A Phase-2b, Double-Blind, Randomized Controlled Trial to Evaluate the Activity and Safety of Inebilizumab in Anti-N-methyl-D-aspartate receptor (NMDAR) Encephalitis and Assess Markers of Disease
一项 2b 期、双盲、随机对照试验,旨在评估 Inebilizumab 在抗 N-甲基-D-天冬氨酸受体 (NMDAR) 脑炎中的活性和安全性并评估疾病标志物
基本信息
- 批准号:10185824
- 负责人:
- 金额:$ 400.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-15 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcuteAddressAdmission activityAdverse eventAffectAgeAntibodiesAntibody FormationAntibody TherapyAntibody titer measurementAutoantibodiesAutoimmune encephalitisB cell therapyB-Cell ActivationB-LymphocytesBehavioralBiologicalBiological MarkersBlast CellBloodBrainCD19 AntigensCD19 geneCXCL13 geneCase SeriesCentral Nervous System DiseasesCerebrospinal FluidCharacteristicsClinical DataClinical TrialsCognitiveConsciousConsensusDataDetectionDeveloped CountriesDiagnosisDisabled PersonsDiseaseDisease MarkerDoseDouble-Blind MethodDysautonomiasEarly treatmentEncephalitisEvaluationFDA approvedFutureGoalsHerpes encephalitisHigh PrevalenceHospitalizationIgG autoantibodiesImmunoglobulin GImmunoglobulinsImmunotherapyIn VitroIndividualIntensive CareIntensive Care UnitsInterleukin-10Interleukin-17Interleukin-6IntravenousIntraventricular InfusionInvestigationLabelLifeMS4A1 geneMeasuresMediatingMemoryMonoclonal AntibodiesMorbidity - disease rateMotorMovement DisordersMusN-Methyl-D-Aspartate ReceptorsNeuraxisNeuromyelitis OpticaNeuronsNeuropsychological TestsOligodendrogliaOutcomeOutcome MeasureParticipantPathogenesisPathogenicityPathologicPatient CarePatient-Focused OutcomesPatientsPenetrancePenetrationPharmaceutical PreparationsPhasePhase III Clinical TrialsPlacebosPlasmaPlasma CellsPlasmablastPrediction of Response to TherapyPrevalenceProspective StudiesQuality of lifeRandomizedRandomized Controlled TrialsResourcesRouteSafetyScreening procedureSeizuresSerious Adverse EventSeverity of illnessSiteSteroidsSurfaceSurface AntigensTherapeutic Monoclonal AntibodiesTimeWalkingWorkblood-brain barrier penetrationcontrol trialcytokinecytotoxicdesigndisabilityefficacious treatmentexecutive functionexperiencefunctional outcomeshumanized monoclonal antibodiesindexingnervous system disorderoff-label drugoutcome predictionphase III trialprimary outcomeprospectivepsychiatric symptomresponserituximabtreatment grouptreatment responderstreatment responseyoung adult
项目摘要
N-methyl-D-aspartate receptor (NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis, with prevalence exceeding herpes encephalitis in industrialized nations. Typically, the disease affects patients age 10-50 causing prominent psychiatric symptoms, associated with declining consciousness, seizures, movement disorders and life-threatening dysautonomia. Intensive care, including cardiorespiratory support is required in 75% of cases. The diagnosis is confirmed by detection of IgG autoantibodies against central nervous system NMDAR in the cerebrospinal fluid. Despite the severity of the illness, NMDAR encephalitis is a treatable neurological disease, with retrospective case series establishing the benefit of off- label intravenous steroids and immunoglobulins. These treatments are presumed to work through effects on IgG NMDAR autoantibody levels in the CSF, although prospective data informing predictors of treatment responses are limited. Even with prompt treatment, ~50% of patients remain disabled, requiring prolonged hospital admissions. Various off-label therapies have been proposed as “second-line” treatments in NMDAR encephalitis. The majority of second-line treatments target circulating B-cells with various degrees of blood brain penetrance and efficacy, and poor consensus on the timing, dose and route of delivery of candidate agents. High-quality evidence is needed to inform the treatment of NMDAR encephalitis. Inebilizumab is a promising therapeutic monoclonal antibody for the treatment of NMDAR encephalitis. This humanized monoclonal antibody against the B-cell surface antigen CD19 was recently shown to be safe and efficacious in the treatment of neuromyelitis optica spectrum disorder—another antibody-mediated disorder of the central nervous system. Compared to other off label B-cell depleting therapies, such as rituximab, inebilizumab not only depletes CD20+ B-cells, but also CD20- plasma blasts and plasma cells, resulting in robust, broad and sustained suppression of B-cell expression. The Extinguish Trial will randomize 116 participants with moderate-to-severe NMDAR encephalitis to receive either inebilizumab or placebo in addition to first-line therapies. Patient outcomes will be ascertained at standard intervals using the modified Rankin scale and accepted safety measures (primary outcomes at 16 weeks), together with comprehensive well-validated neuropsychological tests, bedside cognitive screening tools, quality of life/ functional indices, and outcome prediction measures. Clinical data will be combined with quantitative measures of NMDAR autoantibody titers and cytokines implicated in B-cell activation and antibody production within the intrathecal compartment to identify treatment responders, inform the biologic contributors to outcomes, and evaluate for biomarkers that may serve as early predictors of favorable outcomes in future clinical trials in NMDAR encephalitis. The results of the Extinguish Trial will immediately impact patient care and will facilitate the design and implementation of future clinical trials in patients with autoimmune encephalitis.
N-甲基-D-天冬氨酸受体(NMDAR)脑炎是自身免疫性脑炎最常见的原因之一,在工业化国家的流行率超过疱疹性脑炎。通常,该疾病影响10-50岁的患者,引起显著的精神症状,与意识下降、癫痫发作、运动障碍和危及生命的自主神经功能障碍相关。75%的病例需要重症监护,包括心肺支持。通过检测脑脊液中抗中枢神经系统NMDAR的IgG自身抗体确认诊断。尽管疾病严重,但NMDAR脑炎是一种可治疗的神经系统疾病,回顾性病例系列确定了标签外静脉注射类固醇和免疫球蛋白的益处。推测这些治疗通过对CSF中IgG NMDAR自身抗体水平的影响起作用,尽管告知治疗应答预测因子的前瞻性数据有限。即使得到及时治疗,约50%的患者仍然残疾,需要延长住院时间。已提出各种标签外疗法作为NMDAR脑炎的“二线”治疗。大多数二线治疗靶向循环B细胞,具有不同程度的血脑屏障和功效,并且对候选药剂的递送时间、剂量和途径缺乏共识。需要高质量的证据来指导NMDAR脑炎的治疗。Inebilizumab是治疗NMDAR脑炎的有前景的治疗性单克隆抗体。这种针对B细胞表面抗原CD 19的人源化单克隆抗体最近被证明在治疗神经肌视神经谱系障碍-另一种抗体介导的中枢神经系统疾病中是安全和有效的。与其他超说明书B细胞耗竭疗法(如利妥昔单抗)相比,inebilizumab不仅耗竭CD 20 + B细胞,而且耗竭CD 20-浆母细胞和浆细胞,导致对B细胞表达的稳健、广泛和持续抑制。Extinguish试验将随机分配116名患有中度至重度NMDAR脑炎的参与者,除一线治疗外,还接受inebilizumab或安慰剂。将使用改良兰金量表和公认的安全性指标(第16周时的主要结局)以及全面有效的神经心理学测试、床旁认知筛查工具、生活质量/功能指数和结局预测指标,以标准时间间隔确定患者结局。临床数据将与NMDAR自身抗体滴度和涉及鞘内B细胞活化和抗体产生的细胞因子的定量测量相结合,以识别治疗应答者,告知结局的生物学贡献者,并评价可作为未来NMDAR脑炎临床试验中有利结局的早期预测因子的生物标志物。Extinguish试验的结果将立即影响患者护理,并将促进未来自身免疫性脑炎患者临床试验的设计和实施。
项目成果
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