The effects of REGRANEX on the incidence of and time to complete healing in lower extremity diabetic neuropathic ulcers were assessed in four randomized controlled studies (Studies 1-4). Of 922 subjects studied, 478 received either REGRANEX 0.003% or 0.01%. All study participants had lower extremity diabetic neuropathic ulcers that extended into the subcutaneous tissue or beyond [Stages III and IV of the International Association of Enterostomal Therapy (IAET) guide to chronic wound staging]. Ninety-three percent of the subjects enrolled in these four trials had foot ulcers. The remaining 7% of the subjects had ankle or leg ulcers. The diabetic ulcers were of at least 8 weeks duration and had an adequate blood supply (defined as T cpO 2> 30 mm Hg). In the four trials, 95% of the ulcers measured in area up to 10 cm 2, and the median ulcer size at baseline ranged from 1.4 cm 2to 3.5 cm 2. 

All treatment groups received a program of good ulcer care consisting of initial complete sharp debridement, a non-weight-bearing regimen, systemic treatment for wound-related infection if present, moist saline dressings changed twice a day, and additional debridement as necessary. REGRANEX 0.003% or 0.01% or placebo was applied once a day and covered with a saline moistened dressing. After approximately 12 hours, the gel was gently rinsed off and a saline moistened dressing was then applied for the remainder of the day. Subjects were treated until complete healing, or for a period of up to 20 weeks. Subjects were considered a treatment failure if their ulcer did not show an approximately 30% reduction in initial ulcer area after eight to ten weeks of therapy.

Results of the primary endpoints from 4 independent studies, shown as incidence of complete ulcer closure within 20 weeks, for all treatment arms are given in Figure 1. In each study, REGRANEX in conjunction with good ulcer care was compared to placebo gel plus good ulcer care or good ulcer care alone.

In Study 1, a multicenter, double-blind, placebo-controlled trial of 118 subjects, the incidence of complete ulcer closure for REGRANEX 0.003% (n=61) was 48% versus 25% for placebo gel (n=57; p=0.02, logistic regression analysis).

In Study 2, a multicenter, double-blind, placebo-controlled trial of 382 subjects, the incidence of complete ulcer closure for REGRANEX 0.01% (n=123) was 50% versus 36% for REGRANEX 0.003% (n=132) and 35% for placebo gel (n=127). Only REGRANEX 0.01% was significantly different from placebo gel (p=0.01, logistic regression analysis).

The primary goal of Study 3, a multicenter controlled trial of 172 subjects, was to assess the safety of vehicle gel (placebo; n=70) compared to good ulcer care alone (n=68). The study included a small (n=34) REGRANEX 0.01% arm. Incidences of complete ulcer closure were 44% for REGRANEX, 36% for placebo gel and 22% for good ulcer care alone.

In Study 4, a multicenter, evaluator-blind, controlled trial of 250 subjects, the incidences of complete ulcer closure in the REGRANEX 0.01% arm (n=128) (36%) and good ulcer care alone (n=122) (32%) were not statistically different.

In general, where REGRANEX was associated with higher incidences of complete ulcer closure, differences in the incidence first became apparent after approximately 10 weeks and increased with continued treatment (Table 3).

In a 3-month follow-up period where no standardized regimen of preventative care was utilized, the incidence of ulcer recurrence was approximately 30% in all treatment groups, demonstrating that the durability of ulcer closure was comparable in all treatment groups.