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

Primary Purpose

Sleep Disordered Breathing, Able Bodied

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Acetazolamide + supplemental oxygen + PAP therapy
Zolpidem + PAP therapy
Buspirone + PAP therapy
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sleep Disordered Breathing focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • John D. Dingell VA Medical Center, Detroit, MIRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

acetazolamide

zolpidem

buspirone

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
October 2, 2019
Last Updated
June 1, 2023
Sponsor
VA Office of Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT04118387
Brief Title
Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment
Acronym
CSA
Official Title
Central Sleep Apnea: Physiologic Mechanisms to Inform Treatment
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 7, 2021 (Actual)
Primary Completion Date
June 28, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development

4. Oversight

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
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
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
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
200 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
acetazolamide
Arm Type
Active Comparator
Arm Description
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.
Arm Title
zolpidem
Arm Type
Active Comparator
Arm Description
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.
Arm Title
buspirone
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Acetazolamide + supplemental oxygen + PAP therapy
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Zolpidem + PAP therapy
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Buspirone + PAP therapy
Intervention Description
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.
Primary Outcome Measure Information:
Title
CO2 reserve
Description
CO2 reserve is the requisite change to induce central apnea is referred to as the CO2 reserve, which can be positive or negative.
Time Frame
120 days
Title
Central apnea indices
Description
Central apnea indices is used to indicate the severity of central sleep apnea
Time Frame
120 days
Secondary Outcome Measure Information:
Title
Controller gain
Description
Controller gain is a ventilatory response to changes in end-tidal PCO2
Time Frame
120 days
Title
Plant gain
Description
Plant gain is blood gas response to a change in ventilation. This measure represents the effectiveness of the "plant" in eliminating CO2.
Time Frame
120 days
Title
Carotid body function
Description
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.
Time Frame
120 days
Title
Peripheral chemoreflex sensitivity
Description
Peripheral chemoreflex sensitivity is measured either via brief hypoxia or a single breath of CO2.
Time Frame
120 days
Title
Respiratory arousal threshold
Description
The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal.
Time Frame
120 days
Title
% stable breathing
Description
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.
Time Frame
120 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
M S Badr, MD
Phone
(313) 374-2038
Email
sbadr@med.wayne.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
M Safwan Badr, MD
Organizational Affiliation
John D. Dingell VA Medical Center, Detroit, MI
Official's Role
Principal Investigator
Facility Information:
Facility Name
John D. Dingell VA Medical Center, Detroit, MI
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201-1916
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Edi Levi, MD
Phone
(313) 576-4451
Email
edi.levi@va.gov
First Name & Middle Initial & Last Name & Degree
Erin Olgren, PhD MS
Phone
(313) 576-4448
Email
erin.olgren@va.gov
First Name & Middle Initial & Last Name & Degree
M Safwan Badr, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Central Sleep Apnea : Physiologic Mechanisms to Inform Treatment

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