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：
10598060
负责人：
Garth R Swanson
金额：
$ 23.44万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598060
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 Marketing 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 beta diversity 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 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）的第一线治疗所有UC处方的81％，市场份额为15亿。但是，要求5-ASA 频率和优化，35％的患者失败诱导疗法和52％的患者无法维持在12个月时缓解，需要加强对免疫调节剂或生物制剂的治疗副作用和成本。这突出了UC中的一个关键挑战，该挑战是应对较大的间和内部挑战。疾病进展和可变异性的患者变异性响应治疗。时间疗法是根据宿主昼夜节律的医疗干预时间，以优化药物反应和最小化毒性，这是对药物响应的大变异性的一种解释。长期我们研究的目的是建立一个假设，即在一天中适当的管理时间口服，每天与宿主昼夜节律保持一致的每天5-ASA治疗将改善亚临床炎症和微生物结构/功能，并增加粘膜5-ASA水平。为了检验这一假设，对小型R01进行试验和可行性临床试验（PAS-20-160）的响应并检验我们的假设，我们提议进行六个月的单个中心，随机跨界试验试验，涉及60个受试者非活性UC [Mayo评分≤2，内窥镜分数0-1]，但亚临床炎症[粪便calprotectin> 50 mcg/g] 每天稳定剂量一次5-ASA药物。所有受试者将被随机分为每天5-ASA 药物一天中的两次不同：要么在06：00 - 10:00 H或18:00 - 22:00 h之间。三种疾病评估将在以下方面进行：1）在随机化之前入学； 2）第3个月，第一次完成臂（条件1）和3）第6个月，在第二臂完成后（条件2）。我们将评估时间影响我们的年度疗法方案：1）亚临床炎症（AIM 1）：a）粪便calrotectin; b）肠壁正直; 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以及功能（AIM 2）; 3）5-ASA代谢：a）粘膜水平增加5-ASA和b）粘膜NAT活性（目标3）。此外，最佳的5-ASA处理（即目标1-3）将取决于宿主计时型，这将是受经过验证的问卷，休息效果学和尿褪黑激素的监测。结果的结果创新的提案将确定计时疗法在UC治疗中的关键作用，并为试点数据提供未来更大的多中心临床试验。年代疗法将允许采用个性化医学方法结合了昼夜节律生物学，以提高效率并最大程度地减少UC治疗中的耐心。