Oleogel-S10 Phase 3 study "EASE" for epidermolysis bullosa: study design and rationale.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare, genetic diseases that affect the integrity of epithelial tissues, most notably the skin. Patients experience recurrent skin wounding, with severity depending on type, sub-type, and mutation. Oleogel-S10, a formulation of birch bark extract, has demonstrated efficacy in a Phase 2 trial assessing re-epithelialization of wounds in EB. EASE (NCT03068780, EudraCT 2016-002066-32) is a randomized, Phase 3, placebo-controlled study designed to determine the efficacy of Oleogel-S10 versus placebo in patients with EB. METHODS: EASE is a Phase 3, two-phase study comprising a 90-day, double-blind, randomized, placebo-controlled phase, followed by 24 months of open-label, single-arm follow-up. Patients with junctional EB, dystrophic EB, or Kindler syndrome and target wounds (10 - 50cm2) present for > 21 days and < 9 months, are randomized in a 1:1 ratio to receive wound dressings according to local standard of care with or without Oleogel-S10. Placebo is based on the Oleogel-S10 vehicle, which is sunflower oil formulated to have a consistency indistinguishable from that of the active product. The primary endpoint of the trial, directed by the US health authority according to the required study endpoints for chronic cutaneous ulcer and burn wounds, is to compare the efficacy of Oleogel-S10 versus placebo according to the proportion of patients with complete closure of the target wound within 45 ± 7 days of treatment. Additional EB-focused endpoints include wound burden, patient-reported outcomes, and safety. RESULTS: Results of the primary endpoint are anticipated to be available by H2 2019. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03068780 . EudraCT, 2016-002066-32. Registered on 3 March 2017.

Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.

Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care-based interventions. Opioid-based therapies underpin pain care in EB; however, they are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid-based medicines (CBMs) have been studied increasingly for pain conditions of various aetiologies and pose as a novel dimension for pain care in EB. We present three patients with EB who were prescribed pharmaceutical-grade sublingually administered CBMs comprising tetrahydrocannabinol and cannabidiol. All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake.

Reliability of photographic analysis of wound epithelialization assessed in human skin graft donor sites and epidermolysis bullosa wounds.

BACKGROUND: In many clinical trials on cutaneous healing, wound closure is the primary endpoint and single most important outcome parameter, making precise assessment of this time point one of utmost importance. The assessment of wound closure can be performed either by subjective clinical inspection or with a variety of methodologies anticipated to provide more objective data. The aim of this study was to examine intra- and interrater variability of blinded photographic analysis of wound closure of human partial thickness wounds, as well as the reliability of remote photographic analysis of wounds with that of direct clinical assessment. METHODS: Two plastic surgeons, a dermatologist, and a maxillofacial surgeon constituted our rater panel. High-resolution images of patient wounds derived from two randomized controlled clinical trials (EU Clinical Trials Register numbers EudraCT 2009-017418-56 (registered 12 January 2010) and EudraCT 2010-019945-24 (registered 13 July 2010)) were individually assessed by the blinded, experienced study raters. The reliability of photographic image analysis was tested using intraclass and interclass correlation. The validity of photographic image analysis was correlated with clinical assessments of documented time to heal from the study centers' files. RESULTS: The results demonstrated that the mean intraclass correlation coefficient of all four examiners was excellent (r = 0.79; 95% confidence interval (CI), 0.61, 1.00)). The interrater correlation coefficient was good (r = 0.67; 95% CI, 0.57, 1.00)) and therefore acceptable. The agreement between remote visual assessment and clinical assessment at the time of healing was good (r = 0.64; 95% CI, 0.52, 0.76)) with an overall difference of about 1 day. CONCLUSIONS: Remote photographic analysis of cutaneous wounds is a feasible instrument in clinical open-label studies to evaluate time to wound closure. We found that it was a reliable method of measuring wound closure that correlated satisfactorily with clinical judgment, bolstering the potential relevance in the current era of evolving application and dependency in the field of telemedicine. TRIAL REGISTRATION: EU Clinical Trials Register EudraCT numbers 2009-017418-56 (date of registration: 12 January 2010) and 2010-019945-24 (date of registration: 13 July 2010).

Epidermolysis bullosa: report of three cases treated with homeopathy.

Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by recurrent blistering as a result of even minor traction of epithelial lined tissues, most remarkably the skin. Associated morbidity is serious for all patients affected due to the presence of large areas of denudated skin thus susceptible to infection. There is currently no available treatment in conventional medicine. This article reports the case of 3 children successfully treated with individualized homeopathic medicines.

Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study.

Dilated cardiomyopathy (DC) has been reported in severe epidermolysis bullosa (EB) subtypes. Poor nutritional status, low carnitine levels, selenium deficiency, chronic iron overload, drugs and viral etiology have been proposed as potential contributors. This was a retrospective, descriptive, multicenter study describing EB patients that developed DC, and determining potential pre-disposing risk factors. Fifteen patients were enrolled in the study; 11 of them were male subjects (73%). Eighty-seven per cent of the participants had dystrophic EB and 13% had junctional EB. Mean age at diagnosis of DC was 12.18 +/- 4.99 years. Chronic anemia was diagnosed in 13 of 15 patients (86.7%). Sixty per cent of patients had prior red blood cell transfusions. At diagnosis, selenium levels were low in 55% of the patients (n = 11) and total carnitine levels were low in 45% of the patients (n = 11). Systolic function was moderately impaired, with a mean shortening fraction of 19.38% (SD = 5.04, n = 8). After a mean follow-up period of 6.3 +/- 4.8 years, six patients were alive without being on any medications (40.0%), two were alive on medications (13.3%) and seven had died (46.7%). Limitations of the study was that it was a retrospective chart review with relatively small sample size. Retrospective chart review, relatively small sample size. This study substantiates the association between DC and EB. Currently, there is no single risk factor identified in EB patients that leads to DC. Further prospective studies are needed.

[Epidermolysis bullosa acquisita: diagnosis by optic immunofluorescent demonstration of junctional antigens and vitamin E treatment]. / Epidermolysis bullosa acquisita: Diagnostik durch immunfluoreszenzoptische Darstellung von junktionalen Antigenen und behandlung mit Vitamin E.

In a patient with epidermolysis bullosa acquisita the characteristic dermolytic cleavage was demonstrated by electron microscopy and by mapping of antigenic determinants (type IV collagen, laminin, bullous pemphigoid antigen) of the dermal-epidermal junction. The latter method represents a rapid and reliable way to determine the cleavage plane in diseases which display subepidermal blister formation at the light-microscopic level. The classification of epidermolysis bullosa acquisita is still under dispute. Due to its highly characteristic clinical, ultrastructural, and immunologic features and pending further experimental data, epidermolysis bullosa acquisita should be regarded as a separate disease entity; its lumping together with cicatricial pemphigoid, as proposed by some authors appears speculative. Therapy of epidermolysis bullosa acquisita is generally regarded as difficult; following a 3-year course of high dose vitamin E therapy our patient underwent complete clearing; the possibility of a spontaneous remission, on the other hand, cannot be unequivocally ruled out.