Clinical trial NCT03993262: Trial to Evaluate Efficacy and Safety of Bortezomib in Patients with Severe Autoimmune Encephalitis
Official title: A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients with Severe Autoimmune Encephalitis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Autoimmune Encephalitis
Keywords: autoimmune disease
autoimmune encephalitis
bortezomib
NMDAR
LGI1
encephalitis
Lead sponsor: Jena University Hospital
Sponsor class: OTHER
Collaborators: name: Federal Ministry of Education and Reserach (BMBF)
First posted: 2019-06-20
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 randomization will be done centrally and stratified by site. Block randomization of variable block sizes will be used.
Primary purpose: TREATMENT

Brief summary: 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.

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)

Primary outcomes:
measure: modified Rankin-Score (mRS)
timeFrame: 17 weeks after first administration of the study drug
Secondary outcomes:
measure: modified Rankin-Score (mRS)
timeFrame: 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
measure: Length of in-hospital stay / length of ICU stay
timeFrame: until 17 weeks after first administration of the study drug
measure: Immune response
timeFrame: at study start and 17 weeks after first administration of the study drug
measure: neurocognitive function assessed by Montreal Cognitive Assessment
timeFrame: at study start and 17 weeks after first administration of the study medication
measure: neurocognitive function assessed by Mini-Mental Status Test
timeFrame: at study start and 17 weeks after first administration of the study medication
measure: neurocognitive function assessed by Rey Auditory Verbal Learning Test
timeFrame: at study start and 17 weeks after first administration of the study medication
measure: neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire
timeFrame: at study start and 17 weeks after first administration of the study medication
measure: safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections
timeFrame: until 17 weeks after first administration of the study drug
measure: safety of Bortezomib regarding polyneuropathy
timeFrame: until 17 weeks after first administration of the study drug
measure: safety of Bortezomib regarding increase of liver enzymes
timeFrame: until 17 weeks after first administration of the study drug
measure: Secondary infections due to Bortezomib
timeFrame: until 17 weeks after first administration of the study drug
measure: Hematotoxicity events due to Bortezomib
timeFrame: until 17 weeks after first administration of the study drug
measure: Gastrointestinal toxicity due to Bortezomib
timeFrame: until 17 weeks after first administration of the study drug
measure: total Glasgow Coma Scale (GCS)
timeFrame: 3, 6, 9, 13 and 17 weeks after first administration of the study drug
measure: Destruction marker UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1) in serum and liquor
timeFrame: at baseline visit and 17 weeks after first administration of the study drug
measure: Destruction marker Neurofilament light chain (in serum and liquor)
timeFrame: at baseline visit and 17 weeks after first administration of the study drug
measure: Destruction markers GFAP (glial fibrillary acidic protein) in serum and liquor
timeFrame: at baseline visit and 17 weeks after first administration of the study drug
measure: Destruction marker TAU proteins in serum and liquor
timeFrame: at baseline visit and 17 weeks after first administration of the study drug
Other outcomes:
Locations:
city: München
country: Germany
facility: Ludwig-Maximilians-Universität München, Klinikum Großhadern
state: Bayern
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller Neurologie
city: Bochum
country: Germany
facility: Ruhr-Universität Bochum, St. Josef Hospital, Klinik für Neurologie
city: Düsseldorf
country: Germany
facility: University Hospital Düsseldorf, Clinic for Neurology
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Neurologische Klinik
city: Essen
country: Germany
facility: Universitätsklinikum Essen (AöR), Klinik für Neurologie
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt (Main), Clinic for Neurology
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald, Klinik und Poliklinik für Neurologie
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen Georg-August-Universität, Klinik für Neurologie
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für Neurologie
city: Kiel
country: Germany
facility: Klinik für Neurologie UKSH, Campus Kiel
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurologie
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie
city: Münster
country: Germany
facility: Universitätsklinikum Münster Klinik für Neurologie
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Neurologie Neurologische Ambulanz
Study officials:
affiliation: University Hospital Jena
name: Christian Geis, Prof.
role: STUDY_DIRECTOR
References:
citation: 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.