NorLeu3-A(1-7) stimulation of diabetic foot ulcer healing: results of a randomized, parallel-group, double-blind, placebo-controlled phase 2 clinical trial

Abstract

This randomized, double-blind, placebo-controlled Phase 2 clinical trial explored NorLeu(3)-A(1-7) (DSC127) safety and healing efficacy in diabetic foot ulcers. Patients with chronic, noninfected, neuropathic, or neuroischemic plantar Wagner Grade 1 or 2 foot ulcers (n = 172) were screened for nonhealing. Subjects were randomized to receive 4 weeks' once-daily topical treatment with 0.03% DSC127 (n = 26), 0.01% DSC127 (n = 27), or Placebo (n = 24), followed by 20 weeks' standard of care. DSC127 was assessed for safety (including laboratory values and adverse events), primary efficacy (% ulcers completely epithelialized at Week 12), and durability of effect. Baseline, demography, and safety parameters were compared between intent-to-treat groups and were comparable. Dose-response curves for DSC127 effect on % area reduction from baseline at Week 12 (40% placebo; 67% 0.01% DSC127; 80% 0.03% DSC127) and 24 (23% placebo; 53% 0.01% DSC127; 95% 0.03% DSC127) followed a log-linear pattern for both intent-to-treat and per-protocol populations. Covariate analysis compared reduction in ulcer area, depth, and volume from baseline; reductions in the 0.03% DSC127 group were greater at Weeks 12 and 24. Placebo-treated ulcers healed in a median 22 weeks vs. 8.5 weeks for 0.03%DSC127 (p = 0.04). This study provides preliminary evidence that DSC127 is safe and effective in accelerating the healing of diabetic foot ulcers.

Conflict of interest statement

Conflict of Interest: Dr. Rodgers and Dr. diZerega are the inventors of NorLeu3-A(–7). The other authors have no conflicts.

© 2012 by the Wound Healing Society.

Figures

Figure 1

Consort Diagram Describing Study Subject Disposition.

Figure 2

Cumulative proportion of ulcers that healed during the 24-week study interval for the subjects in the per protocol population that received either Placebo vehicle (n=24), 0.01% DSC127 (n=24), or 0.03% DSC127 (n=26). Subjects were followed on a weekly basis through study Week 12 (Treatment Phase) and for an additional 12 weeks (Durability Phase). Note subjects with ulcers healed before Week 12 were followed for an additional 12 weeks to assess durability of the healed ulcer. At Week 4, there was a relative increase in the proportion of ulcers healed in the 0.03% DSC127 group compared with the Placebo and 0.01% DSC127 groups.

Figure 3

Dose-response curves for DSC127 effect on % area reduction from baseline at Weeks 12 and 24 followed a log-linear pattern similar for ITT and PP populations.

Figure 4

The 0.03% DSC127 Group had a greater reduction in ulcer area from baseline than the Placebo group at 12 and 24 weeks and in both PP and ITT populations. Some Placebo-treated ulcers enlarged between Week 12 and Week 24, while all ulcers treated with 0.03% DSC127 continued to heal. There was no difference between the 0.01% DSC127 group and the Placebo-treated control (data not shown). Analysis was conducted using a repeat measure mixed model, with treatment and visit as main effects, treatment visit interaction effect, and baseline as covariate.

Figure 5

This figure shows the median study week that the ulcers healed for the subjects in the PP and ITT populations following treatment with either Placebo vehicle or 0.03% DSC127. There was a significant reduction in time to ulcer healing in the 0.03% DSC127 group as compared to the Placebo vehicle group for the PP population (Kaplan Meier estimated median time to heal at Week 24; p-value from the log rank test for the ITT and PP Population).

Figure 6

Cumulative proportion of ulcers that healed during the 12-week Treatment Phase of the study for the subjects in the ITT population that received treatment with Placebo vehicle (n=24) and 0.03% DSC127 (n=26), as well as for the PP population (Placebo, n=21; 0.03% DSC127, n=20). At Week 12 there was a relative increase in the proportion of ulcers that healed in the group that received 0.03% DSC127 compared to the Placebo group for both the ITT (n=26, p=0.148) and the PP (n=20, p=0.089) populations. The cumulative proportion of ulcers that healed during the 24-week study showed a significant increase in the percent of ulcers that healed in the PP group (Placebo, 52% vs. 0.03% DSC127, 85%, p<0.05) and approached significance in the ITT population (Placebo, 45% vs. 0.03% DSC127, 73%, p=0.053). Analysis was conducted using a logistic model with treatment as a main effect.