Active post-marketing surveillance of the intralesional administration of human recombinant epidermal growth factor in diabetic foot ulcers

Abstract

Background: After several exploratory and confirmatory clinical trials, the intralesional administration of human recombinant epidermal growth factor (hrEGF) has been approved for the treatment of advanced diabetic foot ulcers (DFU). The aim of this work was to evaluate the effectiveness and safety of this procedure in medical practice.

Methods: A prospective, post-marketing active pharmacosurveillance was conducted in 41 hospitals and 19 primary care polyclinics. Patients with DFU received hrEGF, 25 or 75 μg, intralesionally 3 times per week until complete granulation of the ulcer or 8 weeks maximum, adjuvant to standard wound care. Outcomes measured were complete granulation, amputations, and adverse events (AE) during treatment; complete lesion re-epithelization and relapses in follow-up (median: 1.2; maximum 4.2 years).

Results: The study included 1788 patients with 1835 DFU (81% Wagner's grades 3 or 4; 43% ischemic) treated from May 2007 to April 2010. Complete granulation was observed in 76% of the ulcers in 5 weeks (median). Ulcer non-ischemic etiology (OR: 3.6; 95% CI: 2.8-4.7) and age (1.02; 1.01-1.03, for each younger year) were the main variables with influence on this outcome. During treatment, 220 (12%) amputations (171 major) were required in 214 patients, mostly in ischemic or Wagner's grade 3 to 5 ulcers. Re-epithelization was documented in 61% of the 1659 followed-up cases; 5% relapsed per year. AE (4171) were reported in 47% of the subjects. Mild or moderate local pain and burning sensation, shivering and chills, were 87% of the events. Serious events, not related to treatment, occurred in 1.7% of the patients.

Conclusions: The favorable benefit/risk balance, confirms the beneficial clinical profile of intralesional hrEGF in the treatment of DFUs.

Figure 1

Risk-benefit analysis. Given p(x | benefit) by the probability distribution function for benefit (complete granulation) and p(x | risk) by the probability distribution function for risk (moderate and severe adverse events or amputation) then the Bayes Factor (B_br) is: $B_{\mathit{br}}=\frac{p\left(x|\mathit{benefit}\right)}{p\left(x|\mathit{risk}\right)}$ representing a summary of the evidence provided by the data in favor of benefit (red), as opposed to risk (blue). A value larger than 1 means a favorable benefit-risk ratio. In this case: Bayes factor = 5.4; difference between probabilities: 61% (95% CI: 59%–64%).

Figure 2

Kaplan-Meier curves for survival time according to A) whether the ulcer healed or not; B) ulcer etiology or C) whether the affected limb was amputated or not.