Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment

NCT04118387 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: NURR-001-19SI01CX001944
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (2)

• 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.

  120 days

• Central apnea indices

  Central apnea indices is used to indicate the severity of central sleep apnea

  120 days

Secondary Outcomes (6)

• Controller gain

  120 days

• Plant gain

  120 days

• Carotid body function

  120 days

• Peripheral chemoreflex sensitivity

  120 days

• Respiratory arousal threshold

  120 days

Study Arms (3)

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.

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.

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.

Drug: Buspirone + PAP therapy

Interventions

Acetazolamide + supplemental oxygen + PAP therapy DRUG

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.

acetazolamide

Buspirone + PAP therapy DRUG

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.

buspirone

Zolpidem + PAP therapy DRUG

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.

zolpidem

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

John D. Dingell VA Medical Center, Detroit, MI

Detroit, Michigan, 48201-1916, United States

RECRUITING

MeSH Terms

Conditions

Sleep Apnea Syndromes; Sleep Apnea, Central

Interventions

Acetazolamide; Zolpidem; Buspirone

Condition Hierarchy (Ancestors)

Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Thiadiazoles; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridines; Spiro Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Pyrimidines; Polycyclic Compounds

Study Officials

• M Safwan Badr, MD

  John D. Dingell VA Medical Center, Detroit, MI

  PRINCIPAL INVESTIGATOR

Central Study Contacts

M S Badr, MD

CONTACT

(313) 576-1000; sbadr@med.wayne.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 2, 2019
• First Posted: October 8, 2019
• Study Start: January 7, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)