Trial document




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  DRKS00017497

Trial Description

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Title

A multicenter randomized, controlled, double-blinded trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis

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Trial Acronym

Generate-Boost

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URL of the Trial

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Brief Summary in Lay Language

Autoimmune Encephalitis is a disorder of the central nervous system caused by bodily substances, called antibodies. Antibodies normally help the body to prevent infections. However, in this disorder, the antibodies turn against the body itself and especially against cells in the brain and disturb the normal brain function. They are therefore called autoantibodies.
There is no specific therapy for patients with autoimmune encephalitis so far. At the moment, the symptoms are treated with approved medications such as cortisone and immunotherapies also used in oncology. These therapies are unspecified and aim to reduce the number of autoantibodies and to contain the autoimmune process. In this trial we aim to test a new therapy option: in this therapy the body cells producing autoantibodies will be specifically targeted by a substance called bortezomib.
The trial addresses patients with severe autoimmune encephalitis. The aim of the trial is to evaluate the efficacy and safety of bortezomib in patients with severe autoimmune encephalitis.

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Brief Summary in Scientific Language

Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA receptor or LGI1. So far, no specific therapy exists for this disease. Actual treatment includes combination therapies aiming for a reduction of pathogenic antibodies and containing the autoimmune process. In first line, patients are treated with plasmapharesis and cortisone. In second line, Rituximab and/or cyclophosphamide are administered. The response to these treatments are, however, often delayed and insufficient.
Therefore, we need a specific therapy aiming at the antibody-producing plasma cells.
Bortezomib is a proteasome inhibitor which interferes with NF-kB and the ubiquitin proteasome signaling pathway. Bortezomib acts preferably on cells with high protein synthesis - like plasma cells - and induces cell death in these cells. Bortezomib is used since more than a decade in chemotherapy of the multiple myeloma. Additionally, it is reported for systemic autoimmune diseases like lupus erythematodes that bortezomib leads to a depletion of plasma cells and therefore reduces the number of pathogenic antibodies and improves clinical outcome. The therapeutic potential of bortezomib for NMDAR encephalitis is described in a first case series with 5 patients.

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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

  •   DRKS00017497
  •   2019/11/12
  •   2019/09/04
  •   yes
  •   Approved
  •   2019-1523-AMG_ff, Ethikkommission der Friedrich-Schiller-Universität Jena an der Medizinischen Fakultät
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Secondary IDs

  •   2019-001423-12 
  •   NCT03993262  (clinicaltrials.gov )
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Health Condition or Problem studied

  •   autoimmune encephalitis
  •   G04 -  Encephalitis, myelitis and encephalomyelitis
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Interventions/Observational Groups

  •   1 to 3 cycles Bortezomib with 1,3mg/m2 body surface subcuteanous + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
  •   1 to 3 cycles placebo (NaCl solution) subcuteanous + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist, caregiver, data analyst
  •   Placebo
  •   Treatment
  •   Parallel
  •   II
  •   Yes
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Primary Outcome

modified Rankin-Score 17 weeks after first administration of the trial medication

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Secondary Outcome

• mRS and GCS-Scores 3, 6, 9 and 13 weeks after first administration of the trial medication; GCS Score also 17 weeks after first administration of the trial medication

• Length of in-hospital stay / length of ICU stay

• Antibody titer and destruction markers (in serum and liquor)

• cellular immune response (FACS analysis of liquor) at study start and 17 weeks after first administration of the study medication

• neurocognitive function (MoCA, MMST, RAVLT and NPI) at study start and 17 weeks after first administration of the study medication

Outcome regarding safety:
• Number of serious adverse events from study start until 17 weeks after first administration of the study medication

• safety of Bortezomib regarding polyneuropathy, increase of liver enzymes, hematotoxicity, gastrointestinal toxicity and secondary infections

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2020/07/23
  •   50
  •   Multicenter trial
  •   National
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Inclusion Criteria

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

• Clinical diagnosed severe autoimmune encephalitis (mRS ≥ 3)
• auto-antibodies against neuronal surface proteins in the liquor or serum, proof not older than 4 weeks prior to randomisation
• pretreatment with Rituximab
• Age ≥18 Jahre
• signed informed consent
• women of childbearing potential (up to 2 years after menopause): negative pregnancy test

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Exclusion Criteria

• breast-feeding
• acute infiltrative pulmonary disease
• acute infiltrative pericardial disease
• malignant tumor and current chemotherapy
• current participation in another interventional study
• previous participation in this study
• known hypersensitivity to an ingredient of the investigational product
• continued therapy with glucocorticoids / Rituximab during the study (last administration must be prior to the first dose of the investigational product)

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Addresses

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    • Friedrich-Schiller-Universität Jena
    • 07737  Jena
    • Germany
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    • Universitätsklinikum Jena Klinik für Neurologie
    • Mr.  Prof. Dr.  Christian  Geis 
    • Am Klinikum1
    • 07747  Jena
    • Germany
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    • Universitätsklinikum Jena Klinik für Neurologie
    • Mr.  Prof. Dr.  Christian  Geis 
    • Am Klinikum1
    • 07747  Jena
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung Dienstsitz Berlin
    • Friedrichstraße 130 B
    • 10117  Berlin
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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