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

Abstract

Background: Autoimmune 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.Methods: Generate-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. 50 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 as well as mRS and Glasgow coma scale scores throughout the trial up to week 17. General and bortezomib-specific adverse events are monitored continuously. Discussion: The 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. Trial registration: Clinicaltrials.gov, NCT03993262. Registered June 20, 2019;https://www.clinicaltrials.gov/ct2/show/NCT03993262German Clinical Trials Register, DRKS00017497

Autoimmun vermittelte Enzephalitis

“…Der Proteasom-Inhibitor Bortezomib ist eine neue vielversprechende Therapieoption bei Patienten mit neuronalen Oberflächen-Antikörpern und einem therapieresistentem Verlauf 18 und wird daher zurzeit sogar in einer Placebo-kontrollierten klinischen Studie als Add-on-Behandlung zu Rituximab evaluiert 19 . Insgesamt handelt es sich bei den Immuntherapien um ein wachsendes Feld mit immer weiteren, neu entstehenden Therapieoptionen wie z.…”

Are Antibody Panels Under‐Utilized in Movement Disorders Diagnosis? Yes

“…For example, in disease with predominantly compliment activating IgG1 antibodies (eg, AQP4), Eculizumab is a promising option, while it less likely to benefit those with a mainly IgG4 driven disease (eg, IgLON5). Thus, with trials investigating specific treatments in molecularly defined disease and a better understanding of the underlying immunology, recommendations for treatment will become more specific for each disease in the future 35 …”