Section of Translational Neuroimmunology, Hans Berger Department of Neurology, Jena University Hospital, Am Klinikum 1, 07747, Jena, Germany.
Center of Clinical Studies, Jena University Hospital, Jena, 07747, Germany.
Trials. 2020 Jul 8;21(1):625. doi: 10.1186/s13063-020-04516-7.
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.
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. 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.
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.
Clinicaltrials.gov , NCT03993262 . Registered June 20, 2019; German Clinical Trials Register, DRKS00017497.
自身免疫性脑炎是一种中枢神经系统（CNS）自身免疫性疾病的新谱，其特征为针对神经元表面抗原的致病性自身抗体。临床表现从急性到亚急性脑病，伴有神经和精神症状，在严重情况下会出现危及生命的自主功能障碍。目前尚无批准的治疗方法，也没有对照临床试验的数据。患者通常接受免疫疗法的多种组合治疗。然而，免疫疗法对产生抗体的细胞的作用，因此对致病性自身抗体水平的作用不足。因此，治疗反应有时会延长，需要长时间的强化护理治疗，在严重情况下也会出现不可逆转的缺陷。这项试验将研究硼替佐米（一种已知选择性耗尽浆细胞的蛋白酶体抑制剂）在接受利妥昔单抗治疗但反应不足的严重自身免疫性脑炎患者中的疗效和安全性。
Generate-Boost 是一项由研究者发起的、多中心、双盲、随机对照的 II 期试验，将在德国 GENERATE（德国自身免疫性脑炎研究网络）网络中的专门神经科医院进行。符合条件的患者为患有严重自身免疫性脑炎（改良 Rankin 量表，mRS≥3）、针对神经元表面抗原的自身抗体、并接受利妥昔单抗预处理的成年患者。将 50 名患者随机分为 1:1 组，接受最多 3 个周期（每个周期 21 天，皮下应用 4 次）的硼替佐米或安慰剂。所有患者将同时接受地塞米松、阿昔洛韦和复方磺胺甲噁唑治疗。主要疗效终点是首次治疗应用后 17 周时的 mRS 评分。次要终点是神经认知功能、抗体滴度、神经元细胞损伤标志物、重症监护病房/住院时间以及整个试验过程中的 mRS 和格拉斯哥昏迷量表评分至第 17 周。持续监测一般和硼替佐米特异性不良事件。
该研究的预期结果是获得关于严重和难以治疗的自身免疫性脑炎的假设驱动治疗选择的首次可靠数据。如果在这些情况下硼替佐米治疗有效，这将为纳入当前指南提供依据。
Clinicaltrials.gov，NCT03993262。注册于 2019 年 6 月 20 日；德国临床试验注册处，DRKS00017497。
