Reversible Effect of Falling Ventilatory Drive in Drive-dependent OSA

Obstructive sleep apnea (OSA) is a highly prevalent disorder that has major consequences for cardiovascular health, neurocognitive function, risk of traffic accidents, daytime sleepiness, and quality of life. For years, a "classic" model of OSA has been used to describe the disorder, which fails to capture it's complexity. Recently, a model for OSA called drive-dependent OSA was discovered be more prevalent in the OSA population. The drive-dependent subgroup benefits exclusively from increased ventilation, increased dilator muscle activity, and reduced event risk when drive spontaneously rises. This study seeks to provide direct evidence that reducing the loss of drive prevents the loss of ventilation, pharyngeal muscle activity, and thus the onset of OSA respiratory events, specifically in "drive-dependent" but not "classic" OSA. This will be achieved using CO2 delivered at precise times during breaths in sleep to prevent loss of overall ventilatory drive.

Study Overview

• Status: Recruiting
• Conditions: OSA
• Intervention / Treatment: Other: Dynamic CO2; Other: Sham CO2

Detailed Description

This is a detailed physiological study, with gold-standard measurements of ventilatory drive and dilator muscle activity, we aim to mitigate falling drive with carefully-timed inspired CO2 administration in patients with (N=18) and without (N=18) drive-dependent OSA. We will test the hypothesis that OSA events are preventable by mitigating falling drive exclusively in drive-dependent OSA.

Subjects will attend a virtual Screening and Consent visit to assess eligibility for enrollment. Participants will take part in a video call with the consenting doctor to obtain consent (Zoom). After consent, patients will first attend a baseline routine sleep study to confirm eligibility and establish baseline characteristics. Patients will subsequently attend an overnight physiology study with gold standard instrumentation (ventilation and ventilatory drive, see below) to establish OSA phenotype (presence/absence of drive-dependent OSA).

Finally, an overnight physiological intervention study dedicated to mitigating ventilatory drive decline with carefully-timed inspired CO2 stimulation will be performed.

At the Dynamic CO2 Study, we will also record upper airway dilator muscle activity (multiunit genioglossus electromyography, EMG). Once respiratory events begin, an investigator will switch the 4-way tap to deliver 2% inspired CO2 during the first 3-4 recovery breaths following a respiratory event. Consequently, end-tidal CO2 will no longer drop as abruptly to lower levels, and thus on the return to sleep, ventilatory drive will not decline as seen during the prior event. Sham interventions (medical air) will also be performed (1:1) to ensure that event risk is not lowered trivially due to spontaneous event resolution or deepening sleep with time. If necessary to precisely control end-tidal CO2 and ventilatory drive, we will 1) raise the magnitude to a maximum of 6%CO2 (in 14% O2) for a single breath intervention, or 2) lower the magnitude to 1.0% or 1.5% via dilution. The first 30 mins of each study will be dedicated to identifying the optimal dose, before formal interventions with alternating shams proceed.

Data analysis

Apneas, hypopneas, sleep stages and arousals from sleep will be scored using current AASM guidelines (hypopneas defined by at least a 30% reduction in airflow in conjunction with either 3% desaturation or arousal) by a technician blinded to the study condition.

For each physiology night, breath-by-breath tables will be made describing ventilation, ventilatory drive, and genioglossus activity. Ensemble average analysis of breath-by-breath signals (ventilatory drive, ventilation, genioglossus EMG) will be used to examine the extent to which ventilation (∆Flow) and genioglossus EMG (∆EMGgg) rise on average during the subsequent "event period" with the ventilatory drive stimulation (∆Drive) compared to the prior reference event (red shading). The reduction in probability of a (clinically-scored) respiratory event will be recorded. The same variables will be calculated from using sham interventions.

Statistical Analysis

The quantitative primary outcome variable will be the continuous probability of a respiratory event after the active inspired CO2 intervention; the difference in this outcome variable between intervention and sham (i.e. sham-corrected effect) will be evaluated using mixed model logistic regression analysis (logit link function). The primary comparison will be whether the sham-corrected reduction in event likelihood is greater in drive-dependent OSA vs. classic OSA subgroups (per intervention × subgroup interaction, fixed effects). Subject will be included as a random effect. Results will be expressed as an odds ratio with 95%CI. P<0.05 will indicate statistical significance.

Secondary analysis will replace the binary intervention term (independent variable) with a continuous term describing the average increase in ventilatory drive with the intervention (∆Drive), allowing odds of event resolution to be expressed per unit increase in drive (per 100% eupnea) for each phenotype. This magnitude of effect will be contrasted with the magnitude observed in the prior observational analyses (odds ratio = 6.8 in drive-dependent OSA); similarity of magnitude will be taken as support for reversibility in the observational studies.

Additional secondary analysis will replace the binary event likelihood term (dependent variable) with the increase in ventilation (∆Flow, linear model) and the increase in genioglossus EMG (∆EMGgg, linear model), which will enable us to quantify how much ventilation and dilator muscle activity is saved when drive decline is mitigated (for each OSA subgroup). Sensitivity analysis will examine whether arousal threshold modifies the efficacy of the drive intervention (intervention × arousal threshold interaction term).

Power analysis

Sample size is based on the primary outcome model: 36 patients will provide 90% power to detect a odds ratio of 3.0 for response to intervention in drive-dependent OSA vs. classic OSA subgroups (assuming sham-corrected probability of response in drive-dependent OSA = 0.63 [0.33-0.60], average [95% prediction interval] and 0.36 [0.14-0.67] in non-drive dependent OSA; N=1000 simulations, probabilities are conservative estimates based on the observational data). Power is also >90% to detect a 20%eupnea greater increase in ventilation in drive-dependent OSA vs. non drive dependent OSA (uncertainty based on preliminary data). Power is >80% to detect a 20% baseline greater increase in genioglossus EMG in drive-dependent OSA vs. non drive dependent OSA (uncertainty based on preliminary data).

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Scott Sands, PhD; Phone Number: 8579280341; Email: sasands@bwh.harvard.edu
• Study Contact Backup: Name: Atqiya Aishah, PhD; Email: aaishah@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Scott SANDS, PhD; Email: sasands@partners.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed OSA (AHI≥15 events/h reported in a PSG performed within 1 year) or Suspected OSA (snoring, sleepiness, witnessed apneas, other clinical symptoms)
• Use of CPAP or other therapies is acceptable; individuals will be asked to withhold treatment for 3 days before each study visit. Individuals who are occupational drivers or operate heavy machinery will not be asked to withhold treatment.

Exclusion Criteria:

• Any unstable medical conditions
• Conditions that could meaningfully raise the cardiovascular risks of brief low-dose hypercapnic-hypoxic inspired gas mixture: heart failure (LVEF<45% if known), recent cardiovascular event (<12 mo), recent cerebrovascular event (<12 mo)*
• Medications known to depress ventilatory drive (e.g. opioids, barbiturates)
• Conditions likely to increase arousability from sleep: insomnia
• Other sleep disorders that may complicate establishment of sleep: periodic limb movements (periodic limb movement arousal index > 10/hr), narcolepsy, or parasomnias
• For intramuscular electrodes and catheter: allergy to lidocaine
• Highly-sensitive gag reflex. Patients with a self-reported 'highly-sensitive gag reflex', including an affirmative response to 'Do you sometimes gag when brushing your teeth?', will not take part in the physiology studies given the placement of an esophageal catheter
• For intramuscular electrodes: use of aspirin or other oral anti-platelets / anti-coagulants
• For oronasal mask: severe claustrophobia

• Pregnancy or nursing

  • We do not intend to exclude patients with controlled cardiovascular disease (hypertension of any severity, arrhythmias, stents) common in the OSA patient population. The transient gas mixture interventions are mild, short-lived, and act to slow the spontaneous recovery of blood gas levels to prevent cyclic upper airway obstruction as opposed to exacerbating them. Control of breathing studies commonly increase inspired CO2/reduce inspired oxygen (using higher concentrations via rebreathing tests for longer durations) in patients with a range of comorbidities including heart failure. The level of hypercapnic-hypoxia used is equivalent to taking slightly smaller breaths (by about a third, for the standard dose gas mixture 2%CO2/18.5%O2) for several breaths, or skipping a breath (for the highest dose gas mixture 6%CO2/14%O2), physiological changes that typically cause no noticeable oxygen desaturation, and are minimal compared with the effects of the larger ventilation reduction that accompanies OSA.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dynamic CO2 within Drive-Dependent OSA; During sleep, before ~30 distinct respiratory events, we will administer ~2% CO2 for ~3-4 breaths.	Other: Dynamic CO2; 2% inspired CO2 for 2-4 breaths
Active Comparator: Dynamic CO2 within Classic OSA; During sleep, before ~30 distinct respiratory events, we will administer ~2% CO2 for ~3-4 breaths.	Other: Dynamic CO2; 2% inspired CO2 for 2-4 breaths
Sham Comparator: Sham CO2 within Drive-Dependent OSA; During sleep, Sham CO2 (air) will be administered for ~3-4 breaths before respiratory events.	Other: Sham CO2; Air
Sham Comparator: Sham CO2 within Classic OSA; During sleep, Sham CO2 (air) will be administered for ~3-4 breaths before respiratory events.	Other: Sham CO2; Air

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in odds of respiratory event	Active versus sham ventilatory drive intervention, difference between drive-dependent OSA and classic OSA subgroups	1 night

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in odds of respiratory event per unit increase in ventilatory drive	Active versus sham ventilatory drive intervention, difference between drive-dependent OSA and classic OSA subgroups	1 night
Increase in ventilation	Active versus sham ventilatory drive intervention, difference between drive-dependent OSA and classic OSA subgroups	1 night
Increase in ventilation per unit increase in ventilatory drive	Difference between drive-dependent OSA and classic OSA subgroups	1 night
Increase in peak genioglossus muscle activity	Active versus sham ventilatory drive intervention, difference between drive-dependent OSA and classic OSA subgroups	1 night
Increase in peak genioglossus muscle activity per unit increase in ventilatory drive	Difference between drive-dependent OSA and classic OSA subgroups	1 night

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Study Director: Dillon Gilbertson, Brigham and Women's Hospital and Harvard Medical School; Principal Investigator: Scott Sands, PhD, Brigham and Women's Hospital and Harvard Medical School

Study record dates

Study Major Dates

• Study Start (Estimated): March 27, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: October 16, 2023
• First Submitted That Met QC Criteria: October 16, 2023
• First Posted (Actual): October 19, 2023

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: 2023P002401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified data will be shared freely with collaborating scientists at any time and more broadly to other scientists 12 months following all planned publications using the data.
• IPD Sharing Time Frame: Deidentified data will be shared freely with collaborating scientists at any time and more broadly to other scientists 12 months following all planned publications using the data.
• IPD Sharing Access Criteria: Requests should be made in writing to the lead investigator.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No