Sleep ApneaPhase 3CALM-OSANCT07332442
Continuous Positive Airway Pressure, Arousability and Links to Mechanisms in Obstructive Sleep Apnea
A Phase 3 study testing Eszopiclone in people with Sleep Apnea and Obstructive Sleep Apnea, run by Yale University at 1 site in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sleep Apnea, Obstructive Sleep Apnea
- What is being tested?
- Eszopiclone
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 250 participants
- Where
- 1 siteUnited States
- Study dates
- 18 May 2026to Jun 2030
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Able to provide informed consent.
- Clinically confirmed new diagnosis of OSA:
- Polysomnography AHI ≥ 10 per hour of sleep and/or
- Home sleep apnea testing, respiratory even index, REI ≥ 10 per hour of recording
Who cannot join
- 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
Show all 13Show fewer
- 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 .
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Iouri Kreinin, MD contact
United States1 site, 1 recruiting
- Recruiting
Yale Centers for Sleep Medicine
North Haven, Connecticut, 06347
About this study
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.
Read the 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.
- Conditions
- Sleep Apnea, Obstructive Sleep Apnea
- Being tested
- Eszopiclone, Placebo
- Keywords
- Continuous Positive Airway Pressure (CPAP), sleep apnea, hypnotic, mechanism, arousability
- Medical subject headings
- Sleep Apnea Syndromes, Sleep Apnea, Obstructive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EszopicloneDrug
3mg for < 65 and 2mg for ≥ 65 years
PlaceboDrug
Matched placebo
| Study group | Role | What they receive |
|---|---|---|
| Eszopiclone | Experimental | 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 Receives: Drug: Eszopiclone |
| Placebo | Placebo comparator | 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 Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
CPAP adherence
Mean daily average of CPAP use over 3 months
Measured: 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.
Measured: Baseline, 1-, 2- and 3-months
Secondary outcomes (26)
Mean Epworth Sleepiness Scale score Scores
Sleep questionnaire of subjective sleepiness. Total score range of 0-24; scores above 10 suggest excessive sleepiness.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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)
Measured: 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).
Measured: 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.
Measured: 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.
Measured: Baseline and 3-months
Mean concentration F2-isprostane
Mean concentration F2-isprostane (pg/ml) in the blood to assess oxidative stress.
Measured: Baseline and 3-months
Mean concentration oxidized LDL
Mean concentration oxidized LDL (pg/ml) in the blood to assess oxidative stress.
Measured: Baseline and 3-months
Mean morning concentration cortisol
Mean concentration cortisol (pg/ml) in the blood to assess autonomic activation.
Measured: Baseline and 3-months
Mean concentration norepinephrine
Mean concentration norepinephrine (pg/ml) in the blood to assess autonomic activation.
Measured: 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
Measured: Baseline and 3-months
Blood pressure variability
Blood pressure variability during a single 24-hour period at baseline and 3-month
Measured: Baseline and 3-months
Mean nighttime BP dipping
Mean nighttime BP dipping during a single 24-hour period at baseline and 3-month
Measured: Baseline and 3-months
Mean CPAP pressure over 3 months
Measured nightly from cloud-based remote monitoring adherence system
Measured: Assessed daily over 3 months
Mean residual AHI over 3 months
Measured nightly from cloud-based remote monitoring adherence system
Measured: Assessed daily over 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jan 2026
- Study start18 May 2026
- Primary completionJan 2030 (estimated)
- Study completionJun 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Sleep ApneaStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- randomized, double-blind controlled clinical trial with 3 month follow up.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 250 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), ResMed Foundation
- Responsible party
- Sponsor
- Investigators
- Audrey Zinchuk,, MD, MHS, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07332442
- Sponsor's protocol ID
- 2000040345
- Other IDs
- 1R01HL179077-01
- Acronym
- CALM-OSA
- Status last verified
- Jun 2026
- First submitted
- 23 Dec 2025
- Last updated
- 3 Jun 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Continuous Positive Airway Pressure, Arousability and Links to Mechanisms in Obstructive Sleep Apnea
- ClinicalTrials.gov ID
- NCT07332442
- Acronym / sponsor ID
- CALM-OSA / 2000040345
- Conditions
- Sleep Apnea, Obstructive Sleep Apnea
- Keywords
- Continuous Positive Airway Pressure (CPAP), sleep apnea, hypnotic, mechanism, arousability
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 250 participants (estimated)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI), ResMed Foundation
- Study start
- 18 May 2026 (actual)
- Primary completion
- Jan 2030 (estimated)
- Study completion
- Jun 2030 (estimated)
- First posted
- 12 Jan 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- randomized, double-blind controlled clinical trial with 3 month follow up.
| Arm | Type | Receives |
|---|---|---|
| Eszopiclone | Experimental | Drug: EszopicloneParticipants 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 |
| Placebo | Placebo comparator | Drug: PlaceboParticipants 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Able to provide informed consent.
- Clinically confirmed new diagnosis of OSA:
Key exclusion criteria (13 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Eszopiclone3mg for < 65 and 2mg for ≥ 65 years | Drug | Eszopiclone |
| PlaceboMatched placebo | Drug | Placebo |
Primary outcome
CPAP adherence
Time frame: Daily over 3 months
Mean daily average of CPAP use over 3 months
Flanker inhibitory control and attention test
Time frame: Baseline, 1-, 2- and 3-months
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.
26 secondary outcomes
Mean Epworth Sleepiness Scale score Scores
Time frame: Baseline, 1-, 2-and 3-months
Mean Functional Outcomes of Sleep Questionnaire (FOSQ) short form score
Time frame: Baseline, 1-, 2-and 3-months
Mean Insomnia Severity Index score (ISI) Scores
Time frame: Baseline, 1-, 2-and 3-months
Mean PROMIS Sleep Disturbance score Scores
Time frame: Baseline, 1-, 2-and 3-months
Mean PROMIS Sleep-Related Impairment score Scores
Time frame: Baseline, 1-, 2-and 3-months
Mean time to complete Trail Making Test (TMT) A and B
Time frame: Baseline, 1-, 2-and 3-months
Mean processing speed of Pattern Comparison Processing Speed Test
Time frame: Baseline, 1-, 2-and 3-months
Mean reaction time of Psychomotor vigilance test (PVT)
Time frame: Baseline, 1-, 2-and 3-months
Mean percent accuracy of Change Card Sort Test
Time frame: Baseline, 1-, 2-and 3-months
Mean percent correct recall of Verbal Paired Associates A-B task
Time frame: Baseline and 3-months
Mean OSA alleviation at 3 months
Time frame: 3 months
Mean percent hypoxic burden
Time frame: Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Mean sleep depth score
Time frame: Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Arousal intensity
Time frame: Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Ventilatory burden
Time frame: Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit
Mean concentration Neurofilament Light Chain (NfL)
Time frame: Baseline and 3-months
Mean concentration Aβ40
Time frame: Baseline and 3-months
Mean concentration F2-isprostane
Time frame: Baseline and 3-months
Mean concentration oxidized LDL
Time frame: Baseline and 3-months
Mean morning concentration cortisol
Time frame: Baseline and 3-months
Mean concentration norepinephrine
Time frame: Baseline and 3-months
Mean systolic and diastolic blood pressure (BP)
Time frame: Baseline and 3-months
Blood pressure variability
Time frame: Baseline and 3-months
Mean nighttime BP dipping
Time frame: Baseline and 3-months
Mean CPAP pressure over 3 months
Time frame: Assessed daily over 3 months
Mean residual AHI over 3 months
Time frame: Assessed daily over 3 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jun 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Iouri Kreinin, MD contact
Audrey Zinchuk,, MD, MHS principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Eszopiclone in people with Sleep Apnea and Obstructive Sleep Apnea, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 3 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Andrey Zinchuk, MD, MHS (475-655-6199, andrey.zinchuk@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
CPAP adherence (time frame: Daily over 3 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jun 2026.