One-year safety, healing and amputation rates of Wagner 3-4 diabetic foot ulcers treated with cryopreserved umbilical cord (TTAX01).

An open label, multicenter 16-week trial of cryopreserved human umbilical cord (TTAX01) was previously undertaken in 32 subjects presenting with a Wagner grade 3 or 4 diabetic foot ulcer, with 16 (50%) of these having confirmed closure following a median of one product application (previous study). All but two subjects (30/32; 94%) consented to participate in this follow-up study to 1-year postexposure. No restrictions were placed on treatments for open wounds. At 8-week intervals, subjects were evaluated for adverse events (AEs) and wound status (open or closed). Average time from initial exposure to end of follow-up was 378 days (range 343-433), with 29 of 30 (97%) subjects completing a full year. AEs were all typical for the population under study, and none were attributed to prior exposure to TTAX01. One previously healed wound re-opened, one previously unconfirmed closed wound remained healed, and nine new wound closures occurred, giving 25 of 29 (86.2%) healed in the ITT population. Three of the new closures followed the use of various tissue-based products. Three subjects whose wounds were healed required subsequent minor amputations due to osteomyelitis, one of which progressed to a major amputation (1/29; 3.4%). One additional subject underwent two minor amputations prior to healing. Overall, the study found TTAX01 to be safe in long-term follow-up and associated with both a low rate of major amputation and a higher than expected rates of healing.

An open-label trial of cryopreserved human umbilical cord in the treatment of complex diabetic foot ulcers complicated by osteomyelitis.

Clinical trials of potential new therapies for diabetic foot ulcers rarely enroll patients whose wounds extend to muscle, fascia, or bone with clinical and radiographic evidence of underlying osteomyelitis. An open-label, multicenter trial of cryopreserved human umbilical cord (TTAX01) was undertaken in 32 subjects presenting with such complex wounds with a mean duration of 6.1 ± 9.0 (range: 0.2-47.1) months and wound area at screening of 3.8 ± 2.9 (range: 1.0-9.6) cm2 . Aggressive surgical debridement at baseline resulted in 17 minor amputations and an increase in mean wound area to 7.4 ± 5.8 (range: 1.1-28.6) cm2 . All subjects were placed on systemic antibiotics for at least 6 weeks in conjunction with baseline application of TTAX01. Repeat applications were made at no less than 4-week intervals over the 16-week trial. Initial closure occurred in 18 of 32 (56%) wounds, with 16 (50%) of these having confirmed closure in 16 weeks with a median of one-product application. Cases with biopsy confirmed osteomyelitis (n = 20) showed initial closure in 12 (60%) wounds and confirmed closure in 10 (50%) wounds. Four of the five ulcers presenting as recurrences experienced confirmed closure. Mean overall time to healing was 12.8 ± 4.3 weeks. Mean wound area reduction from baseline was 91% for all wounds. Of the 16 wounds without confirmed closure during the 16-week treatment period, five (31.3%) achieved 99-100% wound area reduction by their final visit. The product was well tolerated. Two minor amputations occurred during the study period due to recurrent or persistent osteomyelitis; however, there were no major amputations.

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.

The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-arrested allogeneic keratinocytes and fibroblasts.

OBJECTIVE: To examine patient and wound variables presumed to influence healing outcomes in the context of therapeutic trials for chronic venous leg ulcers. METHODS: This double-blind, vehicle-controlled study was conducted with randomized assignment to one of four cell therapy dose groups (n = 46, 43, 44, 45) or vehicle control (n = 50). A 2-week run-in period was used to exclude rapid healers and those with infection or uncontrolled edema. This was a multicenter (ambulatory, private, hospital-based and university-based practices, and wound care centers in North America) study. Adults ≥ 18 years old with chronic venous insufficiency associated with an uninfected venous leg ulcer (2-12 cm(2) area, 6-104 weeks' duration) were included in the study. Excluded were pregnant or lactating women, wounds with exposed muscle, tendon or bone, patients unable to tolerate compression bandages, or patients who had exclusionary medical conditions or exposure to certain products. Exclusion during run-in included patients with infection, uncontrolled severe edema or with healing rates ≥ 0.349 cm/2 wk. Screen fail rate was 37% (134/362), and the withdrawal rate was~10% (23 of 228). Growth-arrested neonatal dermal fibroblasts and keratinocytes were delivered via pump spray in a fibrin sealant-based matrix, plus a foam dressing and four-layer compression bandaging. Treatment continued for 12 weeks or until healed, whichever occurred first. Patient demographic and wound-related variables were evaluated for influence on complete wound healing in all patients, as well as the subsets of treated and control patients. RESULTS: Wound duration (P = .004) and the presence of specific quantities of certain bacterial species (P < .001) affected healing in the vehicle group, while healing in the cell-treated groups was influenced by wound duration (P = .012), wound area (P = .026), wound location (P = .011), and specific quantities of certain bacterial species (P = .002). Age, sex, race, diabetes, HbA1C, peripheral neuropathy, and serum prealbumin did not significantly affect healing. Body mass index was positively associated with healing in cell-treated patients. CONCLUSIONS: Wound duration is a quantifiable surrogate for one or more undefined variables that can have a profound negative effect on venous leg ulcer healing. Although cell therapy overcame barriers to healing, the only specific barrier identified was the presence of certain bacterial species. Interventional trials of potentially effective new therapies can be most informative when patients with suspected barriers to healing are included. The specific measurement of candidate barriers such as microbial pathogens, wound inflammatory state, and fibroblast function should be considered in future randomized trials to improve our understanding of the basis for chronicity.

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.

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.