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Study Design
A prospective, randomized, controlled, multi-center study was conducted to evaluate the safety and efficacy of Apligraf in comparison to an Active Control treatment, saline moistened gauze in the treatment of diabetic neuropathic foot ulcers. The study population included consenting patients who were between 18 and 80 years old, with a 1cm2 - 16cm2 full-thickness foot ulcer which extended through the dermis but without tendon, muscle or bone exposure and of neuropathic etiology of at least two weeks duration, located on the plantar, medial or lateral surface of the foot at least 2cm away from any other ulcers on the same extremity.

The study participants were required to be diagnosed diabetics with type 1 or type 2 diabetes, a HbA1C between 6% and 12% and available for six-month follow-up. Patients were excluded for ulcers with tracts or tunnels, a clinical infection at the study ulcer site, ABI > 0.65, active Charcot's foot at the study extremity, a study ulcer that healed > 30% from post-debridement at Study Day -7 to Day 0, renal dialysis, history of alcohol or substance abuse within one year, acute or chronic hepatitis, receiving corticosteroids, immuno-suppressive agents, radiation therapy or chemotherapy one month prior to study enrollment, or enrollment in clinical studies evaluating a device within the past thirty days or within the past three months for pharmaceuticals or biologics.

Two hundred and seventy-seven patients were entered into the screening phase of the study. Sixty-nine patients did not meet inclusion/exclusion criteria. Of the 208 patients treated in the study, 112 received Apligraf and 96 received Active Control therapy. Twenty-two patients per group were discontinued prior to Study Month 6. Patients received 12 weeks of treatment and three additional months of follow-up. Complete wound closure was evaluated by or on 12 weeks. Patients were evaluated weekly for the first 12 weeks with mid-week visits for dressing changes from Day 0 through Week 5 and follow-up visits at Months 4, 5 and 6.

Both treatment groups received good ulcer care consisting of sharp debridement, saline moistened dressings and a non-weight bearing regimen. All patients in the Apligraf treatment group received Apligraf at Day 0. At Study Weeks 1, 2, 3 and 4, if Apligraf coverage was less than 100% and the wound was not progressing to healing then an additional Apligraf unit was applied. A maximum of five Apligraf applications was allowed. The Apligraf was dressed with saline-moistened non-adherent dressing, tape, dry gauze, petrolatum gauze and gauze wrap. The Control treated patients received saline-moistened non-adherent dressing, tape, saline moistened gauze, dry gauze, petrolatum gauze and gauze wrap from Day 0 through Study Week 4.

Patients in both treatment groups who did not heal by Study Week 5 were treated with saline-moistened non-adherent gauze, dry gauze, petrolatum gauze and gauze wrap from Study Week 5 through Study Week 12. The patients were instructed to change this dressing two times per day without disturbing the saline moistened non-adherent gauze.

Patients were instructed to avoid weight bearing on the affected foot throughout the duration of the study. During the first six weeks patients were instructed to use crutches or a wheelchair. Each patient was fitted with a customized tri-density sandal. These sandals were to be worn throughout the entire study.

In keeping with good medical practice, early detection and treatment of ulcer infection using standard procedures was advised.

Study Endpoints:
The primary study endpoint was 100% study wound closure by or on Study Week 12. 'Complete Wound Closure' was defined as full epithelialization of the wound with the absence of drainage. 'Epithelialization' was defined as a thin layer of epithelium visible on the open wound surface.

The primary efficacy endpoint was examined using a time to 100% study wound closure analysis that evaluated the incidence of 100% study wound closure per unit time. A categorical analysis that evaluated the incidence of 100% study wound closure by or on Study Week 12 was performed as a supporting analysis.

Secondary endpoint measurements included: undermining, maceration, exudate, granulation, eschar, fibrin slough, and overall assessment from baseline to the six-month visit.