复发型多发性硬化患者序贯使用那他珠单抗-阿仑单抗治疗（SUPPRESS）试验——第一部分：原理与目标

The sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS) trial - Part I: Rationale and objectives.

作者信息

Hussain Rehana Z, Sguigna Peter V, Okai Annette, Wright Crystal, Madinawala Mariam, Bass Ann D, Cutter Gary R, Manouchehri Navid, Stuve Olaf

机构信息

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

North Texas Institute of Neurology & Headache, Plano, TX, USA.

出版信息

J Cent Nerv Syst Dis. 2022 Aug 29;14:11795735221123911. doi: 10.1177/11795735221123911. eCollection 2022.

DOI:10.1177/11795735221123911

PMID:36062026

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9434668/

Abstract

BACKGROUND

Natalizumab is a recombinant humanized monoclonal antibody (mAb) against α4-integrin that is approved for relapsing forms of multiple sclerosis (MS). Natalizumab is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), and with disease reactivation after cessation of treatment that is likely mediated by an accumulation of pro-inflammatory lymphocytes in the blood during therapy. Alemtuzumab is a mAb against CD52 that reduces the number of peripheral lymphocytes.

RATIONALE

To determine if treatment with alemtuzumab after natalizumab reduces disease activity in patients with relapsing forms of MS. This review article will outline the rationale and objectives of the sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS; ClinicalTrials.gov ID: NCT03135249) trial in greater detail than would be feasible in a manuscript that summarizes the study results.

METHODS

The SUPPRESS trial is single arm, open-label, multicenter, efficacy pilot study that aims to establish a disease-free state over a 24-months period in patients who received the natalizumab- alemtuzumab sequential therapy. Participants will be recruited from four different sites. The primary endpoint is the annualized relapse rate (ARR) from the time of cessation of natalizumab treatment. Key secondary endpoint is freedom of relapse at 12-months, the number of new/enlarging T2 lesions on magnetic resonance imaging (MRI), and the number of gadolinium (Gd)-enhancing lesions on MRI. An exploratory endpoint is the Expanded Disability Status Scale (EDSS), retinal nerve fiber layer (RNFL) thickness assessment by optic coherence tomography (OCT) and assessment of quality of life (QoL) measures by a pre-defined, self-administered testing battery. To evaluate immunological effects, blood leukocytes will be collected and immunophenotyped by multi-parameter flow cytometry.

CONCLUSION

The SUPPRESS trial will provide clinical, imaging, and biological data to determine whether sequential natalizumab to alemtuzumab combination therapy establish a disease-free state in patients with relapsing forms of MS.

摘要

背景

那他珠单抗是一种抗α4整合素的重组人源化单克隆抗体（mAb），已被批准用于复发型多发性硬化症（MS）。那他珠单抗与进展性多灶性白质脑病（PML）发生风险增加相关，且与治疗停止后疾病重新激活有关，这可能是由治疗期间血液中促炎性淋巴细胞的蓄积介导的。阿仑单抗是一种抗CD52的mAb，可减少外周淋巴细胞数量。

原理

为了确定在接受那他珠单抗治疗后使用阿仑单抗治疗是否能降低复发型MS患者的疾病活动度。这篇综述文章将比总结研究结果的手稿更详细地概述复发型多发性硬化症患者序贯那他珠单抗-阿仑单抗治疗（SUPPRESS；ClinicalTrials.gov标识符：NCT03135249）试验的原理和目标。

方法

SUPPRESS试验是一项单臂、开放标签、多中心的疗效试点研究，旨在使接受那他珠单抗-阿仑单抗序贯治疗的患者在24个月内达到无病状态。参与者将从四个不同地点招募。主要终点是从那他珠单抗治疗停止时起的年化复发率（ARR）。关键次要终点是12个月时无复发、磁共振成像（MRI）上新出现/扩大的T2病变数量以及MRI上钆（Gd）增强病变数量。一个探索性终点是扩展残疾状态量表（EDSS）、通过光学相干断层扫描（OCT）评估视网膜神经纤维层（RNFL）厚度以及通过预先定义的自我管理测试组评估生活质量（QoL）指标。为了评估免疫效应，将采集血液白细胞并通过多参数流式细胞术进行免疫表型分析。