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000153279 037__ $$aDZNE-2020-01276
000153279 041__ $$aEnglish
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000153279 1001_ $$aWickel, Jonathan$$b0
000153279 245__ $$aGenerate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis
000153279 260__ $$aLondon$$bBioMed Central$$c2020
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000153279 520__ $$aBackgroundAutoimmune 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.
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000153279 650_2 $$2MeSH$$aAcyclovir
000153279 650_2 $$2MeSH$$aAdult
000153279 650_2 $$2MeSH$$aAutoantibodies: blood
000153279 650_2 $$2MeSH$$aBortezomib: adverse effects
000153279 650_2 $$2MeSH$$aBortezomib: therapeutic use
000153279 650_2 $$2MeSH$$aClinical Trials, Phase II as Topic
000153279 650_2 $$2MeSH$$aDexamethasone
000153279 650_2 $$2MeSH$$aDouble-Blind Method
000153279 650_2 $$2MeSH$$aDrug Therapy, Combination
000153279 650_2 $$2MeSH$$aEncephalitis: drug therapy
000153279 650_2 $$2MeSH$$aEncephalitis: immunology
000153279 650_2 $$2MeSH$$aGermany
000153279 650_2 $$2MeSH$$aGlasgow Coma Scale
000153279 650_2 $$2MeSH$$aHashimoto Disease: drug therapy
000153279 650_2 $$2MeSH$$aHashimoto Disease: immunology
000153279 650_2 $$2MeSH$$aHumans
000153279 650_2 $$2MeSH$$aImmunotherapy
000153279 650_2 $$2MeSH$$aMulticenter Studies as Topic
000153279 650_2 $$2MeSH$$aProspective Studies
000153279 650_2 $$2MeSH$$aProteasome Inhibitors: adverse effects
000153279 650_2 $$2MeSH$$aProteasome Inhibitors: therapeutic use
000153279 650_2 $$2MeSH$$aRandomized Controlled Trials as Topic
000153279 650_2 $$2MeSH$$aTime Factors
000153279 650_2 $$2MeSH$$aTreatment Outcome
000153279 650_2 $$2MeSH$$aTrimethoprim, Sulfamethoxazole Drug Combination
000153279 7001_ $$aChung, Ha-Yeun$$b1
000153279 7001_ $$aPlatzer, Stephanie$$b2
000153279 7001_ $$aLehmann, Thomas$$b3
000153279 7001_ $$0P:(DE-2719)2810931$$aPrüss, Harald$$b4$$udzne
000153279 7001_ $$aLeypoldt, Frank$$b5
000153279 7001_ $$aGünther, Albrecht$$b6
000153279 7001_ $$aScherag, André$$b7
000153279 7001_ $$00000-0002-9859-581X$$aGeis, Christian$$b8$$eCorresponding author
000153279 773__ $$0PERI:(DE-600)2040523-6$$a10.1186/s13063-020-04516-7$$gVol. 21, no. 1, p. 625$$n1$$p625$$tTrials$$v21$$x1745-6215$$y2020
000153279 8564_ $$uhttps://link.springer.com/article/10.1186/s13063-020-04516-7
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