Treatment of Systemic Lupus Erythematosus (SLE) with N-acetylcysteine (NAC)

N-乙酰半胱氨酸 (NAC) 治疗系统性红斑狼疮 (SLE)

• 批准号: 9173167
• 负责人: Michael P McDermott
• 金额: $ 20.25万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9173167
• 关键词: Acetaminophen; Acetylcysteine; Address; Adopted; Adverse effects; Affect; Antidotes; Antioxidants; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Blood; Case Report Form; Cell Lineage; Clinical; Clinical Protocols; Clinical Trials; Clinical assessments; Collaborations; Communication; Conceptions; Consent Forms; Controlled Clinical Trials; DNA; Data; Data Collection; Development; Disease; Dose; Double-Blind Method; Enrollment; Ensure; Etiology; FRAP1 gene; Fatigue; Functional disorder; Future; Glutathione; Goals; Grant; Health Food; Human; Immune System and Related Disorders; Immunosuppressive Agents; Inflammatory; Intention; Intervention; Intravenous; Investigational Therapies; Kidney Diseases; Knowledge; Laboratories; Life; Literature; Liver Failure; Lupus; Lymphocyte; Manuals; Mediating; Medical; Metabolic; Monitor; Multi-Institutional Clinical Trial; Multicenter Studies; Multicenter Trials; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Oral; Outcome; Outcome Measure; Oxidative Stress; Pamphlets; Patients; Pharmaceutical Preparations; Pharmacy facility; Phase; Phase II Clinical Trials; Pilot Projects; Placebo Control; Placebos; Policies; Prevalence; Procedures; Process; Production; Proteins; Protocols documentation; Randomized; Randomized Controlled Trials; Reactive Oxygen Species; Regulation; Reporting; Research Design; Research Infrastructure; Research Personnel; Role; Safety; Sampling; Structure; System; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Effect; Titrations; Toxic effect; Transportation; Treatment Efficacy; U-Series Cooperative Agreements; United States; Universities; Urine; Visit; arm; base; belimumab; biomarker-driven; clinical efficacy; data management; data sharing; design; disabling symptom; dosage; effective therapy; electronic data; experience; improved; indexing; lupus prone mice; meetings; mortality; novel; novel strategies; open label; operation; predicting response; primary outcome; response; sample collection; secondary outcome; sensor; treatment duration

ABSTRACT Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Although current therapies afford clinical improvement, they are not curative and are associated with significant side-effects. We previously discovered that a natural antioxidant, glutathione (GSH), is depleted in lymphocytes of SLE patients. We also found that the activation of mechanistic target of rapamycin (mTOR), a sensor of oxidative stress, contributes to abnormal T-cell lineage specification and dysfunction in SLE. In lupus-prone mice, N-acetylcysteine (NAC), which acts a precursor of GSH and an antioxidant by itself, abrogated the disease. While intravenous NAC has been safely used in humans for other indications, it is unavailable as an oral medication by prescription. Therefore, we initiated a randomized, double-blind, placebo-controlled pilot study to evaluate the safety, tolerance, as well as immunological and therapeutic impact of NAC in 36 SLE patients. In this study, NAC was found to be safe, and it improved disease activity, reversed GSH depletion and blocked pro-inflammatory mTOR activation over 3 months. These results clearly warrant confirmation in a trial with longer treatment duration. To address this critical gap in knowledge, we propose a U34 planning grant for a multi-center, randomized, double-blind, placebo-controlled phase II clinical trial of the safety and efficacy of NAC in SLE patients. The aims for this U34 application include: 1) Bringing together lupus clinical trial experts in a multi-center study with a coherent management structure and a clear communication strategy; 2) Refining the Clinical Protocol for determining the safety and efficacy of NAC; the trial conception has been, in response to reviews and NIAMS input, re-designed to ensure a clinically meaningful premise and efficient and affordable trial size using a novel approach and the recently validated SLE Responder Index (SRI) to evaluate primary clinical efficacy outcome; 3) Standardizing clinical assessment techniques to ensure reliability of the primary and secondary outcome measures across the collaborating centers; 4) Designing and implementing a 21 CRF part 11 compliant electronic data capture system (eDC), which will be based on the existing case report forms (CRFs); 5) Establishing centralized monitoring procedures for data collection and management; 6) Finalizing the Data and Safety Monitoring Plan, Standard Operating Procedures, Manual of Operating Procedures, and Investigators Brochure to meet FDA, OHRP and NIAMS requirements for a U01 (multi-site) Clinical Trial Implementation Cooperative Agreement. The preliminary specific aims for the future clinical trial will be to: 1) Confirm safety and determine efficacy of NAC relative to placebo in 210 SLE patients, (105 patients per arm, with up to 20 additional subjects proposed to enroll for titration of NAC to tolerance within a dosage range of 2.4 g/day to 4.8 g/day through an initial 3-month open label period) during a 12-month intervention followed by a 1-month washout; 2) Determine whether the reversal of GSH depletion and blockade of mTOR are sustained over 12 months and predict responsiveness to NAC. This study will establish the role of NAC as a novel, safe, effective, and biomarker-driven approach in the treatment of SLE.

抽象的 全身性红斑狼疮（SLE）是一种潜在的致命自身免疫性疾病。尽管目前的疗法负担得起 临床改进，它们无法治愈，并且与重大副作用有关。我们以前 发现天然抗氧化剂谷胱甘肽（GSH）在SLE患者的淋巴细胞中耗尽。我们也是 发现雷帕霉素（MTOR）的机械靶标的激活是一种氧化应激的传感器，有助于 SLE中的异常T细胞谱系规范和功能障碍。在狼疮易发的小鼠中，N-乙酰半胱氨酸（NAC），该小鼠 它是GSH的前体和抗氧化剂的前体，废除了该疾病。静脉注射NAC已经 安全地用于人类的其他适应症，它不可用作为处方的口服药物。因此，我们 启动了一项随机，双盲的，安慰剂对照的试点研究，以评估安全性，容忍度以及 NAC对36例SLE患者的免疫学和治疗影响。在这项研究中，发现NAC是安全的，并且 改善了疾病活性，逆转GSH耗竭并在3个月内阻止了促炎的MTOR激活。 这些结果显然需要在较长治疗持续时间的试验中确认。解决这个关键差距 知识，我们为多中心，随机，双盲，安慰剂对照的U34计划赠款 NAC患者的安全性和功效的II期临床试验。该U34应用程序的目的包括： 1）将狼疮临床试验专家汇集到具有连贯的管理结构的多中心研究中 清晰的沟通策略； 2）完善确定NAC安全性和功效的临床方案；这 在回应评论和NIAMS输入的情况下，经过审判概念已重新设计，以确保临床上有意义 使用新方法和最近经过验证的SLE响应者的前提，高效且负担得起的试用规模 指数（SRI）评估主要的临床疗效结果； 3）标准化临床评估技术 确保整个协作中心的主要和次要结果度量的可靠性； 4）设计 并实施21 CRF第11部分符合电子数据捕获系统（EDC），该系统将基于 现有案例报告表（CRF）； 5）建立集中式监控程序，以收集数据和 管理; 6）完成数据和安全监控计划，标准操作程序，手册 操作程序和调查人员的手册满足FDA，OHRP和NIAMS对U01的要求 （多站点）临床试验实施合作协议。对未来的初步特定目标 临床试验将是：1）确认安全性并确定NAC相对于安慰剂的功效，在210名SLE患者中， （每只手臂105名患者，最多提议另外20名受试者参加滴定NAC的耐受性 在12个月内，剂量范围为2.4 g/天至4.8 g/day/天的剂量范围/天至最初的3个月开放式标签。 干预，然后进行1个月的冲洗； 2）确定GSH耗竭和阻塞的逆转是否 MTOR持续了12个月，并预测了对NAC的响应能力。这项研究将确定NAC的作用 作为一种新颖，安全，有效和生物标志物驱动的方法，用于治疗SLE。