Intralesional injections of Citoprot-P (recombinant human epidermal growth factor) in advanced diabetic foot ulcers with risk of amputation

Abstract

To investigate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) in advanced diabetic foot ulcers (DFU) A double-blind trial was carried out to test two rhEGF dose levels in type 1 or 2 diabetes patients with Wagner's grade 3 or 4 ulcers, with high risk of amputation. Subjects were randomised to receive 75 (group I) or 25 mug (group II) rhEGF through intralesional injections, three times per week for 5-8 weeks together with standardised good wound care. Endpoints were granulation tissue formation, complete healing and need of amputation. Safety was assessed by clinical adverse events (AEs) and laboratory evaluations. Forty-one patients were included. After 5-8 weeks of treatment, 83% patients in the higher dose group and 61% in group II achieved useful granulation tissue covering more than 98% of the wound area. At long-term assessment, 13 (56.5%) patients healed in group I and 9 (50%) in group II. The mean time to complete healing in group I was 20.6 weeks (95% CI: 17.0-24.2) and 19.5 weeks (16.3-22.7) in group II. After 1-year follow-up, only one patient relapsed. Amputation was not necessary in 65% and 66.7% of groups I and II, respectively. The AEs rates were similar. The most frequent were sepsis (33%), burning sensation (29%), tremors, chills and local pain (25% each). rhEGF local injection enhances advanced DFU healing and reduces the risk of major amputation. No dose dependency was observed.

Figure 1

Study flowchart.

Figure 2

Comparative photos of some patients: (A, B, C) patient IA‐01; (D, E, F) patient IA‐11. (A, D) before treatment; (B, E) at the end of treatment; (C, F) after 1‐year follow‐up.

Figure 3

Representative histological image of neuropathic (A, B) and ischaemic (C, D) ulcers. Samples were collected just before the first Citoprot‐P infiltration (A, C) and after the fifth week of treatment. (B, D). Haematoxylin/eosin staining, magnification ×10. (A) Neuropathic lesion before treatment. At this stage an acute inflammatory infiltration is observed as the only ingredient of the granulation process. Inflammation is diffuse and not polarised. No evidences of matrix production or neovessels are detected. (B) At the fifth week, the matrix appears dense, consolidated and indurated by compact collagen material. The presence of fibroblastoid cells is largely increased. (C) Ischaemic lesion before treatment. Wound matrix appears fibrinoid, non organised and rich in cell and tissue debris. Granulation and inflammatory polarisation processes have not yet set forth. (D) At the fifth week of treatment, the wound matrix looks consolidated, organised and with well‐shaped vessels showing luminal blood (indicated by arrows).