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.

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.

Treatment of Hard-to-heal Diabetic Foot Ulcers With a Hepatic-derived Wound Matrix.

INTRODUCTION: Difficult-to-heal diabetic foot ulcers (DFUs) increase the likelihood of significant pathology and increased health care costs. OBJECTIVE: This study evaluates the ability of a novel hepatic-derived wound matrix (HD-WM) to treat hard-to-heal DFUs. MATERIALS AND METHODS: In total, 53 patients were enrolled and 38 completed per protocol. Patients had ulcers that had been present for at least 90 days and were non-responsive to at least 2 applications of an advanced biologic wound care product. Patients were treated with standard of care and offloading for a 2-week run-in phase. If they satisfied criteria, they were enrolled in the trial and treated with the HD-WM, and then seen weekly for assessment and additional treatment as needed. Patients continued weekly visits until the wound healed or went 12-weeks posttreatment without healing. RESULTS: Mean starting wound size was 3.5 cm2 and mean wound duration was 41.1 weeks. Median previous treatment applications of an advanced biologic were 3.0. Complete closure of the wound occurred in 22 of the 38 patients (57.9%) within the 12-week study period, while 16 of 38 (42.1%) of the wounds had failed to completely heal. The mean time to wound closure was 8.1 weeks; these patients received a median of 1 application of the HD-WM under investigation. Closure of the wound by 50% or greater at week 4 was highly predictive of complete wound closure by 12 weeks. Except for bodily pain (36-Item Short Form Health Survey), which significantly improved in patients whose wounds healed, quality of life measures did not show changes. CONCLUSIONS: The HD-WM under evaluation did well at closing difficult-to-heal wounds with minimal applications. These results are consistent with a previous study on this HD-WM.

A prospective, randomized, controlled clinical trial on the efficacy of a single-use negative pressure wound therapy system, compared to traditional negative pressure wound therapy in the treatment of chronic ulcers of the lower extremities.

Multicenter, phase-4, randomized, comparative-efficacy study in patients with VLUs or DFUs comparing for noninferiority the percentage change in target ulcer dimensions (area, depth, and volume) a single-use negative pressure wound therapy (s-NPWT) system versus traditional NPWT (t-NPWT) over a 12-week treatment period or up to confirmed healing. Baseline values were taken at the randomization visit. Randomized by wound type and size, 164 patients with non-infected DFUs and VLUs were included. The ITT population was composed of 161 patients (101 with VLUs, 60 with DFUs) and 115 patients completed follow-up (64 in the s-NPWT group and 51 in the t-NPWT group) (PP population). The average age for all patients was 61.5 years, 36.6% were women, and treatment groups were statistically similar at baseline. Primary endpoint analyses on wound area reduction demonstrated statistically significant reduction in favor of s-NPWT (p = 0.003) for the PP population and for the ITT population (p < 0.001). Changes in wound depth (p = 0.018) and volume (p = 0.013) were also better with s-NPWT. Faster wound closure was observed with s-NPWT (Cox Proportional Hazards ratio (0.493 (0.273, 0.891); p = 0.019) in the ITT population. Wound closure occurred in 45% of patients in the s-NPWT group vs. 22.2% of patients in the t-NPWT group (p = 0.002). Median estimate of the time to wound closure was 77 days for s-NPWT. No estimate could be provided for t-NPWT due to the low number of patients achieving wound closure. Device-related AEs were more frequent in the t-NPWT group (41 AEs from 29 patients) than in the s-NPWT group (16 AEs from 12 patients). The s-NPWT system met noninferiority and achieved statistical superiority vs. t-NPWT in terms of wound progression toward healing over the treatment period. When NPWT is being considered for the management of challenging VLUs and DFUs, s-NPWT should be considered a first choice over other types of NPWT.

Open-label Extension Phase of a Chronic Diabetic Foot Ulcer Multicenter, Controlled, Randomized Clinical Trial Using Cryopreserved Placental Membrane.

OBJECTIVE: The results of the single-arm, open-label extension phase of the Grafix (cryopreserved placental membrane; CPM; Osiris Therapeutics, Inc, Columbia, MD) multicenter, blinded, randomized, controlled clinical trial for chronic diabetic foot ulcers (DFUs) is reported. MATERIALS AND METHODS: Twenty-six patients in the standard wound care (SWC) arm whose DFUs did not close in the blinded phase chose to receive weekly applications of the CPM in an open-label extension phase. RESULTS: In the extension phase, 17 (65.4%) patients closed their wounds in a median of 34 days and 3 visits. There were fewer total adverse events (AEs) (24 CPM vs. 52 SWC) and index wound-related infections (5 CPM vs. 12 SWC) during the CPM application compared with the number of AEs for the same patients during the SWC treatment in the blinded phase of the trial. CONCLUSIONS: These results corroborate the benefits of this CPM combined with SWC over SWC alone for chronic DFUs previously reported for the blinded randomized phase of the trial, which directly relate to lower health care costs.

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.

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.

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 efficacy and safety of Grafix(®) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial.

In a randomised, controlled study, we compared the efficacy of Grafix(®) , a human viable wound matrix (hVWM) (N = 50), to standard wound care (n = 47) to heal diabetic foot ulcers (DFUs). The primary endpoint was the proportion of patients with complete wound closure by 12 weeks. Secondary endpoints included the time to wound closure, adverse events and wound closure in the crossover phase. The proportion of patients who achieved complete wound closure was significantly higher in patients who received Grafix (62%) compared with controls (21%, P = 0·0001). The median time to healing was 42 days in Grafix patients compared with 69·5 days in controls (P = 0·019). There were fewer Grafix patients with adverse events (44% versus 66%, P = 0·031) and fewer Grafix patients with wound-related infections (18% versus 36·2%, P = 0·044). Among the study subjects that healed, ulcers remained closed in 82·1% of patients (23 of 28 patients) in the Grafix group versus 70% (7 of 10 patients) in the control group (P = 0·419). Treatment with Grafix significantly improved DFU healing compared with standard wound therapy. Importantly, Grafix also reduced DFU-related complications. The results of this well-controlled study showed that Grafix is a safe and more effective therapy for treating DFUs than standard wound therapy.

An open-label, three-arm pilot study of the safety and efficacy of topical Microcyn Rx wound care versus oral levofloxacin versus combined therapy for mild diabetic foot infections.

BACKGROUND: This randomized, prospective, multicenter, open-label study was designed to test whether a topical, electrolyzed, superoxidized solution (Microcyn Rx) is a safe and effective treatment for mildly infected diabetic foot ulcers. METHODS: Sixty-seven patients with ulcers were randomized into three groups. Patients with wounds irrigated with Microcyn Rx alone were compared with patients treated with oral levofloxacin plus normal saline wound irrigation and with patients treated with oral levofloxacin plus Microcyn Rx wound irrigation. Patients were evaluated on day 3, at the end of treatment on day 10 (visit 3), and 14 days after completion of therapy for test of cure (visit 4). RESULTS: In the intention-to-treat sample at visit 3, the clinical success rate was higher in the Microcyn Rx alone group (75.0%) than in the saline plus levofloxacin group (57.1%) or in the Microcyn Rx plus levofloxacin group (64.0%). Results at visit 4 were similar. In the clinically evaluable population, the clinical success rate at visit 3 (end of treatment) for patients treated with Microcyn Rx alone was 77.8% versus 61.1% for the levofloxacin group. The clinical success rate at visit 4 (test of cure) for patients treated with Microcyn Rx alone was 93.3% versus 56.3% for levofloxacin plus saline-treated patients. This study was not statistically powered, but the high clinical success rate (93.3%) and the P value (P = .033) suggest that the difference is meaningfully positive for Microcyn Rx-treated patients. CONCLUSIONS: Microcyn Rx is safe and at least as effective as oral levofloxacin for mild diabetic foot infections.

Initial clinical assessment of a novel wound management system: a case series.

The importance of exudate management for maintaining local moisture balance and avoiding maceration in the chronic wound environment is well established. The authors performed the initial clinical testing of a novel wound management system, Sepaderm (Aalnex, Inc, Irvine, California), designed to vertically wick and sequester excess exudate away from wound/periwound tissues to promote a healthy wound environment. In this series of 14 patients with lower-extremity chronic venous leg and diabetic foot ulcers, the 3-component system was well tolerated and demonstrated the ability to prevent exudate leakage onto periwound tissue and reduce existing pain and itching. All ulcers lasting 1.2 to 360 months were previously treated with standard therapies, including human cell-derived skin substitutes in some of the patients. After treatment with the new system for 7 to 174 days, 8 patients had various degrees of wound closure, ranging from 44% to 100%. The 6 patients who failed to show wound closure were treated with the new system for an average of 5.7 days, but demonstrated other clinical benefits. Future studies in larger patient populations with quantitative wound closure assessments, as well as measurements of exudate, periwound maceration, and pain management, are needed.

Clinical effectiveness of an acellular dermal regenerative tissue matrix compared to standard wound management in healing diabetic foot ulcers: a prospective, randomised, multicentre study.

This 12-week, prospective, randomised, controlled multi-centre study compared the proportion of healed diabetic foot ulcers and mean healing time between patients receiving acellular matrix (AM) (study group) and standard of care (control group) therapies. Eighty-six patients were randomised into study (47 patients) and control (39 patients) groups. No significant differences in demographics or pre-treatment ulcer data were calculated. Complete healing and mean healing time were 69.6% and 5.7 weeks, respectively, for the study group and 46.2% and 6.8 weeks, respectively, for the control group. The proportion of healed ulcers between the groups was statistically significant (P = 0.0289), with odds of healing in the study group 2.7 times higher than in the control group. Kaplan-Meier survivorship analysis for time to complete healing at 12 weeks showed a significantly higher non healing rate (P = 0.015) for the control group (53.9%) compared with the study group (30.4%). After adjusting for ulcer size at presentation, which was a statistically significant covariate (P = 0.0194), a statistically significant difference in non healing rate between groups was calculated (P = 0.0233), with odds of healing 2.0 times higher in the study versus control group. This study supports the use of single-application AM therapy as an effective treatment of diabetic, neuropathic ulcers.