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

摘要 5-氨基水杨酸（5-阿萨）药物是轻度至中度溃疡性结肠炎（UC）的一线治疗药物， 占所有UC处方的81%，市场份额为15亿。尽管5-阿萨 频率和优化，35%的患者诱导治疗失败，52%的患者未能维持 12个月时缓解，需要加强免疫调节剂或生物制剂治疗， 副作用和成本。这凸显了UC面临的一个关键挑战，即解决大型跨部门和内部问题 患者在疾病进展和对治疗反应的变异性方面的变异性。时间疗法是 根据宿主昼夜节律安排医疗干预的时间，以优化药物反应， 最小化毒性，并且是对药物反应的大变异性的一种解释。长期 我们的研究目的是建立一个假设，即一天中适当的时间给予 每日一次口服5-阿萨治疗，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/功能以及增加粘膜5-阿萨水平。为了验证这一假设，在 对小R 01的初步和可行性临床试验（PAS-20-160）的反应，并检验我们的假设，我们 我计划进行一项为期6个月、单中心、随机、交叉的初步试验，涉及60名受试者， 非活动性UC [马约评分≤2，内镜评分0-1]但亚临床炎症[粪便钙卫蛋白> 50 mcg/g] 每天一次稳定剂量的5-阿萨药物所有受试者将随机接受5-阿萨每日一次治疗 每天两个不同的时间给药：06：00 - 10：00或18：00 - 22：00。三种疾病 评估将在以下时间点进行：1）随机化前入组; 2）第3个月，完成首次 臂（条件1），和3）第二臂完成后6个月（条件2）。我们将评估时间影响 我们的时间治疗方案：1）亚临床炎症（目的1）：a）粪便钙卫蛋白; B）肠屏障 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（目的2）;和3）5-阿萨代谢：a）增加5-阿萨的粘膜水平和B）粘膜NAT活性 (Aim 3）。此外，最佳5-阿萨治疗（即，目的1-3）将取决于宿主的生理时钟类型， 通过有效的问卷调查、静息-觉醒活动记录和尿褪黑激素监测。的结果 创新的建议将确立时间疗法在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。时间疗法将允许个性化的医疗方法， 结合了昼夜节律生物学，以提高疗效并最大限度地减少UC治疗的不耐受性。

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.