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Diacerin for the Treatment of Epidermolysis Bullosa Simplex

Primary Purpose

Epidermolysis Bullosa Simplex

Status
Unknown status
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Diacerin cream
Sponsored by
Tel-Aviv Sourasky Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Epidermolysis Bullosa Simplex

Eligibility Criteria

6 Years - 19 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Placebo Comparator

    Arm Label

    Diacerin cream 1%

    ultraphil cream

    Arm Description

    Outcomes

    Primary Outcome Measures

    Number of blisters

    Secondary Outcome Measures

    Number of blisters

    Full Information

    First Posted
    May 27, 2015
    Last Updated
    June 9, 2015
    Sponsor
    Tel-Aviv Sourasky Medical Center
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02470689
    Brief Title
    Diacerin for the Treatment of Epidermolysis Bullosa Simplex
    Official Title
    Diacerin for the Treatment of Epidermolysis Bullosa Simplex
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2015
    Overall Recruitment Status
    Unknown status
    Study Start Date
    June 2015 (undefined)
    Primary Completion Date
    December 2017 (Anticipated)
    Study Completion Date
    undefined (undefined)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Tel-Aviv Sourasky Medical Center

    4. Oversight

    Data Monitoring Committee
    Yes

    5. 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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Epidermolysis Bullosa Simplex

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Crossover Assignment
    Masking
    ParticipantCare ProviderInvestigator
    Allocation
    Randomized
    Enrollment
    50 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Diacerin cream 1%
    Arm Type
    Active Comparator
    Arm Title
    ultraphil cream
    Arm Type
    Placebo Comparator
    Intervention Type
    Drug
    Intervention Name(s)
    Diacerin cream
    Intervention Description
    Diacerin tablet solubule in ultraphil cream
    Primary Outcome Measure Information:
    Title
    Number of blisters
    Time Frame
    4 weeks
    Secondary Outcome Measure Information:
    Title
    Number of blisters
    Time Frame
    3 months period

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    6 Years
    Maximum Age & Unit of Time
    19 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Diagnosis of EBS-DM An age between 6 - 19 Exclusion Criteria: Lack of mutation analysis Intolerance to a component of the cream Pregnancy or Lactation Contemporaneous participation in another clinical trial
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Dvora Cohen, M.A
    Phone
    972-3-6973768
    Email
    dvorac@tlvmc.gov.il
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Eli Sprecher, Prof.
    Organizational Affiliation
    Head of Dermatology Department, Ichilov medical center
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Diacerin for the Treatment of Epidermolysis Bullosa Simplex

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