Trial document




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  DRKS00025711

Trial Description

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Title

Myasthenia gravis - In-depth characterization of antibody-specific pathomechanisms and identification of novel autoantibodies.

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Trial Acronym

MYA-IN-DEPTH

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URL of the Trial

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Brief Summary in Lay Language

Myasthenia gravis (MG) is a rare disease that leads to a disturbance in the transmission of signals from nerves to voluntary muscles. This classically results in an exercise-dependent muscle weakness, which at the beginning often manifests itself in the area of the eye muscles with a drooping eyelid or double vision. In a large number of patients, the disease also “generalizes” i.e. the muscle weakness spreads to the rest of the body, which can then lead to swallowing and chewing disorders as well as weakness of the limb and respiratory muscles.
The cause of this MG is a formation of so-called autoantibodies against a protein molecule that is crucial for the transmission of signals at the neuromuscular synapse. It is known that a defectively regulated immune system is responsible for this, as these autoantibodies are not detectable in healthy individuals.
The majority of myasthenia patients have autoantibodies against the acetylcholine receptor (AChR-ab). Other known autoantibodies are directed against muscle-specific kinase (MuSK-ab) and lipoprotein-related protein 4 (LRP4-ab). However, about 10-15% of myasthenia patients with confirmed myasthenia gravis are "seronegative", i.e. no autoantibodies can be detected in these patients with the methods currently available in routine diagnostics/regular care. This bears the risk of diagnostic uncertainty and is also of therapeutic importance against the background of an increasing antibody-specific treatment. Seronegative myasthenia patients are significantly underrepresented in research and recent therapeutic approaches are almost exclusively aimed at treating patients with acetylcholine receptor-antibodies.
With this project we would like to investigate whether antibody-specific immune responses can be detected in blood and intercostal muscle tissue of myasthenic patients with different autoantibody constellations. The aim is to identify diagnostic, prognostic and therapy response markers to provide a basis for the use of novel antibody-specific treatment approaches. Furthermore, this research project will attempt to identify new autoantibodies in myasthenia patients with previously "seronegative" MG.

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Brief Summary in Scientific Language

The present project is neuroimmunological research with an exploratory study design to characterize autoantibody-specific immune responses in skeletal muscle tissue and blood of patients with myasthenia gravis (MG) with the aim of identifying diagnostic, prognostic, and therapy response markers to provide a basis for the use of antibody-specific therapeutic approaches. Specifically, the aim of the present study is to better understand the molecular and cellular immune mechanisms that contribute to the development and progression of MG. In particular, similarities and differences between autoantibody subgroups will be investigated. Furthermore, this research project will attempt to identify new autoantibodies in patients with previously "seronegative" MG. For this purpose, analysis of immune cells and mediators involved as well as of skeletal muscle tissue are necessary. Immune cells in peripheral blood as well as in muscle tissue will be quantitatively and qualitatively characterized by analysis of different (cell surface) molecules. Furthermore, differences in antibody-specific effector mechanisms of MG will be investigated by neuropathological in-depth investigation of the neuromuscular endplate.

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00025711
  •   2021/09/07
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  •   yes
  •   Approved
  •   EA1/144/21, Ethik-Kommission der Charité -Universitätsmedizin Berlin-
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Secondary IDs

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Health Condition or Problem studied

  •   G70.0 -  Myasthenia gravis
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Interventions/Observational Groups

  •   Seronegative MG patients:
    Intercostal muscle biopsy will be performed only if it results in diagnostic and/or therapeutic consequences (e.g. diagnostic uncertainty or in refractory cases to evaluate the possibility of targeted complement inhibition in case of complement depositioin at the neuromuscular junction).
  •   AchR-ab-positive MG patients ("positive controls"):
    ICM biopsy will only be performed if surgical therapy by means of (thoracoscopic) thymectomy is planned within the scope of standard care
  •   Intercostal muscle biopsy in patients for whom thoracoscopy/thoracotomy is planned as part of standard care for non-myasthenic indications (e.g., traumatic, "negative controls").
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Characteristics

  •   Non-interventional
  •   Other
  •   Other
  •   Open (masking not used)
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  •   Other
  •   Prognosis
  •   Other
  •   N/A
  •   N/A
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Primary Outcome

The study will demonstrate that specific immunological pathomechanisms can be identified depending on the autoantibody status in MG patients.

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Secondary Outcome

Furthermore, it will be investigated whether
1) Autoantibody-specific changes of the neuromuscular endplate can be shown by ultrastructural analysis (electron microscopy)
2) Previously unknown changes in the neuromuscular endplate in MG patients can be detected using novel array tomography (3D electron microscopy) and nanotomy (large-scale digitization for 2D electron microscopy)
3) New autoantibodies against postsynaptic structures of the neuromuscular endplate can be identified in the blood and/or plasma products of seronegative MG patients using indirect immunofluorescence tests (IIFT) and mass spectroscopy.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2021/09/08
  •   150
  •   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

- Patient capable of written informed consent
- Adult patients

MG patients:
- Seronegative MG patients for whom an intercostal muscle biopsy is planned within standard care (i.e. in case of diagnostic uncertainty or in case of therapy refractory disease course to assess the possibility of a targeted complement inhibition)
- AchR-Ak-positive MG patients for whom thymectomy is planned as part of standard care (“positive controls”).

Participants of the control group (“negative controls”):
- Patients for whom a thoracoscopy/thoracotomy is planned for a non-myasthenic indication (e.g. traumatic injuries)

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Exclusion Criteria

Participants in the control group (negative controls):
- Known rheumatic or tumor diseases

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Addresses

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    • Klinik für Neurologie, Charité- Universitätsmedizin Berlin
    • Ms.  Dr. med.  Sarah  Hoffmann 
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • NeuroCure Clinical Research Center (NCRC) derCharité - Universitätsmedizin Berlin
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • Institut für Neuropathologie der Charité - Universitätsmedizin Berlin
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • Klinik für Thoraxchirurgie der Charité - Universitätsmedizin
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • Klinik für Pädiatrie m.S. Neuropädiatrie der Charité - Universitätsmedizin Berlin
    • Augustenburger Platz 1
    • 13353  Berlin
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    • Klinik für Neuropädiatrie der Universitätsklinikum Essen
    • Hufelandstraße 55
    • 45147  Essen
    • Germany
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    • Labor Berlin - Charité Vivantes Services GmbH
    • Sylter Str. 2
    • 13353  Berlin
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    • Department of Immunology, Churchill Hospital
    • Old Road Headington
    • Oxford
    • United Kingdom
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    • Klinik für Neurologie, Charité - Universitätsmedizin Berlin
    • Ms.  Dr. med.  Sarah  Hoffmann 
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • Klinik für Neurologie, Charité - Universitätsmedizin Berlin
    • Ms.  Dr. med.  Sarah  Hoffmann 
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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Sources of Monetary or Material Support

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    • Klinik für Neurologie, Charité - Universitätsmedizin Berlin
    • Ms.  Dr.med.  Sarah  Hoffmann 
    • Charitéplatz 1
    • 10117  Berlin
    • Germany
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    • argenx BV
    • Industriepark-Zwijnaarde 7
    • B-9052  Zwijnaarde-Ghent
    • Belgium
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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