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: 8179855
• 负责人: Andrea Vambutas
• 金额: $ 24.9万
• 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: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8179855
• 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

DESCRIPTION (provided by applicant): 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-1¿ is the quintessential cytokine that mediates the innate immune response. Expression of IL-1¿ 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). PUBLIC HEALTH RELEVANCE: Patients with immune mediated hearing loss are typically treated with corticosteroids. Of those treated, approximately 60% respond, however, that response may be lost over time. Other therapies use to date have proven largely ineffectual in improving hearing. This application proposes a phase I open label clinical trial of Anakinra for corticosteroid- resistant patients to determine if this therapy is efficacious in hearing restoration.

描述（由申请人提供）：自身免疫性内耳疾病（AIED）是一种病因学知之甚少的进行性感音神经性听力损失，约60%的病例适合皮质类固醇治疗。由于未知的机制，这种响应随着时间的推移而丢失。对于皮质类固醇抵抗的AIED患者，很少有治疗方法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反应受试者上，因为他们更容易被识别为一个队列，并且被认为更可能有炎症病因介导他们的感音神经性听力损失。到目前为止，没有有效的治疗干预存在皮质类固醇耐药患者AIED。IL-1是介导先天免疫应答的典型细胞因子。IL-1的表达决定了其他自身免疫性和炎症性疾病中的许多后期适应性T细胞反应。我们有初步证据表明，在AIED的皮质类固醇无应答者中，几个IL-1 <$家族成员受到异常调节，并可能导致类固醇抵抗。到目前为止，已经有有限的研究，在这种疾病的类固醇耐药相关的机制。我们的研究结果提供了阿那白滞素在皮质类固醇耐药（无应答）AIED患者中进行IL-1阻断的基本原理，作为I期开放标签临床试验，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将允许在小规模上测试该假设。如果阿那白滞素对这些患者听力恢复的有效性证据（主要里程碑），我们建议在更大的皮质类固醇耐药AIED患者队列（R33期）中验证阿那白滞素的使用。 公共卫生相关性：免疫介导性听力损失患者通常使用皮质类固醇治疗。在接受治疗的患者中，约60%有反应，但随着时间的推移，这种反应可能会消失。迄今为止使用的其他疗法已被证明在改善听力方面基本无效。本申请提出了阿那白滞素用于皮质类固醇抗性患者的I期开放标签临床试验，以确定该疗法是否在听力恢复中有效。