Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment

Официальное название

Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment

Обзор

Central sleep apnea (CSA) is common in patients with heart failure and those using opioid analgesics. Unfortunately, effective treatment of central apnea remains elusive, pressure therapy given the modest efficiency of positive airway pressure therapy. The focus of this proposal is to identify mechanistic pathways to guide future therapeutic interventions for central sleep apnea based on the strong premise that multi-modality therapy will normalize respiration and hence mitigate adverse long-term consequences of CSA. The investigators' proposed studies will test combination therapies, including positive airway pressure (PAP) plus a pharmacological agent who have heart failure or are using opioid analgesics. The investigators anticipate that findings will inform future clinical trials to improve care and quality of life among Veterans suffering from central sleep apnea, which remains difficult to treat using existing approaches.

Подробное описание

All research activities are on hold due to COVID-19. The investigators updated enrollment start date and the investigators will update primary completion date and study completion date later.

This project is focused on identifying mechanistic pathways to guide future therapeutic interventions for central sleep apnea (CSA) based on the strong premise that multi-modality therapy - aiming to normalize respiration- is the requisite path to mitigating the long-term adverse consequences of CSA. The central hypothesis is that CSA reflects a combination of physiologic perturbations and may require combined modality therapy targeting different parts of the ventilatory feedback loop. The proposed studies will test combination therapies, including PAP plus a pharmacological agent. This will also increase the clinical relevance of the proposed studies since PAP therapy is typically prescribed as the initial treatment of CSA. To achieve the objectives of this proposal, the investigators will test the following three specific aims. Specific Aim (1) is to determine the effect of combination therapy aiming to dampen chemoreceptor sensitivity AND decreasing plant gain. The investigators hypothesize that combined therapy with PAP, acetazolamide and oxygen will be superior to each intervention alone in reducing central apnea-hypopnea index (CAHI) and the CO2 reserve during sleep in patients with central sleep apnea. Specific Aim (2) is to determine the effect of decreasing respiratory-related arousals on the propensity to develop central apnea. The investigators hypothesize that administration of PAP and zolpidem, will decrease respiratory-related arousals, CAHI and the CO2 reserve during sleep in patients with CSA compared to placebo. Specific Aim (3) is to determine the effect of augmenting serotonin A1 receptor activity on breathing during sleep. The investigators hypothesize that administration of PAP and buspirone, a serotonin A1 receptor agonist; will reduce the propensity to central apnea during sleep in Veterans with central sleep apnea. This Novel project seeks to identify physiologic pathways that can, in combination with PAP therapy, improve the effectiveness of treatment for patients with CSA. The proposed studies are innovative, feasible and will provide a much-needed roadmap for future clinical trials that are likely to transform the care of central apnea in Veterans.

Вмешательства

• Препарат Acetazolamide + supplemental oxygen + PAP therapy
  Every participant will undergo measurement of the apneic threshold. The apneic threshold (AT) can be determined by inducing central apnea using non-invasive ventilation (NIV) or eliminating central apnea using supplemental CO2. The requisite change to induce central apnea is referred to as the CO2 reserve, which can be positive or negative. The central apnea index and the apneic threshold will be measured while participants receiving medication or oxygen (or both). In addition, participants will
• Препарат Zolpidem + PAP therapy
  The central apnea index and the apneic threshold will be compared under two conditions: zolpidem or placebo. In addition, participants will get PAP therapy during both the conditions.
• Препарат Buspirone + PAP therapy
  The central apnea index and the apneic threshold will be compared under two conditions: buspirone or placebo. In addition, participants will get PAP therapy during both the conditions.

Первичные конечные точки

• CO2 reserve [Срок оценки: 120 days]
• Central apnea indices [Срок оценки: 120 days]

Вторичные конечные точки (6)

• Controller gain [Срок оценки: 120 days]
• Plant gain [Срок оценки: 120 days]
• Carotid body function [Срок оценки: 120 days]
• Peripheral chemoreflex sensitivity [Срок оценки: 120 days]
• Respiratory arousal threshold [Срок оценки: 120 days]
• % stable breathing [Срок оценки: 120 days]

Критерии участия

Критерии включения

• Men and women Veterans with central sleep apnea, defined as Apnea Hypopnea Index (AHI)>15/hour with CAHI>5/hour, will be included in the experiments

Критерии исключения

• less than 18 years old
• pregnant or breastfeeding female
• have severe respiratory disease that require to be on oxygen
• recent health event that may affect the ability to participate in the study,
• Body Mass Index (BMI) is >40 kg/m2
• significant insomnia
• mental instability
• recent health event that may affect sleep
• if at any time the principal investigator (PI) identifies that a certain drug is not suitable, or are unable to use the device that is used to treat sleep apnea, will be not be allowed to participate in the study

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• John D. Dingell VA Medical Center, Detroit, MI — Detroit

Идентификаторы

NCT: NCT04118387 · NURR-001-19S · I01CX001944

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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