Study of Co-trimoxazole and Proton Pump Inhibition Using Pragmatic Design in Idiopathic Pulmonary Fibrosis - CleanUP-IPF

 特发性肺纤维化是一种纤维化间质性肺疾病，其特征是诊断后中位生存期为3-5年，但表现出不均匀的纵向疾病进展。最近的新药物研究证实了对用力肺活量纵向变化的有益作用，但对临床终点或健康状况的益处不一致。这两种药剂都难以容忍，而且可能过于昂贵。进行临床试验以评估临床终点需要招募大量患者并随访足够长的时间。无法快速招募足够数量的IPF患者意味着许多关键临床问题尚未得到解决。严格的入选标准确保了临床试验中入选的患者 通常与临床实践中所见的不同。仍然迫切需要利用创新的、 务实的研究设计，以确定耐受性良好且廉价的治疗方法，改善IPF患者的临床结局。我们的小组是第一个确定异常的肺部微生物群落与IPF受试者的疾病进展独立相关的小组。额外的初步数据将其与改变宿主反应的循环基因表达特征联系起来。有趣的是，一个研究小组表明，与匹配的安慰剂相比，使用甲氧苄啶/磺胺甲恶唑治疗的IPF患者的临床结局有所改善。所有这些数据表明，异常肺部微生物组与宿主反应中的遗传易感性相互作用可能与IPF临床结局受损相关。我们的主要假设是，IPF患者的抗菌治疗将改善临床结局。我们的长期目标是确定IPF的患者特异性治疗。使用务实的试验设计CleanUP-IPF将消除临床试验入组的许多已知障碍，以招募高度代表临床实践中观察到的患者人群。我们期望证明：1）在IPF中进行大型实用研究是可行的，并将确定FVC以外有临床意义的终点; 2）抗微生物治疗将改善临床结局; 3）遗传易感患者将经历对治疗的不同应答。CleanUP-IPF将彻底改变未来的IPF研究，并提供将改变治疗指南的数据。

 DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis a fibrotic interstitial lung disease characterized by a median survival of 3-5 years post-diagnosis but exhibits heterogeneous longitudinal disease progression. Recent studies of novel agents confirm beneficial effects on longitudinal change in forced vital capacity but inconsistent benefits on clinical endpoints or health status. Both agents are difficult to tolerate and are likely to be prohibitively expensive. Conducting clinical trials to assess clinical endpoints requires that larg numbers of patients are enrolled and followed for a sufficient period of time. The inability to rapidly recruit sufficient numbers of IPF patients means that many key clinical questions have not been addressed. Restrictive inclusion criteria ensure that patients enrolled in clinical trials often differ from those seen in clinical practice. There remains a critical need to use innovative, pragmatic study designs to identify well tolerated and inexpensive therapies which improve clinical outcomes in patients with IPF. Our group was the first to identify that an abnormal lung microbial community is independently associated with disease progression in IPF subjects. Additional preliminary data link this to a circulating gene expression signature of altered host response. Intriguingly, one investigative group has suggested improved clinical outcomes in IPF patients treated with trimethoprim/ sulfamethoxazole compared to a matched placebo. The totality of these data suggests that an abnormal lung microbiome interacting with genetic susceptibility in host response may be associated with impaired clinical outcomes in IPF. Our principal hypothesis is that antimicrobial therapy in IPF patients will improve clinical outcomes. Our long-term goal is to define patient-specific therapy in IPF. Using a pragmatic trial design CleanUP-IPF will remove many of the known obstacles to clinical trial enrollment in order to recruit a patient population that is highly representative of those seen in clinical practice. We anticipate demonstrating that: 1) a large, pragmatic study in IPF is feasible and will identify clinically meaningful endpoints beyond FVC; 2) anti- microbial therapy will improve clinical outcomes; and 3) genetically predisposed patients will experience differential response to therapy. CleanUP-IPF will revolutionize future studies in IPF and provide data that will alter therapeutic guidelines.