Sleep Disordered BreathingPhase 4CSANCT04118387

Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment

A Phase 4 study testing Acetazolamide + supplemental oxygen + PAP therapy, Zolpidem + PAP therapy and Buspirone + PAP therapy in people with Sleep Disordered Breathing and Able Bodied, run by VA Office of Research and Development at 1 site in United States.

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Official record

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Trial summary

Who is it for?: Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for: Sleep Disordered Breathing, Able Bodied
What is being tested?: Acetazolamide + supplemental oxygen + PAP therapy, Zolpidem + PAP therapy and Buspirone + PAP therapy
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 200 participants
Where: 1 siteUnited States
Study dates: 7 Jan 2021to 30 Jun 2027
Phase: Phase 4

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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

Who cannot join

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

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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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

M S Badr, MD contact

(313) 576-1000 ext. 65710

sbadr@med.wayne.edu

United States1 site, 1 recruiting

John D. Dingell VA Medical Center, Detroit, MI
Detroit, Michigan, 48201-1916
Edi Levi, MD, (313) 576-4451, edi.levi@va.gov
Erin Olgren, PhD MS, (313) 576-4448, erin.olgren@va.gov
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About this study

Official title: Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment

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.

Read the detailed description

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.

Conditions: Sleep Disordered Breathing, Able Bodied
Being tested: Acetazolamide + supplemental oxygen + PAP therapy, Zolpidem + PAP therapy, Buspirone + PAP therapy
Keywords: Central sleep apnea, Polysomnography (PSG), Respiratory arousal threshold, Apnea Hypopnea index, Central Apnea Hypopnea Index, Breathing instability, Apneic Threshold (AT), Peripheral chemoreflex sensitivity, CO2 reserve, Plant gain, Controller gain
Medical subject headings: Sleep Apnea Syndromes, Sleep Apnea, Central

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Acetazolamide + supplemental oxygen + PAP therapyDrug
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 get PAP therapy during all the conditions.
Zolpidem + PAP therapyDrug
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.
Buspirone + PAP therapyDrug
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.

Study groups in NCT04118387
Study group	Role	What they receive
acetazolamide	Active comparator	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. Receives: Drug: Acetazolamide + supplemental oxygen + PAP therapy
zolpidem	Active comparator	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. Receives: Drug: Zolpidem + PAP therapy
buspirone	Active comparator	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. Receives: Drug: Buspirone + PAP therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (6)

Controller gain
Controller gain is a ventilatory response to changes in end-tidal PCO2
Measured: 120 days
Plant gain
Plant gain is blood gas response to a change in ventilation. This measure represents the effectiveness of the "plant" in eliminating CO2.
Measured: 120 days
Carotid body function
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.
Measured: 120 days
Peripheral chemoreflex sensitivity
Peripheral chemoreflex sensitivity is measured either via brief hypoxia or a single breath of CO2.
Measured: 120 days
Respiratory arousal threshold
The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal.
Measured: 120 days
% stable breathing
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.
Measured: 120 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

7 Jan 202130 Jun 2027

First posted8 Oct 2019
Study start7 Jan 2021
Primary completion31 Dec 2026 (estimated)
Study completion30 Jun 2027 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Sleep Disordered BreathingStudies of the same condition, open and under way.
More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Model description: 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 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.
Masking: Double blind
Who is masked: Participant, Outcomes assessor
Enrolment: 200 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04118387
Sponsor's protocol ID: NURR-001-19S
Other IDs: I01CX001944
Acronym: CSA
Status last verified: Jul 2026
First submitted: 2 Oct 2019
Last updated: 20 Jul 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Interested in taking part?

M S Badr, MD

(313) 576-1000 ext. 65710

sbadr@med.wayne.edu

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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