Trial document




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  DRKS00005412

Trial Description

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Title

Diacerein for the treatment of epidermolysis bullosa simplex

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Trial Acronym

Diacerein for EBS-DM

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Epidermolysis bullosa simplex is a genetic disease affecting mainly the skin and mucous membranes. Due to the absence or the misfolding of a protein, skin layers don't stick together properly. This leads to blistering to the skin even upon minor trauma. In the case of Epidermolysis bullosa simplex it was seen that also inflammatory components (like interleukin-1beta) are active, which aggravate the disease. The aim of this study is to block interleukin-1beta, thereby rendering more stability to the skin. In the laboratory the active agent "Diacerein" was tested and which showed promising results in terms of increasing cellular stability. Based on these results a pilot study was conducted, also giving promising results, which shall be confirmed in the present study. There, patients will apply a diacerein cream every day for four weeks. A second group of patients will receive placebo. In the following year, the groups will be crossed-over. During the four weeks of application, blisters will be counted and recorded, to see if blister numbers go down. In the following three month blisters will be counted in the absence of the cream, to see when blister numbers start increasing.

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Brief Summary in Scientific Language

Epidermolysis bullosa simplex type Dowling-Meara (EBS-DM) is a rare condition of the skin
and mucous membranes, affecting 1 in about 50.000 people. Up to date, no causal therapy
is available and treatment is restricted to the amelioration of symptoms like pruritus and pain.
Dominant mutations in keratins of basal keratinocytes lead to a conformational change of
these intermediate filament (IF) components, their aggregation in the cytoplasm upon minor
mechanical trauma and subsequently to a collapse of the IF network and the cytolysis of
basal keratinocytes. For K14 based EBS-DM we found, that the inflammatory cytokine
interleukin 1 beta (IL-1ß) is constitutively activated in patient keratinocytes. In a positive
feedback loop, it leads to the activation of the c-jun N-terminal kinase pathway and the
overexpression of K14 and IL-1ß itself. However, when treating patient keratinocytes with IL-
1ß antibody or the small molecule diacerein, expression approximated wildtype levels and
keratinocytes were less susceptible to stress. These results led to a pilot study, in which five
EBS-DM patients were treated with a 1% diacerein cream. The study consisted of an open
phase, during which all patients received 1% diacerein cream to apply underneath both
armpits, and a placebo-controlled phase, where armpits were randomized and patients
received 1% diacerein cream for one armpit and placebo for the other. The outcome of this
study was a statistically significant reduction of blisters during the open phase. During the
double-blinded controlled phase, only one time interval showed a significant difference
between placebo and diacerein. Overall, data analysis was challenging because only three
out of five patients finished the controlled phase per protocol. However, the promising results
during the open phase are very much encouraging the present application. Here, we suggest
a placebo-controlled, randomized, double-blinded trial, including 15 EBS-DM patients (aged
4-19 years). The study design comprises a placebo and an intervention group of patients and
consists of a 4-weeks part for efficiency analysis with the primary endpoint being a reduction
of blister numbers by 40%, and a follow-up, with the secondary endpoint being the time until
the achievement of the initial blister number. Patients will be monitored at their local centers
by a study nurse. This procedure will be done in two subsequent years, with a cross-over of
patient groups. This allows the exclusion of temperature effects, which are known to
influence blistering, and differences in blister numbers between patients are excluded to
influence the result.

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Organizational Data

  •   DRKS00005412
  •   2013/11/06
  •   [---]*
  •   yes
  •   Approved
  •   415-E/1619/10-2013, Ethikkommission des Landes Salzburg
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Secondary IDs

  •   2013-002034-21 
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Health Condition or Problem studied

  •   Q81.0 -  Epidermolysis bullosa simplex
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Interventions/Observational Groups

  •   1% diacerien cream
    Active agent: diacerein
    Application: once daily, topically
  •   placebo
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist, caregiver, assessor, data analyst
  •   Placebo
  •   Supportive care
  •   Crossover
  •   II
  •   Yes
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Primary Outcome

Reduction of blisters within four weeks by 40% in the verum group, in comparison to the placebo group.

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Secondary Outcome

Time span until the reaching of the initial blister number (+/-10%) during the follow-up.

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Countries of Recruitment

  •   Austria
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2014/05/01
  •   15
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   4   Years
  •   19   Years
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Additional Inclusion Criteria

- An age between 4 and 19 years
- Diagnosis of EBS-DM.
- Mutations in the keratin 5 or keratin 14 gene
- signed consent form

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Exclusion Criteria

- other types of EB with mutations in the keratin 5 or keratin 14 gene.
- lack of mutation analysis
- Known or expected intolerance to diacerein a component of the cream (e.g. tartrazin) or substances with a similar structure
- Pregnancy or lactation
- Contemporaneous participation in another clinical trial.
- Patients with hepatic dysfunction
- Relevant other diseases (e.g. acute infections, ...)

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Addresses

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    • Division of Experimental Dermatology and EB House AustriaDepartment of DermatologyUniversity Hospital SalzburgParacelsus Medical UniversityUniversity Hospital for Dermatology
    • ***  *** 
    • Müllner Hauptstraße 48
    • 5020  Salzburg
    • Austria
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    • Division of Experimental Dermatology and EB House AustriaDepartment of DermatologyUniversity Hospital SalzburgParacelsus Medical University
    • ***  *** 
    • Müllner Hauptstraße 48
    • 5020  Salzburg
    • Austria
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    • Division of Experimental Dermatology and EB House AustriaDepartment of DermatologyUniversity Hospital SalzburgParacelsus Medical UniversityUniversity Hospital for Dermatology
    • ***  *** 
    • Müllner Hauptstraße 48
    • 5020  Salzburg
    • Austria
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Sources of Monetary or Material Support

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    • Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
    • Sensengasse 1
    • 1090  Wien
    • Austria
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    • Paracelsus Medical University
    • Strubergasse 21
    • 5020  Salzburg
    • Austria
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Status

  •   Recruiting complete, follow-up complete
  •   2015/10/17
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Trial Publications, Results and other Documents

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