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

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， 二线治疗，如生物制剂和/或结肠切除术，可能与显著的发病率相关 and mortality.溃疡性结肠炎患者住院或最近因急性 由于发作的高风险，它们被排除在传统的2期和3期药物开发试验之外 进行结肠切除术或再次入院需要新的，安全的，有效的治疗方法来优化 这一高风险孤儿群体的结局。溃疡性结肠炎的一个标志是慢性肠粘膜炎 缺氧和炎症，伴随缺氧反应途径和优先 病原性免疫细胞的激活。高压氧治疗包括在高压氧下呼吸100%的氧气。 增加大气压力以增加组织氧合。在第二阶段的试验项目中， 这种粘膜组织氧合的增加导致溃疡性结肠炎患者疾病活动的改善， 结肠炎，炎症标志物的减少，以及在结肠炎期间预防生物制剂或结肠切除术的进展 因急性发作住院治疗。在目前的提案中，我们的目标是：1）确认高压氧的影响 通过多中心， 双盲、假手术对照、III期临床试验。我们进一步探讨有关机制， 高压氧治疗通过研究高压氧特异性 对2）免疫细胞和3）微生物组的影响。高压氧治疗效果的确认 治疗将为溃疡性结肠炎患者的高危人群带来一种新的治疗方法， 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 疾病的发病机制和缺氧，免疫系统和微生物之间的相互作用。

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. 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, phase 3 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) immune 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.