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Abstract：
BACKGROUND: 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.
UNASSIGNED: 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.
BACKGROUND: NCT04540497.
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.
UNASSIGNED: 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.
BACKGROUND: NCT04540497.
摘要：
背景：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，和死亡率。糖皮质激素,IgG4-RD的护理标准，与实质性治疗相关的毒性有关。Inebilizumab,一种针对CD19的抗体,介导被认为与IgG4-RD发病机制有关的CD19+B细胞的快速和持久的消耗.我们描述了第一个国际，prospective,双盲,安慰剂对照试验，以评估B细胞耗竭预防IgG4-RD（MITIGATE）的安全性和有效性。
方法：本研究由具有IgG4-RD专业知识的国际医师小组设计。关键的试验设计决定包括参与者的选择，临床意义的主要和次要终点的定义，照顾标准的住宿，并制定耀斑诊断标准。这项研究被批准在22个国家进行。
■主要疗效终点是在1年随机对照期间从随机分组到第一次中央裁定和研究者治疗的疾病发作的时间。一套小说,专门为这项试验制定了器官特异性耀斑诊断标准，结合症状和体征，实验室发现,影像学研究结果，和病理数据。MITIGATE旨在为主要终点累积39次耀斑，这提供了足够的能力来检测在纳比珠单抗组中65%的相对风险降低。预计160名参与者的注册将实现这一目标。其他端点包括安全、年化耀斑率，无耀斑完全缓解,生活质量措施，和累积糖皮质激素使用。MITIGATE代表第一个随机化，双盲,在IgG4-RD中进行的任何治疗策略的安慰剂对照试验。来自这项研究的数据将提供对IgG4-RD的自然史和病理生理学以及B细胞耗竭作为治疗途径的有效性和安全性的见解。
背景：NCT04540497。
方法：本研究由具有IgG4-RD专业知识的国际医师小组设计。关键的试验设计决定包括参与者的选择，临床意义的主要和次要终点的定义，照顾标准的住宿，并制定耀斑诊断标准。这项研究被批准在22个国家进行。
■主要疗效终点是在1年随机对照期间从随机分组到第一次中央裁定和研究者治疗的疾病发作的时间。一套小说,专门为这项试验制定了器官特异性耀斑诊断标准，结合症状和体征，实验室发现,影像学研究结果，和病理数据。MITIGATE旨在为主要终点累积39次耀斑，这提供了足够的能力来检测在纳比珠单抗组中65%的相对风险降低。预计160名参与者的注册将实现这一目标。其他端点包括安全、年化耀斑率，无耀斑完全缓解,生活质量措施，和累积糖皮质激素使用。MITIGATE代表第一个随机化，双盲,在IgG4-RD中进行的任何治疗策略的安慰剂对照试验。来自这项研究的数据将提供对IgG4-RD的自然史和病理生理学以及B细胞耗竭作为治疗途径的有效性和安全性的见解。
背景：NCT04540497。
