Addressing Critical Knowledge Gaps in Early Diffuse Scleroderma Trial Design

项目总结/文摘

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.