Meaningful Outcome Measures for Pediatrc Lupus Trials

描述（由申请人提供）： 系统性红斑狼疮（SLE）是一种严重的自身免疫性疾病，死亡率上升，主要针对美国少数民族的年轻女性，20%的患者在儿童时期被诊断出来（cSLE）。儿童cSLE的预后比成人差。只有3种药物（阿司匹林，羟氯喹，糖皮质激素）被美国食品和药物管理局完全批准用于成人SLE，但没有用于cSLE。缺乏新药测试可能是SLE和cSLE患者10年生存率85%的主要原因之一，但在过去十年中没有改善。SLE的随机临床试验（RCT），特别是cSLE，由于缺乏标准化的高质量替代标志物，无法在RCT中考虑的短时间内验证新药的效果，因此受到阻碍。本申请的中心假设是成人SLE的改良RCT结局参数（替代标志物）可用于评估儿童cSLE的治疗反应。 我们计划从儿童关节炎和风湿病研究联盟组织的5个儿童风湿病中心招募100名cSLE儿童。将每3个月对受试者进行一次评估（随访：1.5年）。之前开发的RCT软件将用于基于网络的数据输入和研究管理。为了检验本申请的中心假设，追求以下3个具体目标： 一曰：评估美国流变学学会特设委员会提出的SLE成人疾病活动性最小重要差异标准用于cSLE时的有效性。 第二章：前瞻性验证儿童风湿病国际试验组织（PRINTO）和前驱风湿病协作研究组（PRCSG）提出的cSLE改善的初步定义。 第三章：根据PRINTO/PRCSG先前开发的cSLE核心应答变量集，新开发cSLE疾病发作的初步标准。 我们的期望是，这项研究将提供全球疾病变化的有效替代标志物，用作未来cSLE RCT的主要缓解参数。我们将在短时间内确定迫切需要的RCT结果参数，以直接测量cSLE治疗的效果。经验证的替代标志物将简化药物效应的测量，并提供统一判断研究药物对cSLE病程影响的标准。具体来说，我们测试这些参数是否可以用于成人和儿童SLE，可能能够确认这两个群体可以在未来进行研究，药物试验concurrentlty基于类似的反应参数的有效性。这将促进SLE随机对照试验，特别是进一步促进cSLE研究。

DESCRIPTION (provided by applicant): Systemic Lupus Erythematosus (SLE) is a severe autoimmune disease with rising mortality that targets primarily young women of US minorities and 20% of all patients are diagnosed during childhood (cSLE). Children with cSLE have a worse prognosis than adults. There are only 3 medications (aspirin, hydroxychloroquine, gluco-corticoids) that have ever been fully approved for adult SLE by the U.S. Food and Drug Administration, but there are none for cSLE. Lack of testing new drugs is likely one of the main reasons why the 10-year survival of SLE and cSLE patients at 85% has not improved for over a decade. Randomized clinical trials (RCTs) in SLE, but especially cSLE, are hindered by the lack of standardized high-quality surrogate markers to verify the effects of new drugs within the short time frames considered in RCTs. The central hypothesis of this application is that modified RCT outcomes parameters (surrogate markers) of adult SLE can be used to assess treatment responses of children with cSLE. We propose to enroll 100 children with cSLE from 5 pediatric rheumatology centers organized in Childhood Arthritis & Rheumatology Research Alliance. Subjects will be assessed every 3 months (follow-up: 1.5 yrs). Previously developed RCT software will be used for web-based data entry and study management. To test the central hypothesis of the application the following 3 specific aims are pursued: 1: To assess the proposed American College of Rheumatology Ad-hoc Committee criteria for minimal important differences in disease activity of adults with SLE for their validity when used in cSLE. 2: To prospectively validate the preliminary definitions of improvement for cSLE that have been proposed by the Pediatric Rheumatology International Trial Organization (PRINTO) and the Prediatric Rheuamtology Collaborative Study Group (PRCSG). 3: To newly develop preliminary criteria of disease flare in cSLE based on the set of cSLE core response variables that have been previously developed by PRINTO/PRCSG. Our expectations are that this study will provide validated surrogate markers of changes in global diseases to be used as primary response parameters of future cSLE RCTs. We will identify within a short period of time urgently required RCT outcome parameters to directly measure the effects of cSLE treatments. Validated surrogate markers will simplify the measurement of drug effects and provide standards to uniformly judge the effects of study medications on the course of cSLE. Specifically, we test whether these parameters can be used for adults and children with SLE, possibly being able to confirm that both groups can be studied in future, drug trials concurrenlty based on the validity of similar response parameters. This would facilitate SLE RCTs in general and further promote cSLE research in particular.