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.
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
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
250
3mg for \< 65 and 2mg for ≥ 65 years
Matched placebo
Yale Centers for Sleep Medicine
North Haven, Connecticut, United States
RECRUITINGCPAP adherence
Mean daily average of CPAP use over 3 months
Time frame: 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.
Time frame: Baseline, 1-, 2- and 3-months
Mean Epworth Sleepiness Scale score Scores
Sleep questionnaire of subjective sleepiness. Total score range of 0-24; scores above 10 suggest excessive sleepiness.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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)
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline and 3-months
Mean concentration F2-isprostane
Mean concentration F2-isprostane (pg/ml) in the blood to assess oxidative stress.
Time frame: Baseline and 3-months
Mean concentration oxidized LDL
Mean concentration oxidized LDL (pg/ml) in the blood to assess oxidative stress.
Time frame: Baseline and 3-months
Mean morning concentration cortisol
Mean concentration cortisol (pg/ml) in the blood to assess autonomic activation.
Time frame: Baseline and 3-months
Mean concentration norepinephrine
Mean concentration norepinephrine (pg/ml) in the blood to assess autonomic activation.
Time frame: 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
Time frame: Baseline and 3-months
Blood pressure variability
Blood pressure variability during a single 24-hour period at baseline and 3-month
Time frame: Baseline and 3-months
Mean nighttime BP dipping
Mean nighttime BP dipping during a single 24-hour period at baseline and 3-month
Time frame: Baseline and 3-months
Mean CPAP pressure over 3 months
Measured nightly from cloud-based remote monitoring adherence system
Time frame: Assessed daily over 3 months
Mean residual AHI over 3 months
Measured nightly from cloud-based remote monitoring adherence system
Time frame: Assessed daily over 3 months
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