Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: Bortezomib, Placebo.
- Who it may be relevant to
- Registry conditions: Autoimmune Encephalitis. Basic parameters: from 18 years · All.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Germany
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis
Overview
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.
Detailed description
Autoimmune encephalitis is characterized by autoantibodies against neuronal surface antigens like the NMDA (N-methyl-D-aspartate) receptor or LGI1 (Leucin-rich glioma inactivated protein 1). 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 plasmapheresis 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 (nuclear factor 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.
Interventions
- Drug Bortezomib
1 to 3 cycles Bortezomib with 1,3mg/m2 body surface s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle) - Drug Placebo
1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
Primary outcome measures
- modified Rankin-Score (mRS) [Time frame: 17 weeks after first administration of the study drug]
Secondary outcome measures (12)
- modified Rankin-Score (mRS) [Time frame: 3, 6, 9 and 13 weeks after first administration of the study drug; GCS Score also 17 weeks after first administration of the study drug]
- Length of in-hospital stay / length of ICU stay [Time frame: until 17 weeks after first administration of the study drug]
- Immune response [Time frame: at study start and 17 weeks after first administration of the study drug]
- neurocognitive function assessed by Montreal Cognitive Assessment [Time frame: at study start and 17 weeks after first administration of the study medication]
- neurocognitive function assessed by Mini-Mental Status Test [Time frame: at study start and 17 weeks after first administration of the study medication]
- neurocognitive function assessed by Rey Auditory Verbal Learning Test [Time frame: at study start and 17 weeks after first administration of the study medication]
- neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire [Time frame: at study start and 17 weeks after first administration of the study medication]
- safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections [Time frame: until 17 weeks after first administration of the study drug]
- safety of Bortezomib regarding polyneuropathy [Time frame: until 17 weeks after first administration of the study drug]
- safety of Bortezomib regarding increase of liver enzymes [Time frame: until 17 weeks after first administration of the study drug]
- Secondary infections due to Bortezomib [Time frame: until 17 weeks after first administration of the study drug]
- Hematotoxicity events due to Bortezomib [Time frame: until 17 weeks after first administration of the study drug]
Eligibility criteria
Inclusion criteria
- Clinically diagnosed severe autoimmune encephalitis (defined as mRS ≥ 3) with autoantibodies to neuronal surface proteins in cerebrospinal fluid and / or serum
- Pretreatment with rituximab
- Age ≥18 years
- signed informed consent
- Women of childbearing potential (up to 2 years after menopause): negative pregnancy test
Exclusion criteria
- pregnancy/breast-feeding
- acute infiltrative pulmonary and pericardial disease
- malignant tumor under current chemotherapy
- Simultaneous participation in another intervention study
- Previous participation in this study
- Known hypersensitivity to an ingredient of the investigational product
- Continued therapy with glucocorticoids / rituximab during the study duration (last dose must be administered before the first dose of the investigational product)
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: No
Study design
- Allocation
- Randomized
- Model
- Parallel assignment
- Masking
- Quadruple blind
- Primary purpose
- Treatment
Study locations
Germany · 17 centers
- Ludwig-Maximilians-Universität München, Klinikum Großhadern — München
- Universitätsklinikum Würzburg — Würzburg
- Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für Neurologie — Jena
- Medizinische Hochschule Hannover — Hanover
- Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller Neurologie — Berlin
- Ruhr-Universität Bochum, St. Josef Hospital, Klinik für Neurologie — Bochum
- University Hospital Düsseldorf, Clinic for Neurology — Düsseldorf
- Universitätsklinikum Erlangen, Neurologische Klinik — Erlangen
- … and 9 more centers
Publications
- Wickel J, Chung HY, Platzer S, Lehmann T, Pruss H, Leypoldt F, Gunther A, Scherag A, Geis C; GENERATE Study Group. Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis. Trials. 2020 Jul 8;21(1):625. doi: 10.1186/s13063-020-04516-7. PMID 32641101
Identifiers
NCT: NCT03993262 · ZKSJ0120 · 2024-514494-21-00 · 2019-001423-12 · DRKS00017497 · 01GM1908E