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.

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.

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.

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.

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.