Obstructive Sleep Apnea, Sleep Apnea
Conditions
Keywords
Continuous Positive Airway Pressure (CPAP), sleep apnea, hypnotic, mechanism, arousability
Brief 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). 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.
Interventions
DRUGEszopiclone
3mg for \< 65 and 2mg for ≥ 65 years
DRUGPlacebo
Matched placebo
Sponsors
Yale University
National Heart, Lung, and Blood Institute (NHLBI)
ResMed Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
randomized, double-blind controlled clinical trial with 3 month follow up.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 .
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CPAP adherence | Daily over 3 months | Mean daily average of CPAP use over 3 months |
| Flanker inhibitory control and attention test | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Epworth Sleepiness Scale score Scores | Baseline, 1-, 2-and 3-months | Sleep questionnaire of subjective sleepiness. Total score range of 0-24; scores above 10 suggest excessive sleepiness. |
| Mean Functional Outcomes of Sleep Questionnaire (FOSQ) short form score | Baseline, 1-, 2-and 3-months | Measures how sleepiness affects daily life, with scores ranging from 5-20. Higher scores indicate better functioning and less impairment. |
| Mean Insomnia Severity Index score (ISI) Scores | Baseline, 1-, 2-and 3-months | ISI is a validated 7-question survey. The total score range is 0-28 with higher scores indicating more severe insomnia. |
| Mean PROMIS Sleep Disturbance score Scores | Baseline, 1-, 2-and 3-months | T-score mean of 50 and a standard deviation (SD) of 10. Higher scores indicating more sleep disturbance. |
| Mean PROMIS Sleep-Related Impairment score Scores | Baseline, 1-, 2-and 3-months | T-score mean of 50 and a standard deviation (SD) of 10. Higher scores indicating more sleep disturbance. |
| Mean time to complete Trail Making Test (TMT) A and B | Baseline, 1-, 2-and 3-months | 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. |
| Mean processing speed of Pattern Comparison Processing Speed Test | Baseline, 1-, 2-and 3-months | 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. |
| Mean reaction time of Psychomotor vigilance test (PVT) | Baseline, 1-, 2-and 3-months | 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. |
| Mean percent accuracy of Change Card Sort Test | Baseline, 1-, 2-and 3-months | 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. |
| Mean percent correct recall of Verbal Paired Associates A-B task | Baseline and 3-months | 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. |
| Mean OSA alleviation at 3 months | 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 |
| Mean percent hypoxic burden | Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit | 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. |
| Mean sleep depth score | Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit | 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. |
| Arousal intensity | Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit | 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) |
| Ventilatory burden | Baseline and at the night of CPAP and eszopiclone/placebo initiation: 3 weeks after baseline visit | 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). |
| Mean concentration Neurofilament Light Chain (NfL) | Baseline and 3-months | Mean concentration NfL (pg/ml) in the blood to assess neuronal injury and damage. |
| Mean concentration Aβ40 | Baseline and 3-months | Mean concentration Aβ40 (pg/ml) in the blood (usually measured as a ratio with Aβ42 (Aβ42/40 ratio) to assess brain amyloid plaque buildup. |
| Mean concentration F2-isprostane | Baseline and 3-months | Mean concentration F2-isprostane (pg/ml) in the blood to assess oxidative stress. |
| Mean concentration oxidized LDL | Baseline and 3-months | Mean concentration oxidized LDL (pg/ml) in the blood to assess oxidative stress. |
| Mean morning concentration cortisol | Baseline and 3-months | Mean concentration cortisol (pg/ml) in the blood to assess autonomic activation. |
| Mean concentration norepinephrine | Baseline and 3-months | Mean concentration norepinephrine (pg/ml) in the blood to assess autonomic activation. |
| Mean systolic and diastolic blood pressure (BP) | Baseline and 3-months | Mean systolic and diastolic blood pressure during a single 24-hour period at baseline and 3-month |
| Blood pressure variability | Baseline and 3-months | Blood pressure variability during a single 24-hour period at baseline and 3-month |
| Mean nighttime BP dipping | Baseline and 3-months | Mean nighttime BP dipping during a single 24-hour period at baseline and 3-month |
| Mean CPAP pressure over 3 months | Assessed daily over 3 months | Measured nightly from cloud-based remote monitoring adherence system |
| Mean residual AHI over 3 months | Assessed daily over 3 months | Measured nightly from cloud-based remote monitoring adherence system |
Countries
United States
Contacts
CONTACTAndrey Zinchuk, MD, MHS
CONTACTIouri Kreinin, MD
PRINCIPAL_INVESTIGATORAudrey Zinchuk,, MD, MHS
Yale University
Outcome results
None listed