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Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis (Generate-Boost)

Primary Purpose

Autoimmune Encephalitis

Status
Recruiting
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Bortezomib
Placebo
Sponsored by
Jena University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Autoimmune Encephalitis focused on measuring autoimmune disease, autoimmune encephalitis, bortezomib, NMDAR, LGI1, encephalitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Ludwig-Maximilians-Universität München, Klinikum GroßhadernRecruiting
  • Universitätsklinikum WürzburgRecruiting
  • Medizinische Hochschule HannoverRecruiting
  • Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller NeurologieRecruiting
  • Ruhr-Universität Bochum, St. Josef Hospital, Klinik für NeurologieRecruiting
  • University Hospital Düsseldorf, Clinic for NeurologyRecruiting
  • University Hospital Frankfurt (Main), Clinic for NeurologyRecruiting
  • Universitätsmedizin Göttingen Georg-August-Universität, Klinik für NeurologieRecruiting
  • Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für NeurologieRecruiting
  • Klinik für Neurologie UKSH, Campus KielRecruiting
  • Universitätsklinikum Leipzig, Klinik und Poliklinik für NeurologieRecruiting
  • Universitätsmedizin Mainz, Klinik und Poliklinik für NeurologieRecruiting
  • Universitätsklinikum Münster Klinik für NeurologieRecruiting
  • Universitätsklinikum Ulm, Klinik für Neurologie Neurologische AmbulanzRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Interventional

Placebo

Arm Description

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)

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

Outcomes

Primary Outcome Measures

modified Rankin-Score (mRS)
modified Rankin-Score from 0 = no symptoms to 6 = death

Secondary Outcome Measures

modified Rankin-Score (mRS)
modified Rankin-Score from 0 = no symptoms to 6 = death
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
Immune response
Antibody titer (in serum and liquor) and cellular immune response (FACS analysis of liquor)
neurocognitive function assessed by Montreal Cognitive Assessment
total score of the Montreal Cognitive Assessment (MoCA) (0 to max. 30 points = best possible result)
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)
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)
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)
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
safety of Bortezomib regarding polyneuropathy
number of polyneuropathy cases
safety of Bortezomib regarding increase of liver enzymes
number of increased liver enzyme values
Secondary infections due to Bortezomib
number of secondary infections
Hematotoxicity events due to Bortezomib
number of hematotoxicity events
Gastrointestinal toxicity due to Bortezomib
number of gastrointestinal toxicity events
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)
Destruction marker UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1) in serum and liquor
Analysis of destruction marker UCH-L1 in serum and liquor
Destruction marker Neurofilament light chain (in serum and liquor)
Analysis of destruction marker Neurofilament light chain in serum and liquor
Destruction markers GFAP (glial fibrillary acidic protein) in serum and liquor
Analysis of destruction marker GFAP in serum and liquor
Destruction marker TAU proteins in serum and liquor
Analysis of destruction marker TAU in serum and liquor

Full Information

First Posted
June 12, 2019
Last Updated
January 31, 2023
Sponsor
Jena University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03993262
Brief Title
Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis
Acronym
Generate-Boost
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

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 13, 2020 (Actual)
Primary Completion Date
March 1, 2024 (Anticipated)
Study Completion Date
October 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Jena University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autoimmune Encephalitis
Keywords
autoimmune disease, autoimmune encephalitis, bortezomib, NMDAR, LGI1, encephalitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
1:1 randomization will be done centrally and stratified by site. Block randomization of variable block sizes will be used.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
The study drug will be provided blinded by the local pharmacy.
Allocation
Randomized
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christian Geis, Prof.
Phone
+49 (0) 3641
Ext
9323413
Email
Christian.Geis@med.uni-jena.de
First Name & Middle Initial & Last Name or Official Title & Degree
Jonathan Wickel, Dr.
Phone
+49 (0) 3641
Ext
9323561
Email
Jonathan.Wickel@med.uni-jena.de
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christian Geis, Prof.
Organizational Affiliation
University Hospital Jena
Official's Role
Study Director
Facility Information:
Facility Name
Ludwig-Maximilians-Universität München, Klinikum Großhadern
City
München
State/Province
Bayern
ZIP/Postal Code
81377
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tania Kümpfel, Prof.
Phone
+49894400
Ext
74435
Email
tania.kuempfel@med.uni-muenchen.de
First Name & Middle Initial & Last Name & Degree
Joachim Havla, Dr.
Phone
+49894400
Ext
74435
Email
joachim.havla@med.uni-muenchen.de
Facility Name
Universitätsklinikum Würzburg
City
Würzburg
State/Province
Bayern
ZIP/Postal Code
97080
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Claudia Sommer, Prof.
Phone
+49931201
Ext
23763
Email
sommer_c@ukw.de
First Name & Middle Initial & Last Name & Degree
Kathrin Doppler, PD Dr.
Phone
+49931201
Ext
23787
Email
doppler_K@ukw.de
Facility Name
Medizinische Hochschule Hannover
City
Hannover
State/Province
Niedersachen
ZIP/Postal Code
30625
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kurt-Wolfram Suehs, PD Dr.
Phone
+49511532
Ext
2495
Email
Suehs.Kurt-Wolfram@mh-hannover.de
First Name & Middle Initial & Last Name & Degree
Martin Stangel, Prof.
Phone
+49511532
Ext
6676
Email
Stangel.Martin@mh-hannover.de
Facility Name
Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller Neurologie
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harald Pruess, PD Dr.
Phone
+49 30 450560
Ext
560
Email
harald.pruess@charite.de
First Name & Middle Initial & Last Name & Degree
Peter Koertvelyessy, Dr.
Phone
+49 30 450560
Ext
164
Email
p.koertvelyessy@dzne.de
Facility Name
Ruhr-Universität Bochum, St. Josef Hospital, Klinik für Neurologie
City
Bochum
ZIP/Postal Code
44791
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ilya Ayzenberg, PD Dr.
Phone
+49 234 509
Ext
6423
Email
Ilya.Ayzenberg@ruhr-uni-bochum.de
First Name & Middle Initial & Last Name & Degree
Ruth Schneider, Dr.
Phone
+49 234 509
Ext
6433
Email
ruth.schneider@rub.de
Facility Name
University Hospital Düsseldorf, Clinic for Neurology
City
Düsseldorf
ZIP/Postal Code
40225
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nico Melzer, PD Dr.
Phone
+4921181
Ext
18978
Email
Nico.Melzer@med.uni-duesseldorf.de
First Name & Middle Initial & Last Name & Degree
Sven G Meuth, Prof. Dr.
Phone
+4921181
Ext
17880
Email
SvenGuenther.Meuth@med.uni-duesseldorf.de
Facility Name
University Hospital Frankfurt (Main), Clinic for Neurology
City
Frankfurt
ZIP/Postal Code
60528
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Felix Rosenow, Prof. Dr.
Phone
+49696301
Ext
84521
Email
rosenow@med.uni-frankfurt.de
First Name & Middle Initial & Last Name & Degree
Adam P Strzelczyk, Prof. Dr.
Phone
+49696301
Ext
5852
Email
AdamPeter.Strzelczyk@kgu.de
Facility Name
Universitätsmedizin Göttingen Georg-August-Universität, Klinik für Neurologie
City
Göttingen
ZIP/Postal Code
37075
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dirk Fitzner, Dr.
Phone
+49 551 39
Ext
65593
Email
d.fitzner@med.uni-goettingen.de
Facility Name
Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für Neurologie
City
Jena
ZIP/Postal Code
07747
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christian Geis, Prof.
Phone
+49-3641
Ext
-9323413
Email
Christian.Geis@med.uni-jena.de
First Name & Middle Initial & Last Name & Degree
Jonathan Wickel, Dr.
Phone
+49 3641
Ext
9323561
Email
Jonathan.Wickel@med.uni-jena.de
Facility Name
Klinik für Neurologie UKSH, Campus Kiel
City
Kiel
ZIP/Postal Code
24105
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Frank Leypoldt, PD Dr.
Phone
+49 431 500
Ext
16209
Email
frank.leypoldt@uksh.de
First Name & Middle Initial & Last Name & Degree
Klarissa Stuerner, Dr.
Phone
+49 431 500
Ext
23816
Email
klarissa.stuerner@uksh.de
Facility Name
Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurologie
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florian Then Berg, Prof. Dr.
Phone
+49 341972
Ext
4320
Email
Florian.ThenBergh@medizin.uni-leipzig.de
First Name & Middle Initial & Last Name & Degree
Lars-Malte Teusser, Dr.
Phone
+49 341972
Ext
4320
Email
lars-malte.teusser@medizin.uni-leipzig.de
Facility Name
Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Stefan Bittner, Prof.
Phone
+49 6131 17
Ext
2805
Email
stefan.bittner@unimedizin-mainz.de
First Name & Middle Initial & Last Name & Degree
Felix Lüssi, PD Dr.
Phone
+49 6131 17
Ext
5278
Email
felix.luessi@unimedizin-mainz.de
Facility Name
Universitätsklinikum Münster Klinik für Neurologie
City
Münster
ZIP/Postal Code
48149
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Oliver M Grauer, PD Dr.
Phone
+49 251 8348
Ext
6814
Email
OliverMartin.Grauer@ukmuenster.de
First Name & Middle Initial & Last Name & Degree
Stjepana Kovac, PD Dr.
Email
stjepana.kovac@ukmuenster.de
Facility Name
Universitätsklinikum Ulm, Klinik für Neurologie Neurologische Ambulanz
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jan Lewerenz, PD Dr.
Phone
+49 731 500
Ext
63146
Email
jan.lewerenz@uni-ulm.de
First Name & Middle Initial & Last Name & Degree
Mabule Senel, Dr.
Phone
+49 731 077
Ext
5265
Email
makbule.senel@uni-ulm.de

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
It is not yet decided in which way and which data exactly will be shared with other researchers.
Citations:
PubMed Identifier
32641101
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.
Results Reference
derived

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

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