Diacerin for the Treatment of Epidermolysis Bullosa Simplex

• Sponsor: Tel-Aviv Sourasky Medical Center
• Information provided by (Responsible Party): michal roll, Tel-Aviv Sourasky Medical Center

Study Description

Brief Summary:

Epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is one of the most severe subtypes of EBS. Blisters and erosions of the skin and mucous membranes upon minor trauma are the consequence of dominantly inherited mutations in either the keratin 5 (K5) or keratin 14 (K14) gene, which encode proteins constituting the intermediate filament (IF) network in basal keratinocytes . Autosomal dominant mutations lead to a conformational change and an increased self-aggregation of the protein. Upon stress, aggregates present in the periphery of the cytoplasm, subsequently leading to the disintegration and collapse of the IF network. Clinically, patients suffer from blistering of the skin and mucous membranes upon minor trauma, resulting in an impaired life quality due to pain and pruritus . In vitro studies on Dowling-Meara keratinocytes revealed a significant upregulation of the pro-inflammatory cytokine interleukin-1beta (IL-1ß). Apart from paracrine effects of IL-1ß upon wounding (e.g. attraction of lymphocytes, activation of dermal fibroblasts), IL-1ß also activates keratinocytes via the cjun N-terminal kinase (JNK) stress pathway. The activation of this pathway leads to the activation of a number of transcription factors and the enhanced transcription of a number of genes, like matrix metalloproteinases, kallikreins, but also IL-1ß itself and K14 . Interestingly, this state of activation is constitutive and was also found in keratinocytes from non-lesional sites. It seems that the upregulation of IL-1ß and K14 in the presence of dominant Dowling-Meara mutations, results in a positive feedback loop, potentially aggravating the EBS-DM phenotype. This was strongly corroborated by the fact that when impairing IL1ß signaling, using IL-1ß neutralizing antibody (IL-1Ab) or the small molecule diacerein, expression levels of IL-1ß and K14 decreased and keratinocytes were much less susceptible to heat shock in vitro . Furthermore, activation levels of JNK widely correlated with expression levels of K14 and IL-1ß. (Wally V et al, 2013). These findings led to the hypothesis that blocking IL-1ß will also lead to an amelioration of the EBSDM phenotype in effected patients. Based on previous in vitro findings diacerein was chosen to be topically applied in a pilot study with five patients suffering from EBS-DM. In that study , each participant received 1% diacerein-cream for one armpit, and placebo for the other (randomized withdrawal). The number of blisters was reduced significantly (left: -78%; right: -66% of baseline) within two weeks and remained significantly below the initial level even during withdrawal in four patients. These findings pointed to a relevant effect of diacerein and provide important information for our confirmative study.

Diacerein is a component of the rhubarb root, which is reported to block the release of active IL-1b by inhibiting plasma membrane-bound IL-1 converting enzyme . Diacerien is already approved for systemic application in osteoarthritis . In general, small molecules (SM) are low molecular weight compounds with biological functions that can influence molecular processes. They allow a symptomatic treatment, offering a short-term benefit for patients in terms of an amelioration of the phenotype. Although this kind of treatment does not correct genetic alterations, it can still be highly beneficial by damping down disease symptoms, thereby increasing life quality and minimizing secondary manifestations.

It is important to emphasize that besides dressings, there are currently no other treatments, therefore, investigators do not prevent an accepted treatment for the patient and there is no risk for the participant. The treatment will be given only to the armpits although the disease can involve other areas, so stopping dressings in the armpits during the study does not risk the patient. Should there be any deterioration of the patient, whether it is related to the treatment with diacerein or not, investigators will stop the use of diacerein.

Condition or disease	Intervention/treatment	Phase
Epidermolysis Bullosa Simplex	Drug: Diacerin cream	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Allocation:	Randomized
Intervention Model:	Crossover Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Diacerin for the Treatment of Epidermolysis Bullosa Simplex
Study Start Date :	June 2015
Estimated Primary Completion Date :	December 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Diacerin cream 1%	Drug: Diacerin cream; Diacerin tablet solubule in ultraphil cream
Placebo Comparator: ultraphil cream	Drug: Diacerin cream; Diacerin tablet solubule in ultraphil cream

Outcome Measures

Primary Outcome Measures :

1. Number of blisters [ Time Frame: 4 weeks ]

Secondary Outcome Measures :

1. Number of blisters [ Time Frame: 3 months period ]

Eligibility Criteria

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Ages Eligible for Study:	6 Years to 19 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Diagnosis of EBS-DM
2. An age between 6 - 19

Exclusion Criteria:

1. Lack of mutation analysis
2. Intolerance to a component of the cream
3. Pregnancy or Lactation
4. Contemporaneous participation in another clinical trial

Contacts and Locations

Contacts

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Contact: Dvora Cohen, M.A	972-3-6973768	dvorac@tlvmc.gov.il

Sponsors and Collaborators

Tel-Aviv Sourasky Medical Center

Investigators

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Principal Investigator:	Eli Sprecher, Prof.	Head of Dermatology Department, Ichilov medical center

More Information

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Responsible Party:	michal roll, Head of Division of Research and Development, Tel-Aviv Sourasky Medical Center
ClinicalTrials.gov Identifier:	NCT02470689 History of Changes
Other Study ID Numbers:	TASMC-15-SE-135-14-CTIL
First Posted:	June 12, 2015
Last Update Posted:	June 12, 2015
Last Verified:	May 2015

Additional relevant MeSH terms:

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Epidermolysis Bullosa; Epidermolysis Bullosa Simplex; Skin Abnormalities; Congenital Abnormalities	Skin Diseases, Genetic; Genetic Diseases, Inborn; Skin Diseases; Skin Diseases, Vesiculobullous