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

Diabetes has become the fastest-rising health crisis in the last few decades in the United States and globally. It is projected that it will affect an average of 11.8% of the adult population (1 in 8.5 adults) worldwide by 2030.¹ The future economic consequences of the disease remain opaque. It is also the seventh leading cause of death worldwide, with 5.2 million diabetes-related deaths reported globally in 2015. In addition, it has a significant global economic burden (US $1.32 trillion in 2015).² One of the more challenging aspects of managing diabetes is DFU,³ which reportedly occurs in 15% of patients with diabetes at least once in their lifetime.⁴ These ulcers are primarily neurogenic and associated with poor blood sugar control, and they are significantly correlated with peripheral neuropathy.⁵ A smaller subset of these ulcers also occurs in feet with malperfusion. Most major lower extremity amputations are preceded by a DFU, often with infection.⁶ In 2008, 4.9% of Medicare fee-for-service beneficiaries with DFU underwent lower extremity amputation, with 17.1% of these occurring in patients with a previous amputation.⁷ The mortality rate associated with lower extremity amputation was 20.6% in that year.

Chronic, nonresponsive DFUs are notoriously difficult to treat, often requiring a strict and costly multitherapy approach comprising appropriate debridement, negative pressure wound therapy, hyperbaric oxygen therapy, and offloading.^8-21 There is no well-recognized SOC or best clinical practice for diabetic foot wounds. Currently, the best clinical practice for plantar diabetic foot wounds is weekly debridement and total contact casting. Unfortunately, only 2% of patients with DFU receive such treatment. One clinically accepted treatment for DFUs uses CAT with a padded outer dressing (both of which are changed daily) to help maintain a physiologically moist microenvironment at the wound surface, thereby encouraging granulation, epithelialization, and wound healing.  When this therapy was first described in 1998, it was reported to achieve a 48% healing rate within 8 weeks.²²

Advanced treatments for DFUs use biologic products that include extracellular matrices derived from animal and human sources²³ or that are manufactured synthetically.²⁴ However, some of these products contain cells from unmatched donors, or are harshly processed to remove pathogen or cellular fragments, which adversely affects the structure and characteristics of the graft.^25,26 Studies comparing the use of tissue-based products such as human amnion and chorion allograft,²⁷ porcine urinary bladder matrix,²⁸ porcine purified reconstituted bilayer matrix,²⁹ fetal bovine collagen,³⁰ and pullulan-collagen hydrogel³¹ with various control treatments in the management of DFUs have reported varying results. One common problem in many of these trials is determining a reasonable and clinically relevant comparator.

Intact FSG is derived from North Atlantic cod skin that has undergone a proprietary process to gently preserve the original form and chemical composition of the fish skin.³² The resulting FSG closely resembles human skin structurally and chemically.^33-35 The naturally porous microstructure of FSG provides the basis for efficient ingrowth of dermal and epidermal cells, as well as capillaries.³⁶ In addition, the rich content of both eicosapentaenoic acid and docosahexaenoic acid omega-3 fatty acids in FSG offers added anti-inflammatory properties.^25,37,38 These unique characteristics make FSG an ideal candidate for use in the management of various wounds.³⁹

Positive results from previous nonrandomized studies investigating the efficacy of FSG in the management of full-thickness DFUs^40,41 led to the development of the current prospective, multicenter, parallel-group, single-masked, randomized controlled trial. The purpose of this study is to assess the efficacy of FSG (Kerecis Omega3 MariGen; Kerecis) compared with the clinically accepted practice of applying CAT (Fibracol Plus Collagen Wound Dressing with Alginate; 3M) in the management of chronic nonresponsive DFUs. The main purpose is to assess the relative benefit of FSG with the primary end point being the absolute percentage of patients who achieved wound closure at 12 weeks. Secondary outcomes included the effect of FSG, healing rate, and PAR. Published interim study results indicated a statistically significant primary end point in favor of FSG.^42,43

The current article (the third of 3 planned articles) represents the completion of the study, which continued to steadily enroll patients during the COVID-19 pandemic. The complete enrollment was analyzed with appropriate statistical analysis of the trial’s combined data set. Furthermore, a cost-utility analysis was conducted to highlight the immediate and long-term economic advantages of using FSG compared with CAT (the current SOC) in the management of DFUs.

Study design and compliance

Detailed protocols for a prospective, multicenter, parallel-group, randomized controlled trial with independent single-masked assessment of wound healing were followed.⁴² The methodology was approved by WIRB-Copernicus Group (WCG IRB; formerly known as Western Institutional Review Board) (Protocol #20190130) and was conducted in compliance with FDA and International Organization for Standardization standards. It also conformed to the ethical guidelines of the Declaration of Helsinki and was registered with ClinicalTrials.gov (ID: NCT04133493). The trial took place between June 2019 and January 2022 and involved 16 centers in the United States.

Recruitment and randomization phases

Inclusion criteria included DFU extending at least through the dermis but not into tendon, muscle, or bone (ie, University of Texas grade 1A/1C), index ulcer duration of 4 weeks to less than 1 year, and ulcer size of 1 cm² to 25 cm². Inclusion criteria based on perfusion status were as follows: dorsal transcutaneous oxygen measurement or skin perfusion pressure greater than 40 mm Hg, ankle-brachial index between 0.7 and 1.3 within 6 months of randomization, or toe-brachial index of 0.6. Offloading of the index ulcer for a minimum of 14 days prior to randomization was required for inclusion. If the wound area was reduced by greater than 20% after 14 days of offloading, the patient was excluded. In addition, patients with index ulcer on the posterior heel were excluded, as were patients on active chemotherapy or systemic steroids, and those with a hemoglobin A_1c level greater than 12%, on renal replacement therapy, or with a serum creatinine level greater than 3.0 mg/dL.

After informed consent was obtained, prospective patients were screened for inclusion in the trial.⁴² Recruited participants underwent a 14-day pretreatment period consisting of sharp debridement, moist wound care (ie, application of CAT, soft roll, and a compressive dressing to the ulcer), and offloading the DFU with a walking boot (A-W0800BLK Equalizer Air Walker; Össur Americas). Use of systemic antibiotics was not permitted during pretreatment. Patients who successfully completed the pretreatment period were randomly assigned to receive either FSG (study arm 1 [treatment]) or continued CAT application (study arm 2 [control]). The authors of the current study acknowledge that total contact casting or a nonremovable boot is the first choice in DFU treatment. Therefore, as with most other prospective trials treating DFUs,  the authors chose a walking boot as the primary means of offloading. The authors propose that in future, all such trials mandate total contact casting prior to initiating tissue-based products.

Treatment phase

The treatment phase lasted a total of 12 weeks. In both study arms, debridement was performed to prepare the wound beds. Using aseptic technique, dressings were then removed from their sterile pouches and cut to a shape resembling that of the wound. In the control arm, CAT was applied premoistened to dry wounds and applied dry to exudating wounds, and every effort was made to ensure the CAT was well apposed to the wound bed and edges. The dressing was then covered with a nonocclusive secondary dressing and fixed to the skin with a nonirritating tape or was covered with a semiocclusive dressing. Patients in the control arm underwent CAT application once weekly by the site investigator and CAT reapplication at home 2 or 3 times weekly by the patients themselves or their caregiver.

The FSG product was rehydrated using standard saline solution before being applied directly to the wound. The product was secured with surgical adhesive strips, sutures, or staples, then covered with a nonadherent dressing (Adaptic Non-Adhering Dressing; 3M) overlaid with a foam
dressing (HydraFoam; DermaRite). Patients received a maximum of 12 weekly applications of FSG during the treatment phase.

All index wounds, regardless of study arm, received an outer padded dressing comprising 4-inch × 4-inch gauze pads, stretch gauze, and self-adherent wrap to achieve optimal bolstering. Ulcers that had not reduced in area by 50% or more at week 7 were considered treatment failures, and those patients were allowed to exit the study and seek other outside treatment. These patients were included in the ITT analysis. Since the patients could not be masked, the therapy patients who were not receiving active therapy were not encouraged, but were allowed, to leave the study protocol if they felt they could receive better therapy outside the protocol; specifically, if they wanted to be treated with another cellular or tissue-based therapy.

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. The use of systemic antibiotics during the treatment phase was permitted without removing the patient from the protocol unless the local infection appeared to be a SAE. Of note, there was no significant use of antibiotics, nor any difference in the use of antibiotics between the 2 groups.

Validation of healing

Ulcer healing was defined as complete (100%) reepithelialization of the wound, without drainage and/or the need for dressing. Healing was initially assessed by the site investigator, with durability of closure confirmed within 2 weeks after ulcer closure was first observed. A panel of independent experts (a vascular surgeon, a podiatrist, and an internal medicine specialist) validated patients’ healing status and reviewed all study-related decisions made by the site investigators.

Long-term assessment of durability of closure

All patients who had previously been enrolled and who completed the 12-week treatment period in either study arm were followed up. This follow-up occurred at a minimum of 6 months post closure and a maximum of 1 year post closure. This allowed for the examination of the rates of ulcer recurrence within one year of treatment. Patients were asked to answer questions about their condition, such as if previous ulcers had reoccurred or if new ulcers had developed, and were requested to provide information about the treatment and orthotic usage for the ulcers.

Study outcomes

The primary outcome of the study was the comparison of the proportion of index ulcers healed at 12 weeks. Wounds were classified as either healed or not healed. Secondary outcomes included time to healing (for DFUs that healed) and mean PAR at 12 weeks (mean PAR at 6 weeks was also noted). The tertiary outcome was ulcer recurrence during the 6- to 12–month follow-up period.

Statistical analysis

The study was powered so that at a sample size of 50 patients in each study arm, there would be 86% power to detect a difference of 0.30 between a treatment group proportion of 0.70 and a control group proportion of 0.40 with a significance of α = .048 (2-sided Z test with pooled variance). The power calculation was based on a proposed closure rate of 70% in the FSG arm and 40% in the CAT arm. Therefore, the ITT data represent the achievement of statistical significance even though neither study arm reached the original closure rate assumptions; after 12 weeks of treatment (ITT), healing was achieved in 56.9% (29 of 51) of ulcers in the FSG arm compared with 31.4% (16 of 51) of ulcers in the CAT arm (P =.0163).

For demographic comparisons, alpha was set at .05 as the level of significance in relation to study arm results, and for primary and secondary end points testing alpha was set at .047. For all end point calculations, a 2-sided Z test with pooled variance was used. Primary analysis was evaluated in terms of ITT and PP and focused on the proportion of index wounds closed at 12 weeks (arm 1 vs arm 2) using χ² (Fisher exact test), adjusted with logistic regression. Secondary analysis included the end points of time to healing within 12 weeks (arm 1 vs arm 2) (Kaplan-Meier log-rank test) and PAR at 12 weeks (arm 1 vs arm 2) (Mann-Whitney test). PAR at 6 weeks (arm 1 vs arm 2) was also noted. All analyses were conducted using R software (version 4.2.1; The R Project for Statistical Computing).

A total of 102 patients were recruited and considered as ITT candidates, with 51 randomized to each study arm: arm 1 (FSG) and arm 2 (CAT). Of those 102 patients, 77 comprised the PP cohort (n = 34 CAT, n = 43 FSG). Twenty-five ITT patients were excluded from the PP analysis due to protocol deviations, such as not adhering to the treatment schedule, loss to follow-up, surgery, amputation, adverse events, and withdrawal because of unsatisfactory treatment response. In addition, the protocol required that patients exit the trial if they were not on track to achieve healing (ie, <50% WAR at 6 weeks). Although all 102 patients were included in the ITT analysis (Figures 1, 2), the patients who exited the study were excluded from time to healing and WAR calculations. It is important to note that removal of patients from WAR calculations favors the CAT arm because there were more nonresponsive patients in that cohort.

Study population

Patients in both study arms were representative of the US diabetes population, that is, there were more males than females, patient age was 55 to 65 years,⁴⁴ and average body mass index was 33.4.⁴⁵ There was a distinct lack of racial and ethnic diversity compared with national demographics, which likely is reflective of site selection. No significant differences were noted between the study arms regarding demographics or wound characteristics (Tables 1, 2). The patient population and wound characteristics were well matched in terms of clinical factors such as comorbidities and ulcer location. Two patients with an ankle-brachial index less than 0.7 were included. These cases were identified somewhat late and handled as protocol deviations.

Wound characteristics

There was no statistical difference between the 2 groups in terms of wound characteristics. The mean and median wound size was 3.9 cm² and 2.4 cm², respectively, in the FSG group compared with 4.9 cm² and 3.0 cm², respectively, in the CAT group(P =.249). Most of the wounds were plantar in both cohorts, with a relatively high number of toe wounds. Because of the heterogeneous locations of the various ulcers, no statistical difference in healing rates by location could be delineated.

Wound closure and area reduction rates

Results from the primary end point for ITT analysis of proportion of healed wounds after 12 weeks of treatment revealed that 56.9% of index ulcers (29 of 51) healed in the FSG arm compared with 31.4% (16 of 51) in the CAT arm (P =.0163); that is, 25.5% (1.8 times) more wounds healed with FSG compared with CAT (Figure 1). The difference between the FSG group and the CAT group began at 4 weeks. Furthermore, on average, more new healed wounds per week were recorded in the FSG arm than in the CAT arm (Figure 2).

Secondary end points including time to healing and mean PAR at 12 weeks and 6 weeks were analyzed for both ITT and PP data. In ITT data, the mean time to healing was 7.31 weeks ± 3.05 weeks standard deviation in the CAT arm (n = 16) and 7.17 weeks ± 2.9 weeks in the FSG arm (n = 29). PP analysis revealed the same results for mean time to healing. The mean PAR at 12 weeks was 64% for 27 patients in the CAT group and 86.3% for 38 patients in the FSG group. The Mann-Whitney test was used to test for differences in ITT and PP analysis, with a significance level of alpha less than .05, and WAR was found to occur significantly faster in the FSG arm than the CAT arm (P =.0283 ITT, P =.0332 PP).

The mean PAR at 6 weeks was 51.6% for 32 patients in the CAT group and 71.6% for 36 patients in the FSG group, in both the ITT and PP analyses. However, Mann-Whitney testing showed no significant difference between the 2 groups at 6 weeks. Additional ITT and PP analyses were conducted; for example, the average number of applications received was 5.9 in the FSG group and 17.1 in the CAT group (assuming 3 applications per week for patients in the CAT group). The median number of applications was 6 for the FSG group and 18 for the CAT group. Photographs demonstrating the course of healing in representative patients who received FSG are shown in Figure 3.

Adverse events

Following the protocol, any unfavorable or unintended medical occurrence that was not related to a preexisting condition and that required surgical or medical intervention was reported as an SAE. Each SAE was reviewed by the primary investigator at the site to decide if it was product- or study-related. A total of 8 SAEs were recorded, with 3 in the FSG arm and 5 in the CAT arm. Two of the 3 SAEs in the FSG group, secondary surgery at the anterior talofibular ligament and amputation of the second toe, were classified as nonrelated to the index ulcers. The third SAE, the need for incision and drainage surgery owing to the presence of exudate in the wound at week 4 and increased size of the ulcer, was classified as potentially related to the product or procedure. In the control arm, all 5 SAEs comprised infection of the index ulcers, with 1 requiring amputation. Overall, regarding product- or study-related SAEs, there was 1 infection in the FSG arm and 5 infections (1 necessitating amputation) in the control arm.
 

Ulcer recurrence

A total of 45 patients achieved healing of their index ulcer during the trial. Of these, 3 patients could not be reached, resulting in 42 patients available for follow-up 6 to 12 months after initial healing (15 CAT, 27 FSG). One ulcer recurrence was reported in the CAT arm (6.7%), and 3 ulcer recurrences were recorded in the FSG arm (11.1%). Of the 4 total recurrences, 3 patients reportedly did not have appropriate offloading footwear. Previous studies have demonstrated that continued use of offloading footwear can effectively prevent ulcer recurrence^46-48; thus, ulcer recurrence in both the CAT and FSG arms of this study were related to patient nonadherence to offloading.

Cost-effectiveness analysis

The cost to achieve wound healing with either FSG or CAT can be simply calculated. Therefore, the cost of not treating a wound with either of these therapies is the true cost differential. The overall cost of therapy requires some minor modeling, and the structure and discussion of the cost model is described here.

The cost of CAT and FSG was calculated using direct real price data from this study. CAT was purchased in boxes containing 12 dressings measuring 2 inches × 2 inches in size at a cost of $46.49 per box from Mercy Supply Collaborative (formerly Mercy Surgical Dressing Group). The cost per individual dressing was $3.87. In this study, however, patients in the CAT arm received dressing changes 3 times per week, with a resulting total cost of product per week of $11.61. In addition, the cost of a 4-inch × 4-inch gauze pad, stretch gauze, and self-adherent wrap was $3.38.

The cost of FSG was calculated using list prices from the manufacturer (current as of September 2022). The proprietary FSG was purchased in boxes of 10 applications each. Multiple sizes are available, and price varies by size. The recruited wounds were sorted by size, with smaller wounds receiving the smaller product sizes and larger wounds receiving the larger product sizes. For purposes of simplification, the resulting total cost of product in the FSG cohort was averaged, for a weekly cost of $509.

The average Medicare reimbursement for in-office application (CPT code 15275) of FSG, including secondary dressing, was $164.38. For the CAT group, the average reimbursement for an at-home nursing care visit was $177.53 and the average Medicare reimbursement for an outpatient visit (CPT code 99212) was $57.45. The costs for each treatment arm are listed in Table 3. The cost to achieve closure in the FSG arm was calculated as follows: (median number of applications × cost of application) + cost of offloading boot = $4089.49. The cost to achieve closure in the CAT arm was as follows: (median number of home applications × cost of application [home nursing cost + CAT cost]) + (median number of office visits × cost of application [CPT 99212 + product cost]) + cost of offloading = $1729.09.

Consequently, the cost of not healing an ulcer becomes the question. Since real data are missing in the ITT analysis, with neither the eventual outcomes nor all therapies employed known for that group, cost was calculated based on PP data because all cost data points were available. Therefore, only the PP 14 of 43 FSG patients that did not heal and 18 of 34 CAT patients that did not heal were considered as part of the calculation. It is more appropriate to only include cost for patients who strictly adhered to the protocol and completed the treatment period.

The cost related to patients who did not heal was $6783.01 in the FSG arm (average, 10 weeks) and $2009.07 in the CAT arm (average, 7 weeks). This does not include data for possible increased infection rate in the CAT arm, nor the possibility of future infections in patients with open wounds regardless of treatment.

The TCOCFSG was calculated as follows: (median cost of closed FSG per patient [$4089.49] × 29 patients) + (median cost of open FSG per patient [$6783.01] × 14 patients) = $213 557.35.

The TCOCCAT was calculated as follows: (median cost of closed CAT per patient [$1729.09] × 16 patients) + (median cost of open CAT per patient [$2009.07] × 18 patients) = $63 828.70.

Therefore,  the total cost per healed ulcer in the FSG group was calculated as follows: TCOCFSG ($213 557.35) / 29 patients = $7364.05.

The total cost per healed ulcer in the CAT group was calculated as follows: TCOCCAT ($63 828.70) / 16 patients = $3989.30. However, if analyzed based on the ITT data, in which the CAT group had significantly more wounds that did not heal, the cost per healed ulcer was $6123.90 in the CAT arm and $9235.20 in the FSG arm.

The true cost benefit of this improved closure rate only becomes apparent when the 1-year cost of treating a patient with a nonhealing ulcer is examined. Using Medicare claims data from 2015 through 2019, Tettelbach et al⁴⁹ calculated the cost of treating an open DFU. Accrued costs based on the average number of treatments received, number of visits to the emergency department, inpatient hospital visits, readmissions, and outpatient visits were analyzed. In 2021 US dollars, the annual TCOC was $29347 (weekly cost, $564.37).

Applying the above analysis to the current data from this trial, 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 TCOCCAT of $790 118 (35 patients × 40 weeks × $564.37) versus a TCOCFSG of $496 646 (22 patients × 40 weeks × $564.37). The cost per therapy per patient for the first year is calculated by adding these numbers to the respective TCOCCAT and TCOCFSG numbers and dividing each by 51 (ITT). This annualized cost per individual is $13 926 for FSG and $16 744 for CAT, a difference of $2818 per patient annually.

A cost analysis by Winters et al⁵⁰ showed evidence of the cost efficiency of FSG versus SOC when validated in comparison to retrospective real-world data in a cohort of patients with DFUs. That study analyzed the cost to achieve wound closure. The current study evaluated the cost benefit in a larger cohort with a randomized sample of patients. Cost-utility analysis demonstrated that treatment of DFUs with FSG in conjunction with SOC is cost-effective compared with SOC treatment alone. The cost savings of $2818 annually per patient results from faster wound closure with FSG as opposed to CAT alone. As Armstrong et al⁵¹ noted, as more wounds are healed the likelihood of amputation decreases.

As expected, the higher cost associated with using advanced therapies, including FSGs, compared with SOC results in a higher cost of treatment initially. However, over the course of 1 year, the current model indicates that use of FSG in conjunction with SOC results in cost savings over SOC alone, even though FSG costs 130 times more than CAT (or approximately 40 times more, taking into account 3 weekly applications of CAT). However, when compared to the reported cost advantages of other advanced therapies, the cost to closure with FSG in this study included the cost of nonhealed ulcers, and thus presented a more realistic cost than only considering the average cost of applications for healed ulcers. It is important to note that the cost of any treatment must include both patients whose ulcers close with a given therapy and those whose ulcers do not close. In general, the greater the number of ulcers that do not close, the higher the cost of a given therapy. The cost of therapy has been discussed elsewhere,^29,49,51,52 but none of those studies included the cost application of the product or the number of patients whose ulcers did not close. In the current study, for those patients with ulcers that did not heal and who did not follow the protocol (PP cohort), the costs were $6123.93 for CAT and $9235.20 for FSG.

Other cost-reduction strategies can be used. In the current study, no limit was set for the number of applications of FSG. However, with any product (but especially FSG), if reduction in wound area of 50% to 66% is not seen after 6 applications, use of the product likely should be terminated; this is clearly a good way to reduce the overall cost of therapy.

In addition, the authors of the current study calculated costs based on the list price of FSG as of September 2022. This was done to be fair to all evaluators. It is important to note that FSG may be available at various prices based on volume and overall usage at an institution; thus, the maximum cost rather than the minimum cost is provided.

Although the findings of this study are positive, they are subject to several limitations that should be taken into consideration and addressed in future research. A larger cohort of patients, encompassing more study sites, would greatly strengthen the statistical analysis. Moreover, inclusion of more diverse patients with a greater variety of DFUs and comorbidities, along with a larger, longer, and more detailed follow-up would afford more robust and inclusive real-world findings. Another difficulty in a trial with a tissue-based therapy is that it is quite difficult to mask the assessor and participant. In addition, non-tissue–based best clinical practice requires multiple dressing changes a week, whereas tissue-based clinical practice requires a single weekly dressing. The necessity of the different dressing regimens, while a real-world problem, introduces a differential in how the wounds are treated between the 2 groups.

This study population represents the sites selected and their geographic locations. Black and Hispanic populations were quite underrepresented in the current trial. Future studies need a greater emphasis on urban centers, which tend to have a higher proportion of people of color. Given recent FDA guidelines, it is likely that in the future all such studies will require a more robust diversity plan.⁵³ However, the female-to-male ratio in the current study is in line with the overall incidence of DFUs.

The recorded dropout rate was 24.5% of the total enrollment, with several reasons for dropping out. This rate falls within the range reported in similar studies in which DFUs were treated using advanced tissue therapies such as porcine small intestine submucosa tri-layer matrix,⁵⁵ dehydrated human amnion/chorion membrane,⁵⁴ and bilayer dermal regeneration template.⁵⁶ Factors that contributed to the withdrawal rate in the current study included protocol violations, loss to follow-up, and the number of SAEs, especially the incidents of infections in the control group, which accounted for removal of these patients from the trial. Although this was a single-masked study, patients in each arm could easily recognize which product they received owing to the differences in appearance of FSG and CAT, and the 2 incidents of patient self-termination were associated with the patient wishing to receive a cellular and/or tissue product as perceived as better than CAT.

The withdrawal rate in this study was largely affected by the global COVID-19 pandemic, which hindered many in-person visits and subsequently led to many patients being lost to follow-up. According to the protocol, patients were terminated if their index ulcers were not reduced by 50% after 6 weeks of consecutive treatment. This allowed patients with unsatisfactory results to exit the study and seek better alternatives. Seven patients exited the study following this guidance. Patients with nonhealing wounds are at risk of infection, osteomyelitis, sepsis, and cellulitis if left untreated; thus, it was appropriate to remove these 7 patients from the trial.

The use of FSG resulted in significantly more healed DFUs within a 12-week period compared with CAT. Of those wounds that had not completely healed at 12 weeks, the mean PAR was significantly greater with FSG treatment compared with CAT. In the PP treatment arm, faster time to closure and increased WAR was achieved in patients treated with FSG than in those treated with CAT. As with all tissue-based therapies, there is an increased cost of using FSG for wound closure. However, use of FSG in patients with DFU results in a reduced overall annualized treatment cost. Further guidelines, such as ceasing therapy with advanced materials if WAR greater than 50% has not been achieved at 6 weeks, may help further reduce the cost of advanced therapy. FSG should be considered a more efficient and cost-effective solution for treating DFUs than a recognized SOC such as CAT. Future studies should compare materials such as FSG with other advanced cellular and/or tissue-based products.