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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 10, 2021
Sponsor:
Information provided by (Responsible Party):
Christian Geis, Jena University Hospital

Study Description
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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.


Condition or disease Intervention/treatment Phase
Autoimmune Encephalitis Drug: Bortezomib Drug: Placebo Phase 2

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.

Study Design
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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 : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Encephalitis
Drug Information available for: Bortezomib

Arms and Interventions
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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)
 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)
 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


Outcome Measures
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Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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)

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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

  9. safety of Bortezomib regarding polyneuropathy [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of polyneuropathy cases

  10. 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

  11. Secondary infections due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of secondary infections

  12. Hematotoxicity events due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of hematotoxicity events

  13. Gastrointestinal toxicity due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of gastrointestinal toxicity events

  14. 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)

  15. 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

  16. 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

  17. 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

  18. 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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)
Contacts and Locations
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Information from the National Library of Medicine

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


Contacts
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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

Locations
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Germany
Ludwig-Maximilians-Universität München, Klinikum Großhadern Not yet 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 Not yet 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   
Universitätsmedizin Göttingen Georg-August-Universität, Klinik für Neurologie Not yet 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 Not yet 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 Not yet 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: Nico Melzer, PD Dr.    +49 251 8348 ext 188    nico.melzer@ukm.de   
Contact: Sven Meuth, Prof.    +49 251 8346 ext 187    sven.meuth@ukm.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   
Sponsors and Collaborators
Jena University Hospital
Investigators
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Study Director: Christian Geis, Prof. University Hospital Jena
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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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 10, 2021
Last Verified: February 2021
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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Christian Geis, Jena University Hospital:
autoimmune disease
autoimmune encephalitis
bortezomib
 NMDAR
LGI1
encephalitis
Additional relevant MeSH terms:
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Encephalitis
Hashimoto Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Thyroiditis, Autoimmune
 Thyroiditis
Thyroid Diseases
Endocrine System Diseases
Bortezomib
Antineoplastic Agents