Background
Research question
Methods/design
Overview of trial design
# | Site/address |
---|---|
01 | Jena University Hospital, Department of Neurology Am Klinikum 1, 07747 Jena, Germany |
02 | University Hospital Schleswig-Holstein Campus Kiel, Neuroimmunology, Department of Neurology and Inst. of Clinical Chemistry Arnold-Heller-Str. 3, Haus 41, 24105 Kiel, Germany |
03 | University Hospital Ulm, Department of Neurology Oberer Eselsberg 45, 89081 Ulm, Germany |
04 | Charité – University Medicine Berlin, Department of Neurology Charitéplatz 1, 10117 Berlin, Germany |
05 | University Hospital Münster, Department of Neurology Albert-Schweitzer-Campus 1, 48149 Münster, Germany |
06 | University Hospital Würzburg, Department of Neurology Josef-Schneider-Straße 11, 97080 Würzburg, Germany |
07 | Medizinische Hochschule Hannover, Department of Neurology Carl-Beuberg-Str. 1, 30625 Hannover, Germany |
08 | Ludwig-Maximilians-University Munich, Institute of Clinical Neuroimmunology and Department of Neurology Marchioninistraße 15, 81377 München, Germany |
09 | Ruhr-University Bochum, St. Josef Hospital, Department of Neurology Gudrunstr. 56, 44791 Bochum, Germany |
Aims
Primary objective
Secondary objectives
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mRS scores 3, 6, 9, and 13 weeks after the first application of study medication
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Glasgow coma scale score 3, 6, 9, 13, and 17 weeks after first application of study medication
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Duration of hospital/ duration of ICU stay
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Neurocognitive function (Montreal Cognitive Assessment Test, MoCA; Mini Mental Status Examination, MMSE; Neuro Psychiatric Inventory, NPI; Rey Auditory Verbal Learning Test, RAVLT) at baseline and 17 weeks after first application of study medication
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Absolute and relative change in auto-antibody and vaccine titers in serum and in the cerebrospinal fluid as well as intrathecal synthesis (CSF; at baseline and 17 weeks after the first application of study medication)
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Immunostatus (differential blood count, IgG, IgM, and IgA fractions)
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Markers of neuronal damage (neurofilament light chain, NFL; Glial fibrillary acidic protein, GFAP; TAU; ubiquitin carboxy-terminal hydrolase L1; UCH-L1) in the serum at baseline and 17 weeks after the first application of study medication
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Change in clonality analysis of B and T cell receptors from bulk NGS sequencing from CSF cells and PBMCs.
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(Serious) adverse events within 17 weeks after the first application of study medication.
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To distinct bortezomib safety: polyneuropathy, increase of liver enzymes, hemotoxicity, gastrointestinal toxicity, infectious events
Eligibility criteria
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Age 18 years or older
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Clinically diagnosed severe autoimmune encephalitis (mRS ≥ 3)
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Antineuronal surface autoantibodies (e.g., NMDA receptor, LGI1, CASPR2, others) in CSF or serum (determined within maximum 4 weeks before randomization)
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Pretreatment with rituximab
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Written informed consent of the patient or legal representative
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Negative pregnancy test in women of child-bearing potential (until 2 years after menopause)
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Pregnancy/lactation
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Acute infiltrating pulmonary disease
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Acute infiltrating pericardial disease
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Malignant tumor with ongoing chemotherapy
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Concomitant participation in other interventional study
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Preceding participation in Generate-Boost
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Known hypersensitivity to bortezomib or dexamethasone
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Ongoing other immunotherapy except for that implicated in the study protocol
Randomization and blinding
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Patient did not receive study medication
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Patient received plasma exchange, immunoadsorption, or any other immunotherapy other than those designated in the study protocol (bortezomib and dexamethasone)
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Patients who developed severe adverse reaction during the first application of study medication and who had to discontinue study medication for that reason
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Patients who received an additional application of study medication despite treatment with study medication was regularly terminated
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Patients that were set on chemotherapy during the trial
Interventions
Neuropathy | Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental activities of daily living, ADL) | Reduction of dose level to 1.0 mg/m2 BSA |
Grade 2 with pain or Grade 3 (severe symptoms; limiting self-care ADL) | Suspension of treatment; if resolved, continuation with reduced dose (one dose level below prior treatment dose); if suspension persists for > 2 weeks, study treatment has to be discontinued. | |
Grade 4 (life-threatening consequences; urgent intervention indicated) | Discontinuation of study treatment | |
Bilirubin | > 1.5× upper limit of normal (ULN) | Reduction of dose level to 0.7 mg/m2 BSA; if additional treatment cycle: depending on tolerability increase of dose level to 1.0 mg/m2 BSA or further reduction to 0.5 mg/m2 BSA |
Thrombopenia/neutropenia | Thrombopenia with < 25.000/μl | Suspension of treatment until resolved If suspension persists for > 2 weeks, study treatment has to be discontinued. |
Neutropenia with fever | ||
Neutropenia with < 750/μl |
Clinical scales and assessment of disease severity
Laboratory parameters and analysis
Antineuronal antibody titers
MRZ reaction and tetanus titer
Additional biomarkers
Peripheral blood mononuclear cells and CSF cells
Data management
Patient safety monitoring
Quality assurance and safety
Sample size/power calculations
Statistical analysis
Stopping rules
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Progressive multifocal leucencephalopathy
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Posterior reversible encephalopathy syndrome
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Severe reactions due to immune complexes, e.g., proliferative glomeruolonephritis and polyarthritis
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Grade 4 bortezomib-induced neuropathy (life-threatening) or severe autonomous neuropathy
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Grade 3 bortezomib-induced neuropathy (severe symptoms, activity of daily living significantly affected) or grade 2 neuropathy (moderate symptoms, activity of daily living affected) with pain lasting longer than 2 weeks
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Absolute neutrophil count < 750/μl after pausing bortezomib for 2 weeks
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Absolute thrombocyte count < 25,000/μl after pausing bortezomib for 2 weeks