A literature search was conducted using the following key words: Non-healing; wound; chronic; diabetic foot; foot ulcer; venous leg ulcer; guidelines; wound healing; skin substitutes; dermal skin substitute; human skin allograft; randomized trial; standard of care; venous leg ulcer; skin grafts; wound dressing; human derived products; animal derived products; FDA regulations. The literature search was filtered to locate articles within 5-10 years, full-text articles, clinical trials, and systematic reviews. In general, improved health outcomes of interest include patient quality of life and function.
Chronic wounds are described as wounds which have been unable to re-epithelialize after one to three months of treatment. More than 90% of chronic wounds in the United States (U.S.) are a result of diabetic ulcers, venous stasis ulcers, and decubitus ulcers. Chronic wounds may be described as vascular ulcers (e.g., venous and arterial), diabetic ulcers, and pressure ulcers (local tissue hypoxia). These types of chronic wounds impact patient quality of life due to impaired mobility, pain, and substantial morbidity.1-3
Evidence-Based Guidelines for Standard of Care
Evidence-based guidelines indicate that standard of care (SOC) treatment of lower extremity ulcers (e.g., diabetic foot ulcers [DFUs] and/or venous leg ulcers [VLUs]) may include mechanical offloading, infection control, mechanical compression, limb elevation, debridement of necrotic tissue, management of systemic disease and medications, nutrition assessment, tissue perfusion and oxygenation, education regarding care of the foot, callus, and nail and fitting of shoes, and counseling on the risk of continued tobacco use. In addition, maintenance of a moist wound environment through appropriate dressings facilitates development of healthy granulation tissue and epithelialization and thus may potentiate complete healing at a wound site. Dressings are an integral part of wound management by not only maintaining a moist environment but by stopping contamination and absorbing exudate.7-12
A comprehensive assessment of patients and their wounds will also facilitate appropriate care by identifying and correcting systemic causes of impaired healing. The presence of a severe illness or systemic disease and drug treatments such as immunosuppressive drugs and systemic steroids may inhibit wound healing by changes in immune functioning, metabolism, inflammation, nutrition, and tissue perfusion. Therefore, this information in conjunction with a detailed history of the wound itself is essential.3,9
A vascular evaluation is also vital for all chronic wounds. Palpation of pulses may be problematic in cases of medial arterial calcification. An ankle-brachial index (ABI) should be taken for patients with a questionable pulse deficit although the ABI levels may be falsely elevated with medial arterial calcification. The patient is considered to have impaired arterial perfusion when the ABI is below 0.9. To supplement ankle-brachial studies, toe blood pressure readings, pulse volume recordings, transcutaneous oxygen measurements (TCOMs), and skin perfusion pressure measurements have been suggested as acceptable benchmarks for the prediction of wound healing.3
Venous ulcers require a series of diagnostic testing to verify superficial or deep venous reflux, perforator incompetence, and chronic (or acute) venous thrombosis. In this regard, venous duplex ultrasound is recommended and if the venous duplex ultrasound does not provide definitive diagnostic information, a venous plethysmography is recommended. Patients with mixed arterial and venous disease require a combination of arterial and venous noninvasive testing. The use of a Class 3 (most supportive) high-compression method is strongly recommended in the treatment of venous ulcers. High strength compression may be applied using techniques such as multilayered elastic compression, inelastic compression, Unna boot, compression stockings, and others. The extent of compression should be modified for patients with mixed venous/arterial disease.3,10
The clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum10 recommend that patients with VLUs have the ulcer classified using the Clinical class, Etiology, Anatomy, and Pathophysiology (CEAP) classification (confirmed by duplex scan). The Venous Clinical Severity Score (VCSS) is recommended to assess changes in response to therapy. Specific classification of venous disease is essential for standardization of venous disease severity and evaluation of treatment efficiency.
The Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine has recommended a SOC treatment schedule for DFUs that includes weekly to monthly wound evaluations of wound size and healing progress, infection control, debridement of all devitalized tissue and surrounding callus material, dressings that maintain a moist wound environment, control of exudate, and avoiding maceration of adjacent intact skin. Adequate glycemic control of hemoglobin A1c (HbA1c < 7%) is also recommended to reduce the incidence of DFUs and infections and periodic assessments of appropriate footwear and/or off-loading device.7,13
Regulation of Skin Substitutes
Despite standard of care and advancements in various moisture retaining synthetic occlusive dressings, many chronic wounds fail to heal. The development of skin substitutes has been employed to be used as an adjunct to established chronic wound care methods to increase the chances of healing.1,13 Skin substitutes can be organized into the following groups: 1) Human-derived products regulated as human cells, tissues, and cellular and tissue-based products (HCT/Ps); 2) Human and human/animal-derived products regulated through premarket approval (PMA) by the U.S. Food and Drug Administration (FDA); 3) Animal-derived products regulated under the 510(k) process; and 4) Synthetic products regulated under the 510(k) process.4-6
Human tissue can be obtained from human donors, processed, and used in exactly the same role in the recipient, such as a dermal replacement to be placed in a wound as a skin substitute (regulated as HCT/Ps). These products may be regulated under the Biologics License Application (BLA) (under the Public Health Service Act [PHS Act]) or PMA (under the Federal Food, Drug, and Cosmetic Act [FD&C Act]), depending on their composition and primary mode of action. Amniotic/chorionic-based products are HCT/Ps as defined in 21 CFR 1271.3(d) and must meet criteria in 21 CFR 1271 and 361 of the PHS Act. The HCT/Ps not regulated under 361 are regulated as drugs as defined under section 201(g) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. In order to legally market a drug that is also a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after a showing of safety and efficacy for the product's intended use.6
Evidence-Based Guidelines for Skin Substitutes
Skin substitutes are a heterogeneous group of biological and/or synthetic elements that allow the temporary or permanent occlusion of wounds. Dermal substitutes may vary from skin xenografts or allografts to a combination of autologous keratinocytes over the dermal matrix, but all have a mutual goal to attain resemblance with an individual’s skin to the greatest extent possible.13 Skin substitutes are recommended as an adjunct to the established SOC treatment protocols for wound care to increase the chances of healing. In this regard, evidence-based guidelines recommend wound bed preparation prior to the application of any biologically active dressing which includes complete removal of slough, debris and/or necrotic tissue.14 Skin substitutes are recommended in conjunction with SOC treatment for DFUs that have failed to demonstrate more than 50% wound area reduction after a minimum of four weeks of standard wound care measures.7 For VLUs, if substantial wound improvement is not demonstrated after a minimum of four-six weeks of standard wound care measures, skin substitutes are recommended in addition to SOC treatment and compression therapy.10
The Agency for Healthcare Research and Quality (AHRQ) provided an evidenced-based technical brief for skin substitutes for treating chronic wounds.2 This technical brief was developed to describe assorted products that may be considered skin substitutes in the U.S., which are utilized for the treatment of chronic wounds. In addition, systems utilized to classify skin substitutes were assessed, randomized controlled trials (RCTs) involving skin substitutes were reviewed, and recommendations were made regarding best practices for future studies. A systematic search of the published literature since 2012 was conducted for systematic reviews/meta-analyses, RCTs, and prospective nonrandomized comparative studies studying commercially available skin substitutes for individuals with DFUs, VLUs, pressure ulcers, and arterial leg ulcers.
Seventy-six skin substitutes were identified and categorized using the Davison-Kotler classification system, a method structured according to cellularity, layering, replaced region, material used, and permanence. Of these, 68 (89%) were categorized as acellular dermal substitutes, largely replacements from human placental membranes and animal tissue sources. Acellular dermal substitutes prepared from natural biological materials are the most common commercially available skin substitute product for treating or managing chronic wounds. Cellularity is a significant difference among skin substitutes as the presence of cells raises the rejection risk and production complexity. This category includes decellularized donated human dermis (14 products recognized), human placental membranes (28 products recognized), and animal tissue (21 products recognized). Less products are prepared from synthetic materials (two products recognized) or a blend of natural and synthetic materials (two products recognized). A limited number of skin substitute products are acellular replacements for both the epidermis and dermis (one product recognized). Only eight products were recognized that contain cells and would be classified in the cellular grouping.
Three systematic reviews and 22 RCTs studied the utilization of 16 distinct skin substitutes, comprising acellular dermal substitutes, cellular dermal substitutes, and cellular epidermal and dermal substitutes in DFUs, pressure ulcers, and VLUs. Twenty-one ongoing studies (all RCTs) assessed an additional nine skin substitutes with comparable classifications. It was noted that studies seldom reported clinical outcomes, such as amputation, wound recurrence at least two weeks after treatment ended, or patient-related outcomes, such as return to function, pain, exudate, and odor. This review found that more studies are needed to assess the effectiveness of most skin substitutes and studies need to be better designed and include clinically relevant outcomes.
Of the 22 included RCTs, 16 studies contrasted a skin substitute with SOC. The SOC for each wound type involved sharp debridement, glucose control, compression bandages for VLUs, pressure redistribution support surfaces for pressure ulcers, infection control, offloading, and daily dressing changes with a moisture-retentive dressing, such as an alginate or hydrocolloid type dressing. Though 85% of the studies examining acellular dermal substitutes portrayed the experimental intervention as favorable over SOC for wound healing and quicker time to heal, inadequate data is available to determine whether wound recurrence or other sequela are less frequent with acellular dermal substitutes. Only three studies contrasted cellular dermal substitutes with SOC. Clinical evidence for cellular dermal substitutes may be limited by the lack of robust, well-controlled clinical trials.
Of the six head-to-head comparative studies, results from five studies did not show substantial differences between skin substitutes in outcomes measured at the latest follow-up (>12 weeks). One study concluding at 12 weeks described a substantial difference in wound healing favoring an acellular dermal skin substitute over a cellular epidermal and dermal skin substitute. Another study compared two acellular dermal substitutes and seemed to have deliberately underpowered one arm of the study as statistical significance was not sought or expected for this study arm. Of the two studies reporting on recurrence, one study described comparable recurrence, while the other study reported no recurrence at 26 weeks. The current evidence base, as portrayed by the authors for the literature reviewed, may be inadequate to determine whether one skin substitute product is superior to another.2
Industry sponsored most of the studies reviewed; 20 of the 22 RCTs in this review, which presents concerns regarding bias for these studies. This AHRQ technical brief also noted that a skin substitute’s commercial availability is not a reflection of its legal status. Manufacturers self-determine whether their human cells, tissues, or cellular or tissue-based product (HCT/P) may be marketed without FDA preapproval and frequently misunderstand or mischaracterize the conditions they must meet for the product to be regulated solely for communicable disease risk. The Code of Federal Regulations (CFR) was referenced; 21 CFR 1271.10(a). Also, the ‘FDA Announces Comprehensive Regenerative Medicine Policy Framework’5 was referenced.
Systemic Review and Meta-Analysis
Santema et al16 provided a systematic review and meta-analysis to assess the efficiency of skin substitutes utilized for the treatment of DFUs regarding ulcer healing and limb salvage. Using the Cochrane Collaboration methodology, 17 clinical trials were identified, which included a total of 1,655 randomized study participants with diabetic foot ulceration. The number of study participants per clinical trial ranged from 23 to 314. Fourteen studies included chronic or difficult to heal ulcers that were present for a minimum of 2, 4, or 6 weeks.
Skin substitutes were contrasted with SOC in 13 trials. The results collectively demonstrated that SOC treatment, together with skin substitutes, enhance the chances of attaining complete ulcer closure in contrast to SOC alone after 6 to 16 weeks (risk ratio [RR] 1.55, 95% confidence interval [CI] 1.30 to 1.85, low quality of evidence). Apligraf/Graftskin, Epifix, and Hyalograft 3D were the only individual products that demonstrated a statistically substantial beneficial effect on complete ulcer closure (i.e., full epithelialization without any evidence of drainage or bleeding). Four clinical trials contrasted two different types of skin substitutes, although no product demonstrated a greater effect over another. Sixteen of the trials evaluated the efficacy of a bioengineered skin substitute. Only one trial evaluated the efficacy of a nonbioengineered skin graft.
The total occurrence of lower limb amputations was only reported for two trials and the results for these two trials collectively produced a substantially lower amputation rate for individuals treated with skin substitutes (RR 0.43, 95% CI 0.23 to 0.81), though the absolute risk difference (RD) was small (-0.06, 95% CI -0.10 to -0.01, very low quality of evidence). Of the included studies, 16 reported on adverse events (AEs) in different ways, although there were no reports of a substantial difference in the incidence of AEs between the intervention and the control group. Additionally, support of long-term effectiveness is lacking, and cost-effectiveness is unclear. Noted limitations included a variable risk of bias among the studies, the lack of blinding (i.e., study participants and investigators knew which patients were receiving the experimental therapy and which patients were receiving the standard therapy), and 15 of the studies conveyed industry involvement; the majority of which did not indicate if the industry applied any limitations regarding data analysis or publication.16
Jones et al17 provided a fourth update for a systematic literature review to evaluate the effect of skin grafts for the treatment of VLUs. Using the Cochrane Collaboration methodology, one new trial was identified, generating a total of 17 RCTs, which included a total of 1,034 study participants. The studies comprised participants of any age, in any care setting, and with VLU. Given the process for diagnosis of venous ulceration differed between studies, a standard definition was not applied. The trials also involved study participants with arterial, mixed, neuropathic, and diabetic ulcers provided that the outcomes for patients with venous ulcers were conveyed separately. To be included in the review, trials also had to report at least one of the primary outcomes (i.e., objective measures of healing, such as relative or absolute rate of change in ulcer area, time for complete healing, or proportion of ulcers healed within the trial period).
Eleven studies contrasted a graft with SOC. Two of these studies (102 patients) contrasted an autograft with a dressing, three studies (80 patients) contrasted a frozen allograft with a dressing, and two studies (45 patients) contrasted a fresh allograft with a dressing. Two studies (345 patients) contrasted a tissue-engineered skin (bilayer artificial skin) with a dressing. In two studies (97 patients) a single-layer dermal replacement was contrasted with SOC.
Six studies contrasted alternative skin grafting techniques. The first study (92 patients) contrasted an autograft with a frozen allograft, a second study (51 patients) contrasted a pinch graft (autograft) with a porcine dermis (xenograft), the third study (110 patients) contrasted growth-arrested human keratinocytes and fibroblasts with a placebo, the fourth study (10 patients) contrasted an autograft delivered on porcine pads with an autograft delivered on porcine gelatin microbeads, the fifth study (92 patients) contrasted a meshed graft with a cultured keratinocyte autograft, and the sixth study (50 patients) contrasted a frozen keratinocyte allograft with a lyophilized (freeze-dried) keratinocyte allograft.
Overall, the results show that substantially more ulcers healed when treated with bilayer artificial skin than with dressings. There was inadequate evidence from the other trials to establish whether other types of skin grafting improved the healing of venous ulcers. The authors concluded that bilayer artificial skin, used together with compression bandaging, improves venous ulcer healing contrasted with a simple dressing plus compression.
It was noted that the overall quality of the studies reviewed was poor, thus affecting the risk of inherent bias. Many of the studies did not convey inclusion criteria, insufficient information was provided regarding randomization techniques, and withdrawals and AEs were inadequately reported. Deficient data regarding withdrawals and the inclination to perform per-protocol analyses rather than intention-to-treat (ITT) analyses signify that the outcomes in the original study documentation may be biased.17
Clinical Trials for Skin Substitutes for Diabetic Foot Ulcers
Barbul et al18 conducted a retrospective, matched-cohort study to establish the efficacy of a cryopreserved human bioactive split-thickness skin allograft (BSA) (i.e., TheraSkin®) plus SOC when contrasted to SOC alone for the treatment of diabetic ulcers. Data was obtained from electronic medical records (EMRs) of an initial pool of 650,309 diabetic ulcers for patients treated at 470 outpatient wound care centers in the U.S. from January 1, 2012 to October 25, 2018.
Primary inclusion criteria included: 1) Adults ≥ 18 years of age; 2) DFU, Wagner grade 1-4 present for ≥ 30 days for individuals diagnosed with Type 1 or Type 2 diabetes; 3) Ulcer sited on foot, leg, or toe; and 4) Wound area ≥ 1 cm2 and ≤ 50 cm2. Primary exclusion criteria included: 1) Ulcers treated at skilled nursing facilities; 2) Ulcers treated with advanced biological products other than BSA; 3) Individuals in the control cohort who received any cellular and/or tissue-based products; and 4) Individuals who showed ≥ 50% closure of their wounds four weeks before the study treatment period.
Following elimination of ineligible patients and those missing important information (i.e., wound characteristics) and/or lack of treatment documentation, data included a total of 778 patients who were treated with the BSA (treatment cohort) (mean age 65.67) and these study participants were paired with 778 patients (mean age 62.95) drawn from a pool of 126,864 patients treated with SOC alone (control cohort), by utilizing propensity matching to create almost identical cohorts. Complications and comorbidities for both groups included Alzheimer’s disease, coronary artery disease, cellulitis, chronic obstructive pulmonary disease, congestive heart failure, end stage renal disease, immunosuppressive conditions, morbid obesity, peripheral vascular disease (arterial and venous), smoking status, and venous insufficiency. Although the disparity in body mass index (BMI) improved with propensity matching, a noteworthy difference remained between groups with those in the BSA cohort having a substantially higher mean BMI than those in the control cohort (p < 0.002).
Both cohorts received SOC treatment involving debridement, offloading, and application of any kind of nonbiologic wound dressings, such as hydrogels, saline-moistened gauze, and antimicrobial dressings. Study participants who received a BSA may have utilized any or all of the same dressings.
Amputation rates and recurrence at three months, six months, and one year after wound closure were analyzed. Diabetic ulcers were 59% more likely to close in the treatment cohort contrasted to the control cohort (p=0.0045). The healing rates with the BSA were greater than with SOC across multiple subsets, but the most substantial improvement was noted in the worst wounds that had a duration of 90-179 days prior to treatment (p=0.0073), exposed deep structures (p=0.036), and/or Wagner Grade 4 ulcers (p=0.04). Additionally, the reduction in recurrence was substantial at three months, six months, and one year, with and without initially exposed deep structures (p < 0.05). The amputation rate in the treatment cohort was 41.7% less than that of the control cohort at 20 weeks (0.9% vs. 1.5%, respectively). This study showed that diabetic ulcers treated with a cryopreserved bioactive split-thickness skin allograft were more likely to heal and stay closed contrasted to ulcers treated with SOC alone.18
Cazzell et al19 performed a prospective, randomized, controlled, open-label trial with a primary objective to contrast the healing rates of a human decellularized acellular dermal matrix (D-ADM) for chronic DFUs with a SOC arm and an active comparator, human acellular dermal matrix (ADM) arm for the treatment of DFUs. Secondary objectives studied differences in time to wound closure, economic burden, quality of life questionnaires and product utilization between D-ADM, SOC, and a second active comparator human ADM.
Inclusion criteria included, but was not limited to: 1) Enrolled study participants must have the capability to comply with offloading and dressing change requirements; 2) The wound of focus must have been open and receiving SOC for 30 days with an area ≥ to 1 cm2 and < than 25 cm2; 3) Patient must be between 21 and 80 years of age, have a single DFU of focus with a Wagner Ulcer Classification Grade of 1 or 2, and no infection present; and 4) Patients must have had acceptable circulation to the affected area, specified as having at least one of the following criteria within the past 60 days: TCOM at the dorsum of the foot ≥ 30 mmHg, ABI ranging from 0.8 - 1.2, or at least biphasic Doppler arterial waveforms at the dorsalis pedis and posterior tibial arteries.
Exclusion criteria included, but was not limited to: 1) Patient had wound treatments including biomedical or topical growth factors within 30 days prior to screening; 2) Patient had circulating HbA1c > 12% within 90 days of the screening visit, serum creatinine concentrations of 3.0 mg/dL or > within 30 days before screening; 3) The presence of peripheral vascular disease, active infection or untreated malignancy, Charcot’s disease, or necrosis, purulence, or sinus tracts unable to be removed by debridement; 4) Patient had a revascularization procedure aimed at improving blood flow in the target limb, or received a living skin equivalent within four weeks before screening; and 5) Patient has a sensitivity to lincomycin, gentamicin, polymyxin B, vancomycin, polysorbate 20, N-lauroyl sarcosinate, benzonase, or glycerol.
Patients with a diagnosis of diabetes mellitus on a stable treatment regimen (no modifications in treatment for 30 days prior to screening) who visited the clinic for care of a chronic lower extremity ulcer and met the above inclusion criteria and none of the exclusion criteria were asked to join the study. In this regard, the study enrolled 168 DFU patients in 13 centers across nine states in the U.S. Patients were randomized into one of three treatment arms; D-ADM (DermACELL®), SOC wound management, or GJ-ADM (GraftJacket™) at a ratio of 2:2:1. The authors of this study indicated that the active comparator arm for GJ-ADM was not intended to compare the difference between the ADMs as several articles have reported the safety and efficiency of GJ-ADM; this arm was added to the study to determine a baseline ADM healing rate.
Numbered envelopes holding the treatment designation were arranged by an outside contract research organization and the study investigators were blinded to the randomization codes matching each envelope. After a patient successfully passed screening to be in the study, the investigator would open the envelope to ascertain which randomized arm the patient was assigned to. The ADM is visible upon application; therefore, it would have been impossible to continue blinding the investigator once treatment was applied. Therefore, as a secondary examination to avoid bias, a clinician, blinded to the treatment arm assessed the wound images for confirmation of healing condition.
Initially, the wound beds were debrided with a sharp blade, scissors or Versajet system to remove necrotic tissue for study participants in all three treatment groups. Wound size was recorded using an imaging system pre-and post-debridement as well as before dressing applications. The wound areas were calculated by the imaging system and utilized for subsequent analysis of the wound areas.
Patients in the D-ADM arm and the GJ-ADM arm had the appropriate ADM dressing applied and covered with a nonadherent dressing. A second ADM was applied between two weeks (at a minimum) and 12 weeks (at the latest) after the first D-ADM application. Patients could have a maximum of two ADM applications, which included the first application at baseline. Wounds in the conventional care arm were provided with wound therapy involving alginates, foams, or hydrogels. The treating provider then selected either a moist or dry gauze to be placed over the wound. In all three treatment arms, the dressing covered the wound for a minimum of five days, but no more than nine days, (7 days ± 2 days) until the next visit and dressings were only changed by the study team. Also, during following weekly visits, debridement was used to remove necrotic tissue, as needed. In addition, off-loading utilizing a removable cast walker, diabetic shoe, surgical shoe, walker cast, or a total contact cast was essential for all treatment arms unless the investigator considered it to be inappropriate, such as situations involving a wheelchair bound patient or if the wound was located on the dorsal surface of the foot. Though either removable or nonremovable offloading techniques were permitted, 95% of all patients used some type of removable method; 68% of patients used removable boots and 16% of patients used surgical shoes.
Wounds were assessed on a weekly basis until wound closure was noted or the patient completed 24 weekly follow-up visits. Wound closure was defined as 100% re-epithelialization of the wound without drainage. A second visit was scheduled two weeks after the initial wound closure was noted to verify complete wound closure. Additionally, all healed wounds were followed at 4, 8, and 12 weeks after confirmation of complete wound closure to determine if the wound remained healed.
A total of 168 patients were included in this study: 71 patients in the D-ADM arm, 69 patients in the SOC arm, and 28 patients in the GJ-ADM arm. Patients that withdrew from the study prematurely because of severe adverse events (SAEs), which affected the ability to follow the wound of focus, offloading non-compliance, or ≥ 25% missed visits involved 18 patients in the D-ADM arm, 13 patients in the SOC arm, and five patients in the GJ-ADM arm. To this end, 53 patients remained in the D-ADM arm and 40 of these patients received one application, 56 patients remained in the SOC arm, and 23 patients remained in the GJ-ADM arm and 16 of these patients received only one application. The percentage of overall early withdrawals and the percentage of SAEs were comparable between the three treatment groups based on relative population size (p ≥ 0.05).
Baseline ulcer features, including wound size, were comparable between the three ITT arms. The average age for patients in the D-ADM arm was 59.1, 56.9 in the SOC arm, and 58.5 in the GJ-ADM arm. The mean HbA1c at screening was 8.51% in the D-ADM arm, 8.38% in the SOC arm, and 7.63% in the GJ-ADM arm. Patients diagnosed with Type 2 diabetes involved 93.5% of the enrolled population, with 90.1% randomized to D-ADM, 97.1% randomized to SOC, and 92.9% randomized to GJ-ADM. The treatments prescribed for diabetes control were evenly dispersed across study arms, thus eliminating the potential confounding effect of insulin levels on cell responses and healing. Also, it was noted that almost half of the study participants (41.1%) were current or past smokers and 58.9% had never smoked. Additionally, the majority of patients in all three arms of the study had ulcers classified as Wagner class 2 (ulcers that extend into tendon or capsule); D-ADM arm (83.1%), SOC arm (79.7%), and GJ-ADM arm (82.1%).
Patients were followed for 24 weeks for all three treatment arms. Results for the per protocol population showed that a single application of D-ADM showed a substantially greater wound healing probability in comparison to SOC across all three endpoints at Week 12 (65.0% vs. 41.1%; HR = 1.969; 95% CI = 1.1–3.5; p=0.0123), Week 16 (82.5% vs. 48.1%; HR = 2.397; 95% CI = 1.4–4.1; p=0.0003), and Week 24 (89.7% vs. 67.3%; HR = 2.107; 95% CI = 1.3– 3.5; p=0.0008). Patients in the D-ADM arm who received all applications also demonstrated a substantially greater wound healing probability over SOC during follow-up visits at Week 16 (67.9% vs. 48.1%; HR = 1.716; 95% CI = 1.04–2.831; p=0.0283) and Week 24 (83.7% vs. 67.3%; HR = 1.546; 95% CI = 0.9821–2.435; p=0.0489). The patients in the D-ADM arm who received only one application exhibited wound healing in an average of nine weeks, whereas patients in the conventional arm showed wound healing in an average of 16.5 weeks (p=0.0020). No substantial differences were observed between patients in the GJ-ADM arm and patients in the SOC arm or between patients in the D-ADM and GJ-ADM arms.
The SF-36 v2.0 (Optum, Inc.) was utilized to acquire the perception of general health in eight areas for each study participant. The average, overall SF-36 scores at the end of the study were 425 for D-ADM, 430 for SOC, and 404 for GJ-ADM. There were no substantial differences perceived between treatment arms for the overall total score or in any of the eight areas. Also, a limitation noted for this study indicates that the manufacturer of the D-ADM (DermACELL®) sponsored this trial.19
Driver et al20 conducted The Foot Ulcer New Dermal Replacement Study (FOUNDER) to assess the safety and effectiveness of the Integra Dermal Regeneration Template (IDRT) (i.e., Omnigraft® Dermal Regeneration Matrix) for the treatment of nonhealing DFUs. The study was a multicenter, randomized, controlled, parallel group clinical trial performed under an Investigational Device Exemption. This study was designed based on guidelines from the FDA for creating products to treat chronic cutaneous ulcers. The FOUNDER study involved 32 clinical sites and 307 patients that were randomized into two parallel groups.
The primary inclusion criteria included: 1) Established Type 1 or Type 2 diabetes with a HbA1c ≤ 12%; 2) Patients ≥ 18 years of age; 3) Presence of a full-thickness neuropathic ulcer positioned distal to the malleolus; 4) The ulcer of focus must have been in existence for greater than 30 days with the ulcer area between 1 and 12 cm2 post-debridement; and 5) Satisfactory vascular perfusion as defined by ABI ≥ 0.65 and ≤ 1.2 or toe pressure > 50 mmHg or transcutaneous oxygen pressure (TcPO2) > 40 mmHg or doppler ultrasound consistent with sufficient blood flow to the affected extremity.
The primary exclusion criteria were active infection involving osteomyelitis, exposed capsule, tendon, or bone, and reduction of wound ≥ 30% during the screening interval. The trial was separated into three phases: screening/run-in, randomization/treatment, and follow-up. Patients entered the screening/run-in phase after providing written consent and underwent a series of screening evaluations and a 14-day run-in period in which patients received SOC treatment on the ulcer of focus to establish eligibility for the study. The following procedures were performed during the run-in period for the ulcer of focus: 1) Infection and exudate evaluation; 2) Sharp debridement; 3) Measurement of the deepest aspect (post-debridement); 4) Photograph (pre- and post-debridement); 5) Tracing for planimetric evaluation (post-debridement); 6) SOC that involved sharp debridement followed by application of a moist wound therapy consisting of 0.9% sodium chloride gel and a secondary dressing involving a nonadherent foam dressing, an outer gauze wrap, and an offloading/protective device (i.e., Active Offloading Walker [boot and/or shoe]); and 7) Patients were instructed on the SOC treatment for daily dressing changes.
Other patient evaluations conducted during the run-in period included: A medical history; medication usage; therapies; physical examination; and neuropathic, laboratory, and vascular perfusion assessments. Once the patients completed the screening/run-in phase, patients were then assessed to determine continued satisfaction of eligibility criteria. The ulcer of focus was then debrided using sharp debridement prior to the first treatment. Also, a planimetric evaluation was performed (blindly by a central laboratory).
Patients with study ulcers that had healed < 30% in the run-in period were randomized using a software algorithm at a central location in mixed blocks of two and four in a 1:1 ratio to the active or control treatment. Randomization was stratified by study location and wound size (≤ 3 cm2 versus > 3 cm2). Treatment started on the day of randomization as assigned and the treatment phase continued until the patient had 100% wound closure or for up to 16 weeks. The SOC was the control treatment and the IDRT was the active treatment. The SOC treatments were just as described in the screening/run-in phase and daily dressing changes were done either by the patient in the control group or by a trained caregiver.
For the active treatment group, fenestrating and meshing of the IDRT was acceptable to allow for drainage and in the presence of exudating wounds or hematomas. The IDRT was placed on the debrided wound, trimmed to size, and secured with sutures or staples, and covered with a secondary dressing. When the collagen layer was replaced by new tissue, typically in 14 to 21 days after application, the silicone layer of the IDRT was removed. Re-applications of the IDRT were done as deemed necessary by the investigator. The site personnel performed the secondary dressing changes for the active treatment group on a weekly basis.
Wounds were assessed on a weekly basis during the treatment phase or until wound closure was noted. A visit was scheduled one week after the initial wound closure was noted to verify complete wound closure. An additional visit was then scheduled for confirmation of wound closure. Following completion of the treatment phase, all patients were followed every four weeks during the 12-week follow-up phase.
Complete closure of the ulcer of focus during the treatment phase (16 weeks) (defined as 100% re-epithelialization of the wound surface with no discernable exudate and without drainage or dressing needs), was substantially greater in the active group (51%; 79/154) in contrast to the control group (32%; 49/153, p=0.001). Comparable results were observed when wound closure was evaluated by computerized planimetry: 50% (77/154) in the active group and 31% (48/153) in the control group (p=0.001). The probabilities of complete wound closure established at the end of the treatment phase were 2.2 times higher (95% CI = 1.4, 3.5; p=0.001) for the active group contrasted with the control group. Assessment using planimetric data to evaluate wound closure was consistent with an odds ratio of 2.2 (95% CI = 1.3, 3.5; p=0.001). When complete wound closure was evaluated at 12 weeks, the results were substantially different between the two groups (45% active [70/154] vs. 20% control [31/153]; p < 0.001). The probabilities of complete wound closure at 12 weeks were 3.3 times higher (95% CI = 2.0, 5.4; p < 0.001) for the active group contrasted with the control group. The average number of applications per individual, including the initial application, for the active group was one (range 1–15).
The degree of decrease in wound size was 7.2% per week for the active group vs. 4.8% per week for the control group (p=0.012). At the end of the follow-up phase, ulcer recurrence was experienced by 19% of the active treatment group and by 26% of the control treatment group (p=0.32). Quality of life data demonstrated substantial improvements in physical functioning (p=0.047) and bodily pain (p=0.033) for the active group contrasted with the control group.
Most AEs in both groups were mild. Severe AEs were incurred by 15.6% of patients in the active group and by 26.8% in the control group (p=0.016). Moderate AEs were incurred by 31.8% of patients in the active group and by 42.5% of patients in the control group (p=0.053). The AEs possibly linked to study treatment were comparable in both treatment groups (7/154 [4.5%] in the active group vs. 8/153 [5.2%] in the control group). Also, a limitation noted for this study is the manufacturer of the IDRT used in the active treatment group sponsored this trial.20
Lavery et al21 performed a prospective, multi-center, randomized, single-blinded study to contrast the effectiveness of a human viable wound matrix (hVWM) (i.e., Grafix®) to standard wound care in treating chronic DFUs from May 2012 to April 2013. The primary outcome was the percentage of patients with complete wound closure by 12 weeks. Complete wound closure was defined as 100% re-epithelialization with no wound drainage. Secondary outcomes encompassed the time to wound closure, AEs, and wound closure in a crossover phase.
Primary inclusion criteria included: 1) Established Type 1 or Type 2 diabetic patients 18-80 years of age; 2) Diabetic ulcer present for four to 52 weeks; and 3) Diabetic ulcer positioned below the malleoli on the plantar or dorsal surface of the foot and ulcer 1 to 15 cm2 in size. Primary exclusion criteria included: 1) HbA1c above 12%; 2) Indication of active infection, including osteomyelitis or cellulitis; 3) Insufficient circulation to the affected foot defined by an ABI < 0.70 or > 1.30, or toe brachial index ≤ 0.50 or Doppler study with insufficient arterial pulsation; 4) Exposed muscle, tendon, bone, or joint capsule; and 5) Decrease of wound area by ≥ 30% during the screening period.
After a one week screening period, patients were randomized to the active treatment arm (i.e., hVWM) or control treatment arm (i.e., standard wound care) in a 1:1 ratio. Patients in the active treatment group received an application of hVWM once a week (± 3 days) for up to 84 days (blinded treatment phase). Patients in the control group received SOC wound therapy once a week (± 3 days) for up to 84 days and wounds were cleaned and surgically debrided to remove all non-viable soft tissue from the wound by scalpel, tissue nippers and/or curettes at each weekly visit.
Wounds in both groups received SOC that involved surgical debridement, off-loading and non-adherent dressings and either saline moistened gauze or an absorbent foam dressing for moderately draining wounds. Also, an outer dressing was applied. In addition, walking boots were provided for patients with wounds on the sole of the foot and post-op shoes were provided for patients with wounds on the dorsum of the foot or at the ankle.
Patients were evaluated weekly at the clinical site. Patients who attained complete wound closure then continued to be assessed during the follow-up phase, twice during the first month and then monthly for two additional visits. Patients in the control group whose wounds were not closed by the end of the blinded treatment phase were able to receive the hVWM in the open-label treatment phase, in which the hVWM was applied weekly for up to 84 days.
During screening, 139 patients were assessed. A total of 42 patients failed screening and of these, six were excluded due to a decrease of their wound areas by ≥ 30% during the screening period. A total of 97 patients were randomized: 50 to the active treatment arm and 47 to the control arm.
The percentage of patients who attained complete wound closure was substantially higher in the active treatment group (62%) compared with the control group (21%, P=0.0001). The average time for healing was 42 days in the active treatment arm contrasted with 69.5 days in the control arm (P=0.019). There were less AEs in the active arm (44% versus 66%, P=0.031) and less wound-related infections (18% versus 36.2%, P=0.044). Among the study participants that healed, ulcers remained closed in 82.1% of patients (23 of 28 patients) in the active group versus 70% (7 of 10 patients) in the control group (P=0.419). The authors concluded that treatment with the hVWM substantially improved DFU healing contrasted with SOC therapy. Also, a limitation noted for this study is the manufacturer of the hVWM used in the active treatment group sponsored this trial.21
Sanders et al22 performed a prospective, multi-center, randomized, controlled trial to contrast an in vitro-engineered, human fibroblast-derived dermal skin substitute (HFDS) (i.e., Dermagraft®) to a biologically active cryopreserved human skin allograft (HSA) (i.e., TheraSkin®) in the treatment of DFUs. The primary objectives were to establish the relative number of DFUs healed (100% epithelization without drainage) and the number of grafts needed by week 12. Secondary objectives involved the percentage of DFUs healed at weeks 16 and 20, time to heal during the study and wound size progression.
Primary inclusion criteria included: 1) Established Type 1 or Type 2 diabetic patients > 18 years of age; 2) HbA1C < 12%; 3) Full-thickness foot ulcer existing > 30 days; 4) Ulcer > 1 cm2 and < 10 cm2 in size with at least 2 cm between study ulcer and other ulcers; and 5) ABI > 0.65, toe pressure > 50 mmHG, and TcPO2 > 20 mmHG. Primary exclusion criteria included: 1) Wound infection or gangrene of the foot; 2) Patient has received oral or parenteral corticosteroids, immune-suppressive or cytotoxic drugs within the last 12 months; and 3) Treatment with growth factors or bioengineered skin substitutes within the past 30 days.
A total of 23 patients participated in the study at two hospital-based wound care centers in three phases. During the first phase, screening was performed, and eligible patients were randomly assigned to the HFDS treatment group (12 patients) (mean age 57) or the HSA treatment group (11 patients) (mean age 60) using a series of sealed envelopes employing a block randomization technique that described the treatment to be applied. During the second phase (one week later), the treatment phase started and continued for 12 weeks. All wounds (both groups) were debrided to remove nonviable tissue and callous from the wound surface and adjacent wound perimeter and then cleansed with saline. Afterwards, the initial application of the biologically active product was applied as randomly assigned and all wounds were then covered with a non-adherent dressing and were offloaded with ½ inch felt as part of an aperture type of device. All patients were then given a healing sandal developed from a surgical shoe or a fixed ankle boot.
Patients in the HSA group received a product application every other week and patients in the HFDS group were treated every week with wounds prepared as described above prior to application of the product. Since both products have a distinctive appearance, it was not possible to conceal the type of product used during wound assessments. Wounds were photographed at each visit and the margins of the wounds were traced along the inner edge of the margins.
At week 12, patients with an unhealed wound continued into the third phase (follow-up) for treatment and assessment for up to eight more weeks. After the week 12 visit, no additional biologically active products were used in either treatment group. In this phase, wounds were treated with saline-moistened gauze and debridement as needed.
Patients with ulcers verified to be healed were scheduled for a confirmatory visit. Patients with incomplete wound closure continued to be evaluated though week 20; subsequent treatment was then provided outside the scope of the study.
There were no substantial differences discerned between patient demographics and wound attributes at baseline in the two treatment groups. At week 12, seven (63.6%) wounds in the HSA treatment group versus four (33.3%) in the HFDS treatment group were healed (P=0.0498). At the end of week 20, 90.91% of wounds in the HSA group versus 66.67% of wounds in the HFDS group were healed (P=0.4282). Among the subset of wounds that healed during the first 12 weeks of treatment, a mean of 4.36 (range 2-7) HSA grafts were applied versus 8.92 (range 6-12) in the HFDS subset group (P < 0.0001, SE 0.77584). Time to healing in the HSA group was substantially less (8.9 weeks) than in the HFDS group (12.5 weeks) (log-rank test, P=0.0323). The results of this study showed that, after 12 weeks of care, DFUs treated with HSA are probably twice as likely to heal as DFUs managed with HFDS with about half the number of grafts required. Limitations noted for this study are the small sample size and the manufacturer of the HSA product used in one of the active treatment groups sponsored this trial.22
Zelen et al23 performed a prospective, randomized, controlled, multicenter study to evaluate the healing rates, safety, and cost using an open-structure human reticular acellular dermis matrix (HR-ADM) (i.e., AlloPatch® Pliable™) plus SOC to facilitate wound closure in DFUs compared to treatment with SOC alone. The trial was conducted from December 2014 to November 2015 at five outpatient wound care centers in Virginia and Ohio.
Primary inclusion criteria included: 1) Patients with Type 1 or Type 2 diabetes with a non-healing neuropathic foot ulcer that failed a minimum of four weeks of documented conservative care; 2) Adequate renal function as shown by a serum creatinine level < 3.0 mg/dl; and 3) Sufficient circulation to the affected extremity within the past 60 days as evidenced by TCOM with result ≥ 30 mmHg, ABI with result of ≥ 0.7 and ≤ 1.2 or Doppler arterial waveforms, which were triphasic or biphasic at the ankle of the affected leg.
All eligible patients meeting inclusion and exclusion criteria were treated with SOC alone, which included surgical debridement, for a two week screening period and patients whose index wound had not healed greater than 20% at two weeks were then considered eligible for the study. A total of 40 study participants were eligible for enrollment in the study and were randomized to HR-ADM plus SOC (n = 20) (HR-ADM applications weekly) or SOC alone (n = 20) (daily dressing changes). There were no significant group differences regarding patient and wound attributes, with the exception of the average wound area, which was larger in the HR-ADM group (4.7 cm2) contrasted with the SOC group (2.7 cm2).
The primary outcome of this study focused on a comparison of wound healing at six weeks using HR-ADM plus SOC versus SOC alone. Wounds were considered as healed if there was complete (100%) re-epithelization with no drainage and no need for a dressing. Secondary outcomes involved comparing healing at 12 weeks, time to heal at 6 and 12 weeks, graft count, wastage, and assessment of product cost to closure. An ITT method was utilized for all analyses. At six weeks, 65% (13/20) of the HR-ADM-treated ulcers had healed contrasted with 5% (1/20) of the ulcers treated with SOC alone (P=0.00028). The decrease in the wound area size between the groups changed significantly over time, with an average time to heal within six weeks of 28 days (95% CI: 22–35 days) for the HR-ADM group contrasted with 41 days (95% CI: 40–43 days) for the SOC group. After adjusting for area of wound at randomization, the hazard ratio (HR) for HR-ADM contrasted with SOC was 168 (95% CI: 10–2704), P=0.00036. Ten study participants from the SOC group (50%) and one patient from the HR-ADM group (5%) discontinued the study at six weeks per protocol as their wound failed to decrease in area by at least 50%.
At 12 weeks, 80% (16/20) of the HR-ADM-treated ulcers had healed contrasted with 20% (4/20) of the ulcers treated with SOC alone (P=0.00036). The average time to heal within 12 weeks was 40 days (95% CI: 27–52 days) for the HR-ADM group contrasted with 77 days (95% CI: 70–84 days) for the SOC group (P=0.00014).
The average number of HR-ADM grafts used to achieve closure per ulcer was 4.7 (SD=3.3). The average percentage of wastage (healed wounds only) was 51.7% (SD: 10.7; n = 16). There was no occurrence of increased AEs or SAEs between groups, or any AEs related to the graft. This study concluded that the use of HR-ADM plus SOC is more effective in the treatment of DFUs than with SOC alone. This study was limited by the patients unblinded to treatment allocation and the study was also funded by the manufacturer of the HR-ADM graft.23
Clinical Trials for Skin Substitutes for Venous Leg Ulcers
Cazzell24 conducted a multicenter, randomized, controlled, open-label trial designed to evaluate the safety and efficacy of human decellularized acellular dermal matrices (D-ADM) contrasted with SOC management in patients with chronic VLUs. This exploratory pilot study included eight implanting surgeons from seven medical centers in five states that enrolled patients with VLUs. The study participants were randomly assigned to the D-ADM (i.e., Dermacell AWM®) treatment arm or a SOC treatment arm in a 2:1 ratio. Numbered envelopes holding the treatment designation were arranged by an outside contract research organization and the study investigators were blinded to the randomization codes matching each envelope. After a patient successfully passed screening to be in the study, the investigator would open the envelope to ascertain which randomized arm the patient was assigned to. The D-ADM is visible upon application; therefore, it would have been impossible to continue blinding the investigator once treatment was applied. Therefore, as a secondary examination to avoid bias, a blinded, independent adjudicator also assessed the healing condition of all wounds.
Primary inclusion criteria included: 1) Adults ≥ 21 and ≤ 80 years of age; 2) Presence of a single target VLU with a CEAP ulcer classification Grade 6; 3) Duration of the target VLU ≥ 60 days; 4) Absence of infection; 5) VLU area ≥ 1 cm2 and < 25 cm2, depth ≤ 9 mm; and 6) Able to comply with offloading and dressing change stipulations.
Primary exclusion criteria included: 1) HbA1c < 12% within 90 days of screening visit; 2) Serum creatinine ≥ 3.0 mg/dL within 30 days of screening; 3) Application of biomedical, topical growth factors or living skin equivalents to the target VLU within 30 days of screening; 4) Recent revascularization procedure to increase blood flow in the target limb; 5) Sensitivity to possible D-ADM processing reagents (e.g., gentamicin, polymyxin B, vancomycin, N-lauroyl sarcosinate, Benzonase, glycerol); and 6) Manifestation of severe peripheral vascular disease, active infection, untreated malignancy, active Charcot’s disease, necrosis, purulence, or sinus tracts in the ulcer unable to be removed by debridement.
Eighteen patients were included in the D-ADM arm (mean age 64.6) and 10 patients in the control arm (mean age 61.8). Initially, all wounds for both groups were debrided to remove necrotic tissue utilizing a sharp blade, scissors, or Versajet system. Wound size was recorded using an imaging system pre-and post-debridement as well as before dressing application. Patients in the treatment arm had the D-ADM applied and covered with a nonadherent dressing. A second D-ADM was applied between two weeks (at a minimum) and 12 weeks (at the latest) after the first D-ADM application. Patients could have a maximum of two D-ADM applications, which included the first application at baseline.
Wounds in the SOC arm were provided with wound therapy involving alginates, foams, or hydrogels. The treating provider then selected either a moist or dry gauze to be placed over the wound and left in place for 7 ± 2 days, which was only to be removed during weekly visits. During the weekly visits, debridement was used to remove necrotic tissue, as needed.
Compression therapy was used in the treatment and control arms. Wounds were assessed on a weekly basis until wound closure was noted or the patient completed 24 weekly follow-up visits. Wound closure was defined as 100% re-epithelialization of the wound without drainage. A second visit was scheduled two weeks after the initial wound closure was noted to verify complete wound closure. Additionally, all healed wounds were followed at 4, 8, and 12 weeks after confirmation of complete wound closure to determine if the wound remained healed.
The primary outcome of the study contrasted the full wound closure rates between the two groups. The second outcome of the study involved contrasting the decrease in wound size over time, time to wound closure, and treatment-related AEs. Twenty-eight patients completed at least 12 weeks of follow-up; 18 patients in the D-ADM arm and 10 in the SOC arm. Of the 18 patients receiving the D-ADM, nine (50%) received a second application during the study. At 24 weeks, patients in the D-ADM arm demonstrated a strong trend of reduction in the wound area, with a mean reduction of 59.6%, in comparison to the SOC arm, with a mean reduction of 8.1%. Also, the wound areas in the SOC arm increased more than 100% in size for one-third (3/9) of the patients. Furthermore, healed ulcers in the D-ADM arm stayed closed at a significantly greater rate after initial confirmation of complete wound closure than healed ulcers in the control arm. Limitations noted for this study included a small patient population with an unbalanced proportion between the two groups (2:1) that ensured a low probability of achieving statistical significance, the lack of blinding for the study investigators, and the study was funded by the manufacturer of the D-ADM graft.24
Harding et al25 conducted an open label, prospective, multicenter, randomized controlled study that assessed the human fibroblast-derived dermal substitute (HFDS) (i.e., Dermagraft®) in addition to four-layer compression therapy contrasted with compression therapy alone in the treatment of VLUs. The primary outcome variable was the proportion of patients with completely healed study ulcers by 12 weeks. Complete healing was characterized by having a closed wound (with full epithelization and no exudate or scab) for two consecutive weekly visits.
Primary inclusion criteria included: 1) Individuals ≥ 18 years of age referred to participating facilities/clinics in the United Kingdom (UK), Canada or the U.S.; 2) Presence of a VLU between the knee and ankle existing for at least two months and ≤ 5 years prior to screening; 3) Size of VLU 3-25 cm2 without exposure of muscle, tendon or bone; 4) Presence of a clean, granulating base with negligible adherent slough, suitable for a skin graft; and 5) ABI of 0.8 to 1.2 and reflux of > 0.5 seconds in saphenous, calf perforator or popliteal veins as confirmed by duplex ultrasonography.
Primary exclusion criteria included: 1) Individuals with ulcers caused by a medical condition other than venous insufficiency; 2) Presence of sinus tracts in ulcer; 3) Signs of a wound infection (purulence and/or odor), cellulitis and/or verified osteomyelitis; 4) Morbid obesity; 5) Skin disease near study ulcer; 6) Malignant disease within the past five years; and 7) Severe peripheral vascular disease or renal disease, congestive heart failure, cell anemia, thalassemia or uncontrolled diabetes. Also, individuals who had received immune suppressants, systemic corticosteroids, cytotoxic chemotherapy, or topical steroids for more than two weeks and within one month of initial screening or who had a history of radiation at the ulcer site were not eligible to participate in the study. In addition, patients who had received an investigational drug within 30 days of randomization or had been previously treated with an HFDS and/or other tissue-engineered materials were also excluded from the study.
All patients received a SOC dressing treatment during the screening period; each ulcer was covered with a layer of non-adherent dressing followed by a four-layer compression bandage. During the twoweek screening period, ulcers were evaluated weekly to establish absence of necrotic tissue and infection and the presence of a vascular bed. Ulcers that decreased in size (cm2) by < 50% while under compression therapy during the two week screening period for the trial were eligible for randomization into the study.
Of the 573 patients screened, 207 failed screening (36%). The primary causes for screening failure were study ulcers decreasing in size by more than 50% during screening, study ulcers less than 3 cm2 at randomization and patients without indication of venous reflux. The remaining 366 patients were randomized to receive treatment at a total of 25 centers: 19 in the UK, 1 in Canada and 5 in the U.S. The ITT population (patients who received treatment at baseline and had a follow-up visit post-baseline) included 186 patients in the HFDS group and 180 patients in the control group with a mean age of 68.5 years. Patients were randomized to receive an application of HFDS plus the four-layer compression bandage therapy (active) or the four-layer compression bandage therapy alone (control). Patients randomized to the active treatment group received the HFDS applied to the wound at weeks 0, 1, 4 and 8.
A total of 10% (19 of 186) of patients in the HFDS group discontinued the trial early contrasted with 23% (41 of 180) of patients in the control group. The causes for early discontinuation were AEs (3% in the HFDS group versus 6% in the control group), patient’s own request (2% versus 9%), patient lost to follow-up (2% versus 3%) and ‘other’ (4% from each group).
Sixty-four (34%) of 186 patients in the HFDS group demonstrated healing by week 12 contrasted with 56 (31%) of 180 patients in the control group (P=0.235). For ulcers ≤ 12 months duration, 49 (52%) of 94 patients in the HFDS group contrasted with 36 (37%) of 97 patients in the control group healed at 12 weeks (P=0.029). For ulcers ≤ 10 cm2, complete healing at week 12 was shown in 55 (47%) of 117 patients in the HFDS group contrasted with 47 (39%) of 120 patients in the control group (P=0.223). The most common AEs were wound infection, cellulitis, and skin ulcer. The occurrence of AEs was not significantly different between the treatment and control groups. Statistical significance was not achieved for the primary outcome of patients with VLUs completely healed by 12 weeks. Also, a limitation noted for this study is the manufacturer of the HFDS used in the control group helped sponsor this trial.25