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

Abstract

Conclusion: Venous ulcers can be healed with a spray formulation of allogeneic neonatal keratinocytes and fibroblasts without the need for tissue engineering. Summary: Venous insufficiency results from venous valve dysfunction or venous obstruction, or both, of the superficial or deep veins. Subsequent venous hypertension results in edema, tissue inflammation, and microcirculatory destruction. The end result can be a venous ulcer that can be notoriously difficult to heal, with many not responding to standard compression therapy. Surgery can result in reduced recurrence of venous ulceration, but no interventions on veins themselves have been shown to speed healing of chronic venous ulcers (Barwell JR, et al, Lancet 2004;363:1854-9). Nonsurgical therapies for venous ulceration have used tissue constructs of allogeneic adult keratinocytes. Such tissue constructs are fragile and have required incorporation of one or more dermis-like substitutes for delivery of the keratinocytes to the wound. In a large randomized controlled trial, repeated application of a tissue construct demonstrated an improvement in venous ulcer healing compared with standard compression therapy (Falanga V, Arch Dermatol 1998;134;293-300). However, allogeneic cells do not engraft. It is therefore unclear if an elaborate tissue construct is actually needed. HP802-247 is composed of cryopreserved allogeneic growth-arrested fibroblasts and keratinocytes derived from neonatal foreskin (Goedkoop R, Dermatol 2010;220:114-20). Success of foreskin-derived allogeneic keratinocytes in a two-component fibrin glue suggest that these cells can deliver essential growth factors to a nonhealing wound without the need for an elaborate tissue construct. In this study, the authors delivered growth-arrested allogeneic neonatal keratinocytes and fibroblasts to nonhealing venous ulcers using a spray, without an elaborate tissue construct. Outpatients from 28 centers in the United States and Canada with up to three ulcers, venous reflux confirmed by duplex ultrasound imaging and sufficient arterial flow for healing were randomized in a phase 2, double-blind, placebo-controlled trial. The study required that one ulcer measure between 2 and 12 cm in area and had persisted for 6 to 104 weeks. Randomization was by computer-generated block method in a 1:1:1:1:1 ratio to 5.0 × 105 cells/mL every 7 days or every 14 days, or 0.5 × 105 cells/mL every 7 days or every 14 days, or to vehicle alone every 7 days. All experimental groups received four-layer compression bandages. Trial monitors, trial sponsors, investigators, center personal, and patients were all masked to treatment allocation. The primary end point was the mean percentage change in wound area at the end of 12 weeks. Analysis was by intention to treat. There were 45 patients assigned to 5.0 × 105 cells/mL every 7 days, 44 patients to 5.0 × 105 cells/ mL every 14 days, 43 patients to 0.5 × 105 cells/mL every 7 days, 46 patients to 0.5 × 105 cells/mL every 14 days, and 50 patients to vehicle alone. There were 205 patients who completed all required study visits. Primary outcome analysis demonstrated greater mean reduction in wound area associated with active treatment compared with vehicle (P = .0446), with the dose of 0.5 × 105 cells/mL every 14 days showing the largest improvement compared with vehicle (15.98%, 95% confidence interval, 5.56-26.41; P = .0028). Adverse events were the same in all groups, with new skin ulcers and cellulitis occurring in >5% of patients. Comment: This was a large well-conducted randomized trial suggesting benefit in healing of venous leg ulcers with a spray application of allogeneic cells. This study, combined with previous work, suggested that allogeneic cell therapy for venous leg ulcers is likely to be effective. A larger study of the optimum dose of HP802-247 compared with standard therapy for venous leg ulcers seems indicated.