Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment

Phase 4

Recruiting

• Conditions: Sleep Disordered Breathing; Able Bodied
• Interventions: Drug: Zolpidem + PAP therapy; Drug: Acetazolamide + supplemental oxygen + PAP therapy; Drug: Buspirone + PAP therapy

• Registration Number: NCT04118387
• Lead Sponsor: VA Office of Research and Development

Brief Summary

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.

Detailed Description

All research activites are on hold due to COVID-19. We updated enrollment start date and we 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.

Study Timeline

• Study First Submitted: 2019-10-02
• Study First Submitted QC: 2019-10-04
• Study First Posted: 2019-10-08
• Study Start: 2021-01-07
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-09
• Last Update Posted: 2025-04-10
• Primary Completion: 2026-06-30
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

• 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

Exclusion Criteria

• 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
zolpidem	Zolpidem + PAP therapy	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 Veterans with CSA compared to PAP plus placebo.
acetazolamide	Acetazolamide + supplemental oxygen + PAP therapy	To determine the effect of dampening chemoreceptor sensitivity AND decreasing plant gain. The investigators hypothesize that combined therapy with PAP, acetazolamide and oxygen will be superior to PAP plus each intervention alone or placebo in reducing CAHI and the CO2 reserve during sleep in Veterans with CSA.
buspirone	Buspirone + PAP therapy	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 CSA compared to PAP plus placebo.

Primary Outcome Measures

Name	Time	Method
Central apnea indices	120 days	Central apnea indices is used to indicate the severity of central sleep apnea
CO2 reserve	120 days	CO2 reserve is the requisite change to induce central apnea is referred to as the CO2 reserve, which can be positive or negative.

Secondary Outcome Measures

Name	Time	Method
Controller gain	120 days	Controller gain is a ventilatory response to changes in end-tidal PCO2
Respiratory arousal threshold	120 days	The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal.
Carotid body function	120 days	This measure represents the activity of the carotid bodies. It is measured by the decrease in ventilation in response to a single breath of 100% oxygen.
Plant gain	120 days	Plant gain is blood gas response to a change in ventilation. This measure represents the effectiveness of the "plant" in eliminating CO2.
Peripheral chemoreflex sensitivity	120 days	Peripheral chemoreflex sensitivity is measured either via brief hypoxia or a single breath of CO2.
% stable breathing	120 days	To assess breathing stability, the investigators will measure % stable breathing using minute ventilation (VE) and tidal volume (VT) coefficient of variation as indices of breathing instability.

Trial Locations

Locations (1)

John D. Dingell VA Medical Center, Detroit, MI; 🇺🇸 Detroit, Michigan, United States