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
About this trial
This is an interventional treatment trial for Epidermolysis Bullosa Simplex
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
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
NCT ID
NCT02470689
First Posted
May 27, 2015
Last Updated
June 9, 2015
Sponsor
Tel-Aviv Sourasky Medical Center
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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