Stopping Hydroxychloroquine In Elderly Lupus Disease (SHIELD)

此U01应用程序盾(停止羟氯喹(HCQ)治疗老年狼疮)如下 完成R34，并迫切需要为管理建立基于证据的协议 关于老年狼疮患者，这是一个受到最少关注的话题。需要数据来准确地称重 在眼部累积接触HCQ与疾病发作风险之间的平衡，该人群可能 比年轻患者有更多的非活动性疾病。尽管在感染方面有安全的记录 与传统的免疫抑制剂相比，HCQ视网膜毒性的风险随着继续使用而上升。 使用敏感护理方法的评估表明，近三分之一的患者出现视网膜 损坏。停止使用HCQ的决定是困难的；然而，临床平衡应该指导这一考虑 尤其是那些病情稳定并服药多年的患者。作为狼疮患者的长寿 改善，这可能增加影响HCQ清除的合并症(例如，肾功能不全)， 对毒性的疗效预计会降低。在老龄化人口中，疾病活动可能会减弱，这推动了 这一比率甚至进一步下降。该U01的目的是进行第三阶段随机双盲安慰剂试验 关于系统性红斑狼疮患者停用氢氯喹酮安全性的多中心非劣势对照临床试验 ≥现年60岁。中心假设是，在稳定/静止的患者中，可以安全地停止使用HCQ 根据血清学、细胞因子和免疫指标评估疾病活动性和闪光 转录剪裁侧写。接受研究的人群将是330名患者，他们至少符合其中一种分类 系统性红斑狼疮的标准(ACR、SLICC、EULAR/SLICC)是≥60年，目前每天至少服用200mgHCQ至少 年龄至少7年，病情稳定。患者将被随机分为安慰剂组或活动组，并进行跟踪观察 每两个月一次，为期一年，以评估疾病活动和耀斑。受试者将从纽约大学招募(彼得 Izmirly，Jill Buyon)，阿尔伯特·爱因斯坦(Anna Broder)，HSS(Jane Salmon)，哥伦比亚(Anca Askanase)，OMRF(Joan Merrill)、宾夕法尼亚州立大学(Nancy Olsen)和加州大学洛杉矶分校(Maureen McMahon)。主要的结果将是发生 在随访期间出现中度/重度耀斑。样本量基于13%的中度/重度预测 留在HCQ的患者的闪光率和等于10%的绝对差值的非劣势边缘 在小组之间。试验基础设施已按照美国国立卫生研究院的指导方针建立并完成 来自获奖的R34的以下交付成果：由具有所有地点的sirB支持的模范招聘；研究 包括生物标记物研究和综合统计分析计划的协议.操作手册 程序；电子数据采集系统；数据管理计划；研究药物的采购；以及培训 支持人员。预计这项试验将对我们老龄化的狼疮患者的护理产生重大影响， 提供自身免疫参数的分子图景，可以识别适合药物治疗的患者 调整。

This U01 application SHIELD (Stopping Hydroxychloroquine (HCQ) In Elderly Lupus Disease) follows completion of an R34 and is driven by the exigency to establish evidence-based protocols for the management of aging lupus patients, a topic that has received minimal attention. Data are needed to accurately weigh the balance between accumulating ocular exposure of HCQ versus the risk of disease flare in a population that may have more inactive disease than younger patients. Despite a track record of safety with regard to infection compared to traditional immunosuppressive agents, the risk of HCQ retinal toxicity escalates with continued use. Evaluation using sensitive standard of care approaches suggests nearly a third of patients accrue retinal damage. The decision to discontinue HCQ is difficult; however clinical equipoise should guide this consideration especially in patients who have been stable and on the medication for years. As the longevity of lupus patients improves, which may increase comorbidities that affect HCQ clearance (e.g., renal insufficiency), the ratio of efficacy to toxicity is expected to decrease. That disease activity may wane in the aging population drives the ratio down even further. The purpose of this U01 is to conduct a Phase III, randomized, double-blind placebo controlled, multi-center, non-inferiority clinical trial to address the safety of withdrawal of HCQ in SLE patients ≥60 years old. The central hypothesis is that HCQ can be safely discontinued in stable/quiescent patients assessed by validated disease activity and flare instruments in the context of serologic, cytokine and transcriptomic profiling. The population under study will be 330 patients who fulfill at least one of the classification criteria (ACR, SLICC, EULAR/SLICC) for SLE, are ≥60yrs, are currently taking at least 200 mg HCQ daily for at least 7yrs and have stable disease. Patients will be randomized to either the placebo or active arm and followed every 2 months for one year to assess disease activity and flares. Subjects will be recruited from NYU (Peter Izmirly, Jill Buyon), Albert Einstein (Anna Broder), HSS (Jane Salmon), Columbia (Anca Askanase), OMRF (Joan Merrill), Penn State (Nancy Olsen), and UCLA (Maureen McMahon). The primary outcome will be the occurrence of a moderate/severe flare during follow-up. Sample size is based on the projection of a 13% moderate/severe flare rate in patients remaining on HCQ and a non-inferiority margin equal to a 10% absolute difference in rates between groups. The trial infrastructure has been established in compliance with NIH guidelines and completion of the following deliverables from the awarded R34: model recruitment supported by an sIRB with all sites; study protocol with inclusion of biomarker studies and comprehensive statistical analysis plan; manual of operating procedures; electronic data capture system; data management plan; acquisition of study drugs; and training of support staff. It is anticipated that this trial will significantly impact the care of our aging lupus population and provide a molecular landscape of autoimmune parameters that may identify patients appropriate for medication adjustments.