EPISALVAN Gel Ref.[50043] Active ingredients: Betulin

Pharmacotherapeutic group: Preparation for treatment of wounds and ulcers
ATC code: D03AX13

Mechanism of action and pharmacodynamic effects

The active substance accelerated re-epithelialization in an in vitro wound scratch assay using human primary keratinocytes at the dosage of 1 μg/ml, and in a porcine ex vivo wound healing model at the dosage of 10 µg/ml. The precise mechanism of action of the active substance in wound healing in humans is not known.

Clinical efficacy and safety

Three Phase III studies were conducted to assess the efficacy and safety of Episalvan in the treatment of partial thickness wounds of the skin: two studies which investigated split-thickness skin graft donor site wounds, which included a total of 219 patients (ITT: N=217), and one further study in 61 patients with Grade 2a burn wounds (ITT: N=57). Patients with deeper burn wounds (Grade 2b) were not included.

The 219 patients with split-thickness skin graft donor site wounds had a mean age of 53 years; their donor site mean wound size was 81.5 cm². In the burn wound study with 61 patients, the mean study wound area was 216 cm²; the total burn injury of these patients was larger and affected 5.8% of the total body surface area.

The Phase III studies were blindly evaluated, prospective, intra-individually controlled, randomised, multicentre trials. The target wound area of each patient was divided into two treatment areas of approximately the same size; the treatment allocation to the two halves of the wound (distal vs. proximal) was determined by randomisation (in the burn trial, two similar wounds could be used). Episalvan plus wound dressing was applied to half of the wound area, and the same kind of nonadhesive wound dressing alone was applied to the other half as the control in the split-thickness skin graft donor site studies. In the Grade 2a burn wound study an octenidine containing antiseptic wound gel and fatty gauze dressing were used as control. Application was at each wound dressing change every third to fourth day until full wound closure up to 28 days for the split-thickness skin graft trials, and every other day up to 21 days for the Grade 2a burn trial. Photographs of the wound were taken at each visit for the blinded evaluation.

The primary endpoint for the two split-thickness skin graft trials was the intra-individual difference in time to wound closure (at least 95% epithelialisation) based on blinded photo evaluations. Median time to wound healing was 14 days. Wound halves treated with Episalvan healed faster than the wound halves treated with standard of care (mean 1.1 days according to primary endpoints, p<0.0001, two-sided paired t-test).

Table 2. Overview of efficacy results: intra-patient difference in time to wound closure:

^a Based on 2-sided paired t-test
Intention-to-treat (ITT) data set.
‘Primary’ vs. ‘secondary’ blinded read: In the primary blinded read evaluation a rigorous quality check was implemented to assure blinding of the observers. In consequence a substantial number of photographs were excluded and not presented in the primary blinded read because of apparent gel residues. The secondary blinded read was conducted with all photographs presented to the blinded observers.
‘Very conservative calculation’ means that the first observation of wound closure was taken as time of wound closure. Difference in time to wound closure was set to 0 for photo series rated as ‘not evaluable’. If wound closure was not observed in a wound half photo series, it was calculated to have occurred one day after the last photograph in the series.
‘Less conservative calculation’ differs from the ‘very conservative calculation’ in one aspect: If wound closure was not observed in a wound half photo series, it was calculated to have occurred not one day, but approximately 3 days later (the mean time interval between wound dressing changes in the studies).
CI: 95% confidence interval; MTWDC: mean time to wound dressing change; N: number of patients in the analysis set; STSG Split-thickness skin graft.

The primary endpoint for the Grade 2a burn wound trial was the percentage of patients with earlier healing (at least 95% epithelialisation) based on blinded photo evaluations. Median time to wound healing was 7.3 days. Of the patients with a between-treatment difference in wound healing (N=35), the percentage of patients who showed earlier healing (primary endpoint) of their Episalvan treated wound half (85.7% [95% CI: 69.7%, 95.2%]) was higher than those who showed earlier healing of their standard of care control treated wound half (14.3% [95% CI: 4.8%, 30.3%]) (p<0.0001, binomial test).

In follow-up visits at 3 months and 12 months after the day of surgery or of burn injury the treated wound halves were found to be equal in the majority of patients with regard to pigmentation, redness, texture and hair growth of the regenerated epidermis. For a subset of patients blinded photo-evaluation indicated better results for Episalvan treated wound halves compared to standard of care in pigmentation, redness and texture of the former wound areas.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Episalvan in one or more subsets of the paediatric population for the treatment of skin injuries (see section 4.2 for information on paediatric use).