TY  - JOUR
AU  - Wickel, Jonathan
AU  - Chung, Ha-Yeun
AU  - Platzer, Stephanie
AU  - Lehmann, Thomas
AU  - Prüss, Harald
AU  - Leypoldt, Frank
AU  - Günther, Albrecht
AU  - Scherag, André
AU  - Geis, Christian
TI  - 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
JO  - Trials
VL  - 21
IS  - 1
SN  - 1745-6215
CY  - London
PB  - BioMed Central
M1  - DZNE-2020-01276
SP  - 625
PY  - 2020
AB  - BackgroundAutoimmune encephalitis is a new spectrum of autoimmune disorders of the central nervous system (CNS), which are characterized by pathogenic autoantibodies against neuronal surface antigens. Clinical presentations range from acute to subacute encephalopathy with neurological and psychiatric symptoms, and life-threatening autonomic dysfunction in severe cases. There exist no approved therapies nor is data available from controlled clinical trials. Patients are usually treated with diverse combinations of immunotherapy. However, effect of immunotherapy on antibody-producing cells and thus on levels of pathogenic autoantibodies is insufficient. Therefore, therapeutic response is sometimes prolonged with necessity of long-time intensive care treatment and also irreversible deficits occur in severe cases. This trial will investigate the efficacy and safety of bortezomib, a proteasome inhibitor known to selectively deplete plasma cells, in patients with severe autoimmune encephalitis who have been treated with rituximab with insufficient response.MethodsGenerate-Boost is an investigator-initiated, multicenter, double-blinded, randomized controlled phase II trial which will be conducted in specialized neurological hospitals within the GENERATE (GErman NEtwork for Research on AuToimmune Encephalitis) network in Germany. Adult patients with severe autoimmune encephalitis (modified Rankin scale, mRS ≥ 3), autoantibodies against neuronal surface antigens, and pretreatment with rituximab are eligible for study participation. Fifty patients will be randomized 1:1 and undergo up to 3 cycles (each 21 days with 4 s. c. applications) of bortezomib or placebo. All patients will receive concomitant medication with dexamethasone, acyclovir and co-trimoxazole. The primary efficacy endpoint is the mRS score 17 weeks after first treatment application. Secondary endpoints are neurocognitive function, antibody titers, markers of neuronal cell damage, length of ICU/hospital stay, and mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously.DiscussionThe expected outcome of the study is to obtain first reliable data on a hypothesis-driven therapeutic option in severe and difficult-to-treat autoimmune encephalitis. If treatment with bortezomib is beneficial in these cases, this will be the basis for implementation in the current guidelines.
KW  - Acyclovir
KW  - Adult
KW  - Autoantibodies: blood
KW  - Bortezomib: adverse effects
KW  - Bortezomib: therapeutic use
KW  - Clinical Trials, Phase II as Topic
KW  - Dexamethasone
KW  - Double-Blind Method
KW  - Drug Therapy, Combination
KW  - Encephalitis: drug therapy
KW  - Encephalitis: immunology
KW  - Germany
KW  - Glasgow Coma Scale
KW  - Hashimoto Disease: drug therapy
KW  - Hashimoto Disease: immunology
KW  - Humans
KW  - Immunotherapy
KW  - Multicenter Studies as Topic
KW  - Prospective Studies
KW  - Proteasome Inhibitors: adverse effects
KW  - Proteasome Inhibitors: therapeutic use
KW  - Randomized Controlled Trials as Topic
KW  - Time Factors
KW  - Treatment Outcome
KW  - Trimethoprim, Sulfamethoxazole Drug Combination
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7346383
C6  - pmid:32641101
DO  - DOI:10.1186/s13063-020-04516-7
UR  - https://pub.dzne.de/record/153279
ER  -