Addressing Critical Knowledge Gaps in Early Diffuse Scleroderma Trial Design

项目总结/摘要 该提案的总体目标是改善早期弥漫性全身性疾病的临床试验设计， 硬化症（SSc）患者通过使用临床观察队列，以解决三个关键的差距， 知识这三个关键的知识差距包括：1）疾病的持续时间应该如何 最佳定义为使用皮肤变化作为主要结局的试验的入选标准，2）如果 试验设计或分析应按Ssc相关自身抗体分层，3）效应 霉酚酸酯（MMF）大小对早期弥漫性SSc皮肤厚度评分影响。具体目标 1将确定最合适的疾病发作定义，首先是非雷诺症状 与第一个SSC可归因的症状相比，将疾病持续时间定义为临床 试验入选标准。如果临床试验可以改进，则将确定具体目标2 通过根据Ssc相关自身抗体（抗Scl 70或抗RNA）对试验参与者进行分层 聚合酶3）。对于特定目的1和2，已经存在的前瞻性收集的临床 匹兹堡大学硬皮病中心的观察性队列将用于 分析.在特定目标3中，一个接受以下治疗的早期弥漫性SSc患者的观察性队列 将创建MMF，并提供疾病信息供未来试验使用 特征、药物使用和皮肤评分。为了实现这一点， 既往存在和前瞻性随访的接受MMF治疗的早期弥漫性SSc患者队列， 匹兹堡数据库将与一个新招募的额外的早期扩散的队列相结合 接受MMF治疗的SSc患者组成观察性混合队列。新进 患者将丰富以3个月时间间隔采集的随访皮肤评分数据，并添加 皮肤基因表达的样本。我们将对接受MMF治疗的患者进行匹配分析。 我们的历史非MMF治疗的早期弥漫性SSc患者的混合队列，并评估其效果 治疗6个月和12个月时皮肤上的MMF大小。MMF处理的潜在应用 队列作为未来潜在开放标签研究的比较组或对照组 治疗早期弥漫性SSc或评估新的研究药物在早期 阶段试验，允许将MMF作为正在进行的背景治疗。知识来自于 每一个建议的目的都可以应用于正在进行的早期弥漫性SSc临床试验， 试验处于计划阶段。

Project Summary/Abstract The overall goal of this proposal is to improve clinical trial design for early diffuse systemic sclerosis (SSc) patients by using a clinical observational cohort to address three crucial gaps in knowledge. These three critical knowledge gaps include 1) how disease duration should be optimally defined as an inclusion criterion for trials using skin change as a primary outcome, 2) if trial design or analysis should be stratified by SSc-associated autoantibody, and 3) the effect size of mycophenolate mofetil (MMF) on skin thickness score in early diffuse SSc. Specific Aim 1 will determine the most appropriate definition of disease onset, first non-Raynaud symptom compared to the first SSc-attributable symptom, by which to define disease duration as a clinical trial inclusion criterion. Specific Aim 2 will then establish if clinical trials may be improved through stratification of trial participants by SSc-associated autoantibody (anti-Scl70 or anti-RNA polymerase 3). For Specific Aims 1 and 2, the already existing, prospectively collected clinical observational cohort of the University of Pittsburgh Scleroderma Center will be used for analysis. In Specific Aim 3 an observational cohort of early diffuse SSc patients treated with MMF will be created and made available for future trial use with information on disease characteristics, medication use and skin scores over a one year period. To accomplish this, the pre-existing and prospectively followed cohort of early diffuse SSc patients treated with MMF in the Pittsburgh database will be combined with a newly recruited additional cohort of early diffuse SSc patients treated with MMF to form an observational hybrid cohort. The newly-recruited patients will enrich the follow-up skin score data taken at 3-month time intervals and add samples for skin gene expression. We will perform a matched analysis of the MMF-treated hybrid cohort to our historical non-MMF treated early diffuse SSc patients and assess the effect size of MMF on skin at 6 and 12 months of therapy. Potential applications of a MMF-treated cohort are as a comparator or control group for future open label studies of potential therapeutics for early diffuse SSc or to assess the effect of new investigational drugs in early phase trials when MMF is allowed as ongoing background therapy. The knowledge gained from each of the proposal Aims can be applied to both ongoing early diffuse SSc clinical trials and trials in the planning stage.