An open-label, proof-of-concept study assessing the effects of bromelain-based enzymatic debridement on biofilm and microbial loads in patients with venous leg ulcers and diabetic foot ulcers.

BACKGROUND: Most chronic wounds contain biofilm, and debridement remains the centerpiece of treatment. Enzymatic debridement is an effective tool in removing nonviable tissue, however, there is little evidence supporting its effect on planktonic and biofilm bacteria. OBJECTIVE: This study evaluated the effects of a novel BBD agent on removal of nonviable tissue, biofilm, and microbial loads in patients with chronic ulcers. MATERIALS AND METHODS: Twelve patients with DFU or VLU were treated with up to 8 once-daily applications of BBD and then followed for an additional 2 weeks. Punch biopsy specimens were collected and analyzed for biofilm, and fluorescence imaging was used to measure bacterial load. RESULTS: Ten patients completed treatment, and 7 achieved complete debridement within a median of 2 applications (range, 2-8). By the end of the 2-week follow-up period, the mean ± SD reduction in wound area was 35% ± 38. In all 6 patients who were positive for biofilm at baseline, the biofilm was reduced to single individual or no detected microorganisms by the end of treatment. Red fluorescence for Staphylococcus aureus decreased from a mean of 1.09 cm² ± 0.58 before treatment to 0.39 cm² ± 0.25 after treatment. BBD was safe and well tolerated. CONCLUSION: Preliminary data suggest that BBD is safe and that it can be used to effectively debride DFU and VLU, reduce biofilm and planktonic bacterial load, and promote reduction in wound size.

A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study.

OBJECTIVE: Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone. RESEARCH DESIGN AND METHODS: Patients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapy-both in addition to optimal SOC. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks. A group sequential design was used for the study with three predetermined analyses and hard stopping rules once 73, 146, and ultimately 220 patients completed the 12-week treatment phase. RESULTS: At the first analysis point, the active TWO2 arm was found to be superior to the sham arm, with a closure rate of 41.7% compared with 13.5%. This difference in outcome produced an odds ratio (OR) of 4.57 (97.8% CI 1.19, 17.57), P = 0.010. After adjustment for University of Texas Classification (UTC) ulcer grade, the OR increased to 6.00 (97.8% CI 1.44, 24.93), P = 0.004. Cox proportional hazards modeling, also after adjustment for UTC grade, demonstrated >4.5 times the likelihood to heal DFUs over 12 weeks compared with the sham arm with a hazard ratio of 4.66 (97.8% CI 1.36, 15.98), P = 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P = 0.013). CONCLUSIONS: This sham-controlled, double-blind randomized controlled trial demonstrates that, at both 12 weeks and 12 months, adjunctive cyclical pressurized TWO2 therapy was superior in healing chronic DFUs compared with optimal SOC alone.

A multicenter, randomized, single-blind trial comparing the efficacy of viable cryopreserved placental membrane to human fibroblast-derived dermal substitute for the treatment of chronic diabetic foot ulcers.

Randomized controlled clinical trials, the gold standard to determine treatment efficacy against control, have demonstrated advantages of skin substitutes for the treatment of chronic diabetic foot ulcers in comparison to standard of care. However, randomized controlled clinical trials comparing efficacy between two or more skin substitutes are very limited. With growing numbers of new skin substitutes, such studies are essential for treatment and policy-making decisions by wound care providers and payers. In this study, we analyzed clinical outcomes and product cost between a viable cryopreserved placental membrane (vCPM) and a human fibroblast-derived dermal substitute (hFDS) for the treatment of chronic diabetic foot ulcers in a prospective, multicenter, single-blind study. The outcomes of 62 patients were analyzed: 31 patients in the vCPM treatment group and 31 patients in the hFDS treatment group. Utilizing a non-inferiority trial design and the established treatment regimen of 8 applications for hFDS, we demonstrated that vCPM was not inferior to hFDS for the proportion of patients achieving complete wound closure (9.68, 90% CI: [10.67, 28.94]). However, preliminary findings show that vCPM may have better outcomes for wounds ≤ 5 cm2 : 81.3% (13/16) of wounds in the vCPM group vs. 37.5% (6/16) of wounds in the hFDS group reached complete closure at the end of treatment (p = 0.0118). A preliminary product cost analysis for wounds ≤ 5 cm2 may show significant savings for patients treated with vCPM. Average per-patient costs during the course of treatment were $3,846 and $7,968 (p < 0.0001) for vCPM and hFDS patients, respectively. These results may be used as guidance to wound care providers and payers.

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.

A clinical trial of Integra Template for diabetic foot ulcer treatment.

Individuals with diabetes mellitus are at an increased risk of developing a diabetic foot ulcer (DFU). This study evaluated the safety and efficacy of Integra Dermal Regeneration Template (IDRT) for the treatment of nonhealing DFUs. The Foot Ulcer New Dermal Replacement Study was a multicenter, randomized, controlled, parallel group clinical trial conducted under an Investigational Device Exemption. Thirty-two sites enrolled and randomized 307 subjects with at least one DFU. Consented patients were entered into the 14-day run-in phase where they were treated with the standard of care (0.9% sodium chloride gel) plus a secondary dressing and an offloading/protective device. Patients with less than 30% reepithelialization of the study ulcer after the run-in phase were randomized into the treatment phase. The subjects were randomized to the control treatment group (0.9% sodium chloride gel; n = 153) or the active treatment group (IDRT, n = 154). The treatment phase was 16 weeks or until confirmation of complete wound closure (100% reepithelialization of the wound surface), whichever occurred first. Following the treatment phase, all subjects were followed for 12 weeks. Complete DFU closure during the treatment phase was significantly greater with IDRT treatment (51%) than control treatment (32%; p = 0.001) at sixteen weeks. The median time to complete DFU closure was 43 days for IDRT subjects and 78 days for control subjects in wounds that healed. The rate of wound size reduction was 7.2% per week for IDRT subjects vs. 4.8% per week for control subjects (p = 0.012). For the treatment of chronic DFUs, IDRT treatment decreased the time to complete wound closure, increased the rate of wound closure, improved components of quality of life and had less adverse events compared with the standard of care treatment. IDRT could greatly enhance the treatment of nonhealing DFUs.