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Trial record 4 of 14 for:    Autoimmune encephalitis

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 : Not yet recruiting
First Posted : June 20, 2019
Last Update Posted : June 20, 2019
Sponsor:
Information provided by (Responsible Party):
Jena University Hospital

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.


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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
Estimated Study Start Date : October 1, 2019
Estimated Primary Completion Date : July 1, 2022
Estimated Study Completion Date : December 31, 2022


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




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

  12. 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)

  13. Destruction markers (in serum and liquor) [ Time Frame: at study start and 17 weeks after first administration of the study drug ]
    Analysis of destruction markers (Neurofilament light chain, GFAP, TAU, UCH-L1) 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
Criteria

Inclusion Criteria:

  • Clinical diagnosed severe autoimmune encephalitis (mRS ≥ 3) with auto-antibodies against neuronal surface proteins in the liquor or serum
  • pretreatment with Rituximab
  • Age ≥18 years
  • signed informed consent

Exclusion Criteria:

  • pregnancy/breast-feeding
  • acute infiltrative pulmonary and pericardial disease

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. Dr. med. +49 (0) 3641 ext 9323413 Christian.Geis@med.uni-jena.de
Contact: Jonathan Wickel, Dr. med. +49 (0) 3641 ext 9323561 Jonathan.Wickel@med.uni-jena.de

Locations
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Germany
University Hospital Jena, Clinic for Neurology
Jena, Germany, 07747
Sponsors and Collaborators
Jena University Hospital

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Responsible Party: Jena University Hospital
ClinicalTrials.gov Identifier: NCT03993262     History of Changes
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: June 20, 2019
Last Verified: June 2019
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 Jena University Hospital:
autoimmune disease
autoimmune encephalitis
bortezomib
NMDAR
LGI1
encephalitis
Additional relevant MeSH terms:
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Encephalitis
Thyroiditis, Autoimmune
Hashimoto Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Thyroiditis
Thyroid Diseases
Endocrine System Diseases
Dexamethasone
Dexamethasone acetate
Bortezomib
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action