Hyperbaric Oxygen Therapy for Ulcerative Colitis Patients Hospitalized for Moderate to Severe Flares: A Phase 3 Multi-Center, Randomized, Double-Blind, Sham-Controlled Trial

项目摘要 溃疡性结肠炎是美国最昂贵的医疗条件之一， 在急性发作住院期间发生的这些费用的金额。相当大比例的 因急性发作而住院的溃疡性结肠炎患者对静脉内类固醇没有反应， 需要二线治疗，如生物制剂和/或结肠切除术，这可能与显著的 发病率和死亡率。正在住院或最近住院的溃疡性结肠炎患者 传统的2期和3期药物开发试验排除了急性发作，因为 风险他们是进展到结肠切除术或再次入院。新颖、安全、有效的治疗方法， 需要优化这一高风险孤儿人群的结局。溃疡性结肠炎的一个标志是慢性的 肠粘膜缺氧和炎症，伴随缺氧反应功能障碍 途径和包括嗜中性粒细胞在内的致病性免疫细胞的优先激活。高压氧 治疗包括在增加的大气压力下呼吸100%的氧气，以增加组织 氧合。在一项2期临床试验中，我们证明了这增加了粘膜的氧合， 组织导致溃疡性结肠炎中疾病活动的改善，炎性标志物的减少， 以及在急性发作住院期间防止进展为生物制剂或结肠切除术。在 目前的建议，我们的目标是1）确认高压氧治疗对疾病结果的影响， 溃疡性结肠炎急性发作住院患者通过一个多中心，双盲，假， 对照临床试验我们进一步的目标是探索高压氧通过 治疗通过研究高压氧对2）中性粒细胞的特异性作用来改善疾病活动性， 上皮细胞，和3）微生物组。高压氧治疗的疗效确认 将为溃疡性结肠炎患者的高危人群提出一种新的治疗方法， 传统上被排除在传统临床试验计划之外，同时也促进了我们对 疾病的发病机制以及缺氧、免疫系统和微生物组之间的相互作用。

PROJECT SUMMARY Ulcerative colitis is one of the most expensive medical conditions in the United States, with a considerable amount of these costs being incurred during hospitalizations for acute flares. A substantial proportion of ulcerative colitis patients hospitalized for acute flares will fail to respond to intravenous steroids and require second line therapies such as biologics and/or colectomy, which can be associated with significant morbidity and mortality. Ulcerative colitis patients who are hospitalized or have recently been hospitalized for acute flares are excluded from traditional phase 2 and 3 drug development trials because of how high risk they are for progression to colectomy or re-admission. Novel, safe, and effective treatments are needed to optimize outcomes in this high-risk orphan population. A hallmark of ulcerative colitis is chronic intestinal mucosal hypoxia and inflammation, with an accompanying dysfunction in hypoxia response pathways and preferential activation of pathogenic immune cells including neutrophils. Hyperbaric oxygen therapy involves breathing 100% oxygen under increased atmospheric pressure to increase tissue oxygenation. In a phase 2 trial program we demonstrated that this increased oxygenation of mucosal tissue leads to improvements in disease activity in ulcerative colitis, reductions in inflammatory markers, and prevention of progression to biologics or colectomy during hospitalizations for acute flares. In the current proposal we aim to 1) confirm the impact of hyperbaric oxygen therapy on disease outcomes in ulcerative colitis patients hospitalized for acute flares through a multi-center, double-blind, sham- controlled, clinical trial. We further aim to explore the mechanisms through which hyperbaric oxygen therapy improves disease activity by studying the hyperbaric oxygen specific effects on 2) neutrophils and epithelial cells, and 3) the microbiome. Confirmation of treatment efficacy for hyperbaric oxygen therapy would bring forward a novel therapy for a high-risk population of ulcerative colitis patients who are traditionally excluded from traditional clinical trial programs, while also advancing our understanding of disease pathogenesis and the interplay between hypoxia, the immune system, and the microbiome.