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Diacerin for the Treatment of Epidermolysis Bullosa Simplex

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02470689
Recruitment Status : Unknown
Verified May 2015 by michal roll, Tel-Aviv Sourasky Medical Center.
Recruitment status was:  Not yet recruiting
First Posted : June 12, 2015
Last Update Posted : June 12, 2015
Information provided by (Responsible Party):
michal roll, Tel-Aviv Sourasky Medical Center

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

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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

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

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

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

Information from the National Library of Medicine

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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02470689

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Contact: Dvora Cohen, M.A 972-3-6973768

Sponsors and Collaborators
Tel-Aviv Sourasky Medical Center
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Principal Investigator: Eli Sprecher, Prof. Head of Dermatology Department, Ichilov medical center
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Responsible Party: michal roll, Head of Division of Research and Development, Tel-Aviv Sourasky Medical Center Identifier: NCT02470689    
Other Study ID Numbers: TASMC-15-SE-135-14-CTIL
First Posted: June 12, 2015    Key Record Dates
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