Suvorexant: A Dual Orexin Receptor Antagonist for Treating Sleep Disturbance inPosttraumatic Stress

Suvorexant：一种双重食欲素受体拮抗剂，用于治疗创伤后应激障碍的睡眠障碍

• 批准号: 10589068
• 负责人: SABRA INSLICHT
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10589068
• 关键词: Accounting; Addendum; Adverse effects; Arousal; Autonomic nervous system; Binding; Biological; Cardiovascular Diseases; Central Nervous System; Clinical; Clinical Trials; DSM-V; Disease; Distress; Dose; Double-Blind Method; Drops; Drowsiness; Drug Targeting; Emotional; FDA approved; Fright; Generations; Impairment; Inflammation; Interview; Learning; Life; Measures; Mediating; Mediator; Memory; Mental Depression; Metabolic syndrome; Military Personnel; Moods; Neuropeptides; Nightmare; Patient Self-Report; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Phase IV Clinical Trials; Pittsburgh Sleep Quality Index; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Quality of life; Randomized; Reporting; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Severities; Site; Sleep; Sleep disturbances; Sleeplessness; Startle Reaction; Stress; Symptoms; System; Testing; Time; Titrations; Trauma; Veterans; Wakefulness; Wrist; actigraphy; antagonist; combat; design; efficacy evaluation; efficacy testing; falls; flexibility; functional disability; hypocretin; improved; improvement on sleep; indexing; learning extinction; physical conditioning; poor sleep; pre-clinical; primary outcome; promoter; receptor; reduce symptoms; secondary outcome; side effect; sleep onset; sleep regulation; stress reactivity; suicidal; vigilance; week trial

Posttraumatic stress disorder (PTSD) is a common consequence of combat that is manifested in part by trauma-related hyperarousal and reactivity, seen in increased startle responses and impaired sleep that result from central and autonomic nervous system alterations. In fact, disturbed sleep is the most prevalent symptom endorsed by PTSD patients and is potentially debilitating in many domains of functioning (1, 2). As a relatively non-stigmatizing symptom, it is no surprise that disturbed sleep is often the reason that motivates Veterans with PTSD to seek treatment (3, 4). However, most drugs that target sleep result in unwanted side effects, such as next day somnolence, which can impact functioning in both military and civilian life. Furthermore, aside from several SSRI's that are only moderately effective in improving PTSD, little progress has been made toward advancing pharmacological treatments for PTSD and in Veterans. Preclinical evidence suggests that the orexin neuropeptide system may be a shared mechanism accounting for both sleep disturbance and PTSD. Orexin is a central promoter of wakefulness involved in regulation of sleep, and in fear learning and emotional memory. The dual orexin receptor antagonist, suvorexant, is the first of a new class of medications recently FDA-approved to treat insomnia. In contrast to previous generations of treatments used for patients with PTSD that provide delayed and often inadequate symptom relief, suvorexant holds promise of delivering immediate relief for pressing sleep concerns while also potentially reducing PTSD symptoms by targeting a biological mechanism that may account for both conditions. While its efficacy for insomnia has been strongly supported by clinical trials (5-8), the potential benefit of suvorexant on trauma- related sleep disturbance and on PTSD symptoms has not been examined, nor has it been evaluated for safety and tolerability in Veterans. We propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IV clinical trial to test the efficacy and safety of suvorexant on trauma-related sleep disturbance and PTSD symptoms in Veterans. We will use a flexible dose design of suvorexant with a 2-week titration followed by a 10-week steady-dose phase. We predict that suvorexant, as compared to placebo, will result in a greater decrease in insomnia on the Insomnia Severity Index (ISI) over the 12-week trial. We also predict that suvorexant, as compared to placebo, will result in a greater reduction in non-sleep PTSD symptoms in the Clinician Administered PTSD Scale for DSMV (CAPS-5) over the 12-week trial. Secondarily, we will examine potential objectively measured wrist actigraphy as a biological mechanism of clinical improvement with as well as concomitant effects on PTSD-related nightmares using the Pittsburgh Sleep Quality Index-PTSD addendum (PSQI-A). Pending a significant effect of suvorexant on PTSD, we will perform exploratory analyses to evaluate whether sleep improvement mediates the effect of suvorexant on PTSD symptoms. We will also examine safety and tolerability of suvorexant compared to placebo (including depression, mood, vigor, suicidality, and daytime somnolence, psychomotor vigilance, and functional disability). Results from this study will provide substantive rationale for the use of Suvorexant in the treatment of Veterans with these concerns. This study will be the first to examine a selective orexin-receptor antagonist in a Veteran sample with PTSD. Suvorexant is an accessible, non-stigmatized medication whose use and safety has been well-established in non-mental- health settings. It has outstanding promise for treating common and distressing symptoms in Veterans as well as civilians with trauma-related sleep disturbance and PTSD.

创伤后应激障碍（PTSD）是战斗的常见后果，部分表现为 创伤相关的过度觉醒和反应，表现为惊吓反应增加和睡眠受损， 中枢和自主神经系统的改变事实上，睡眠障碍是最普遍的症状 PTSD患者认可，并且在许多功能领域中可能使人衰弱（1，2）。作为一个相对 非污名化的症状，这是毫不奇怪，睡眠不安往往是原因，激励退伍军人 与PTSD寻求治疗（3，4）。然而，大多数针对睡眠的药物都会产生不必要的副作用， 例如第二天嗜睡，这可能影响军队和平民生活功能。此外，除了 从几种SSRI在改善创伤后应激障碍方面只有中等效果， 致力于推进创伤后应激障碍和退伍军人的药物治疗。 临床前证据表明，食欲素神经肽系统可能是一个共同的机制，占 睡眠障碍和创伤后应激障碍食欲素是参与睡眠调节的觉醒的中心促进剂， 以及恐惧学习和情绪记忆。双重食欲素受体拮抗剂，苏沃雷生，是第一个 FDA最近批准的一种治疗失眠的新药。与前几代相比， 用于PTSD患者的治疗提供延迟且通常不充分的症状缓解，suvorexant 有望立即缓解紧迫的睡眠问题，同时也可能减少创伤后应激障碍 通过针对可能导致这两种情况的生物机制来治疗症状。虽然它的功效， 临床试验强烈支持失眠（5-8），suvorexant对创伤的潜在益处- 相关的睡眠障碍和创伤后应激障碍症状尚未检查，也没有评估 在退伍军人中的安全性和耐受性 我们提出了一个两个地点平行组，随机，双盲，安慰剂对照的IV期临床试验， 测试苏沃雷生对创伤相关睡眠障碍和PTSD症状的有效性和安全性， 老兵我们将使用灵活的剂量设计，先进行2周滴定，然后进行10周滴定。 稳定剂量阶段。我们预测，与安慰剂相比，苏沃雷生将导致 在为期12周的试验中，失眠严重程度指数（ISI）。我们还预测，苏沃雷生， 与安慰剂相比，在临床医生中， 在为期12周的试验中使用DSMV（CAPS-5）的PTSD量表。其次，我们将研究潜在的 客观测量腕关节活动记录作为临床改善的生物学机制， 使用匹兹堡睡眠质量指数-PTSD附录对PTSD相关噩梦的伴随影响 （PSQI-A）。在苏沃雷生对创伤后应激障碍有显著影响之前，我们将进行探索性分析， 睡眠改善是否介导苏沃雷生对PTSD症状的影响。我们亦会研究 与安慰剂相比，苏沃雷生的安全性和耐受性（包括抑郁、情绪、活力、自杀倾向和 日间嗜睡、精神警觉和功能障碍）。这项研究的结果将提供 使用苏沃雷生治疗有这些问题的退伍军人的实质性依据。本研究 将是第一个在患有创伤后应激障碍的退伍军人样本中检测选择性食欲素受体拮抗剂的人。Suvorexant 是一种可获得的，非污名化的药物，其使用和安全性在非精神疾病中已经得到了很好的证实， 卫生环境。它有突出的承诺，为治疗常见的和令人痛苦的症状，以及退伍军人 患有创伤性睡眠障碍和创伤后应激障碍的平民