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

A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis

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.

Study Overview

• Status: Recruiting
• Conditions: Autoimmune Encephalitis
• Intervention / Treatment: Drug: Bortezomib; Drug: Placebo

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 Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christian Geis, Prof.; Phone Number: 9323413 +49 (0) 3641; Email: Christian.Geis@med.uni-jena.de
• Study Contact Backup: Name: Jonathan Wickel, Dr.; Phone Number: 9323561 +49 (0) 3641; Email: Jonathan.Wickel@med.uni-jena.de

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Recruiting
    • Charité - Universitätsmedizin Berlin, Klinik für Neurologie mit Experimenteller Neurologie
    • Contact: Harald Pruess, PD Dr.; Phone Number: 560 +49 30 450560; Email: harald.pruess@charite.de
    • Contact: Peter Koertvelyessy, Dr.; Phone Number: 164 +49 30 450560; Email: p.koertvelyessy@dzne.de
  • Bochum, Germany, 44791
    • Recruiting
    • Ruhr-Universität Bochum, St. Josef Hospital, Klinik für Neurologie
    • Contact: Ilya Ayzenberg, PD Dr.; Phone Number: 6423 +49 234 509; Email: Ilya.Ayzenberg@ruhr-uni-bochum.de
    • Contact: Ruth Schneider, Dr.; Phone Number: 6433 +49 234 509; Email: ruth.schneider@rub.de
  • Düsseldorf, Germany, 40225
    • Recruiting
    • University Hospital Düsseldorf, Clinic for Neurology
    • Contact: Nico Melzer, PD Dr.; Phone Number: 18978 +4921181; Email: Nico.Melzer@med.uni-duesseldorf.de
    • Contact: Sven G Meuth, Prof. Dr.; Phone Number: 17880 +4921181; Email: SvenGuenther.Meuth@med.uni-duesseldorf.de
  • Erlangen, Germany, 91054
    • Not yet recruiting
    • Universitätsklinikum Erlangen, Neurologische Klinik
    • Contact: Veit Rothhammer, Prof. Dr.; Email: Veit.Rothhammer@uk-erlangen.de
    • Contact: Thanos Tsaktanis, Dr.; Email: Thanos.Tsaktanis@uk-erlangen.de
  • Essen, Germany, 45147
    • Not yet recruiting
    • Universitätsklinikum Essen (AöR), Klinik für Neurologie
    • Contact: Carlos Quesada, Dr.; Email: Carlos.Quesada@uk-essen.de
    • Contact: Refik Pul, Dr.; Email: Refik.Pul@uk-essen.de
  • Frankfurt, Germany, 60528
    • Recruiting
    • University Hospital Frankfurt (Main), Clinic for Neurology
    • Contact: Felix Rosenow, Prof. Dr.; Phone Number: 84521 +49696301; Email: rosenow@med.uni-frankfurt.de
    • Contact: Adam P Strzelczyk, Prof. Dr.; Phone Number: 5852 +49696301; Email: AdamPeter.Strzelczyk@kgu.de
  • Greifswald, Germany, 17475
    • Not yet recruiting
    • Universitätsmedizin Greifswald, Klinik und Poliklinik für Neurologie
    • Contact: Marie Suesse, PD Dr.; Email: Marie.Suesse@med.uni-greifswald.de
    • Contact: Felix von Podewils, Prof. Dr.; Email: Felix.vonPodewils@med.uni-greifswald.de
  • Göttingen, Germany, 37075
    • Recruiting
    • Universitätsmedizin Göttingen Georg-August-Universität, Klinik für Neurologie
    • Contact: Dirk Fitzner, Dr.; Phone Number: 65593 +49 551 39; Email: d.fitzner@med.uni-goettingen.de
  • Jena, Germany, 07747
    • Recruiting
    • Universitätsklinikum Jena, Sektion Translationale Neuroimmunologie, Klinik für Neurologie
    • Contact: Christian Geis, Prof.; Phone Number: -9323413 +49-3641; Email: Christian.Geis@med.uni-jena.de
    • Contact: Jonathan Wickel, Dr.; Phone Number: 9323561 +49 3641; Email: Jonathan.Wickel@med.uni-jena.de
  • Kiel, Germany, 24105
    • Recruiting
    • Klinik für Neurologie UKSH, Campus Kiel
    • Contact: Frank Leypoldt, PD Dr.; Phone Number: 16209 +49 431 500; Email: frank.leypoldt@uksh.de
    • Contact: Klarissa Stuerner, Dr.; Phone Number: 23816 +49 431 500; Email: klarissa.stuerner@uksh.de
  • Leipzig, Germany, 04103
    • Recruiting
    • Universitätsklinikum Leipzig, Klinik und Poliklinik für Neurologie
    • Contact: Florian Then Berg, Prof. Dr.; Phone Number: 4320 +49 341972; Email: Florian.ThenBergh@medizin.uni-leipzig.de
    • Contact: Lars-Malte Teusser, Dr.; Phone Number: 4320 +49 341972; Email: lars-malte.teusser@medizin.uni-leipzig.de
  • Mainz, Germany, 55131
    • Recruiting
    • Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie
    • Contact: Stefan Bittner, Prof.; Phone Number: 2805 +49 6131 17; Email: stefan.bittner@unimedizin-mainz.de
    • Contact: Felix Lüssi, PD Dr.; Phone Number: 5278 +49 6131 17; Email: felix.luessi@unimedizin-mainz.de
  • Münster, Germany, 48149
    • Recruiting
    • Universitätsklinikum Münster Klinik für Neurologie
    • Contact: Oliver M Grauer, PD Dr.; Phone Number: 6814 +49 251 8348; Email: OliverMartin.Grauer@ukmuenster.de
    • Contact: Stjepana Kovac, PD Dr.; Email: stjepana.kovac@ukmuenster.de
  • Ulm, Germany, 89081
    • Recruiting
    • Universitätsklinikum Ulm, Klinik für Neurologie Neurologische Ambulanz
    • Contact: Jan Lewerenz, PD Dr.; Phone Number: 63146 +49 731 500; Email: jan.lewerenz@uni-ulm.de
    • Contact: Mabule Senel, Dr.; Phone Number: 5265 +49 731 077; Email: makbule.senel@uni-ulm.de
  • Bayern
    • München, Bayern, Germany, 81377
      • Recruiting
      • Ludwig-Maximilians-Universität München, Klinikum Großhadern
      • Contact: Tania Kümpfel, Prof.; Phone Number: 74435 +49894400; Email: tania.kuempfel@med.uni-muenchen.de
      • Contact: Joachim Havla, Dr.; Phone Number: 74435 +49894400; Email: joachim.havla@med.uni-muenchen.de
    • Würzburg, Bayern, Germany, 97080
      • Recruiting
      • Universitätsklinikum Würzburg
      • Contact: Claudia Sommer, Prof.; Phone Number: 23763 +49931201; Email: sommer_c@ukw.de
      • Contact: Kathrin Doppler, PD Dr.; Phone Number: 23787 +49931201; Email: doppler_K@ukw.de
  • Niedersachen
    • Hannover, Niedersachen, Germany, 30625
      • Recruiting
      • Medizinische Hochschule Hannover
      • Contact: Kurt-Wolfram Suehs, PD Dr.; Phone Number: 2495 +49511532; Email: Suehs.Kurt-Wolfram@mh-hannover.de
      • Contact: Martin Stangel, Prof.; Phone Number: 6676 +49511532; Email: Stangel.Martin@mh-hannover.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: isotonic NaCl solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
modified Rankin-Score (mRS)	modified Rankin-Score from 0 = no symptoms to 6 = death	17 weeks after first administration of the study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
safety of Bortezomib regarding polyneuropathy	number of polyneuropathy cases	until 17 weeks after first administration of the study drug
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 infections due to Bortezomib	number of secondary infections	until 17 weeks after first administration of the study drug
Hematotoxicity events due to Bortezomib	number of hematotoxicity events	until 17 weeks after first administration of the study drug
Gastrointestinal toxicity due to Bortezomib	number of gastrointestinal toxicity events	until 17 weeks after first administration of the study drug
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Jena University Hospital
• Investigators: Study Director: Christian Geis, Prof., University Hospital Jena

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2020
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: June 12, 2019
• First Submitted That Met QC Criteria: June 19, 2019
• First Posted (Actual): June 20, 2019

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: bortezomib; autoimmune disease; autoimmune encephalitis; encephalitis; NMDAR; LGI1
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Thyroid Diseases; Thyroiditis, Autoimmune; Thyroiditis; Neuroinflammatory Diseases; Encephalitis; Autoimmune Diseases of the Nervous System; Hashimoto Disease; Antineoplastic Agents; Bortezomib
• Other Study ID Numbers: ZKSJ0120; 2019-001423-12 (EudraCT Number); DRKS00017497 (Registry Identifier: DRKS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: It is not yet decided in which way and which data exactly will be shared with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No