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@ARTICLE{Wickel:153279,
      author       = {Wickel, Jonathan and Chung, Ha-Yeun and Platzer, Stephanie
                      and Lehmann, Thomas and Prüss, Harald and Leypoldt, Frank
                      and Günther, Albrecht and Scherag, André and Geis,
                      Christian},
      title        = {{G}enerate-{B}oost: 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},
      journal      = {Trials},
      volume       = {21},
      number       = {1},
      issn         = {1745-6215},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2020-01276},
      pages        = {625},
      year         = {2020},
      abstract     = {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.},
      keywords     = {Acyclovir / Adult / Autoantibodies: blood / Bortezomib:
                      adverse effects / Bortezomib: therapeutic use / Clinical
                      Trials, Phase II as Topic / Dexamethasone / Double-Blind
                      Method / Drug Therapy, Combination / Encephalitis: drug
                      therapy / Encephalitis: immunology / Germany / Glasgow Coma
                      Scale / Hashimoto Disease: drug therapy / Hashimoto Disease:
                      immunology / Humans / Immunotherapy / Multicenter Studies as
                      Topic / Prospective Studies / Proteasome Inhibitors: adverse
                      effects / Proteasome Inhibitors: therapeutic use /
                      Randomized Controlled Trials as Topic / Time Factors /
                      Treatment Outcome / Trimethoprim, Sulfamethoxazole Drug
                      Combination},
      cin          = {AG Prüß},
      ddc          = {610},
      cid          = {I:(DE-2719)1810003},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC7346383},
      pubmed       = {pmid:32641101},
      doi          = {10.1186/s13063-020-04516-7},
      url          = {https://pub.dzne.de/record/153279},
}