Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment (CSA)

• ClinicalTrials.gov Identifier: NCT04118387
• Recruitment Status: Recruiting
• First Posted: October 8, 2019
• Last Update Posted: January 14, 2021
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Sleep Disordered Breathing; Able Bodied	Drug: Acetazolamide + supplemental oxygen + PAP therapy; Drug: Zolpidem + PAP therapy; Drug: Buspirone + PAP therapy	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• 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.
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment
• Actual Study Start Date: January 7, 2021
• Estimated Primary Completion Date: May 31, 2023
• Estimated Study Completion Date: November 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: acetazolamide; 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; 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.
Active Comparator: zolpidem; 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; 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.
Active Comparator: buspirone; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. 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.
2. Central apnea indices [ Time Frame: 120 days ]
   Central apnea indices is used to indicate the severity of central sleep apnea

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Contacts

Contact: M S Badr, MD; (313) 374-2038; sbadr@med.wayne.edu

Locations

United States, Michigan

John D. Dingell VA Medical Center, Detroit, MI; Recruiting

Detroit, Michigan, United States, 48201

Contact: Edi Levi, MD (313) 576-4451 edi.levi@va.gov

Contact: Erin Olgren, PhD MS (313) 576-4448 erin.olgren@va.gov

Principal Investigator: M Safwan Badr, MD

Sponsors and Collaborators

VA Office of Research and Development

Investigators

• Principal Investigator: M Safwan Badr, MD; John D. Dingell VA Medical Center, Detroit, MI

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT04118387
• Other Study ID Numbers: NURR-001-19S; I01CX001944 ( U.S. NIH Grant/Contract )
• First Posted: October 8, 2019
• Last Update Posted: January 14, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:

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

Additional relevant MeSH terms:

Sleep Apnea Syndromes; Respiratory Aspiration; Sleep Apnea, Central; Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Pathologic Processes; Acetazolamide; Zolpidem; Buspirone; Sleep Aids, Pharmaceutical; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; GABA-A Receptor Agonists; GABA Agonists; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anticonvulsants; Carbonic Anhydrase Inhibitors; Enzyme Inhibitors; Diuretics; Natriuretic Agents; Anti-Anxiety Agents; Tranquilizing Agents