A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis

Phase 2

Recruiting

Conditions: autoimmune encephalitis

Registration Number: 2024-514494-21-00

Lead Sponsor: Friedrich-Schiller-Universitaet Jena

Brief Summary: Evaluation of the efficacy and safety of bortezomib in patients with severe autoantibody-positive 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.

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 50

Inclusion Criteria

Clinically diagnosed severe autoimmune encephalitis (defined as mRS ≥ 3)

Autoantibodies against neuronal surface proteins in cerebrospinal fluid or serum serum, detection must not be older than 4 weeks, calculated before randomization

Pre-treatment with rituximab

Age ≥ 18 years

Written informed consent of the patient or the patient “under witness” (if the patient cannot write for motor reasons) cannot write themselves) or the legal representative (=guardian) or the authorized representative

Potentially fertile patient (up to 2 years after menopause): negative pregnancy test

Exclusion Criteria

Lactation

Acute infiltrative lung disease

Acute infiltrative pericardial disease

Malignant tumor under ongoing or newly started chemotherapy

Concurrent participation in another intervention study

Previous participation in this study

Known hypersensitivity to any ingredient of the investigational product

Continued therapy with glucocorticoids/rituximab during the duration of the study (last administration must be completed before first administration of investigational product)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
mRS 17 weeks after first administration of the investigational product		mRS 17 weeks after first administration of the investigational product

Secondary Outcome Measures

Name	Time	Method
mRS and GCS 3, 6, 9 and 13 weeks after first administration of the investigational product; GCS 17 weeks after first administration of the investigational product		mRS and GCS 3, 6, 9 and 13 weeks after first administration of the investigational product; GCS 17 weeks after first administration of the investigational product
Length of stay in hospital/intensive care unit		Length of stay in hospital/intensive care unit
Antibody titers and destruction markers (in serum and cerebrospinal fluid), cellular immune response (FACS, in cerebrospinal fluid) at the baseline visit and 17 weeks after first administration of the investigational product		Antibody titers and destruction markers (in serum and cerebrospinal fluid), cellular immune response (FACS, in cerebrospinal fluid) at the baseline visit and 17 weeks after first administration of the investigational product
Neurocognitive function (MoCA, MMST, VLMT and NPI) at the baseline visit and 17 weeks after the first visit and 17 weeks after first administration of the investigational product		Neurocognitive function (MoCA, MMST, VLMT and NPI) at the baseline visit and 17 weeks after the first visit and 17 weeks after first administration of the investigational product
Number of all (serious) adverse events within 17 weeks after the first 17 weeks after first administration of the investigational product		Number of all (serious) adverse events within 17 weeks after the first 17 weeks after first administration of the investigational product
Bortezomib safety with regard to polyneuropathy, increase in liver enzymes liver enzymes, hematotoxicity, gastrointestinal toxicity and secondary infections.		Bortezomib safety with regard to polyneuropathy, increase in liver enzymes liver enzymes, hematotoxicity, gastrointestinal toxicity and secondary infections.

Trial Locations

Locations (17): Universitaetsklinikum Erlangen AöR
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Erlangen, Germany
Charite Universitaetsmedizin Berlin KöR
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Berlin, Germany
Universitaetsklinikum Schleswig-Holstein AöR
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Kiel, Germany
Universitaet Leipzig
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Leipzig, Germany
Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz KöR
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Mainz, Germany
Universitaetsklinikum Wuerzburg AöR
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Wuerzburg, Germany
Universitaetsklinikum Ulm AöR
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Ulm, Germany
Universitaetsklinikum Duesseldorf AöR
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Duesseldorf, Germany
Universitaetsklinikum Frankfurt AöR
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Frankfurt Am Main, Germany
Universitaet Muenster
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Muenster, Germany
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Universitaetsklinikum Erlangen AöR
🇩🇪Erlangen, Germany
Veit Rothhammer
Site contact
+4991318533001
Veit.Rothhammer@uk-erlangen.de