<br>Inebilizumab 在 IgG4 相关疾病中的疗效和安全性：随机对照试验方案,Rheumatology and Therapy

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Inebilizumab 在 IgG4 相关疾病中的疗效和安全性：随机对照试验方案
Rheumatology and Therapy ( IF 2.9 ) Pub Date : 2023-10-04 , DOI: 10.1007/s40744-023-00593-7
Cory Perugino ₁ , Emma L Culver ₂ , Arezou Khosroshahi ₃ , Wen Zhang ₄ , Emanuel Della-Torre ₅ , Kazuichi Okazaki ₆ , Yoshiya Tanaka ₇ , Matthias Löhr ₈ , Nicolas Schleinitz ₉ , Judith Falloon ₁₀ , Dewei She ₁₀ , Daniel Cimbora ₁₀ , John H Stone _{1,

11}

Affiliation

Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
Translational Gastroenterology Unit, John Radcliffe Hospital, and Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Division of Rheumatology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
Unit of Immunology, Rheumatology, Allergy, and Rare Diseases (UnIRAR), San Raffaele Hospital, Milan, Italy.
Department of Internal Medicine, Kansai Medical University Kori Hospital, Osaka, Japan.
The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm, Sweden.
Département de Medecine Interne, CHU Timone, AP-HM, Aix-Marseille Université, Marseille, France.
Horizon Therapeutics, Rockville, MD, USA.
Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Suite Yawkey 4, Boston, MA, 02114, USA.

介绍

免疫球蛋白 G4 相关疾病（IgG4-RD）是一种使人衰弱的多器官疾病，其特征是反复发作导致器官功能障碍、生活质量下降和死亡。糖皮质激素是 IgG4-RD 的标准治疗，与大量治疗相关毒性相关。Inebilizumab 是一种针对 CD19 的抗体，可介导被认为与 IgG4-RD 发病机制有关的 CD19⁺ B 细胞的快速持久耗竭。我们描述了第一个国际、前瞻性、双盲、安慰剂对照试验，以评估 B 细胞耗竭预防 IgG4-RD 耀斑（MITIGATE）的安全性和有效性。

方法

该研究由具有 IgG4-RD 专业知识的国际医生小组设计。关键的试验设计决策包括受试者的选择、具有临床意义的主要和次要终点的定义、护理标准的调整以及发作诊断标准的制定。该研究已获准在 22 个国家/地区进行。

计划成果

主要疗效终点是在 1 年随机对照期间从随机分组到首次集中裁决和研究者治疗的疾病发作发生的时间。专门为该试验制定了一套新颖的器官特异性发作诊断标准，包括症状和体征、实验室检查结果、影像学研究结果和病理数据。MITIGATE 的目标是在主要终点累积 39 次耀斑，这提供了足够的把握度来检测 inebilizumab 组 65% 的相对风险降低。预计 160 名参与者的入学将实现这一目标。其他终点包括安全性、年化耀斑率、无耀斑完全缓解、生活质量指标和累积糖皮质激素使用。MITIGATE 代表了 IgG4-RD 中首次针对任何治疗策略进行的随机、双盲、安慰剂对照试验。这项研究的数据将深入了解 IgG4-RD 的自然病程和病理生理学，以及 B 细胞耗竭作为一种治疗途径的有效性和安全性。

试用注册

NCT04540497。

"点击查看英文标题和摘要"

Efficacy and Safety of Inebilizumab in IgG4-Related Disease: Protocol for a Randomized Controlled Trial

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a debilitating multiorgan disease characterized by recurring flares leading to organ dysfunction, decreased quality of life, and mortality. Glucocorticoids, the standard of care for IgG4-RD, are associated with substantial treatment-related toxicity. Inebilizumab, an antibody directed against CD19, mediates the rapid and durable depletion of CD19⁺ B cells thought to be involved in IgG4-RD pathogenesis. We describe the first international, prospective, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-cell depletion for flare prevention in IgG4-RD (MITIGATE).

Methods

The study was designed by an international panel of physicians with expertise in IgG4-RD. Critical trial design decisions included the selection of participants, definition of clinically meaningful primary and secondary endpoints, accommodation of standard of care, and development of flare diagnostic criteria. The study is approved for conduct in 22 countries.

Planned Outcomes

The primary efficacy endpoint is time from randomization to the occurrence of the first centrally adjudicated and investigator-treated disease flare during the 1-year randomized controlled period. A set of novel, organ-specific flare diagnostic criteria were developed specifically for this trial, incorporating symptoms and signs, laboratory findings, imaging study results, and pathology data. MITIGATE aims to accrue 39 flares for the primary endpoint, which provides sufficient power to detect a relative risk reduction of 65% in the inebilizumab group. It is anticipated that enrollment of 160 participants will achieve this goal. Additional endpoints include safety, annualized flare rate, flare-free complete remission, quality-of-life measures, and cumulative glucocorticoid use. MITIGATE represents the first randomized, double-blind, placebo-controlled trial of any treatment strategy conducted in IgG4-RD. Data from this study will provide insights into the natural history and pathophysiology of IgG4-RD and the efficacy and safety of B-cell depletion as a therapeutic avenue.

Trial Registration

NCT04540497.

更新日期：2023-10-05

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