Birkenrindenextrakt (1) – Filsuvez®

• Clinical trials
  • The pharmaceutical manufacturer submits data from the multicentre, double-blind, randomised, placebo-controlled, marketing authorisation-supporting Phase III trial BEB-13 (hereinafter referred to as the EASE trial) for the benefit assessment.

Children, adolescents and adults aged 6 months and over with wounds associated with dystrophic or junctional epidermolysis bullosa

• In summary, the additional benefit of birch bark extract is assessed as follows: for children, adolescents and adults aged 6 months and over with wounds associated with dystrophic or junctional epidermolysis bullosa, there is a hint of a minor additional benefit.
• Overall, there is a hint of a minor additional benefit from birch bark extract.
• The certainty of the evidence is therefore classified as ‘hint’.
• mortality
  • Fatalities were recorded in the EASE study as part of the safety assessment.
  • No deaths occurred.
• Morbidity – complete wound closure
  • Against this background, complete wound closure represents a patient-relevant endpoint in the present therapeutic indication.
  • The endpoint of wound closure was defined in the EASE study as the first occurrence of complete re-epithelialisation without exudate in the predefined EB target wound and refers to the wound status of the EB target wound, which was selected at baseline based on the target wound criteria (superficial wound measuring 10–50 cm² and aged ≥ 21 days to < 9 months, not located in the anogenital region).
  • Operationalisation via clinical assessment of the wound is therefore considered the most appropriate method of measuring wound closure.
  • For the endpoint of first complete wound closure of the EB target wound within 45 days as assessed clinically, there is a statistically significant difference between birch bark extract and placebo.
  • Due to uncertainties arising from a tipping-point analysis of the primary analysis, as well as regarding the persistence of complete wound closure, this endpoint is subject to uncertainty.
  • A tipping-point analysis of the primary analysis shows that the effect estimate is subject to uncertainties.
  • Depending on the scenario, the result for this endpoint was no longer significant when as few as one person was replaced, and certainly by the time three people had been replaced.
  • For the majority of wound closures recorded in the primary analysis, no confirmation could be documented after 7 days as part of the supportive analysis.
• Morbidity – Wound status – Change in EB target wound size
  • The proportion of patients with a closed wound or a wound that had improved compared with baseline was recorded both according to clinical assessment in combination with a patient self-assessment and according to a blinded assessment based on photographic documentation, and was evaluated post hoc.
  • Uncertainties remain, as it is unclear how patients’ self-assessment of wound status was conducted and which wound characteristics were taken into account in the assessment of wound improvement.
  • As no difference between the treatment groups was observed either in the present endpoint regarding the change in EB target wound size or in other endpoints such as pain, itching or wound infection, and in view of the uncertainties described, the endpoint ‘change in EB target wound size’ cannot be used to derive an additional benefit, regardless of its relevance to patients, and is presented here merely as supplementary information.
• Morbidity – Overall wound burden
  • In the EASE study, the endpoint ‘Body Surface Area Percentage (BSAP)’ – the percentage of the body surface area affected by superficial EB wounds – was recorded to assess the overall wound burden.
  • As no difference between the treatment groups was observed either in this endpoint (percentage of body surface area affected by superficial EB wounds) or in other endpoints such as pain, itching or wound infection, the endpoint ‘percentage of body surface area affected by superficial EB wounds’ cannot be used to derive any additional benefit, regardless of its relevance to patients, and is therefore presented for supplementary information only.
  • Furthermore, EB activity was presented using the Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) as a further measure of overall wound burden.
  • Due to uncertainties regarding its validity, the endpoint ‘EB activity’ is also not used to derive any additional benefit.
• Morbidity – Wound infection
  • Given the potentially serious consequences of wound infections, such as sepsis, this endpoint is considered patient-relevant in the present therapeutic indication.
  • No statistically significant difference was observed between birch bark extract and placebo for the wound infection endpoint.
• quality of life
  • No usable data were available regarding quality of life.
• Side effects
  • In the analyses presented on the overall rates of AEs, SAEs, severe AEs and therapy discontinuations due to AEs, no statistically significant differences were observed between birch bark extract and placebo.
  • Due to the concurrent recording of events related to the underlying condition, uncertainties remain regarding the interpretation of results in the ‘side effects’ category.
  • Overall, despite these remaining uncertainties, birch bark extract showed neither advantages nor disadvantages in terms of side effects.
• Overall assessment
  • For the benefit assessment of birch bark extract in the treatment of children, adolescents and adults aged 6 months and over with wounds associated with dystrophic or junctional epidermolysis bullosa (EB), the EASE study provides evaluable results on mortality, morbidity and side effects.
  • No deaths occurred in the EASE study.
  • In the morbidity endpoint category, the patient-relevant endpoints of complete wound closure, wound infection, pain, itching and sleep disturbance were recorded.
  • Due to uncertainties arising from a tipping-point analysis of the primary analysis, as well as regarding the persistence of complete wound closure, this endpoint is subject to uncertainty.
  • No usable data on health-related quality of life are available in the study.
  • Taking the available results as a whole, a minor additional benefit of birch bark extract is observed, based on the advantage observed at the endpoint of complete wound closure.

Courtesy translation only, please refer to the German original.