2/2 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

2/2 认知行为疗法和曲唑酮对基于客观睡眠持续时间的失眠表型的睡眠和血压的影响：一项序贯队列/随机对照试验

• 批准号: 10581992
• 负责人: Wendy C King
• 金额: $ 44.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581992
• 关键词: Adult; Age; Blood Pressure; Cardiovascular system; Characteristics; Classification; Clinical; Clinical Trials; Cognitive Therapy; Cohort Studies; Collaborations; Communication; Data; Data Coordinating Center; Decision Making; Disease; Disease remission; Double-Blind Method; Down-Regulation; Drug Prescriptions; Electrocardiogram; Ensure; Evidence based treatment; Functional disorder; Funding; Genetic; Goals; Guidelines; Health; Health Care Costs; Home Blood Pressure Monitoring; Hydrocortisone; Hypertension; Impairment; Individual; Knowledge; Laboratories; Measures; Mediating; Mental Health; Metabolic; Monitor; Occupational Health; Outcome; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Placebo Control; Placebos; Polysomnography; Preparation; Process; Protocols documentation; Publications; Quebec; Randomized; Randomized, Controlled Trials; Recommendation; Recording of previous events; Research Design; Research Personnel; Risk; Salivary; Sampling; Severities; Site; Sleep; Sleeplessness; Statistical Data Interpretation; Symptoms; Testing; Time; Training; 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; clinical research site; cohort; comparative efficacy; data management; data sharing; efficacy evaluation; hypothalamic-pituitary-adrenal axis; improved; indexing; off-label use; post intervention; precision medicine; predicting response; primary outcome; protocol development; randomized placebo controlled trial; recruit; response; secondary outcome; sex; side effect; treatment effect; treatment guidelines; treatment response

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.

失眠是与心血管不良，代谢和心理健康相关的普遍健康问题 结果。以前提出的亚型基于传统的临床指标的可靠性和有效性差 并且尚未证明对指导失眠治疗决策有用。基于大量的初步数据 在各个领域和几个调查组中，我们已经确定了特定的表型，失眠 睡眠时间短（ISS），这与不良健康结果的风险增加有关，更多 下丘脑 - 垂体 - 肾上腺（HPA）轴激活的物理高伴形，较差 对失眠（CBT-I）的认知行为治疗的反应。拟议的研究代表下一个 我们以前观察的逻辑扩展：确定CBT-I在患有患者中的效率 血压升高（BP）的成年人中的ISS与失眠，睡眠持续时间正常（INS），并且 检查非驱动器中曲唑酮对CBT-I的效率。建议将CBT-I作为第一线 失眠和曲唑酮的治疗是一种广泛的处方，但对失眠症的药物已广为人知。 此外，我们的试验数据还显示了ISS和INS中的CBT-I和曲唑酮的差异效率：曲唑酮， 但是CBT-I不增加客观的总睡眠时间（TST），并降低ISS中的BP和晚期皮质醇。我们将 进行四个位点队列研究，然后在600名成人（≥18Y）失眠中进行安慰剂对照的RCT。这 队列研究将检查CBT-L在ISS表型和INS表型（n = 300）中的CBT-L效率， 由多摄影学（PSG）TST定义。随后的RCT将比较曲唑酮V的效率。 CBT-I非驱动器中的安慰剂。四个研究网站的研究人员（好时，丹佛，匹兹堡和魁北克） 拥有NIH资助的机械和临床试验的合作历史悠久 研究。我们的主要结果将是8周的失眠症缓解，定义为失眠严重程度指数 （ISI）<8; ISI是失眠症状的金标准自我报告测量。次要结果将包括 ISI（连续），客观（即PSG和行动摄影）的睡眠效率度量（在CBT-I队列研究中） 以及TST，HBP和晚期皮质醇（在曲唑酮位置RCT中）。在探索性分析中，我们将测试 甚至皮质醇的变化是否介导曲唑酮对客观TST和HBP的影响。结果会 在治疗结束后的8周零6个月进行评估以评估治疗的耐用性 效果。证明CBT-I随着失眠表型的函数的差异效率将有助于目标 精密医学，该医学根据临床表型和生理学指导治疗 尽管建议将CBT-I作为所有失眠的成年人的一线治疗 ISS表型中的反应将导致重新考虑该当前指南，以代替与患者的相匹配 治疗表型。证明曲唑酮在cbt-i非造物中的效率将填充一个明显的 失眠治疗中的重要知识差距与当前广泛的标签使用情况有关。