Chronotherapy of 5-Aminosalicylic Acid in Ulcerative Colitis: A Randomized Crossover Trial

5-氨基水杨酸治疗溃疡性结肠炎的时间疗法：随机交叉试验

基本信息

批准号：
10385736
负责人：
Garth R Swanson
金额：
$ 31.4万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-07 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10385736
关键词：
Acetates Acetyltransferase Address Affect Anti-Inflammatory Agents Apical Arthritis Bacteria Biological Products Butyrates Cell physiology Chronic Chronotherapy Circadian Rhythms Clinical Clinical Trials Colon Communities Cross-Over Trials Data Dimensions Disease Disease Progression Disease remission Dose E-Cadherin Effectiveness Enrollment Enzymes Feces Flare Flexible fiberoptic sigmoidoscopy Frequencies Future Gastrointestinal tract structure Histology Hospitalization Hour Hyperlipidemia Immunomodulators Inflammation Inflammatory Inflammatory Bowel Diseases Ingestion Intervention Leukocyte L1 Antigen Complex Location Malignant Neoplasms Medical Medicine Melatonin Mesalamine Metabolism Metagenomics Methods Mission Monitor Mucous Membrane Multi-Institutional Clinical Trial National Institute of Diabetes and Digestive and Kidney Diseases Neoadjuvant Therapy Operative Surgical Procedures Oral Administration Patients Permeability Persons Pharmaceutical Preparations Physiology Propionates Proteins Proteobacteria Protocols documentation Questionnaires Randomized Research Rest Rheumatoid Arthritis Shotguns Steroids Structure System Testing Time Toxic effect Ulcerative Colitis Variant Volatile Fatty Acids Work Wrist actigraphy arm chemotherapy circadian circadian biology circadian regulation claudin-1 protein colon cancer treatment cost drug metabolism fecal microbiome gut microbiome gut microbiota healing human disease improved innovation intestinal barrier medication compliance metabolomics microbial microbial community microbiome microbiota mucosal microbiota occludin optimal treatments pathogenic bacteria patient variability personalized medicine pilot trial prevent response side effect sugar treatment choice treatment optimization treatment response urinary

项目摘要

ABSTRACT 5-aminosalicylic acid (5-ASA) medications are first line treatment for mild to moderate Ulcerative Colitis (UC), comprise 81% of all UC prescriptions, and have a market share of 1.5 billion. However, despite 5-ASA frequency and optimization, 35% of patients fail induction therapy and 52% of patients fail to maintain remission at 12 months, requiring step up therapy to immunomodulators or biologics which have increased side effects and cost. This highlights a key challenge in UC which is to address the large inter- and intra- patient variabilities in both disease progression and variability in response to treatment. Chronotherapy is the timing of medical interventions according to the host circadian rhythms in order to optimize drug response and minimize toxicity, and is one explanation for the large variability in response to medications. The long-term objective of our research is to establish the hypothesis that is that appropriate time of day of administration of oral, once daily 5-ASA therapy in alignment with the host circadian rhythms will improve subclinical inflammation and microbial structure/function and increase mucosal 5-ASA levels. To test this hypothesis, In response to the small R01 for pilot and feasibility clinical trials (PAS-20-160) and to test our hypothesis, we propose to conduct a six month, single center, randomized crossover pilot trial involving 60 subjects with inactive UC [Mayo score ≤2, endoscopic score 0-1] but subclinical inflammation [stool calprotectin > 50 mcg/g] on a stable dose of once daily 5-ASA medication. All subjects will be randomized to once daily 5-ASA medications two different times of the day: either between 06:00 – 10:00 h or 18:00 – 22:00 h. Three disease assessments will performed at: 1) enrollment just before randomization; 2) month 3, at the completion of first arm (condition 1), and 3) month 6, after completion of the second arm (condition 2). We will assess time impact of our chronotherapy protocol on: 1) subclinical inflammation (Aim 1): a) stool calprotectin; b) intestinal barrier integrity; and c) endoscopic/histology scores; 2) Microbiota: mucosal and stool microbiota structure and function (Aim 2); and 3) 5-ASA metabolism: a) increase mucosal levels of 5-ASA and b) mucosal NAT activity (Aim 3). In addition, optimal 5-ASA treatment (i.e., Aims 1-3) will depend upon host chronotype which will be monitored by validated questionnaires, rest-wake actigraphy, and urinary melatonin. The results of this innovative proposal will establish a key role for chronotherapy in the treatment of UC and provide pilot data for the future larger multicenter clinical trials. Chronotherapy will allow for a personalized medicine approach that incorporates circadian biology to improve efficacy and minimize intolerance in treatment of UC.

抽象的 5-氨基水杨酸 (5-ASA) 药物是轻度至中度溃疡性结肠炎 (UC) 的一线治疗，占所有 UC 处方的 81%，市场份额为 15 亿美元。频率和优化，35% 的患者诱导治疗失败，52% 的患者维持治疗失败 12 个月时缓解，需要加强免疫调节剂或生物制剂的治疗，这些药物已增加这凸显了 UC 的一个关键挑战，即解决大的内部和外部问题。疾病进展和治疗反应的变异性是患者的变量。根据宿主的昼夜节律安排医疗干预的时间，以优化药物反应和最大限度地减少毒性，这是对药物的长期反应存在巨大差异的一种解释。我们研究的目的是建立一个假设，即一天中服用药物的适当时间口服、每日一次 5-ASA 治疗与宿主昼夜节律一致将改善亚临床症状炎症和微生物结构/功能并增加粘膜 5-ASA 水平为了检验这一假设。为了响应小型 R01 的试点和可行性临床试验 (PAS-20-160) 并检验我们的假设，我们提议进行一项为期六个月的单中心随机交叉试点试验，涉及 60 名受试者非活动性 UC [Mayo 评分 ≤2，内镜评分 0-1]，但亚临床炎症 [粪便钙卫蛋白 > 50 mcg/g] 每日一次稳定剂量的 5-ASA 药物治疗所有受试者将被随机分配至每日一次 5-ASA。一天中的两个不同时间服用药物：06:00 – 10:00 或 18:00 – 22:00 之间。评估将在以下时间进行：1) 随机分组前入组；2) 第 3 个月，第一次完成时臂（条件 1）和 3）第 6 个月，在第二臂（条件 2）完成后，我们将评估时间影响。我们的时间疗法方案涉及：1) 亚临床炎症（目标 1）：a) 粪便钙卫蛋白；b) 肠道屏障；完整性；和 c) 内窥镜/组织学评分；2) 微生物群：粘膜和粪便微生物群结构和功能（目标 2）；和 3) 5-ASA 代谢：a) 增加粘膜 5-ASA 水平和 b) 粘膜 NAT 活性（目标 3）此外，最佳 5-ASA 治疗（即目标 1-3）将取决于宿主的时间型。通过经过验证的问卷、静息活动记录仪和尿褪黑激素进行监测。创新提案将确立时间疗法在 UC 治疗中的关键作用，并为以下方面提供试点数据：未来更大规模的多中心临床试验将允许个性化医疗方法。结合昼夜节律生物学来提高 UC 治疗的疗效并最大程度地减少不耐受。