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

摘要 5-氨基水杨酸(5-ASA)药物是治疗轻中度溃疡性结肠炎(UC)的一线药物， 占UC处方总数的81%，市场占有率为15亿。然而，尽管5-ASA 频率和优化，35%的患者诱导治疗失败，52%的患者无法维持 12个月后缓解，需要加强对增加的免疫调节剂或生物制品的治疗 副作用和成本。这凸显了统一通信中的一个关键挑战，即解决大量的内部和内部 患者在疾病进展和对治疗的反应方面的变异性。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 将毒性降至最低，这是对药物反应差异较大的一个解释。长期的 我们研究的目的是建立一个假设，即一天中合适的给药时间 口服，每天一次，配合宿主昼夜节律的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，在 对用于试点和可行性临床试验(PAS-20-160)的小型R01的响应，并验证我们的假设，我们 建议进行一项为期六个月的单中心随机交叉试验，受试者为60名 非活动期UC[Mayo评分≤2，内窥镜评分0-1]，但亚临床炎症[大便钙保护素和GT；50微克/克] 每天服用一次稳定剂量的5-ASA药物。所有受试者将随机接受每日一次的5-ASA 一天中有两种不同的服药时间：06：00-10：00或18：00-22：00。 评估将在以下时间进行：1)在随机化之前登记；2)3个月，在完成第一个 ARM(条件1)，以及3)6个月，在第二个ARM完成(条件2)之后。我们将评估时间影响 我们的计时治疗方案：1)亚临床炎症(目标1)：a)大便钙保护素；b)肠道屏障 完整性；以及c)内窥镜/组织学评分；2)微生物区系：粘膜和粪便微生物区系结构和 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，最佳的5-ASA处理(即目标1-3)将取决于寄主的年型 通过有效问卷、休息-觉醒活动描记和尿褪黑激素监测。这样做的结果 创新的提案将确立时间疗法在UC治疗中的关键作用，并为 未来更大规模的多中心临床试验。时间疗法将允许一种个性化的医学方法， 结合昼夜节律生物学，以提高疗效和最大限度地减少UC的治疗不耐受。

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.