Clinical trial NCT04118387: Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment
Official title: Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
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
CO2 reserve
Plant gain
Controller gain
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2019-10-08
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Specific Aim (1) is to determine the effect of combination therapy aiming to dampen chemoreceptor sensitivity AND decreasing plant gain. We 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. We 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. We 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: CO2 reserve
timeFrame: 120 days
measure: Central apnea indices
timeFrame: 120 days
Secondary outcomes:
measure: Controller gain
timeFrame: 120 days
measure: Plant gain
timeFrame: 120 days
measure: Carotid body function
timeFrame: 120 days
measure: Peripheral chemoreflex sensitivity
timeFrame: 120 days
measure: Respiratory arousal threshold
timeFrame: 120 days
measure: % stable breathing
timeFrame: 120 days
Other outcomes:
Locations:
city: Detroit
country: United States
facility: John D. Dingell VA Medical Center, Detroit, MI
state: Michigan
Study officials:
affiliation: John D. Dingell VA Medical Center, Detroit, MI
name: M Safwan Badr, MD
role: PRINCIPAL_INVESTIGATOR
References: