title: Granulation response and partial wound closure predict healing in clinical trials on advanced diabetes foot ulcers treated with recombinant human epidermal growth factor.
abstract: 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.
  
  
  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.
authors.affiliation: Center for Genetic Engineering and Biotechnology, Clinical Research Direction, Havana, Cuba. carmen.valenzuela@cigb.edu.cu
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Valenzuela-Silva
authors.forename: Ángela D
authors.initials: ÁD
authors.lastname: Tuero-Iglesias
authors.forename: Elizeth
authors.initials: E
authors.lastname: García-Iglesias
authors.forename: Odalys
authors.initials: O
authors.lastname: González-Díaz
authors.forename: Amaurys
authors.initials: A
authors.lastname: Del Río-Martín
authors.forename: Isis Belkis
authors.initials: IB
authors.lastname: Yera Alos
authors.forename: José I
authors.initials: JI
authors.lastname: Fernández-Montequín
authors.forename: Pedro A
authors.initials: PA
authors.lastname: López-Saura
mesh_terms: D000368:Aged; D017719:Diabetic Foot / Q000188:drug therapy*; D004311:Double-Blind Method; D004815:Epidermal Growth Factor / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D004815:Epidermal Growth Factor