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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 : Not yet recruiting
First Posted : June 20, 2019
Last Update Posted : February 10, 2020
Sponsor:
Information provided by (Responsible Party):
Christian Geis, Jena University Hospital

Tracking Information
First Submitted Date  ICMJE June 12, 2019
First Posted Date  ICMJE June 20, 2019
Last Update Posted Date February 10, 2020
Estimated Study Start Date  ICMJE February 1, 2020
Estimated Primary Completion Date July 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 29, 2019)
  • 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
  • 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
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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
  • safety of Bortezomib regarding polyneuropathy [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of polyneuropathy cases
  • 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
  • Secondary infections due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of secondary infections
  • Hematotoxicity events due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of hematotoxicity events
  • Gastrointestinal toxicity due to Bortezomib [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of gastrointestinal toxicity events
  • 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)
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • 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
  • 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
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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
  • safety of Bortezomib regarding polyneuropathy [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of polyneuropathy cases
  • 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
  • safety of Bortezomib regarding secondary infections [ Time Frame: until 17 weeks after first administration of the study drug ]
    number of secondary infections
  • 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)
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis
Official Title  ICMJE A Multicenter Randomized, Controlled, Double-blinded Trial to Evaluate Efficacy and Safety of Bortezomib in Patients With Severe Autoimmune Encephalitis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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
Condition  ICMJE Autoimmune Encephalitis
Intervention  ICMJE
  • 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)
  • 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
Study Arms  ICMJE
  • 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)
    Intervention: Drug: Bortezomib
  • 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)
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 19, 2019)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date July 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03993262
Other Study ID Numbers  ICMJE ZKSJ0120
2019-001423-12 ( EudraCT Number )
DRKS00017497 ( Registry Identifier: DRKS )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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.
Responsible Party Christian Geis, Jena University Hospital
Study Sponsor  ICMJE Jena University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Christian Geis, Prof. University Hospital Jena
PRS Account Jena University Hospital
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP