1/2 Cognitive Behavioral Therapy and Trazodone Effects on Sleep and Blood Pressure in Insomnia Phenotypes Based on Objective Sleep Duration: A Sequential Cohort/Randomized Controlled Trial

基于客观睡眠持续时间的 1/2 认知行为疗法和曲唑酮对失眠表型睡眠和血压的影响：序贯队列/随机对照试验

• 批准号: 10590135
• 负责人: Daniel J. Buysse
• 金额: $ 185.17万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590135
• 关键词: Adult; Age; Blood Pressure; Cardiovascular system; Characteristics; Classification; Clinical; Clinical Trials; Cognitive Therapy; Cohort Studies; Collaborations; Data; Decision Making; Disease; Disease remission; Double-Blind Method; Down-Regulation; Drug Prescriptions; Evidence based treatment; Functional disorder; Funding; Genetic; Goals; Guidelines; Health; Health Care Costs; Home Blood Pressure Monitoring; Hydrocortisone; Impairment; Individual; Knowledge; Measures; Mediating; Mental Health; Metabolic; Occupational Health; Outcome; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Placebo Control; Placebos; Polysomnography; Quebec; Randomized; Randomized, Controlled Trials; Recommendation; Recording of previous events; Research Personnel; Risk; Salivary; Sampling; Severities; Side; Site; Sleep; Sleeplessness; Symptoms; Testing; Time; Trazodone; United States National Institutes of Health; Validity and Reliability; actigraphy; base; blind; blood pressure elevation; blood pressure reduction; cardiovascular disorder risk; clinical phenotype; clinical practice; cohort; comparative efficacy; diaries; efficacy evaluation; hypothalamic-pituitary-adrenal axis; improved; indexing; off-label use; precision medicine; predicting response; primary outcome; randomized placebo controlled trial; response; secondary outcome; sex; side effect; treatment effect; treatment guidelines; treatment response; trial design

PROJECT SUMMARY Insomnia is a prevalent health problem associated with adverse cardiovascular, metabolic, and mental health outcomes. Previously proposed subtypes, based on traditional clinical measures, have poor reliability and validity and have not proven useful for guiding insomnia treatment decisions. Based on a large base of preliminary data from various domains and several investigative groups, we have identified a particular phenotype, insomnia with short sleep duration (ISS), that is associated with increased risk for adverse health outcomes, greater physiological hyperarousal as indicated by hypothalamic-pituitary-adrenal (HPA) axis activation, and worse response to Cognitive-Behavioral Treatment for Insomnia (CBT-I). The proposed study represents the next logical extension of our previous observations: To determine the efficacy of CBT-I in individuals with ISS vs. Insomnia with normal sleep duration (INS) among adults with elevated blood pressure (BP), and to examine the efficacy of trazodone among non-remitters to CBT-I. CBT-I is recommended as first-line treatment for insomnia, and trazodone is a widely-prescribed but grossly understudied medication for insomnia. In addition, our pilot data demonstrate differential efficacy of CBT-I and trazodone in ISS and INS: trazodone, but not CBT-I, increases objective total sleep time (TST), and lowers BP and evening cortisol in ISS. We will conduct a 4-site cohort study followed by a placebo-controlled RCT in 600 adults (≥18y) with insomnia. The cohort study will examine the efficacy of CBT-l among individuals with ISS vs. INS phenotypes (n=300 each), defined by polysomnographic (PSG) TST. The subsequent RCT will compare the efficacy of trazodone vs. placebo among CBT-I non-remitters. Investigators at the 4 study sites (Hershey, Denver, Pittsburg, and Quebec) have a long history of collaboration and successful completion of NIH-funded mechanistic and clinical trial studies. Our primary outcome will be the insomnia remission at 8 weeks, defined as Insomnia Severity Index (ISI) <8; ISI is the gold-standard self-report measure of insomnia symptoms. Secondary outcomes will include ISI (continuous), objective (i.e., PSG and actigraphy) measures of sleep efficiency (in the CBT-I cohort study) and TST, HBP, and evening cortisol (in the trazodone-placebo RCT). In exploratory analyses, we will test whether changes in evening cortisol mediate the effect of trazodone on objective TST and HBP. Outcomes will be assessed at 8 weeks and 6 months following the end of treatment to evaluate the durability of treatment effects. Demonstrating a differential efficacy of CBT-I as a function of insomnia phenotype would aid the goals of precision medicine, which directs therapy on the basis of clinical phenotypes and physiology as well as genetics. Although CBT-I is recommended as first-line treatment for all adults with insomnia, finding a worse response in the ISS phenotype will lead to reconsidering this current guideline in lieu of matching patients’ phenotype to treatment. Demonstrating the efficacy of trazodone among CBT-I non-remitters will fill an obvious and important knowledge gap in insomnia treatment l as it pertains to its current wide-spread off-label use.

项目摘要 失眠是一种普遍存在的健康问题，与心血管、代谢和心理健康不良有关 结果。以前提出的亚型，基于传统的临床措施，有较差的信度和效度 并且还没有被证明对指导失眠治疗决策有用。根据大量的初步数据 我们从各个领域和多个研究小组中发现了一种特殊的表型，即失眠症， 睡眠时间短（ISS），与不良健康结果的风险增加有关， 下丘脑-垂体-肾上腺（HPA）轴激活所指示的生理性过度觉醒，以及更糟的情况 认知行为治疗（CBT-1）。这项研究代表了下一个 我们先前观察的逻辑延伸：为了确定CBT-I在患有以下疾病的个体中的疗效， 在血压（BP）升高的成年人中，ISS与正常睡眠时间（INS）的Increase，以及 检查曲唑酮在CBT-I非缓解者中的疗效。建议将CBT-I作为一线 治疗失眠，曲唑酮是一种广泛使用但研究严重不足的失眠药物。 此外，我们的试验数据证明了CBT-1和曲唑酮在ISS和INS中的不同疗效：曲唑酮， 而非CBT-I，增加客观总睡眠时间（TST），降低ISS的血压和夜间皮质醇。我们将 在600例失眠症成人（≥ 18岁）中进行4中心队列研究，随后进行安慰剂对照RCT。的 群组研究将检查CBT-1在具有ISS与INS表型的个体中的功效（各n=300）， 由多导睡眠图（PSG）TST定义。随后的随机对照试验将比较曲唑酮与 CBT-I非缓解者中的安慰剂。4家研究中心（好时、丹佛、汉堡和魁北克）的研究者 有着悠久的合作历史，并成功完成了NIH资助的机制和临床试验 问题研究我们的主要结果将是8周时的失眠缓解，定义为失眠严重程度指数 (ISI)<8; ISI是失眠症状自我报告的金标准。次要结局将包括 ISI（连续）、客观（即，PSG和体动仪）测量睡眠效率（CBT-I队列研究） 以及TST、HBP和夜间皮质醇（曲唑酮-安慰剂RCT）。在探索性分析中，我们将测试 夜间皮质醇的变化是否介导曲唑酮对客观TST和HBP的影响。成果将 在治疗结束后8周和6个月进行评估，以评价治疗的持久性 方面的影响.证明CBT-I作为失眠表型的函数的不同功效将有助于实现以下目标： 精准医学，指导治疗的基础上，临床表型和生理，以及 遗传学虽然CBT-I被推荐为所有成人失眠症的一线治疗，但发现更糟糕的是， ISS表型的反应将导致重新考虑目前的指南，以代替匹配患者的 表型到治疗。证明曲唑酮在CBT-I非缓解者中的疗效将填补一个明显的 以及失眠治疗中的重要知识缺口，因为它涉及其当前广泛的标签外使用。