Continuous Positive Airway Pressure, Arousability and Links to Mechanisms in Obstructive Sleep Apnea (CALM-OSA)

The study design is a randomized, controlled clinical trial to test the hypothesis that arousal threshold (ArTH) will affect how individuals with obstructive sleep apnea (OSA, Apnea-Hypopnea Index (AHI) of 10/hour of higher) respond to CPAP therapy regarding adherence and cognitive function (executive function). Investigators hypothesize that raising ArTH with eszopiclone will improve adherence to CPAP and neurocognitive function with CPAP therapy. Investigators also hypothesize that a lower baseline ArTH is associated with worse CPAP adherence, while a higher baseline ArTH is associated with improved neurocognitive outcomes with CPAP therapy.

Study Overview

• Status: Recruiting
• Conditions: Obstructive Sleep Apnea; Sleep Apnea
• Intervention / Treatment: Drug: Placebo; Drug: Eszopiclone

Detailed Description

Primary Objective The primary objective of this study is to determine whether raising arousal threshold (ArTH) in OSA will improve response to CPAP therapy in people with OSA, where response includes factors such as adherence, change in executive function (Flanker Inhibitory Control test) and cardiovascular function (flow mediated vasodilatation, an exploratory outcome).

Secondary Objective The secondary objective[s] of this study are to understand the mechanisms by which raising ArTH may improve adherence to CPAP, neurocognitive and cardiovascular function. The mechanisms investigated include sleep duration, depth, CPAP level and tolerance, hypoxia, patient symptoms, biomarkers of neuronal damage, oxidative stress and sympathetic activation.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Andrey Zinchuk, MD, MHS; Phone Number: 475-655-6199; Email: andrey.zinchuk@yale.edu
• Study Contact Backup: Name: Iouri Kreinin, MD; Email: iouri.kreinin@yale.edu

Study Locations

• United States
  • Connecticut
    • North Haven, Connecticut, United States, 06347
      • Recruiting
      • Yale Centers for Sleep Medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Able to provide informed consent.

• Clinically confirmed new diagnosis of OSA:

  1. Polysomnography AHI ≥ 10 per hour of sleep and/or
  2. Home sleep apnea testing, respiratory even index, REI ≥ 10 per hour of recording

Exclusion Criteria:

• Known non-OSA related conditions associated with sleep-disordered breathing (e.g., a central disorder of hypersomnolence, neurological, neuromuscular, or pulmonary disorder)
• Use of sleep-inducing medications (e.g., other non-benzodiazepine sedative hypnotic-drugs [e.g., zoldpidem], benzodiazepines, non-selective antihistamines, trazodone, opiates, barbituates)
• Known hypersensitivity reaction to eszopiclone
• Contraindications to its use based on medical history or function (e.g., dizziness at baseline or established mobility problems or imbalance)
• History of complex sleep behaviors (e.g., NREM or REM parasomnias)
• Concomitant use of ≥ 2 servings of alcohol per night or other CNS depressant for 2 weeks prior or throughout the study
• Sleep opportunity of less than 7 hours
• Severe active depression or other mental health disorders (e.g., schizophrenia, bipolar disorder, personality disorder).
• History of sleep-walking, sleep-driving, and engaging in other activities while not fully awake
• History of motor vehicle accidents related to sleepiness and/or motor vehicle "near misses" (e.g. sleepiness during driving or lane changes)
• Severe hepatic impairment (liver function tests 2 X the upper limit of normal)
• Unstable medical condition (e.g., decompensated heart failure, end-stage chronic obstructive pulmonary disease, end-stage renal disease)
• Females of childbearing potential who are pregnant, breastfeeding, or intend to become pregnant, and women who are in the process of egg donation .

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eszopiclone; Participants will receive eszopiclone the night of the laboratory split-night polysomnography (PSG, sleep monitoring with and without CPAP therapy). Following polysomnography, participants continue with eszopiclone and CPAP therapy	Drug: Eszopiclone; 3mg for < 65 and 2mg for ≥ 65 years
Placebo Comparator: Placebo; Participants will receive placebo the night of the laboratory split-night polysomnography (PSG, sleep monitoring with and without CPAP therapy). Following polysomnography, participants continue with placebo and CPAP therapy	Drug: Placebo; Matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CPAP adherence	Mean daily average of CPAP use over 3 months	Daily over 3 months
Flanker inhibitory control and attention test	Executive function is assessed using the validated NIH Toolbox Cognition Battery's Flanker inhibitory control and attention test. In a Flanker task, participants are required to indicate the left-right orientation of a centrally presented stimulus while inhibiting attention to the potentially incongruent stimuli that surround it (i.e., the flankers, typically two on either side). Primary outcome is the overall percent of correct responses in incongruent trials.	Baseline, 1-, 2- and 3-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Epworth Sleepiness Scale score Scores	Sleep questionnaire of subjective sleepiness. Total score range of 0-24; scores above 10 suggest excessive sleepiness.	Baseline, 1-, 2-and 3-months
Mean Functional Outcomes of Sleep Questionnaire (FOSQ) short form score	Measures how sleepiness affects daily life, with scores ranging from 5-20. Higher scores indicate better functioning and less impairment.	Baseline, 1-, 2-and 3-months
Mean Insomnia Severity Index score (ISI) Scores	ISI is a validated 7-question survey. The total score range is 0-28 with higher scores indicating more severe insomnia.	Baseline, 1-, 2-and 3-months
Mean PROMIS Sleep Disturbance score Scores	T-score mean of 50 and a standard deviation (SD) of 10. Higher scores indicating more sleep disturbance.	Baseline, 1-, 2-and 3-months
Mean PROMIS Sleep-Related Impairment score Scores	T-score mean of 50 and a standard deviation (SD) of 10. Higher scores indicating more sleep disturbance.	Baseline, 1-, 2-and 3-months
Mean time to complete Trail Making Test (TMT) A and B	Administered on standardized paper form by research associate. Both parts of the Trail Making Test consist of 25 circles distributed over a sheet of paper and participant connect numbers (Part A) and numbers with letters (Part B) in ascending order. Mean time to connect the "trail" in minutes.	Baseline, 1-, 2-and 3-months
Mean processing speed of Pattern Comparison Processing Speed Test	Administered by participants via an iPad to assess processing speed. Participants are asked to quickly determine whether two stimuli are the same or not the same. Mean time in seconds.	Baseline, 1-, 2-and 3-months
Mean reaction time of Psychomotor vigilance test (PVT)	Administered by participants via a computer to complete psychomotor vigilance task at the same time in the morning. Mean time in minutes to complete assessment of daytime vigilance = 1/reaction-time.	Baseline, 1-, 2-and 3-months
Mean percent accuracy of Change Card Sort Test	Administered by participants via an iPad to assess cognitive flexibility and attention. The participant is asked to match a series of picture pairs to a target picture.	Baseline, 1-, 2-and 3-months
Mean percent correct recall of Verbal Paired Associates A-B task	Administered by participants via an iPad with audio instructions and feedback to assess recall. The participant is asked to recall A-B verbal paired associates word-pairs. Immediate recall occurs before sleep and delayed recall occurs after sleep.	Baseline and 3-months
Mean OSA alleviation at 3 months	Defined as: therapeutic efficacy × adjusted CPAP adherence. The therapeutic efficacy for OSA is "[AHI-baseline - AveAHI-3-months on CPAP] / AHI-baseline" and the adjusted CPAP adherence is objective AveCPAP use / AveSleep time (both in hours) over 3 months	3 months
Mean percent hypoxic burden	Hypoxic burden (HB) is a sleep apnea metric that quantifies the total oxygen deprivation by measuring the depth and duration of blood oxygen drops (desaturations) during sleep, expressed as %-minutes per hour.	Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Mean sleep depth score	Sleep depth will be measured by an Odds Ratio Product (ORP), a continuous metric based on quantitative analysis of the EEG power spectra. High values indicate deeper sleep, with a range of 0 - 2.5.	Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Arousal intensity	Arousal intensity is measured on a scale between 0 and 9 (most intense) using a validated automated wavelet transformation method (Azarbarizin et al., Sleep 2014)	Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Ventilatory burden	The average ventilatory burden per event is defined as the multiplication of the average ventilation during the respiratory event (i.e., event depth) and average duration of respiratory events. The total ventilatory burden (percentage eupnea × min/h) for each participant is defined as the multiplication of respiratory event rate (events/h) and average ventilatory area per event (percentage eupnea × min/event).	Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Mean concentration Neurofilament Light Chain (NfL)	Mean concentration NfL (pg/ml) in the blood to assess neuronal injury and damage.	Baseline and 3-months
Mean concentration Aβ40	Mean concentration Aβ40 (pg/ml) in the blood (usually measured as a ratio with Aβ42 (Aβ42/40 ratio) to assess brain amyloid plaque buildup.	Baseline and 3-months
Mean concentration F2-isprostane	Mean concentration F2-isprostane (pg/ml) in the blood to assess oxidative stress.	Baseline and 3-months
Mean concentration oxidized LDL	Mean concentration oxidized LDL (pg/ml) in the blood to assess oxidative stress.	Baseline and 3-months
Mean morning concentration cortisol	Mean concentration cortisol (pg/ml) in the blood to assess autonomic activation.	Baseline and 3-months
Mean concentration norepinephrine	Mean concentration norepinephrine (pg/ml) in the blood to assess autonomic activation.	Baseline and 3-months
Mean systolic and diastolic blood pressure (BP)	Mean systolic and diastolic blood pressure during a single 24-hour period at baseline and 3-month	Baseline and 3-months
Blood pressure variability	Blood pressure variability during a single 24-hour period at baseline and 3-month	Baseline and 3-months
Mean nighttime BP dipping	Mean nighttime BP dipping during a single 24-hour period at baseline and 3-month	Baseline and 3-months
Mean CPAP pressure over 3 months	Measured nightly from cloud-based remote monitoring adherence system	Assessed daily over 3 months
Mean residual AHI over 3 months	Measured nightly from cloud-based remote monitoring adherence system	Assessed daily over 3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow mediated vasodilation (FMD) - exploratory	FMD is a standard non-invasive technique for assessing endothelial function. FMD will be obtained using a standard method by a trained RA at the same time of the day after the baseline PSG and the 3-month follow-up. Two-dimensional longitudinal images will be acquired using Doppler ultrasound to assess arterial diameter and flow velocity (resting and hyperemic). Resting blood flow is estimated by time-averaging the pulsed Doppler signal obtained from a mid-vessel sample volume. The blood pressure cuff is then inflated to >50 mmHg above systolic pressure to occlude arterial inflow for 5 minutes. A cuff is then deflated, and a pulse wave and longitudinal images are obtained at 10 seconds and 60 seconds (hyperemia). The FMD is the percent increase in vessel diameter from baseline to hyperemia.	baseline and 3 months

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); ResMed Foundation
• Investigators: Principal Investigator: Audrey Zinchuk,, MD, MHS, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2026
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): June 1, 2030

Study Registration Dates

• First Submitted: December 23, 2025
• First Submitted That Met QC Criteria: January 8, 2026
• First Posted (Actual): January 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: sleep apnea; Continuous Positive Airway Pressure (CPAP); mechanism; hypnotic; arousability
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Wake Disorders; Apnea; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Piperazines; Eszopiclone
• Other Study ID Numbers: 2000040345; 1R01HL179077-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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