Acetazolamide to Improve Clinically Important Outcomes in Obstructive Sleep Apnea Patients with a High Loop Gain Endotype

项目总结/摘要 研究计划：在全球范围内，每8个成年人中就有一个患有阻塞性睡眠呼吸暂停（OSA）， 睡眠，白天嗜睡，并增加许多健康问题的风险，包括认知障碍，心脏病， 攻击和中风。不幸的是，一半的OSA患者无法使用持续气道正压通气 治疗，并由于有限的替代选择，大多数仍然未经治疗。但阻塞性睡眠呼吸暂停综合征是一种异质性疾病， 现在可以量化个体患者中OSA的潜在机制（"内型"）， 操纵和提供一个明确的途径，开发OSA药物治疗作为替代这些患者。 通气不稳定（"高回路增益"）促成三分之一患者的OSA发病机制。PI的数据 表明乙酰唑胺--一种安全、低成本（0.66美元/天）、每日一次的药物，可以降低环路增益--可以 显著改善OSA及其后遗症在一些患者，并可能特别有利于患者 高环路增益内型。然而，先前的研究通常没有测量环路增益和临床上的数据。 重要的成果很少。为了更好地确定乙酰唑胺对患者护理的价值，PI将进行 一项随机、安慰剂对照、交叉试验，测试乙酰唑胺是否用于一般OSA患者4周 改善OSA严重程度（目标1）和临床重要结局（目标2），并评估预测因子/机制 （包括环路增益），以帮助更准确地识别可能的响应者。 职业发展计划：PI，博士克里斯Schmickl医学博士/博士，有很强的流行病学背景， 生物统计学和临床睡眠医学。这个K23奖项将为他提供受保护的时间和培训， 实现他的长期目标，成为一个独立的医生，科学家，翻译生理见解， 为无法使用当前疗法的OSA患者提供精确的药物治疗。 为了实现这一长期目标，Schmickl博士将在三个关键领域发展高级技能， 与他来自加州大学圣地亚哥分校的多元化和杰出的导师/顾问团队的专业知识保持一致：1）OSA病理学- 生理学（Malhotra/Owens/Nemati博士）; 2）设计/执行临床试验（Jain博士）; 3）评估 临床重要结局（Drs Banks/Taub）。根据差距分析， 精心设计，平衡实践研究经验与补充课程， 强调负责任的研究行为的重要性。明确的目标和里程碑， 用于跟踪奖励期间的进度。所获得的数据和技能将使PI能够扩展这一点 与R01一起研究乙酰唑胺（和/或其他干预措施）在病理性 生理学定义的可能应答者亚组。更广泛地说，这个奖项将使他能够发展 为许多目前未经治疗的OSA患者提供新型，高影响力，精确的干预措施，从而加入 NHLBI的使命是提高所有人的健康，使他们能够活得更长，更充实的生活。

PROJECT SUMMARY/ABSTRACT Research Plan: Worldwide, one in 8 adults has obstructive sleep apnea (OSA) which results in disturbed sleep, daytime sleepiness, and increases the risk for many health issues including cognitive impairment, heart attacks and strokes. Unfortunately, half of OSA patients are unable to use continuous positive airway pressure therapy, and due to limited alternative options, most remain untreated. But OSA is a heterogenous condition, and mechanisms underlying OSA in individual patients (“endotypes”) can now be quantified, allowing targeted manipulation and providing a clear avenue to develop OSA drug therapy as an alternative for such patients. Ventilatory instability (“high loop gain”) contributes to OSA pathogenesis in one third of patients. The PI’s data suggests that acetazolamide—a safe, low-cost ($0.66/day), once daily drug which lowers loop gain—can markedly improve OSA and its sequelae in some patients, and may be particularly beneficial for patients with a high loop gain endotype. However, prior studies generally did not measure loop gain and data on clinically important outcomes are scarce. To define better acetazolamide’s value for patient-care, the PI will conduct a randomized, placebo-controlled, crossover trial, testing if 4 weeks of acetazolamide in general OSA patients improves OSA severity (aim 1) and clinically important outcomes (aim 2), and assess predictors/mechanisms (including loop gain) of changes in these outcomes (aim 3) to help identify likely responders more precisely. Career Development Plan: The PI, Dr Chris Schmickl MD/PhD, has a strong background in epidemiology, biostatistics and clinical sleep medicine. This K23 award will provide him with the protected time and training to achieve his long-term goal of becoming an independent physician-scientist, translating physiological insights into precision pharmacotherapy for patients with OSA who are unable to use current therapies. To achieve this long-term goal Dr Schmickl will develop advanced skills in three key domains which perfectly align with the expertise of his diverse and outstanding mentor/advisor team from UC San Diego: 1) OSA patho- physiology (Drs Malhotra/Owens/Nemati); 2) Designing/executing clinical trials (Dr Jain); and 3) Assessing clinically important outcomes (Drs Banks/Taub). Based on a gap analysis, a comprehensive training plan was designed which carefully balances hands-on research experiences with complementary coursework, and emphasizes the importance of a responsible conduct of research. Clear objectives and milestones have been defined to track progress during the award. The acquired data and skills will allow the PI to expand on this work with an R01 studying the long-term effects of acetazolamide (and/or other interventions) in patho- physiologically defined subgroups of likely responders. More broadly, this award will enable him to develop novel, high-impact, precision interventions for the many currently untreated OSA patients, thereby joining the NHLBI mission to enhance the health of all individuals so that they can live longer and more fulfilling lives.