Subconjunctival Sirolimus for the Treatment of Autoimmune Active Anterior Uveitis

结膜下西罗莫司治疗自身免疫性活动性前葡萄膜炎

• 批准号: 8149212
• 负责人: Hatice Sen
• 金额: $ 6.24万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149212
• 关键词: Anterior uveitis; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Process; Cystoid Macular Edema; Disease; Enrollment; Extravasation; Eye; Flare; Growth Factor; Immunosuppressive Agents; Infection; Inflammatory; Injection of therapeutic agent; Letters; Morbidity - disease rate; Patients; Pharmaceutical Preparations; Phase; Physiologic Intraocular Pressure; Production; Randomized; Safety; Signal Transduction; Sirolimus; Steroids; T-Cell Proliferation; Time; Uveitis; active method; anterior chamber

Objective: Uveitis refers to intraocular inflammatory diseases that are an important cause of visual loss. Standard systemic immunosuppressive medications for uveitis can cause significant adverse effects and many patients continue to experience disease flare-ups. Sirolimus suppresses cytokine-driven T-cell proliferation and thus, inhibits the production, signaling and activity of many growth factors relevant to uveitis. Subconjunctival sirolimus administration could reduce or eliminate the need for topical and/or systemic immunosuppressive drugs that could result in reduced morbidity. This protocol will investigate subconjunctival sirolimus as a possible treatment for active anterior uveitis. Study Population: Five participants with active anterior uveitis will be initially accrued in this study. Participants must require treatment for their uveitis with systemic and/or topical anti-inflammatory medications at high frequency intervals greater than or equal to three times daily (T.I.D.) or local steroid treatment (periocular steroid injections) is contraindicated because of significant intraocular pressure (IOP) elevation with local steroid treatments in the past (i.e., steroid responder), have at least a grade of 1+ for anterior chamber cells and have visual acuity of at least 20/400 in the study eye. Up to seven participants may be enrolled, as two participants may be replaced if they require the use of additional medications for the treatment of uveitis (other than topical steroids) in their active non-study eye prior to their Week 4 study visit. Design: This is a Phase I, non-randomized, prospective and uncontrolled single-center study to evaluate subconjunctival sirolimus as a treatment for active anterior uveitis. All participants will receive a single 30 L (1,320 g) subconjunctival sirolimus injection in the study eye at baseline and will be followed for 16 weeks post-injection. Outcome Measures: The primary outcome is the number of participants who experience at least a 2-step reduction in inflammation1 within four weeks post-injection. Secondary outcomes include changes in visual acuity and anterior chamber cells,1 the number of participants who experience a disease flare1 within the 16-week study duration and, of the participants who experience a disease flare, the number of days to disease flare from baseline. Secondary outcomes also include the presence or extent of cystoid macular edema, the amount of retino-vascular leakage and changes in retinal thickening. Safety outcomes include the number and severity of systemic and ocular toxicities, adverse events and infections, the proportion of participants who experience vision loss of 15 ETDRS letters and the number of participants who experience a substantial rise in elevated IOP.

目的：葡萄膜炎是眼内炎症性疾病，是导致视力下降的重要原因。葡萄膜炎的标准全身免疫抑制药物可引起显著的不良反应，许多患者继续经历疾病发作。西罗莫司可抑制烟碱驱动的T细胞增殖，从而抑制与葡萄膜炎相关的许多生长因子的产生、信号传导和活性。结膜下西罗莫司给药可减少或消除对局部和/或全身免疫抑制药物的需求，从而降低发病率。本方案将研究结膜下西罗莫司作为活动性前葡萄膜炎的可能治疗方法。 研究人群：本研究最初将招募5例活动性前葡萄膜炎受试者。受试者必须需要使用全身和/或局部抗炎药物治疗葡萄膜炎，频率间隔大于或等于每日三次（T.I.D.）或局部类固醇治疗（眼周类固醇注射）是禁忌的，因为过去局部类固醇治疗会导致眼内压（IOP）显着升高（即，类固醇反应者），在研究眼中具有至少1+级的前房细胞和至少20/400的视敏度。最多可入组7例受试者，因为如果2例受试者在第4周研究访视前需要使用其他药物治疗活动性非研究眼的葡萄膜炎（外用类固醇除外），则可替换2例受试者。 设计图：这是一项I期、非随机、前瞻性和非对照单中心研究，旨在评价结膜下西罗莫司治疗活动性前葡萄膜炎的疗效。所有受试者将在基线时在研究眼接受单次30 L（1，320 g）西罗莫司结膜下注射，并在注射后随访16周。 结果测量：主要结果是注射后四周内炎症至少减少2步的参与者数量。次要结局包括视力和前房细胞的变化，1在16周研究期间发生疾病发作的受试者人数1，以及发生疾病发作的受试者中，从基线到疾病发作的天数。次要结果还包括黄斑囊样水肿的存在或程度、视网膜血管渗漏的量和视网膜增厚的变化。安全性结局包括全身和眼部毒性、不良事件和感染的数量和严重程度，经历15个ETDRS字母的视力丧失的参与者比例以及经历IOP升高大幅上升的参与者数量。