Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

The influence of adequate debridement and placental-derived allografts on diabetic foot ulcers.

OBJECTIVE: To determine the role of debridement when patients are using placental-derived allografts (PDAs), data from two prospective, multicentre, randomised controlled trials (RCTs) were evaluated for the quality or adequacy of debridement on diabetic foot ulcers (DFUs) treated with PDAs. Results were compared with real-world findings via a retrospective analysis of 2015-2019 Medicare claims for DFUs. METHOD: Debridement adequacy in the prospective RCTs was adjudicated by three blinded wound care specialists. Treatments included two PDAs, dehydrated human amnion/chorion membrane (DHACM, n=54) or dehydrated human umbilical cord (DHUC, n=101), compared with standard of care (SOC, n=110). The key outcome was the influence of adequate debridement on rates of complete closure within 12 weeks. Additionally, a retrospective analysis of 2015-2019 Medicare claims for DFUs that received routine debridement at intervals ranging from every 1-7 days (18,900 total episodes), 8-14 days (35,728 total episodes), and every 15 days or greater (34,330 total episodes) was performed. RESULTS: Within the RCTs, adequate debridement occurred in 202/265 (76%) of patients, 90/110 (82%) SOC ulcers, 45/54 (83%) of DHACM-treated ulcers, and in 67/101 (66%) of DHUC-treated ulcers. Complete closure occurred in 150/202 (74%) of adequately debrided ulcers, and in only 13/63 (21%) of ulcers without adequate debridement, p<0.0001. Debridement was the most significant factor for closure even when controlling for other clinical characteristics. Within the Medicare claims data 21% (18,900/88,958) of episodes treated with SOC only had debridement intervals of ≤7 days. Short debridement intervals in combination with the use of DHACM demonstrated statistically significant better outcomes than SOC including: 65% fewer major amputations (p<0.0001), higher DFU resolution rates (p=0.0125), 42% fewer emergency room visits (p<0.0001) and reduced usage of other hospital resources (admissions and readmissions). CONCLUSION: Prospectively collected data examining the quality of debridement and retrospectively analysed data examining the frequency of debridement supports routine adequate wound debridement, particularly at intervals of seven days, as an essential component of wound care. Optimal use of placental-derived allografts improves outcomes and lowers the use of healthcare resources.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

Fetal bovine acellular dermal matrix for the closure of diabetic foot ulcers: a prospective randomised controlled trial.

AIM: The purpose of this clinical trial was to evaluate the safety and efficacy of a fetal bovine acellular dermal matrix (FBADM) plus standard of care (SOC) for treating hard-to-heal diabetic foot ulcers (DFUs). METHOD: A prospective, multi-centre, randomised controlled trial was carried out. The study included a 2-week run-in period, a 12-week treatment phase and a 4-week follow-up phase. The primary endpoint was complete wound closure at 12 weeks. RESULTS: Twenty-one US sites enrolled and randomised 226 patients with hard-to-heal DFUs. The study was terminated early due to the COVID-19 pandemic, which led to a modified intent-to-treat (mITT) population of 207 patients, with 103 in the FBADM group and 104 in the SOC group. Of these participants, 161 completed the study per protocol (mPP population), with 79 receiving FBADM, and 82 without. At the first analysis point, patients treated with FBADM were found to be significantly more likely to achieve complete wound closure compared with SOC alone (mITT: 45.6% versus 27.9% p=0.008; mPP: 59.5% versus 35.6% p=0.002). The difference in outcome yielded an odds ratio of 2.2 (95% confidence interval (CI): 1.2, 3.9; p=0.008). Median time to closure within 12 weeks was 43 days for the FBADM group compared to 57 days for the SOC group (p=0.36). The median number of applications of FBADM to achieve closure was one. Adverse events were similar between groups and no product-related serious adverse events occurred. CONCLUSIONS: These results indicate that in many cases a single application of FBADM in conjunction with SOC offers a safe, faster and more effective treatment of DFUs than SOC alone.

Health economics for treatment of diabetic foot ulcers: a cost-effectiveness analysis of eight skin substitutes.

AIM: Skin substitutes are frequently used to treat chronic diabetic foot ulcers (DFU), and many different options are available. While the clinical efficacy of many products has been evaluated, a comprehensive cost-effectiveness analysis comparing the most popular skin substitutes and using the most recent cost data has been lacking. METHODS: This study compared eight skin substitutes using published efficacy rates combined with the Centers for Medicare and Medicaid Services (CMS) 2018 cost data. The study criteria resulted in the inclusion of seven studies that described efficacy rates for treatment of DFUs using the skin substitutes. RESULTS: The results revealed wide discrepancies between these skin substitutes for the costs of treatments and healing rates in hospital outpatient departments and physician office settings. Healing rates for 12 and 16 weeks ranged from 28% to 68%, while the average cost for treating one DFU varied from $2001 to $14,507 and $1207 to $8791 in the hospital outpatient department and physician's office setting, respectively. The estimated patient share of costs for treating a single DFU ranged from $400 to $2901 and $241 to $1758 in the hospital outpatient department and physician's office setting, respectively. Most importantly, the estimated number of wounds healed out of 100 DFUs per $1000 expenditure with each patient ranged from 3.9-26.5 DFUs in the hospital outpatient department, and 4.3-36.4 DFUs in the physicians' office setting. CONCLUSIONS: This study revealed that the costs of a skin substitute itself did not necessarily correlate with its healing efficacy. These results provide a comprehensive cost-effectiveness analysis to enable integrated health-care systems, health professionals and reimbursement payers to make informed value decisions when treating DFUs.

A Prospective, Multicenter, Single-Arm Clinical Trial for Treatment of Complex Diabetic Foot Ulcers with Deep Exposure Using Acellular Dermal Matrix.

OBJECTIVE: This prospective, multicenter study evaluated the efficacy and safety of an acellular dermal matrix allograft, DermACELL (D-ADM; LifeNet Health, Virginia Beach, Virginia), in the treatment of large, complex diabetic foot ulcers (DFUs) that probed to tendon or bone. METHODS: Inclusion criteria were Wagner grade 3 or 4 DFUs between 4 weeks and 1 year in duration. All participants received one application of D-ADM at baseline and could receive one additional application if wound healing arrested. Ulcers were assessed weekly for 16 weeks using a laser measuring device. RESULTS: Sixty-one participants were enrolled, with an average wound area of 29.0 cm; 59 of these ulcers showed exposed bone. The entire per-protocol population (n = 47) achieved 100% granulation. The mean time to 100% granulation was 4.0 weeks with an average of 1.2 applications of D-ADM. Mean percent wound area reduction was 80.3% at 16 weeks. Those DFUs 15 cm or smaller were substantially more likely to close than DFUs larger than 29 cm (P = .0008) over a 16-week duration. No complications were associated with the use of the studied matrix. CONCLUSIONS: The D-ADM demonstrated the ability to rapidly reduce the size of large, complex DFUs with exposed bone. Some wounds did not completely heal by 16 weeks; however, the significant reduction in size suggests that these large, complex wounds may heal if given more time.

A Randomized Controlled Trial Comparing a Human Acellular Dermal Matrix Versus Conventional Care for the Treatment of Venous Leg Ulcers.

INTRODUCTION: Venous leg ulcers (VLUs) are often chronic and difficult to treat, which makes alternative options to conventional care necessary to improve ulcer healing rates. While human acellular dermal matrices (ADMs) have shown promise in treating diabetic foot ulcers, no comparative studies have been published regarding VLU treatment. Decellularized ADMs (D-ADMs) have been used successfully in the treatment of a wide variety of wound repairs and may be effective in treating VLUs. OBJECTIVE: This study is a multicenter, randomized, controlled, open-label trial designed to evaluate the safety and efficacy of D-ADM compared with conventional wound care management in patients with chronic ulcers of the lower extremity. MATERIALS AND METHODS: Patients were randomly assigned to receive either D-ADM or standard of care (control) in a 2:1 ratio. Treatment began at week 0 and wounds were evaluated on a weekly basis until wound closure was observed or the patient completed 24 weekly follow-up visits. RESULTS: Eighteen patients were included in the D-ADM arm and 10 patients in the control arm. There was a strong trend of reduction in percent wound area for D-ADM patients with an average reduction of 59.6% at 24 weeks versus 8.1% at 24 weeks for control patients. In addition, healed ulcers in the D-ADM arm remained closed at a substantially higher rate after termination than healed ulcers in the control. CONCLUSIONS: In this report, the authors note the successful increase in healing rates and rate of percent wound closure as compared with conventional care options.

A confirmatory study on the efficacy of dehydrated human amnion/chorion membrane dHACM allograft in the management of diabetic foot ulcers: A prospective, multicentre, randomised, controlled study of 110 patients from 14 wound clinics.

A randomised, controlled multicentre clinical trial was conducted at 14 wound care centres in the United States to confirm the efficacy of dehydrated human amnion/chorion membrane allograft (dHACM) for the treatment of chronic lower extremity ulcers in persons with diabetes. Patients with a lower extremity ulcer of at least 4 weeks duration were entered into a 2-week study run-in phase and treated with alginate wound dressings and appropriate offloading. Those with less than or equal to 25% wound closure after run-in were randomly assigned to receive weekly dHACM application in addition to offloading or standard of care with alginate wound dressings, for 12 weeks. A total of 110 patients were included in the intent-to-treat (ITT) analysis, with n = 54 in the dHACM group and n = 56 in the no-dHACM group. Of the participants, 98 completed the study per protocol, with 47 receiving dHACM and 51 not receiving dHACM. The primary study outcome was percentage of study ulcers completely healed in 12 weeks, with both ITT and per-protocol participants receiving weekly dHACM significantly more likely to completely heal than those not receiving dHACM (ITT-70% versus 50%, P = 0.0338, per-protocol-81% versus 55%, P = 0.0093). A Kaplan-Meier analysis was performed to compare the time-to-healing performance with/without dHACM, showing a significantly improved time to healing with the use of allograft, log-rank P < 0.0187. Cox regression analysis showed that dHACM-treated subjects were more than twice as likely to heal completely within 12 weeks than no-dHACM subjects (HR: 2.15, 95% confidence interval 1.30-3.57, P = 0.003). At the final follow up at 16 weeks, 95% of dHACM-healed ulcers and 86% of healed ulcers in the no-dHACM group remained closed. These results confirm that dHACM is an efficacious treatment for lower extremity ulcers in a heterogeneous patient population.

A multicentre prospective randomised controlled comparative parallel study of dehydrated human umbilical cord (EpiCord) allograft for the treatment of diabetic foot ulcers.

The aim of this study was to determine the safety and effectiveness of dehydrated human umbilical cord allograft (EpiCord) compared with alginate wound dressings for the treatment of chronic, non-healing diabetic foot ulcers (DFU). A multicentre, randomised, controlled, clinical trial was conducted at 11 centres in the United States. Individuals with a confirmed diagnosis of Type 1 or Type 2 diabetes presenting with a 1 to 15 cm2 ulcer located below the ankle that had been persisting for at least 30 days were eligible for the 14-day study run-in phase. After 14 days of weekly debridement, moist wound therapy, and off-loading, those with ≤30% wound area reduction post-debridement (n = 155) were randomised in a 2:1 ratio to receive a weekly application of EpiCord (n = 101) or standardised therapy with alginate wound dressing, non-adherent silicone dressing, absorbent non-adhesive hydropolymer secondary dressing, and gauze bandage roll (n = 54). All wounds continued to have appropriate off-loading during the treatment phase of the study. Study visits were conducted for 12 weeks. At each weekly visit, the DFU was cleaned and debrided as necessary, with the wound photographed pre- and post-debridement and measured before the application of treatment group-specific dressings. A follow-up visit was performed at week 16. The primary study end point was the percentage of complete closure of the study ulcer within 12 weeks, as assessed by Silhouette camera. Data for randomised subjects meeting study inclusion criteria were included in an intent-to-treat (ITT) analysis. Additional analysis was conducted on a group of subjects (n = 134) who completed the study per protocol (PP) (EpiCord, n = 86, alginate, n = 48) and for those subjects receiving adequate debridement (EpiCord, n = 67, alginate, n = 40). ITT analysis showed that DFUs treated with EpiCord were more likely to heal within 12 weeks than those receiving alginate dressings, 71 of 101 (70%) vs 26 of 54 (48%) for EpiCord and alginate dressings, respectively, P = 0.0089. Healing rates at 12 weeks for subjects treated PP were 70 of 86 (81%) for EpiCord-treated and 26 of 48 (54%) for alginate-treated DFUs, P = 0.0013. For those DFUs that received adequate debridement (n = 107, ITT population), 64 of 67 (96%) of the EpiCord-treated ulcers healed completely within 12 weeks, compared with 26 of 40 (65%) of adequately debrided alginate-treated ulcers, P < 0.0001. Seventy-five subjects experienced at least one adverse event, with a total of 160 adverse events recorded. There were no adverse events related to either EpiCord or alginate dressings. These results demonstrate the safety and efficacy of EpiCord as a treatment for non-healing DFUs.

Randomized Controlled Trial of Micronized Dehydrated Human Amnion/Chorion Membrane (dHACM) Injection Compared to Placebo for the Treatment of Plantar Fasciitis.

BACKGROUND: Failure of conservative management to reduce/eliminate symptoms of plantar fasciitis (PF) may indicate need for advanced treatments. This study reports Level 1 evidence supporting 3-month safety and efficacy of micronized dehydrated human amnion/chorion membrane (dHACM) injection as a treatment for PF. METHODS: A prospective, single-blind, randomized controlled trial was conducted at 14 sites in the United States. Subjects were randomized to receive 1 injection, in the affected area, of micronized dHACM (n=73) or 0.9% sodium chloride placebo (n=72). Safety/efficacy assessments were conducted at 4 weeks, 8 weeks, 3 months, 6 months, and 12 months postinjection, using visual analog scale (VAS) for pain, Foot Function Index-Revised (FFI-R) score, and presence/absence of adverse events. Primary outcome was mean change in VAS score between baseline and 3 months expressed as difference in means for treatment versus control subjects. Secondary outcome was mean change in FFI-R score between baseline and 3 months expressed as difference in means for treatment versus control subjects. RESULTS: Baseline VAS scores were similar between groups. At the 3-month follow-up, mean VAS scores in the treatment group were 76% lower compared with a 45% reduction for controls ( P < .0001), FFI-R scores for treatment subjects had mean reduction of 60% versus baseline, whereas control subjects had mean reduction of 40% versus baseline ( P = .0004). Of 4 serious adverse events, none were related to study procedures. CONCLUSION: Pain reduction and functional improvement outcomes were statistically significant and clinically relevant, supporting use of micronized dHACM injection as a safe and effective treatment for PF. LEVEL OF EVIDENCE: Level I, prospective randomized trial.

Human placental membrane as a wound cover for chronic diabetic foot ulcers: a prospective, postmarket, CLOSURE study.

OBJECTIVE: To evaluate the safety and efficacy of a chorioamniotic allograft, used as a wound cover for chronic foot ulcers, in patients with diabetes. METHODS: A multicentre, prospective, postmarket study where eligible patients received up to 11 weekly wound cover applications. Computerised planimetry was used to calculate the diabetic foot ulcer (DFU) area each week. The primary endpoint of the study was wound closure assessment. Secondary endpoints included DFU recurrence and morbidity. RESULTS: A total of 63 patients with 64 ulcers were enrolled, after successful completion of a two-week run-in period. Patients were predominantly male and had risk factors for delayed healing. Mean baseline DFU area was 3.8cm2 (standard deviation (SD): 4.8). After 12 weeks, a total of 19 (40%) DFUs had closed. Results varied by size category, 'small' (≤2.0cm2), 'medium' (>2.0-4.0 cm2), and 'large' (>4.0-25.0 cm2), with higher percentage closure in the 'small' DFU group, compared with the 'medium' and 'large' DFUs (57%, 33%, and 10%, respectively). Of those DFUs that closed, the average closure time was 6.5 weeks. There were no unanticipated adverse events. CONCLUSION: Known risk factors for healing, including DFU size, location and duration, affected the outcomes. However, the results are in line with the literature and support the use of the chorioamniotic allograft in chronic and complex cases.

A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix® ) allograft for the treatment of venous leg ulcers.

A randomised, controlled, multicentre clinical trial was conducted to evaluate the efficacy of dehydrated human amnion/chorion membrane (EpiFix) allograft as an adjunct to multilayer compression therapy for the treatment of non-healing full-thickness venous leg ulcers. We randomly assigned 109 subjects to receive EpiFix and multilayer compression (n = 52) or dressings and multilayer compression therapy alone (n = 57). Patients were recruited from 15 centres around the USA and were followed up for 16 weeks. The primary end point of the study was defined as time to complete ulcer healing. Participants receiving weekly application of EpiFix and compression were significantly more likely to experience complete wound healing than those receiving standard wound care and compression (60% versus 35% at 12 weeks, P = 0·0128, and 71% versus 44% at 16 weeks, P = 0·0065). A Kaplan-Meier analysis was performed to compare the time-to-healing performance with or without EpiFix, showing a significantly improved time to healing using the allograft (log-rank P = 0·0110). Cox regression analysis showed that subjects treated with EpiFix had a significantly higher probability of complete healing within 12 weeks (HR: 2·26, 95% confidence interval 1·25-4·10, P = 0·01) versus without EpiFix. These results confirm the advantage of EpiFix allograft as an adjunct to multilayer compression therapy for the treatment of non-healing, full-thickness venous leg ulcers.

Feasibility and Efficacy of a Smart Mat Technology to Predict Development of Diabetic Plantar Ulcers.

OBJECTIVE: We conducted a multicenter evaluation of a novel remote foot-temperature monitoring system to characterize its accuracy for predicting impending diabetic foot ulcers (DFU) in a cohort of patients with diabetes with previously healed DFU. RESEARCH DESIGN AND METHODS: We enrolled 132 participants with diabetes and prior DFU in this 34-week cohort study to evaluate a remote foot-temperature monitoring system (ClinicalTrials.gov Identifier NCT02647346). The study device was a wireless daily-use thermometric foot mat to assess plantar temperature asymmetries. The primary outcome of interest was development of nonacute plantar DFU, and the primary efficacy analysis was the accuracy of the study device for predicting the occurrence of DFU over several temperature asymmetry thresholds. RESULTS: Of the 129 participants who contributed evaluable data to the study, a total of 37 (28.7%) presented with 53 DFU (0.62 DFU/participant/year). At an asymmetry of 2.22°C, the standard threshold used in previous studies, the system correctly identified 97% of observed DFU, with an average lead time of 37 days and a false-positive rate of 57%. Increasing the temperature threshold to 3.20°C decreased sensitivity to 70% but similarly reduced the false-positive rate to 32% with approximately the same lead time of 35 days. Approximately 86% of the cohort used the system at least 3 days a week on average over the study. CONCLUSIONS: Given the encouraging study results and the significant burden of DFU, use of this mat may result in significant reductions in morbidity, mortality, and resource utilization.

A randomized clinical trial of a human acellular dermal matrix demonstrated superior healing rates for chronic diabetic foot ulcers over conventional care and an active acellular dermal matrix comparator.

This study compared the efficacy and safety of a human acellular dermal matrix (ADM), D-ADM, with a conventional care arm and an active comparator human ADM arm, GJ-ADM, for the treatment of chronic diabetic foot ulcers. The study design was a prospective, randomized controlled trial that enrolled 168 diabetic foot ulcer subjects in 13 centers across 9 states. Subjects in the ADM arms received one application but could receive one additional application of ADM if deemed necessary. Screen failures and early withdrawals left 53 subjects in the D-ADM arm, 56 in the conventional care arm, and 23 in the GJ-ADM arm (2:2:1 ratio). Subjects were followed through 24 weeks with major endpoints at Weeks 12, 16, and 24. Single application D-ADM subjects showed significantly greater wound closure rates than conventional care at all three endpoints while all applications D-ADM displayed a significantly higher healing rate than conventional care at Week 16 and Week 24. GJ-ADM did not show a significantly greater healing rate over conventional care at any of these time points. A blinded, third party adjudicator analyzed healing at Week 12 and expressed "strong" agreement (κ = 0.837). Closed ulcers in the single application D-ADM arm remained healed at a significantly greater rate than the conventional care arm at 4 weeks posttermination (100% vs. 86.7%; p = 0.0435). There was no significant difference between GJ-ADM and conventional care for healed wounds remaining closed. Single application D-ADM demonstrated significantly greater average percent wound area reduction than conventional care for Weeks 2-24 while single application GJ-ADM showed significantly greater wound area reduction over conventional care for Weeks 4-6, 9, and 11-12. D-ADM demonstrated significantly greater wound healing, larger wound area reduction, and a better capability of keeping healed wounds closed than conventional care in the treatment of chronic DFUs.

Phase 3 evaluation of HP802-247 in the treatment of chronic venous leg ulcers.

In 2012 we reported promising results from a phase 2 clinical trial of HP802-247, a novel spray-applied investigational treatment for chronic venous leg ulcers consisting of human, allogeneic fibroblasts and keratinocytes. We now describe phase 3 clinical testing of HP802-247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802-247 to show efficacy in these two phase 3 trials was initiated immediately following the initial review of the North American trial results. Four hundred twenty-one patients were enrolled in the North American (HP802-247, 211; Vehicle 210) and 252 in the European (HP802-247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802-247, 61.1%; Vehicle 60.0%; p = 0.5896) or the European (HP802-247, 47.0%; Vehicle 50.0%; p = 0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802-247. Concordance between the two separate, randomized, controlled trials with distinct, nonoverlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks.

Healing Rates in a Multicenter Assessment of a Sterile, Room Temperature, Acellular Dermal Matrix Versus Conventional Care Wound Management and an Active Comparator in the Treatment of Full-Thickness Diabetic Foot Ulcers.

OBJECTIVE: The purpose of this 16-week, multicenter, randomized, controlled trial was to assess the healed ulcer rate of a human acellular dermal matrix, DermACELL, compared with conventional care and a second acellular dermal matrix, Graftjacket, in the treatment of full-thickness diabetic foot ulcers. METHODS: One hundred sixty-eight patients were randomized into DermACELL, conventional care, and Graftjacket treatment arms in a 2:2:1 ratio. Patients in the acellular dermal matrix groups received either 1 or 2 applications of the graft at the discretion of the investigator. Weekly follow-up visits were conducted until the ulcer healed or the endpoint was reached. RESULTS: At 16 weeks, the DermACELL arm had a significantly higher proportion of completely healed ulcers than the conventional care arm (67.9% vs 48.1%; P = .0385) and a nonsignificantly higher proportion than the Graftjacket arm (67.9% vs 47.8%; P = .1149). The DermACELL arm also exhibited a greater average percent reduction in wound area than the conventional care arm (91.4% vs 80.3%; P = .0791) and the Graftjacket arm (91.4% vs 73.5%; P = .0762). The proportion of severe adverse events and the proportion of overall early withdrawals were similar among the 3 groups based on relative population size (P ≥ .05). CONCLUSIONS: The results presented here indicate that DermACELL is an appropriate clinical option in the treatment of diabetic foot ulcers, with significant increases in healing rates and rate of percentage wound closure as compared with conventional care options.

The Management of Diabetic Foot Ulcers with Porcine Small Intestine Submucosa Tri-Layer Matrix: A Randomized Controlled Trial.

Objective: This study demonstrates that superior outcomes are possible when diabetic foot ulcers (DFU) are managed with tri-layer porcine small intestine submucosa (SIS). Approach: Patients with DFU from 11 centers participated in this prospective randomized controlled trial. Qualified subjects were randomized (1:1) to either SIS or standard care (SC) selected at the discretion of the Investigator and followed for 12 weeks or complete ulcer closure. Results: Eighty-two subjects (41 in each group) were evaluable in the intent-to-treat analysis. Ulcers managed with SIS had a significantly greater proportion closed by 12 weeks than for the Control group (54% vs. 32%, p=0.021) and this proportion was numerically higher at all visits. Time to closure for ulcers achieving closure was 2 weeks earlier for the SIS group than for SC. Median reduction in ulcer area was significantly greater for SIS at each weekly visit (all p values<0.05). Review of reported adverse events found no safety concerns. Innovation: These data support the use of tri-layer SIS for the effective management of DFU. Conclusion: In this randomized controlled trial, SIS was found to be associated with more rapid improvement, and a higher likelihood of achieving complete ulcer closure than those ulcers treated with SC.

Central talar dome lesions: a unique surgical approach with incorporation of a talar allograft for joint reconstitution and restoration of function.

Osteochondral lesions of the talus have been documented, reported, and studied since as early as the 19th century. The evolution of classification systems has allowed surgeons to better manage osseous lesions. Most osteochondral lesions of the talus have been categorized as anterolateral, posteromedial, or central with respect to the talar dome and its articulating surface. The complexity of the aforementioned lesions each present their own set of obstacles and, hence, management. Specifically, surgery on a central talar dome lesion is complicated by poor exposure and limited access, proving to be a challenging operation. Preoperative planning, including exhaustive imaging before any talar dome surgery, is imperative. We present a case study that involves the need for a distal tibial chevron (wedge) talus, with incorporation of a cadaveric allograft to fill the defect.