Trial document




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  DRKS00013775

Trial Description

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Title

Adjuvant therapy of severe and/or refractory bullous pemphigoids with immunoadsorption by LIGASORB®, dapsone, prednisolone and topical mometasone fumarate (LiBPem-Study).

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Trial Acronym

LiBPem

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URL of the Trial

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Brief Summary in Lay Language

The LiBPem study investigates the application of immunoadsorption in addition to the combination with Dapsone, Prednisolone (corticosteroid) and topical Mometasonfuroat (corticosteroid) in patients with bullous pemphigoid (BP). The objective is to examine the efficacy, safety and effect of this procedure on the healing of the skin and the dosage of the medications mentioned above when used in combination with immunoadsorption.
Bullous pemphigoid is an autoimmune disease where the body’s immune system is activated against its own tissues (autoimmune reaction). The same mechanism that usually serves to remove foreign infectious agents (pathogens) now attacks the body’s own organs. As part of this immune reaction, proteins are produced, the antibodies. These antibodies recognize certain cells or pathogens and cause their destruction. When antibodies recognize the body’s own cells as with BP, they are called autoantibodies. The targets of these autoantibodies are two proteins which are located in the basal membrane, which is the layer of skin connecting the epidermis and the dermis. Thus, blisters are formed (Pemphix: greek blister) and the skin loses its mechanical stability and easily ruptures.
The cause of this autoimmune disease it not known but it is certainly not triggered by food.
As a new and effective procedure to remove autoantibodies from the blood, the technique of immunoadsorption has already been applied in other bullous autoimmune diseases of the skin, i.e., pemphigus vulgaris.
There are only few reports on the application of IA for BP. Recently, a report was published on the use of IA in 7 patients with BP. Interestingly, these patients showed a quick improvement and a decrease in the number of autoantibodies in the blood, which allowed a quick and sustained reduction in the dose of corticosteroids.
The combination therapy of corticosteroids and Dapsone is a type of therapy that is, given its effectiveness and side effects, already recommended in the recent guidelines for treatment. Ultimately, this therapy is supposed to markedly lower the rate of side effects and the morbidity of patients with pronounced BP.
This study will now investigate the safety of adjuvant immunoadsorption in comparison with medicinal therapy alone.

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Brief Summary in Scientific Language

The objective of this prospective monocentric exploratory pilot study is to collect further data concerning the question whether immunoadsorption constitutes a safe adjuvant therapy option for patients with severe and/or refractory bullous pemphigoid (BP), for which until today the therapy is not standardized. In contrast to the information available for the pemphigus disease this study will advance the limited knowledge on the tolerability and effectiveness of this rational and promising type of therapy. The BP is the most frequent subepidermal blister-producing autoimmune skin disease and affects mostly patients of advanced age. The mean age at diagnosis is about 75 to 80 years. The subepidermal blister formation in BP is caused by circulating antibodies against two hemidesmosomal proteins, BP180 and BP230, where the 16th not-collagenous domain (NC16A) is described as the immunodominant region of BP180. Untreated BP persists with spontaneous remission and new exacerbations, typically for many months or years. Until today the therapy of BP is not standardized, but most often systemic and/or topical corticosteroids are applied which can be combined with corticosteroid sparing medications such as Dapsone, Azathioprine, Mycophenolatmofetil or Tetracycline/Niacinamide. Immunosuppressive medications, however, are linked to a significant level of morbidity and mortality, especially when used long term. Since the pathogenic effect of autoantibodies has also been shown for other bullous autoimmune skin diseases, immunoadsorption (IA) has been applied as an adjuvant therapy for these disorders, especially for Pemphigus vulgaris, as a new and effective procedure for removal of autoantibodies from the peripheral blood.
Immunoadsorption via LigaSorb® (Fresenius Medical Care) is carried out on 3 consecutive days (1 cycle of therapy) and in case of a relapse another cycle is performed.
In addition, patients receive conventional medication with Prednisolone (initially 0.5 mg/kg/d), Dapsone (initially 1.5 mg/kg/d) and topic Mometasonfuroat (initially 2x/d applied to lesions).
Patients will be examined 1, 4, and 8 weeks as well as 3, 6, 9, and 12 month post immunoadsorption. The observational period per patient is 12 month.
The goal of recruitment is 10 patients. The total length of study is 3.5 years.

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Organizational Data

  •   DRKS00013775
  •   2018/05/03
  •   [---]*
  •   yes
  •   Approved
  •   17-185, Ethik-Kommission Universität zu Lübeck Medizinische Fakultät des Universitätsklinikums Schleswig-Holstein
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Secondary IDs

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Health Condition or Problem studied

  •   L12.0 -  Bullous pemphigoid
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Interventions/Observational Groups

  •   Immunoadsorption (IA) is conducted on 3 consecutive days (day 1, 2, 3). In case of relapse with highly elevated autoantibody levels, an additional 3-day- IA-cycle can be conducted.The combination therapy with Prednisolone, Dapsone and Topic mometasonfuroate as described below is recommended in the DGG Guideline for Treatment of severe BP (> 30% of body surface area).
    Prednisolone: Therapy with prednisolone is started at a dose of 0.5mg/kg/d. This dosage refers to the usual recommended dosage in the recent DDG Guideline. The dose of prednisolone given last is given for the duration of one week as long as no further blisters are formed. At blister formation stagnation, prednisolone dose is tapered according to standard guidelines down to a dose of 0 mg.
    Dapsone: At the same time dapsone 1,5mg/KG/d is given until Prednisolone is tapered down to a dose of 0mg. After discontinuation of prednisolon therapy and no new lesion formation for one month, Dapsone is tapered according to standard guidelines down to a dose of 0 mg.
    Mometasonfuroat: Additionally, Mometasonfuroat creme is applied twice a day on Skin lesion areas. Blisters are opend aseptically and treated with pyoctanine solution (as needed). If there is no new blister formation for one week, topical treatment with hydrating cream alone is indicated.
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Characteristics

  •   Non-interventional
  •   Observational study
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   N/A
  •   No
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Primary Outcome

Number and degree of severity (1-5, according to the standard criteria of the WHO) of adverse events within study duration (12 months)

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Secondary Outcome

-time to complete remission under therapy, defined as complete remission of BP lesions
-Duration of complete Remission under therapy
-Number of Patients in Remission, 6 and 12 months post immunoadsorption
-decrease of Anti-BP180-seraautoimmunantibodies, 1, 3, 6, and 12 months post immunoadsorption
-reduction of the clinical disease activity scores (Bullous Pemphigoid Disease Area Index ; BPDAI), 3, 6, 12 months post immunoadsorption
-number of patients with doses of prednisolon <7.5 mg/d (threshold for the cushing-syndrome) 6 and 12 months post immunoadsorption
-number of patients with a Dermatology Life Quality Index (DLQI) score of 2-5 (= small effect on Quality of life), 3, 6, and 12 months post immunoadsorption

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2018/06/29
  •   10
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Patiens with diagnostically confirmed BP (direct immunofluorescence, proof of IgG-reactivity against PB180 in ELISA)
- Age >= 18 years of Age
- written informed consent
- > 30 % of Body surface area with BP-lesions OR
- refractive therapy to conventional immunosuppression / immunomodulation according to the Guidelines of the German Dermatology Society (Deutsche Dermatologische Gesellschaft (Eming et al., j Dtsch Dermatol Ges 2015))

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Exclusion Criteria

- proven oversensitivity against materials and/or medications used in the study (see allergy pass)
- severe coagulopathy
- severe cardiovascular disease (NYHA IV, myocardial infarction within the last 3 months)
- intake of ACE-Inhibitors
- women of child-bearing age who do not use adequate birth control methods
- severe systemic infection (HBsAg-positive chronic active Hepatitis B, Hepatitis C, HIV-infection, florid TBC-infection, acute viral infections (e.g., variella, Zoster Virus, severe HSV-1 infection)
- pregnant or lactating women
- severe congenital immune deficiency
- florid gastro-duodenal ulcer
- active, progressive malignomas, or malignomas which are currently treated with chemo- / immunotherapy. Patients with malignomas in complete Remission have to consult an oncologist Prior to study enrollment
-severe liver and kidney dysfunction (>= 3 times elevated serum-GOT, >= 3 times elevated Serum creatinine
- Hb < 9g/dl or leukopenia < 3000/microliter or thrombocytopenia < 100.000/mircoliter with reduced bone marrow function
- acute or unstable psychiatric diseases with high risk of exacerbation with intake of high-dose prednisolone
- written informed consent not possible
- inadequte knowledge of the German language or illiteracy (questionnaires have to be filled out by the study Patients themselves)
- concurrent participation in another clinical trial

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Addresses

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    • Universitätsklinikum Schleswig-Holstein Campus Lübeck
    • Ratzeburger Allee 160
    • 23538  Lübeck
    • Germany
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    • Klinik für Dermatologie, Allergologie und VenerologieUniversitätsklinikum Schleswig-Holstein Campus Lübeck
    • Mr.  Prof. Dr. med. Dr. rer. nat  Enno  Schmidt 
    • Ratzeburger Allee 160
    • 23538  Lübeck
    • Germany
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    • Klinik für Dermatologie, Allergologie und VenerologieUniversitätsklinikum Schleswig-Holstein Campus Lübeck
    • Ms.  Dr.  Heike  Kross 
    • Ratzeburger Allee 160
    • 23538  Lübeck
    • Germany
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Sources of Monetary or Material Support

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    • Klinik für Dermatologie, Allergologie und VenerologieUniversitätsklinikum Schleswig-Holstein Campus Lübeck
    • Mr.  Prof. Dr. med. Dr. rer. nat  Enno  Schmidt 
    • Ratzeburger Allee 160
    • 23538  Lübeck
    • Germany
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    • Fresenius Medical Care Deutschland GmbH
    • Else-Kroener-Str.1
    • 61352  Bad Homburg
    • Germany
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    •   [---]*
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   Ethikvotum
  •   Studienprotokoll
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* This entry means the parameter is not applicable or has not been set.