Report Shows Significant Healing and Cost Savings for Diabetic Foot Ulcer Management With Fish Skin Graft Versus Collagen Alginate Therapy Advances

Diabetes is a lifelong, challenging condition that is one of the fastest-growing health crises worldwide. This autoimmune disease weighs on patients, caregivers, and US health care system for physical, mental, and financial reasons. To illustrate, 15% of patients with diabetes will develop a diabetic foot ulcer (DFU) at least once in their life. Although there is no one-size-fits-all treatment, DFUs are often treated with advanced therapies such as cellular- and tissue-based therapy products (CTPs). With biologic products, the composition may derive from an animal (eg, porcine), human (eg, amnion and chorion), or synthetic (pullulan-collagen hydrogel) source. These various materials have shown efficacy in creating an optimal wound healing environment for DFUs, and thus warrant closer analysis.

In a recent study published in the April 2023 issue of Wounds: A Compendium of Clinical Research and Practice, investigators reported the results of a randomized controlled clinical trial in which a fish skin graft (FSG) was evaluated against a collagen alginate therapy (standard of care [SOC]) in treating DFUs to assess the relative benefit of the two modalities. The investigators for the study, “Final Efficacy and Cost Analysis of a Fish Skin Graft vs Standard of Care in the Management of Chronic Diabetic Foot Ulcers: A Prospective, Multicenter, Randomized Controlled Clinical Trial,” were John C. Lantis II, MD; Eric J. Lullove, DPM; Brock Liden, DPM; Patrick McEneaney, DPM; Allen Raphael, DPM; Robert Klein, DPM; Christopher Winters, DPM; and Ruby N. Huynh, PhD. In their research, the primary endpoint was wound closure at 12 weeks; secondary outcomes were effectiveness of FSG, rate of healing, and percent of wound area reduction. They also conducted a cost-utility analysis to illustrate the immediate and long-term financial benefits of utilizing FSG compared with the SOC for DFU management.

All ethical guidance (Declaration of Helsinki, Institutional Review Board, patient consent) was followed throughout the trial. The trial is registered (ID: NCT04133493) with ClinicalTrials.gov and was conducted between June 2019 and January 2022 across 16 centers in the United States.

The trial inclusion points included patients having a DFU that extended through the dermis but not to the tendon, bone, or muscle; had a duration of 4 weeks to 1 year old; and measured 1 cm² to 25 cm². Various perfusion status criteria points were also used, such as dorsal transcutaneous oxygen measurement or skin perfusion greater than 40 mm Hg, ankle-brachial index of 0.7 to 1.3 within 6 months of randomization, or toe-brachial index of 0.6. Offloading was also required for 14 days before the patient could be considered for the study; patients who experienced 20% wound area reduction during those 2 weeks were excluded. Those accepted into the trial received pretreatment for 14 days with sharp debridement, moist wound care, and offloading (walker boot) of the DFU. Patients who successfully completed that portion of the protocol were then enrolled in either the experimental (FSG) or control (collagen alginate therapy) group.

The study treatment phase was of 12 weeks’ duration. In both groups, debridement was performed. For the control group, the collagen alginate therapy was applied and covered with a nonocclusive secondary dressing fixed with nonirritating tape or covered with a semiocclusive dressing. Patients in the control group received once-weekly applications by the site investigator and 2 to 3 weekly at-home reapplications by the patient or caregiver. For the study group, the FSG was applied to the wound bed and secured with surgical adhesive strips, sutures, or staples and covered with a nonadherent dressing overlaid by a foam dressing. Patients in the study group received a total of 12 weekly FSG applications during the treatment phase. It is important to note, as the authors comment in their report, that “the major variable in protocol between the 2 study arms was that in the active arm (FSG) all dressing changes were performed in the outpatient clinic setting, whereas in the control arm at least 2 dressing changes per week were performed by the patients themselves, extended caregivers, or family.”

Two important items to note in the study were the validation of healing and long-term assessment of durability of closure. For validation of healing, healing was defined as complete (100%) reepithelialization without drainage and/or need for additional wound dressings. The site investigator initially assessed healing, and durability of closure was assessed 2 weeks later; a group of independent experts validated the healing statuses of all patients and reviewed all study-related decisions made by the site investigators. For the long-term assessment, all study patients (experimental and control) who completed the 12-week study period received follow-up between 6 months and 1 year after closure. Patients were asked a series of questions relating to their ulcer, any recurrence, or new ulcer developments, and if ulcers were present at any point, the patient was asked about their treatment for that respective ulcer.

Lantis and colleagues recruited 102 patients who were representative of the US diabetes population (ie, more males than females, an average body mass index of 33.4 kg/m², and patients aged 55 to 65 years), with 51 patients randomized to each group and 77 of the total 102 comprising the per protocol cohort (43 experimental, 34 control); 25 patients were excluded from the per protocol analysis owing to deviations from the established protocol. The authors reported all 102 patients in the intent-to-treat analysis, but patients who exited the study were removed from calculating time to healing and wound area reduction. “It is important to note that removal of patients from WAR [wound area reduction] calculations favors the [control group],” they state, “because there were more nonresponsive patients in that cohort.”

From the primary endpoint of proportion of ulcers healed at 12 weeks of treatment, the study group (56.9%) outperformed the control group (31.4%) with 25.5% more wounds healing with the FSG compared to the control treatment. Differences began emerging between the 2 groups at the 4-week mark. The secondary endpoint of time to healing was also reported as being more favorable for the experimental group as far as the intent-to-treat and per-protocol analyses. For both data analyses, mean time to healing was reported at 7.31 weeks ± 3.05 standard deviation in the control and 7.27 weeks ± 2.9 standard deviation in the experimental group. The 12-week percent of wound area reduction achieved in the control group was 64% for 27 patients; the experimental group saw a reduction of 86.3% for 38 patients. With the Mann-Whitney test, wound area reduction was noted to be slightly faster in the experimental vs control group (P =.0283 intent-to-treat; P =.0332 per protocol). Interestingly, at the 6-week study point, the Mann-Whitney test did not show a significant difference between the groups, though the experimental group still outperformed the control (71.6% for 36 patients and 51.6% for 32 patients, respectively) in both the intent-to-treat and per-protocol results.

In terms of cost effectiveness, the experimental group had more cost savings than the control group, including those patients who did not achieve full ulcer closure (per protocol: 14 of 43 experimental; 18 of 34 control). According to the authors, “After the end of the 12-week study period (assuming that the nonhealed ulcers would stay open for the remainder of the year), the authors calculated a total cost of care for the [control group] of $790 118 … versus a total cost of care for the [experimental group] of $496 646.” Further, considering the annualized cost per individual of $13 926 for the experimental and $16 744 for the control, this meant a total difference of $2818 per patient, which favors the experimental group.

The authors do note several limitations worth considering: “A larger cohort of patients, encompassing more study sites, would greatly strengthen the statistical analysis.” They also mention a more diverse population with a greater variety of DFUs and comorbidities, and a longer follow-up period, would provide more inclusive real-world data. Additionally, blinding the patient and assessor to CTPs can be challenging, and the weekly changes of FSG versus multiple weekly changes of the control product may pose a study limitation given the treatment differences between the 2 groups. Although similar studies also have a dropout rate of 24.5% for total enrollment, issues such as protocol violations, loss to follow-up, and number of serious adverse events (ie, infection in the control group) resulted in patients being excluded from this recent study. The authors also comment on the COVID-19 pandemic’s influence by saying, “[COVID-19] hindered many in-person visits and subsequently led to many patients being lost to follow-up.”

In summary, using FSG (experimental group) showed a financial and wound healing benefit over the collagen alginate therapy comparator within the 12 weeks of study. Even for wounds that did not fully heal within the 12 weeks, they still showed a significantly greater mean percent of wound area reduction in the experimental group. Furthermore, the total annualized cost savings in managing DFUs with the experimental treatment (FSG) represent a strength of the study results that should merit consideration. The authors note that future studies should compare the FSG with other CTP source materials.