Addressing Critical Knowledge Gaps in Early Diffuse Scleroderma Trial Design

项目摘要/摘要 这项建议的总体目标是改进早期弥漫系统性疾病的临床试验设计。 硬化症(SSC)患者通过临床观察队列来解决以下三个关键差距 知识。这三个关键知识差距包括1)疾病持续时间应该是多少 最佳定义为将皮肤变化作为主要结果的试验的纳入标准，2)如果 试验设计或分析应根据SSc相关自身抗体进行分层，以及3)效果 霉酚酸酯(MMF)大小对弥漫性SSC早期皮肤厚度评分的影响。特定目标 1将确定最合适的疾病发病定义，即第一个非雷诺症状 与第一个SSC可归因症状相比，根据该症状将疾病持续时间定义为临床 试验纳入标准。特定目标2将确定是否可以改进临床试验 通过SSC相关自身抗体(抗Scl70或抗RNA)对试验参与者进行分层 聚合酶3)。对于特定的目标1和2，已经存在的、预期收集的临床 匹兹堡大学硬皮病中心的观察队列将用于 分析。在特定目标3中，对早期弥漫性SSc患者进行观察队列治疗 将创建MMF，并将其与疾病信息一起用于未来的试验使用 特征、用药情况和一年内的皮肤评分。要做到这一点， 接受MMF治疗的早期弥漫性SSC患者的既往和前瞻性随访队列 匹兹堡数据库将与新招募的早期弥散的新队列相结合 使用MMF治疗SSc患者形成一个观察性杂交队列。新入职人员 患者将丰富每3个月一次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 我们对有病史的非MMF治疗的早期弥漫性SSC患者进行杂交队列研究并评估其疗效 治疗6个月和12个月皮肤上MMF的大小。一种经MMF处理后的潜在应用 队列作为未来潜力开放标签研究的参照者或控制组 早期弥漫性SSc的治疗或早期评估新研究药物的效果 允许MMF作为正在进行的本底治疗的阶段试验。从以下方面获得的知识 每项提案的目的都可以应用于正在进行的早期弥漫性SSC临床试验和 试验正处于规划阶段。

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.