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.
Trial 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. Read more about this study
- 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
- Are there results?
- Not yet: the study is under way
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.
United States1 site, 1 recruiting
- 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
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 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.
- 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)
Sponsor and investigators
- Lead sponsor
- VA Office of Research and Development
- Sponsor type
- US federal agency
- Responsible party
- Sponsor
- Investigators
- M Safwan Badr, MD, Principal investigator, John D. Dingell VA Medical Center, Detroit, MI
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
Study at a glance
From the registry record, last updated by the sponsor on 20 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment
- ClinicalTrials.gov ID
- NCT04118387
- Acronym / sponsor ID
- CSA / NURR-001-19S
- Conditions
- Sleep Disordered Breathing, Able Bodied
- Keywords
- Central sleep apnea, Polysomnography (PSG), Respiratory arousal threshold, Apnea Hypopnea index, Central Apnea Hypopnea Index, Breathing instability, Apneic Threshold (AT), Peripheral chemoreflex sensitivity
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 200 participants (estimated)
- Lead sponsor
- VA Office of Research and DevelopmentUS federal agency
- Study start
- 7 Jan 2021 (actual)
- Primary completion
- 31 Dec 2026 (estimated)
- Study completion
- 30 Jun 2027 (estimated)
- First posted
- 8 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 3
- 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.
| Arm | Type | Receives |
|---|---|---|
| acetazolamide | Active comparator | Drug: Acetazolamide + supplemental oxygen + PAP therapyTo 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. |
| zolpidem | Active comparator | Drug: Zolpidem + PAP therapyTo 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. |
| buspirone | Active comparator | Drug: Buspirone + PAP therapyTo 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Acetazolamide + supplemental oxygen + PAP therapyEvery 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. | Drug | acetazolamide |
| Zolpidem + PAP therapyThe 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. | Drug | zolpidem |
| Buspirone + PAP therapyThe 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. | Drug | buspirone |
Primary outcome
CO2 reserve
Time frame: 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.
Central apnea indices
Time frame: 120 days
Central apnea indices is used to indicate the severity of central sleep apnea
6 secondary outcomes
Controller gain
Time frame: 120 days
Plant gain
Time frame: 120 days
Carotid body function
Time frame: 120 days
Peripheral chemoreflex sensitivity
Time frame: 120 days
Respiratory arousal threshold
Time frame: 120 days
% stable breathing
Time frame: 120 days
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Jul 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
M Safwan Badr, MD principal investigator
John D. Dingell VA Medical Center, Detroit, MI
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
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.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact M S Badr, MD ((313) 576-1000 ext. 65710, sbadr@med.wayne.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CO2 reserve (time frame: 120 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Jul 2026.