A phase I clinical trial of Anakinra for Steroid-Resistant AIED

Anakinra 治疗类固醇耐药 AIED 的 I 期临床试验

• 批准号: 8499519
• 负责人: Andrea Vambutas
• 金额: $ 49.16万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499519
• 关键词: Adrenal Cortex Hormones; Autoimmune Process; Autologous; Cells; Clinical; Clinical Trials; Cochlear implant procedure; Dexamethasone; Disease; Etiology; Family member; Hearing; IL1R2 gene; Immune; Immune response; In Vitro; Inflammatory; Interleukin-1; Length; Measurement; Mediating; Molecular Profiling; Patients; Pattern; Perilymph; Phase; Phase I Clinical Trials; Plasma; Recovery; Resistance; Safety; Sensorineural Hearing Loss; Signal Transduction; Steroid Resistance; T cell response; Testing; Therapeutic; Therapeutic Intervention; Time; anakinra; base; cohort; cytokine; hearing impairment; implantation; improved; inner ear diseases; interleukin-1 receptor type II; meetings; novel; open label; peripheral blood; prevent; receptor; response; restoration

Autoimmune Inner Ear Disease (AIED) is a poorly understood etiology of progressive sensorineural hearing loss that is amenable to corticosteroid therapy in approximately 60% of cases. This response is lost over time due to unknown mechanisms. For those corticosteroid resistant AIED patients, few therapeutic alternatives are effective to restore or maintain hearing. The majority of studies on AIED patients have focused on corticosteroid responsive subjects as they have been easier to identify as a cohort, and are believed to be more likely to have an inflammatory etiology mediating their sensorineural hearing loss. To date, no effective therapeutic intervention exists for corticosteroid-resistant patients with AIED. IL-1b is the quintessential cytokine that mediates the innate immune response. Expression of IL-1b dictates many of the later adaptive T-cell responses in other autoimmune and inflammatory disorders. We have preliminary evidence that several IL-1¿ family members are aberrantly regulated in corticosteroid non- responders with AIED, and may contribute to steroid resistance. To date, there have been limited studies on the mechanisms related to steroid resistance in this disorder. Our findings provide the rationale for IL-1 blockade with Anakinra in corticosteroid resistant (non-responders) patients with AIED as a phase I open label clinical trial to determine if use of Anakinra can improve audiometric thresholds in these patients. The R21 will permit testing the hypothesis on a small scale. If evidence of efficacy for hearing restoration with anakinra can be shown in these patients (primary milestone), we propose to validate the use of anakinra in a larger cohort of corticosteroid resistant AIED patients (R33 phase).

自身免疫性内耳病（AIED）是一种病因学知之甚少的进行性感音神经性听力 在大约60%的病例中，皮质类固醇治疗可以缓解这种损失。这种响应会随着时间的推移而丢失 原因不明对于皮质类固醇抵抗的AIED患者， 能有效恢复或维持听力。大多数关于AIED患者的研究都集中在 皮质类固醇应答受试者，因为他们更容易被识别为队列，并且被认为是 更可能有炎症性病因介导他们的感音神经性听力损失。迄今为止， 对于患有AIED的皮质类固醇耐药患者存在治疗干预。 IL-1b是介导先天免疫应答的典型细胞因子。IL-1b的表达决定了 在其他自身免疫性和炎症性疾病中的许多后期适应性T细胞应答。我们有 初步证据表明，几个IL-1 <$家族成员在皮质类固醇非激素治疗中受到异常调节， 反应者与AIED，并可能有助于类固醇耐药性。到目前为止，对以下方面的研究有限： 这种疾病中与类固醇抵抗相关的机制。我们的研究结果为IL-1 阿那白滞素阻滞治疗皮质类固醇耐药（无应答）AIED患者的I期开放标签研究 临床试验，以确定使用阿那白滞素是否可以改善这些患者的听力阈值。R21将 允许在小范围内测试假设。如果阿那白滞素对听力恢复有效的证据可以 在这些患者中显示（主要里程碑），我们建议在一个更大的队列中验证阿那白滞素的使用。 皮质类固醇耐药AIED患者（R33期）。