by a padded dressing comprising 4-in × 4-in gauze, stretch gauze, and self-adherent wrap. The wound was dressed once weekly by the site investigator and 3 times weekly at home by the patients or their caregivers. Both groups received offloading of the DFU with a controlled ankle motion walker boot.

The patients in both study arms had a roll-in period of 14 days in which they received SOC in the form of debridement, offloading, and moist wound care. If the index ulcer reduced in area by 20% or more after 14 days, the patient was not considered resistant to treatment and was excluded from the trial. If the wound area reduced by less than 20%, the patient was randomized and enrolled in the study.

Study outcomes

The primary outcome of the study was the comparison of the proportion of index ulcers healed at 12 weeks. The secondary outcome measures included time to heal (for DFUs that did heal) and wound area reduction by percentage at 12 weeks.

Sample size calculations and statistical analysis

All testing for end points was 2-sided, with alpha set at .05 as the level of significance for demographic comparisons between arms and interim analysis.

The primary analysis consisted of the proportion of index wounds closed at 12 weeks between 2 arms using the χ² test. The end point was also tested using logistic regression, adjusting for age and sex.

The secondary analysis consisted of 2 factors: (1) time to heal within 12 weeks using Kaplan-Meier analysis, and (2) percentage wound area reduction at 12 weeks between the 2 arms using the Mann-Whitney test.

This analysis, which includes a total of 94 patients who had completed the protocol as of the time of this writing, was conducted by pooling the data available from the first 49 patients reported on by Lullove et al¹ with an additional 45 new patients. The study was initiated in August 2019.

At 12 weeks, 63.0% of index ulcers in the acellular FSG arm healed (29 of 46 patients) compared with 31.3% in the control arm (15 of 48 patients) (P =.0036). The mean time to healing was 7 weeks in both groups. The median number of applications of FSG to achieve healing was 6. For wounds that did not heal, the mean wound area reduction at 6 weeks was 69.3% in the FSG arm and 44.2% in the control arm (P =.015). This significant difference continued throughout the 12-week follow-up period, at which time the wound area reduction was 87.1% in the FSG arm and 54.0% in the control arm (P =.0039).

The results presented in this penultimate analysis continue to support the significant difference reported in the initial publication by Lullove et al.¹ In the current analysis of larger cohorts, there is a significant difference in the proportion of healed wounds at week 12, with the FSG group outperforming the SOC group. In addition, there is a significant difference in the percentage of wound area reduction in favor of the FSG group at both the 6-week and 12-week time points.

One limitation of this study is that long-term follow-up is lacking. However, there will be a 1-year follow up, per the protocol, which eventually will be reported separately. Although this is a prospective randomized controlled trial, with appropriate offloading, it is not unreasonable to argue that the SOC in this cohort is becoming an active biologic agent.

These findings, in addition to the cost analysis by Winters et al⁸—which shows that FSG is not only more effective in healing DFUs than SOC but that it also results in lower overall costs—support the use of FSG in the management of DFUs. The findings of this analysis indicate that completion of this study is warranted.