Dehydrated Amnion Chorion Membrane versus standard of care for diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population. METHOD: Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC). RESULTS: The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04). CONCLUSION: In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population. DECLARATION OF INTEREST: This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

Gene therapy for diabetic foot ulcers: Interim analysis of a randomised, placebo-controlled phase 3 study of VM202 (ENGENSIS), a plasmid DNA expressing two isoforms of human hepatocyte growth factor.

To evaluate the status of a 7-month phase 3 study conducted to test the effect of intramuscular injections of VM202 (ENGENSIS), a plasmid DNA encoding human hepatocyte growth factor, into the calf muscles of chronic nonhealing diabetic foot ulcers with concomitant peripheral artery disease. The phase 3 study, originally aimed to recruit 300 subjects, was discontinued because of slow patient recruitment. An unprespecified interim analysis was performed for the 44 subjects enrolled to assess the status and determine the future direction. Statistical analyses were carried out for the Intent-to-Treat (ITT) population and separately for subjects with neuroischemic ulcers, using a t-test and Fisher's exact test. A logistic regression analysis was also conducted. VM202 was safe and potentially should have benefits. In the ITT population (N = 44), there was a positive trend toward closure in the VM202 group from 3 to 6 months but with no statistical significance. Levels of ulcer volume or area were found to be highly skewed between the placebo and VM202 groups. Forty subjects, excluding four outliers in both arms, showed significant wound-closing effects at month 6 (P = .0457). In 23 patients with neuroischemic ulcers, the percentage of subjects reaching complete ulcer closure was significantly higher in the VM202 group at months 3, 4, and 5 (P = .0391, .0391, and .0361). When two outliers were excluded, a significant difference was evident in months 3, 4, 5, and 6 (P = .03 for all points). A potentially clinically meaningful 0.15 increase in Ankle-Brachial Index was observed in the VM202 group at day 210 in the ITT population (P = .0776). Intramuscular injections of VM202 plasmid DNA to calf muscle may have promise in the treatment of chronic neuroischemic diabetic foot ulcers (DFUs). Given the safety profile and potential healing effects, continuing a larger DFU study is warranted with modifications of the current protocol and expansion of enrolling sites.

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.

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.

Toe and flow: essential components and structure of the amputation prevention team.

At the end of an anatomic peninsula, the foot in diabetes is prone to acute and chronic complications involving neuropathy, vasculopathy, and infection. Effective management requires an interdisciplinary effort focusing on this triad. In this article, we describe the key factors leading to foot complications and the critical skill sets required to assemble a team to care for them. Although specific attention is given to a conjoined model involving podiatry and vascular surgery, the "toe and flow" model, we further outline three separate models of care--basic, intermediate, and center of excellence--that can be implemented in the developed and developing world.

Clinical experience using a dehydrated amnion/chorion membrane construct for the management of wounds.

INTRODUCTION: Over time, acute and chronic, nonhealing wounds impose heavy financial and quality-of-life burdens on patients. The introduction of new therapies for wounds is essential in benefiting the patient, and in this report, the clinical experience of various wound care providers treating wounds with dehydrated amnion/chorion membrane (dACM) is presented. OBJECTIVE: This retrospective clinical experience evaluated the effects of dACM in the treatment of 50 acute and chronic wounds of various etiologies. MATERIALS AND METHODS: Retrospective case data of patients who received dACM as part of the course of treatment for a variety of acute and chronic wounds were obtained from 15 wound care institutions. The case data, consisting of patient history, previous wound care treatments, wound types and sizes, dACM applications and adjunctive treatments, and wound outcomes following dACM applications, were analyzed. RESULTS: The mean (standard deviation [SD]) baseline wound areas were recorded for all wounds (N = 50; 11.251 cm2, SD = 15.575), venous leg ulcers (VLUs; n = 14; 18.756 cm2, SD = 20.848), diabetic foot ulcers (DFUs; n = 24; 10.387 cm2, SD = 14.432), and other wounds (n = 12; 4.225 cm2, SD = 2.074), respectively. With a mean of 5.9 (SD = 2.94) dACM applications per wound, 28 of 50 wounds (56%) achieved complete wound closure by the last observation. Of the ones that did not completely close, 9 (18%) had > 90% wound closure, and 8 (16%) had wound closure percentages ranging from 60% to 90% by the last observation. Of the total number of wounds, 45 (90%) had wound closure percentages between 60% to 100%. The median time to complete wound closure (or healing) for all wounds was 102 days (14.57 weeks), and the percent healing rates of all wounds healed at 16 and 24 weeks was 56% and 73%, respectively. For DFUs treated with dACM, the median time to healing was 120 days (17.14 weeks) and the percent healing rates at 16 and 24 weeks were 43% and 59%, respectively. For VLUs treated with dACM, the median time to healing was 90 days (12.86 weeks), with percent healing rates of 56% and 85% at 16 and 24 weeks, respectively. For all other wounds treated with dACM (including pressure ulcers, nonhealing surgical, ischemic, mixed etiology, and nonhealing amputation), the median time to healing was 48 days (6.86 weeks), with percent healing rates of 57% and 100% at 16 and 24 weeks, respectively. CONCLUSIONS: This retrospective case compilation of clinical experiences in patients with various acute and chronic wounds demonstrates that dACM may be beneficial in the treatment of wounds.

Clinical Outcomes for Diabetic Foot Ulcers Treated with Clostridial Collagenase Ointment or with a Product Containing Silver.

Objective: To compare outcomes of diabetic foot ulcers (DFUs) treated with clostridial collagenase ointment (CCO) or silver-containing products, both in combination with sharp debridement as needed. Approach: One hundred two subjects with qualifying DFUs were randomized to daily treatment with either CCO or a silver-containing product for 6 weeks followed by a 4 -week follow-up period. The primary outcome was the mean percent reduction in DFU area. A secondary outcome was the incidence of ulcer infections between groups. Results: At the end of treatment, the mean percent reduction in area from baseline of DFUs treated with CCO was 62% (p < 0.0001) and with silver was 40% (p < 0.0001). The difference between groups-22%-was not statistically significant (p = 0.071). Among ulcers closed by the end of treatment, the mean time to closure was 31.1 ± 9.0 days versus 37.1 ± 7.7 days, respectively (not statistically significant). There was a numerically greater incidence of target ulcer infections in the silver group (11, 21.6%) than in the CCO group (5, 9.8%; p = 0.208). No clinically relevant safety signals were identified in either group. Innovation: CCO treatment can progress a wound toward closure. Ulcer infection prophylaxis may not be sacrificed when treating DFU with CCO in lieu of silver-containing products. Conclusion: Both CCO and silver-containing products promote significant reduction in DFU area over 6 weeks of treatment with no clinically relevant safety concerns. Mean percent reduction in lesion area was numerically (22%) but not significantly greater with CCO compared to silver, as was time to ulcer closure, with an incidence of ulcer infection at least as low as for silver-containing products.

Toe and flow: essential components and structure of the amputation prevention team.

At the end of an anatomical peninsula, the foot in diabetes is prone to short- and long-term complications involving neuropathy, vasculopathy, and infection. Effective management requires an interdisciplinary effort focusing on this triad. Herein, we describe the key factors leading to foot complications and the critical skill sets required to assemble a team to care for them. Although specific attention is given to a conjoined model involving podiatric medicine and vascular surgery, the so-called toe and flow model, we further outline three separate programmatic models of care--basic, intermediate, and center of excellence--that can be implemented in the developed and developing world.