Herbert B. Slade

Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND Many patients with venous leg ulcers do not heal with standard care. HP802-247 is a novel spray-applied cell therapy containing growth-arrested allogeneic neonatal keratinocytes and fibroblasts. We compared different cell concentrations and dosing frequencies of HP802-247 for benefit and harm when applied to chronic venous leg ulcers. METHODS We enrolled adult outpatients from 28 centres in the USA and Canada with up to three ulcers, venous reflux confirmed by doppler ultrasonography, and adequate arterial flow in this phase 2, double-blind, randomised, placebo-controlled trial if at least one ulcer measured 2-12 cm(2) in area and had persisted for 6-104 weeks. Patients were randomly assigned by computer-generated block randomisation in a 1:1:1:1:1 ratio to 5·0×10(6) cells per mL every 7 days or every 14 days, or 0·5×10(6) cells per mL every 7 days or every 14 days, or to vehicle alone every 7 days. All five groups received four-layer compression bandages. The trial sponsor, trial monitors, statisticians, investigators, centre personnel, and patients were masked to treatment allocation. The primary endpoint was mean percentage change in wound area at the end of 12 weeks. Analyses were by intention to treat, excluding one patient who died of unrelated causes before first treatment. This trial is registered with ClinicalTrials.gov NCT00852995. FINDINGS 45 patients were assigned to 5·0×10(6) cells per mL every 7 days, 44 to 5·0×10(6) cells per mL every 14 days, 43 to 0·5 ×10(6) cells per mL every 7 days, 46 to 0·5 ×10(6) cells per mL every 14 days, and 50 to vehicle alone. All required visits were completed by 205 patients. The primary outcome analysis showed significantly greater mean reduction in wound area associated with active treatment compared with vehicle (p=0·0446), with the dose of 0·5 ×10(6) cells/mL every 14 days showing the largest improvement compared with vehicle (15·98%, 95% CI 5·56-26·41, p=0·0028). Adverse events were much the same across all groups, with only new skin ulcers and cellulitis occurring in more than 5% of patients. INTERPRETATION Venous leg ulcers can be healed with a spray formulation of allogeneic neonatal keratinocytes and fibroblasts without the need for tissue engineering, at an optimum dose of 0·5×10(6) cells per mL every 14 days. FUNDING Healthpoint Biotherapeutics.

Clinical and Economic Assessment of Diabetic Foot Ulcer Debridement with Collagenase: Results of a Randomized Controlled Study

BACKGROUND Despite significant advances, the treatment of diabetic foot ulcers (DFUs) remains a major therapeutic challenge for clinicians, surgeons, and other health care professionals. There is an urgent need for new strategies with clinically effective interventions to treat DFUs to reduce the burden of care in an efficient and cost-effective way. OBJECTIVE This randomized trial evaluated and compared the clinical effectiveness, tolerability, and costs of clostridial collagenase ointment (CCO) debridement to that of debridement using saline moistened gauze (SMG) and selective sharp debridement for the treatment of DFUs. METHODS Randomized, controlled, parallel group, multicenter, open-label, 12-week study of 48 patients with neuropathic DFUs randomized to 4 weeks of treatment with either CCO or SMG after baseline surgical debridement. The primary end point was the condition of the ulcer bed at the end of treatment as measured using a standardized wound assessment tool. Secondary end points were the percentage of reduction in wound area and therapeutic response rates. Adverse events were monitored for the tolerability analysis. In addition, a comparative cost-effectiveness analysis was performed from the perspective of the Centers for Medicare and Medicaid Services as a payer. RESULTS Both the CCO and SMG groups had significantly improved wound assessment scores after 4 weeks of treatment (CCO, -2.5, P = 0.007; SMG, -3.4, P = 0.006). Only CCO treatment resulted in a statistically significant decrease from baseline in the mean wound area at the end of treatment (P = 0.0164) and at the end of follow-up (P = 0.012). In addition, the CCO group exhibited a significantly better response rate at the end of follow-up compared with the SMG group (0.92 vs 0.75, P < 0.05). Reported adverse events were similar between the 2 treatment groups. None of the reported adverse events were considered to be related to treatment. The economic analysis indicated that the direct mean costs per responder in the physician office setting of care were

Durability of healing from spray‐applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: A 6‐month follow‐up

832 versus

Reappraising the phototoxicity of tretinoin: a report of four controlled clinical trials

1042 for the CCO group versus the SMG group, whereas the direct mean costs per responder in the hospital outpatient department setting were

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

1607 versus

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

1980. CONCLUSIONS CCO treatment provides equivalent debridement of DFUs similar to SMG while fostering better progress toward healing as measured by decreasing wound area over time and improved response rates at the end of follow-up. In addition, CCO yields a more favorable cost-effectiveness ratio in both the physician office and hospital outpatient department settings of care. ClinicalTrials.gov identifier: NCT01056198.

The effect of ankle range of motion on venous ulcer healing rates

Patients who participated in a Phase 2 trial of HP802‐247 for venous leg ulcers were invited to participate in this 24‐week follow‐up study to assess the durability of healing, document additional ulcer closures, and evaluate posttreatment safety. Consent was given by 90% (206/228), with 80% (183/228) completing all visits. Blinding was retained from the previous trial in which subjects had been randomized to vehicle or one of four cell therapy regimens. Visits were every 8 weeks. Among the 183 subjects, 43% (21/49) previously treated with cells and entering follow‐up with an open wound achieved closure, compared with 35% (7/20) previously treated with vehicle, while 10% (11/106) and 17% (3/18), respectively, experienced reopening of a previously closed wound. Subjects previously treated with cells closed more open wounds than those previously treated with vehicle (OR 1.39, 95% CI 0.47–4.10; p = 0.739), and less subjects with a previously closed wound reopened (OR 0.65, CI 0.16–2.60; p = 0.821); however, these findings were not statistically significant. At the final visit, the difference in proportion of subjects with wounds closed continued to favor the best dose from the prior trial (83% closed vs. 58%, delta 25%). Follow‐up beyond 12 weeks is necessary to evaluate the full benefit of this therapy, as treatment with cells may provide stimulus toward healing that persists for up to several weeks following the last application. The results show that the greater proportional benefit achieved by HP802‐247 relative to standard care after 12 weeks of treatment persists over a meaningful timeframe.

Development of a health care personnel handwash with 6-hour persistence

Background: Retinoids are photoreactive molecules found in skin and retinal tissue. The use of retinoids in pharmacologic doses, applied topically, raises the potential of phototoxicities. Recent review articles and current US drug labeling indicate that tretinoin is a phototoxin. In developing a new formulation of topical all‐trans‐retinoic acid (tretinoin), formal testing of dermal photoreactions was therefore undertaken.

Allogeneic fibroblasts and keratinocytes for venous leg ulcers – Authors' reply

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.

Cell Persistence of Allogeneic Keratinocytes and Fibroblasts Applied in a Fibrin Matrix to Acute, Full Thickness Wounds

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.