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

高压氧治疗因中度至重度发作而住院的溃疡性结肠炎患者：一项 3 期多中心、随机、双盲、假对照试验

• 批准号: 10561414
• 负责人: Lauren Balmert Bonner
• 金额: $ 243.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561414
• 关键词: Acute; Air; Algorithms; Atmospheric Pressure; Bile Acids; Biological Products; Breathing; Caring; Cells; Chronic; Clinical; Clinical Trials; Colectomy; Collection; Disease; Disease Outcome; Dose; Double-Blind Method; Epithelial Cells; Epithelium; Exclusion; Feces; Firmicutes; Flare; Frequencies; Functional disorder; Future; Global Change; HIF1A gene; Hemorrhage; Hospital Costs; Hospitalization; Hospitals; Human; Hyperbaric Oxygen; Hyperbaric Oxygenation; Hypoxia; Immune; Immune system; Infection; Inflammation; Injury; Intestinal Mucosa; Intravenous; Mediating; Medical; Messenger RNA; Metabolism; Metagenomics; Microbe; Morbidity - disease rate; Mucin-2 Staining Method; Mucous Membrane; Mucous body substance; Orphan; Outcome; Oxygen; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Population; Postoperative Period; Prevention; Production; Program Development; Randomized; Rectum; Resolution; Risk; STAT3 gene; Salvage Therapy; Sample Size; Side; Steroid therapy; Steroids; Therapeutic; Tissues; Treatment Effectiveness; Treatment Efficacy; Ulcerative Colitis; United States; Work; arm; bile acid metabolism; clinical remission; cohort; cost; design; digital; drug development; effective therapy; experimental study; gut microbiota; high risk; high risk population; hospital readmission; host-microbe interactions; improved; inflammatory marker; metabolomics; metatranscriptomics; microbial; microbial composition; microbiome; mortality; neutrophil; novel; novel therapeutics; participant enrollment; patient population; phase II trial; pressure; prevent; primary outcome; programs; progression risk; rectal; response; small molecule; tissue injury; tissue oxygenation; transcriptome; transcriptomics; treatment response

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.

项目概要 溃疡性结肠炎是美国最昂贵的医疗疾病之一，有相当大的费用 因急性发作住院期间产生的这些费用金额。相当大比例的 因急性发作而住院的溃疡性结肠炎患者将无法对静脉注射类固醇产生反应，并且 需要二线治疗，例如生物制剂和/或结肠切除术，这可能与显着相关 发病率和死亡率。正在住院或近期住院的溃疡性结肠炎患者 急性发作被排除在传统的 2 期和 3 期药物开发试验之外，因为 他们有进展为结肠切除术或再次入院的风险。新颖、安全、有效的治疗方法 需要优化这一高风险孤儿群体的结果。溃疡性结肠炎的一个特点是慢性 肠粘膜缺氧和炎症，伴有缺氧反应功能障碍 包括中性粒细胞在内的病原性免疫细胞的途径和优先激活。高压氧 疗法包括在增加的大气压力下呼吸 100% 氧气以增加组织 氧合。在第 2 阶段试验计划中，我们证明这会增加粘膜的氧合 组织导致溃疡性结肠炎疾病活动的改善，炎症标志物的减少， 以及预防急性发作住院期间使用生物制剂或结肠切除术的进展。在 目前的提案我们的目标是 1) 确认高压氧治疗对疾病结果的影响 通过多中心、双盲、假手术治疗因急性发作而住院的溃疡性结肠炎患者 对照临床试验。我们进一步的目标是探索高压氧的机制 通过研究高压氧对 2) 中性粒细胞和 上皮细胞，3) 微生物组。确认高压氧治疗的疗效 将为溃疡性结肠炎高危人群提出一种新疗法 传统上被排除在传统临床试验计划之外，同时也增进了我们对 疾病发病机制以及缺氧、免疫系统和微生物组之间的相互作用。