Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis (Generate-Boost)
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ClinicalTrials.gov Identifier: NCT03993262 |
Recruitment Status :
Recruiting
First Posted : June 20, 2019
Last Update Posted : February 28, 2022
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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.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Autoimmune Encephalitis | Drug: Bortezomib Drug: Placebo | Phase 2 |
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.
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 50 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Intervention Model Description: | 1:1 randomization will be done centrally and stratified by site. Block randomization of variable block sizes will be used. |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Masking Description: | The study drug will be provided blinded by the local pharmacy. |
Primary Purpose: | Treatment |
Official Title: | A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis |
Actual Study Start Date : | May 13, 2020 |
Estimated Primary Completion Date : | July 1, 2022 |
Estimated Study Completion Date : | July 31, 2023 |

Arm | Intervention/treatment |
---|---|
Experimental: Interventional
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)
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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 Comparator: Placebo
1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
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Drug: Placebo
1 to 3 cycles placebo (NaCl solution) s.c. + 20mg dexamethasone p.o. on days 1, 4, 8 and 11 (= 1 cycle)
Other Name: isotonic NaCl solution |
- modified Rankin-Score (mRS) [ Time Frame: 17 weeks after first administration of the study drug ]modified Rankin-Score from 0 = no symptoms to 6 = death
- 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 ]modified Rankin-Score from 0 = no symptoms to 6 = death
- Length of in-hospital stay / length of ICU stay [ Time Frame: until 17 weeks after first administration of the study drug ]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
- Immune response [ Time Frame: at study start and 17 weeks after first administration of the study drug ]Antibody titer (in serum and liquor) and cellular immune response (FACS analysis of liquor)
- neurocognitive function assessed by Montreal Cognitive Assessment [ Time Frame: at study start and 17 weeks after first administration of the study medication ]total score of the Montreal Cognitive Assessment (MoCA) (0 to max. 30 points = best possible result)
- neurocognitive function assessed by Mini-Mental Status Test [ Time Frame: at study start and 17 weeks after first administration of the study medication ]total score of the Mini-Mental Status Test (MMST) (0 to max 30 points = best possible result)
- neurocognitive function assessed by Rey Auditory Verbal Learning Test [ Time Frame: at study start and 17 weeks after first administration of the study medication ]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)
- neurocognitive function assessed by Neuropsychiatric Inventory Questionnaire [ Time Frame: at study start and 17 weeks after first administration of the study medication ]total score of the Neuropsychiatric Inventory Questionnaire (NPI) (0 = best score to max 36 (patient) or 60 (caregiver)
- safety of Bortezomib regarding polyneuropathy, increase of liver enzymes and secondary infections [ Time Frame: until 17 weeks after first administration of the study drug ]number of polyneuropathy cases, number of increased liver enzymes, number of secondary infections
- safety of Bortezomib regarding polyneuropathy [ Time Frame: until 17 weeks after first administration of the study drug ]number of polyneuropathy cases
- safety of Bortezomib regarding increase of liver enzymes [ Time Frame: until 17 weeks after first administration of the study drug ]number of increased liver enzyme values
- Secondary infections due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]number of secondary infections
- Hematotoxicity events due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]number of hematotoxicity events
- Gastrointestinal toxicity due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]number of gastrointestinal toxicity events
- total Glasgow Coma Scale (GCS) [ Time Frame: 3, 6, 9, 13 and 17 weeks after first administration of the study drug ]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)
- Destruction marker UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1) in serum and liquor [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]Analysis of destruction marker UCH-L1 in serum and liquor
- Destruction marker Neurofilament light chain (in serum and liquor) [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]Analysis of destruction marker Neurofilament light chain in serum and liquor
- Destruction markers GFAP (glial fibrillary acidic protein) in serum and liquor [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]Analysis of destruction marker GFAP in serum and liquor
- Destruction marker TAU proteins in serum and liquor [ Time Frame: at baseline visit and 17 weeks after first administration of the study drug ]Analysis of destruction marker TAU in serum and liquor

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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)

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03993262
Contact: Christian Geis, Prof. | +49 (0) 3641 ext 9323413 | Christian.Geis@med.uni-jena.de | |
Contact: Jonathan Wickel, Dr. | +49 (0) 3641 ext 9323561 | Jonathan.Wickel@med.uni-jena.de |
Germany | |
Ludwig-Maximilians-Universität München, Klinikum Großhadern | Recruiting |
München, Bayern, Germany, 81377 | |
Contact: Tania Kümpfel, Prof. +49894400 ext 74435 tania.kuempfel@med.uni-muenchen.de | |
Contact: Joachim Havla, Dr. +49894400 ext 74435 joachim.havla@med.uni-muenchen.de | |
Universitätsklinikum Würzburg | Recruiting |
Würzburg, Bayern, Germany, 97080 | |
Contact: Claudia Sommer, Prof. +49931201 ext 23763 sommer_c@ukw.de | |
Contact: Kathrin Doppler, PD Dr. +49931201 ext 23787 doppler_K@ukw.de | |
Medizinische Hochschule Hannover | Recruiting |
Hannover, Niedersachen, Germany, 30625 | |
Contact: Kurt-Wolfram Suehs, PD Dr. +49511532 ext 2495 Suehs.Kurt-Wolfram@mh-hannover.de | |
Contact: Martin Stangel, Prof. +49511532 ext 6676 Stangel.Martin@mh-hannover.de | |
Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller Neurologie | Recruiting |
Berlin, Germany, 10117 | |
Contact: Harald Pruess, PD Dr. +49 30 450560 ext 560 harald.pruess@charite.de | |
Contact: Peter Koertvelyessy, Dr. +49 30 450560 ext 164 p.koertvelyessy@dzne.de | |
Ruhr-Universität Bochum, St. Josef Hospital, Klinik für Neurologie | Recruiting |
Bochum, Germany, 44791 | |
Contact: Ilya Ayzenberg, PD Dr. +49 234 509 ext 6423 Ilya.Ayzenberg@ruhr-uni-bochum.de | |
Contact: Ruth Schneider, Dr. +49 234 509 ext 6433 ruth.schneider@rub.de | |
University Hospital Düsseldorf, Clinic for Neurology | Recruiting |
Düsseldorf, Germany, 40225 | |
Contact: Nico Melzer, PD Dr. +4921181 ext 18978 Nico.Melzer@med.uni-duesseldorf.de | |
Contact: Sven G Meuth, Prof. Dr. +4921181 ext 17880 SvenGuenther.Meuth@med.uni-duesseldorf.de | |
University Hospital Frankfurt (Main), Clinic for Neurology | Recruiting |
Frankfurt, Germany, 60528 | |
Contact: Felix Rosenow, Prof. Dr. +49696301 ext 84521 rosenow@med.uni-frankfurt.de | |
Contact: Adam P Strzelczyk, Prof. Dr. +49696301 ext 5852 AdamPeter.Strzelczyk@kgu.de | |
Universitätsmedizin Göttingen Georg-August-Universität, Klinik für Neurologie | Recruiting |
Göttingen, Germany, 37075 | |
Contact: Dirk Fitzner, Dr. +49 551 39 ext 65593 d.fitzner@med.uni-goettingen.de | |
Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für Neurologie | Recruiting |
Jena, Germany, 07747 | |
Contact: Christian Geis, Prof. +49-3641 ext -9323413 Christian.Geis@med.uni-jena.de | |
Contact: Jonathan Wickel, Dr. +49 3641 ext 9323561 Jonathan.Wickel@med.uni-jena.de | |
Klinik für Neurologie UKSH, Campus Kiel | Recruiting |
Kiel, Germany, 24105 | |
Contact: Frank Leypoldt, PD Dr. +49 431 500 ext 16209 frank.leypoldt@uksh.de | |
Contact: Klarissa Stuerner, Dr. +49 431 500 ext 23816 klarissa.stuerner@uksh.de | |
Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurologie | Recruiting |
Leipzig, Germany, 04103 | |
Contact: Florian Then Berg, Prof. Dr. +49 341972 ext 4320 Florian.ThenBergh@medizin.uni-leipzig.de | |
Contact: Lars-Malte Teusser, Dr. +49 341972 ext 4320 lars-malte.teusser@medizin.uni-leipzig.de | |
Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie | Recruiting |
Mainz, Germany, 55131 | |
Contact: Stefan Bittner, Prof. +49 6131 17 ext 2805 stefan.bittner@unimedizin-mainz.de | |
Contact: Felix Lüssi, PD Dr. +49 6131 17 ext 5278 felix.luessi@unimedizin-mainz.de | |
Universitätsklinikum Münster Klinik für Neurologie | Recruiting |
Münster, Germany, 48149 | |
Contact: Oliver M Grauer, PD Dr. +49 251 8348 ext 6814 OliverMartin.Grauer@ukmuenster.de | |
Contact: Stjepana Kovac, PD Dr. stjepana.kovac@ukmuenster.de | |
Universitätsklinikum Ulm, Klinik für Neurologie Neurologische Ambulanz | Recruiting |
Ulm, Germany, 89081 | |
Contact: Jan Lewerenz, PD Dr. +49 731 500 ext 63146 jan.lewerenz@uni-ulm.de | |
Contact: Mabule Senel, Dr. +49 731 077 ext 5265 makbule.senel@uni-ulm.de |
Study Director: | Christian Geis, Prof. | University Hospital Jena |
Responsible Party: | Christian Geis, Prof. Dr. med., Jena University Hospital |
ClinicalTrials.gov Identifier: | NCT03993262 |
Other Study ID Numbers: |
ZKSJ0120 2019-001423-12 ( EudraCT Number ) DRKS00017497 ( Registry Identifier: DRKS ) |
First Posted: | June 20, 2019 Key Record Dates |
Last Update Posted: | February 28, 2022 |
Last Verified: | February 2022 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Undecided |
Plan Description: | It is not yet decided in which way and which data exactly will be shared with other researchers. |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
autoimmune disease autoimmune encephalitis bortezomib |
NMDAR LGI1 encephalitis |
Encephalitis Hashimoto Disease Brain Diseases Central Nervous System Diseases Nervous System Diseases Thyroiditis, Autoimmune |
Thyroiditis Thyroid Diseases Endocrine System Diseases Bortezomib Antineoplastic Agents |