Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis

Autoimmune Encephalitis Clinical Trial

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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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03993262
• Other study ID #: ZKSJ0120
• Secondary ID: 2019-001423-12DR
• Status: Recruiting
• Phase: Phase 2
• Start date: May 13, 2020
• Est. completion date: April 30, 2026

Study information

• Verified date: March 2024
• Source: Jena University Hospital
• Contact: Christian Geis, Prof.
• Phone: +49 (0) 3641
• Email: Christian.Geis[@]med.uni-jena.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: April 30, 2026
• Est. primary completion date: November 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Autoimmune Diseases of the Nervous System
• Autoimmune Encephalitis
• Encephalitis
• Hashimoto Disease

Intervention

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)
• Placebo
1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)

Locations

Country	Name	City	State
Germany	Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller Neurologie	Berlin
Germany	Ruhr-Universität Bochum, St. Josef Hospital, Klinik für Neurologie	Bochum
Germany	University Hospital Düsseldorf, Clinic for Neurology	Düsseldorf
Germany	Universitätsklinikum Erlangen, Neurologische Klinik	Erlangen
Germany	Universitätsklinikum Essen (AöR), Klinik für Neurologie	Essen
Germany	University Hospital Frankfurt (Main), Clinic for Neurology	Frankfurt
Germany	Universitätsmedizin Göttingen Georg-August-Universität, Klinik für Neurologie	Göttingen
Germany	Universitätsmedizin Greifswald, Klinik und Poliklinik für Neurologie	Greifswald
Germany	Medizinische Hochschule Hannover	Hannover	Niedersachen
Germany	Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für Neurologie	Jena
Germany	Klinik für Neurologie UKSH, Campus Kiel	Kiel
Germany	Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurologie	Leipzig
Germany	Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie	Mainz
Germany	Ludwig-Maximilians-Universität München, Klinikum Großhadern	München	Bayern
Germany	Universitätsklinikum Münster Klinik für Neurologie	Münster
Germany	Universitätsklinikum Ulm, Klinik für Neurologie Neurologische Ambulanz	Ulm
Germany	Universitätsklinikum Würzburg	Würzburg	Bayern

Sponsors (1)

Lead Sponsor	Collaborator
Jena University Hospital

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	modified Rankin-Score (mRS)	modified Rankin-Score from 0 = no symptoms to 6 = death	17 weeks after first administration of the study drug
Secondary	modified Rankin-Score (mRS)	modified Rankin-Score from 0 = no symptoms to 6 = death	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
Secondary	Length of in-hospital stay / length of ICU stay	Number of days in hospital or on ICU for each patient from first administration of the study drug until 17 weeks after first administration of the study drug	until 17 weeks after first administration of the study drug
Secondary	Immune response	Antibody titer (in serum and liquor) and cellular immune response (FACS analysis of liquor)	at study start and 17 weeks after first administration of the study drug
Secondary	neurocognitive function assessed by Montreal Cognitive Assessment	total score of the Montreal Cognitive Assessment (MoCA) (0 to max. 30 points = best possible result)	at study start and 17 weeks after first administration of the study medication
Secondary	neurocognitive function assessed by Mini-Mental Status Test	total score of the Mini-Mental Status Test (MMST) (0 to max 30 points = best possible result)	at study start and 17 weeks after first administration of the study medication
Secondary	neurocognitive function assessed by Rey Auditory Verbal Learning Test	total score of the Rey Auditory Verbal Learning Test (RAVLT) (memory performance assessed by 3 word lists which are read to the patient and should be recalled and repeated by the patient; different proceeding for the 3 word lists)	at study start and 17 weeks after first administration of the study medication
Secondary	neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire	total score of the Neuropsychiatric Inventory Questionnaire (NPI) (0 = best score to max 36 (patient) or 60 (caregiver)	at study start and 17 weeks after first administration of the study medication
Secondary	safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections	number of polyneuropathy cases, number of increased liver enzymes, number of secondary infections	until 17 weeks after first administration of the study drug
Secondary	safety of Bortezomib regarding polyneuropathy	number of polyneuropathy cases	until 17 weeks after first administration of the study drug
Secondary	safety of Bortezomib regarding increase of liver enzymes	number of increased liver enzyme values	until 17 weeks after first administration of the study drug
Secondary	Secondary infections due to Bortezomib	number of secondary infections	until 17 weeks after first administration of the study drug
Secondary	Hematotoxicity events due to Bortezomib	number of hematotoxicity events	until 17 weeks after first administration of the study drug
Secondary	Gastrointestinal toxicity due to Bortezomib	number of gastrointestinal toxicity events	until 17 weeks after first administration of the study drug
Secondary	total Glasgow Coma Scale (GCS)	GCS from 3 to 15 points (sum of 3 subscores eye response (1 to 4 points), motor response (1 to 6 points), verbal response (1 to 5 points); highest score = best score; 1= worst score)	3, 6, 9, 13 and 17 weeks after first administration of the study drug
Secondary	Destruction marker UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1) in serum and liquor	Analysis of destruction marker UCH-L1 in serum and liquor	at baseline visit and 17 weeks after first administration of the study drug
Secondary	Destruction marker Neurofilament light chain (in serum and liquor)	Analysis of destruction marker Neurofilament light chain in serum and liquor	at baseline visit and 17 weeks after first administration of the study drug
Secondary	Destruction markers GFAP (glial fibrillary acidic protein) in serum and liquor	Analysis of destruction marker GFAP in serum and liquor	at baseline visit and 17 weeks after first administration of the study drug
Secondary	Destruction marker TAU proteins in serum and liquor	Analysis of destruction marker TAU in serum and liquor	at baseline visit and 17 weeks after first administration of the study drug