Surrogate End Points for the Treatment of Diabetic Neuropathic Foot Ulcers

Abstract

OBJECTIVE -The goal of this study was to determine whether surrogate markers based primarily on changes in the size of a wound can be used to correctly predict which individuals with diabetic neuropathic foot ulcers will heal after 12 or 20 weeks of care. RESEARCH DESIGN AND METHODS-This is a retrospective cohort study using the Curative Health Services database. As many as 39,918 neuropathic wounds on 20,213 individuals with diabetes were evaluated. Seven surrogates based on changes in wound size were evaluated.RESULTS -Surrogates measured after 2, 4, or 8 weeks of care and based on percentage change in area, log healing rate, and log area ratio discriminated well with respect to differentiating between those wounds that healed and those that did not heal by the 12th or 20th week of care. For example, after 4 weeks of care, the percentage change in area can be used to correctly discriminate 76% of the time between those that healed and those that did not by the 20th week of care.CONCLUSIONS -The surrogate markers can be used in clinical trials such that shorter and smaller trials can be conducted with reasonable accuracy in order to determine which potential new therapeutics should be studied in larger, longer trials. In addition, the surrogates may also benefit clinicians when they are trying to decide whether a wound care therapy will ultimately be successful. Diabetes Care 26:1696 -1700, 2003C linical trials of therapies for individual patients with diabetic neuropathic foot ulcers are limited by the prolonged time period needed to reach the ultimate outcome, a healed wound. In fact, randomized clinical trials usually follow subjects for between 12 and 20 weeks. As a result, the trials are very expensive and patients may be exposed to potentially nonefficacious experimental agents for prolonged periods of time. A valid surrogate marker of complete wound healing would minimize the number of subjects exposed to a potentially unsuccessful treatment and minimize the time required to develop a successful new treatment, thereby improving the efficiency with respect to cost and design needed to successfully screen potential therapeutic agents. Finally, a valid surrogate marker allows for the identification of patients who are not likely to heal by standard methods early in the patient's course of treatment, thereby expediting referral to specialty centers or expediting initiation of stepped treatment algorithms.More than 10 years ago, the rate of healing for patients with diabetic foot ulcers was shown by Pecoraro et al.(1) to statistically differentiate between those patients who eventually healed and those who did not. Studies have also shown that for other chronic wounds, the percent change in the wound area over the initial 4 weeks of therapy, as well as the rate of healing over the initial 4 weeks of therapy, may predict who will ultimately heal (2-8). However, most of these studies were small and did not evaluate diabetic foot ulcers. Surrogate markers require extensive epidemiologic testing to ensure validit...

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