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OBJECTIVE-To determine if partial wound closure surrogate markers proposed for neuropathic, small diabetic foot ulcers (DFUs) can be extended to advanced lesions and if the development of granulation tissue can be used to predict complete healing.
RESEARCH DESIGN AND METHODS-Data from two multicenter, double-blind, randomized clinical trials (one of them placebo controlled) that used intralesional recombinant human epidermal growth factor (rhEGF) to promote granulation and healing were used. For confirmation in a larger sample from common clinical practice, the results of an active postmarketing surveillance of rhEGF treatment of DFUs in 60 healthcare units was included. The surrogates evaluated were percent area change, log healing rate, ratio of log areas, and percent of granulation tissue covering the wound area. The tests used were surrogate final end point correlation, receiver operating characteristic curves to discriminate healers from nonhealers, validation tests using logistic regression models, and the proportion-mediated estimation.
RESULTS-Two weeks >50% granulation, end of treatment >75% granulation, and 16.1% area change showed significant predictive value (>70% correct classification) for final wound closure. The granulation-based variables fulfilled the criterion that the effect of rhEGF treatment on wound closure was mediated by the surrogate.
CONCLUSIONS-This work provides the first evidence for the use of granulation tissue development as a predictor of wound healing in advanced DFUs. These results can be useful for clinical trial design, particularly during the exploratory phase of new products.
Diabetes Care 36:210-215, 2013
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Drag development is a continuous and complicated decision-making process. The use of surrogate end points provides a powerful tool to accel-erate and make decisions more efficient. It reduces the cost and duration of clinical trials during the exploratory phase of drag development and can be accepted by regulatory agencies (1). Specifically for diseases with risk of death or severe incapacity, this issue acquires vital importance. Surrogate end points can be measured earlier and more frequently, so the adherence to treatment is greater and less influenced by concomitant interventions than the final outcome.
Some authors (2-4) have demonstrated that variables based on early wound area reduction (i.e., after 4 weeks of treatment), such as the percent change in area, log healing rate, or log area ratio, can be used as surrogate end points for later complete...