Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

Study Overview
=================
Brief Summary
-----------------
Obstructive sleep apnea (OSA) is a highly prevalent disorder with adverse neurocognitive and cardio-metabolic outcomes. Continuous positive airway pressure (CPAP) is the gold standard therapeutic option to treat airway obstructions during sleep and thus, prevent its adverse cardiovascular and neurocognitive outcomes. Previous clinical trials, however, have largely failed to show a consistent impact of CPAP on these health outcomes. One of the main limitations of these trials may be the inadequate characterization of OSA and its acute physiological consequences. By characterizing OSA based on the apnea-hypopnea index (AHI), there is a potential risk of negative results. In this trial, the investigators intend to tackle this issue, by better characterization of OSA-related physiological consequences during sleep using physiologically driven metrics to capture the burden of OSA-related hypoxemia (hypoxic burden), autonomic response (heart rate burden), and sleep fragmentation (arousal burden).

Official Title
-----------------
Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

Conditions
-----------------
Sleep Apnea

Intervention / Treatment
-----------------
* Device: PAP


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Adults aged 21-80 years. Participants with a previous diagnosis of moderate to severe obstructive sleep will be eligible to enroll and attend the baseline study. Patients with a total apnea-hypopnea index greater than 15 events/hr on the baseline study will be eligible for further participation. Exclusion criteria: Current treatment for obstructive sleep apnea (including CPAP, oral appliances, supplemental oxygen). Patients must be untreated prior to the baseline visit. Use of medications that might depress respiration (including opioids, barbiturates, benzodiazepines, and Z drugs, including zolpidem, zopiclone, eszopiclone, and zaleplon). Active use of non-prescription opioids (e.g., cocaine, methamphetamine) Uncontrolled medical problem or major organ system disease, which, in the opinion of the investigators (PI and Co-Is), would interfere with the evaluation of the subject (e.g., uncontrolled hypertension, unstable coronary heart disease, etc.). History of congestive heart failure, renal insufficiency, systemic neurological condition that could affect respiration. Sleep disordered breathing or respiratory disorders other than obstructive sleep apnea: central sleep apnea (>50% of respiratory events scored as central), chronic hypoventilation/hypoxemia (awake SaO2 < 92% by oximetry) due to chronic obstructive pulmonary disease or other respiratory conditions. Other sleep disorders: periodic limb movements (periodic limb movement arousal index > 10/hr), narcolepsy, or parasomnias. Patients unable or unwilling to use CPAP. Insomnia or insufficient sleep (self-reported inability to sleep >6 hrs night). Pregnancy (women)

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Positive Airway Pressure Device<br>All participants will receive PAP therapy | Device: PAP<br>* Positive airway pressure to treat sleep apnea<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline flow-mediated vasodilation at 12 weeks | Flow mediated vasodilation is studied using high resolution ultrasound of the artery. | 12 weeks | 
| Change from baseline 24-hour mean systolic blood pressure at 12 weeks | Mean systolic blood pressure over a 24-hour period is measured using an ambulatory blood pressure monitor. | 12 weeks | 
| Change from baseline Epworth Sleepiness Scale (ESS) at 12 weeks | Self-reported sleepiness measured using the Epworth Sleepiness Scale (units on a scale). Values range from 0-24; higher values indicate greater sleepiness. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline F2-Isoprostane/Creatinine Ratio at 12 weeks | F2-Isoprostane/Creatinine Ratio, a measure of oxidative stress, is calculated from urine sample. | 12 weeks | 
| Change from baseline Albumin/Creatinine Ratio at 12 weeks | Urinary Albumin/Creatinine Ratio is calculated from urine samples. | 12 weeks | 
| Change from baseline Albumin without Creatinine at 12 weeks | Urinary Albumin is calculated from urine samples. | 12 weeks | 
| Change from baseline Oxidized low-density lipoprotein (LDL) at 12 weeks | Oxidized low-density lipoprotein measurements are calculated through fasting phlebotomy. | 12 weeks | 
| Change from baseline N-terminal pro b-type natriuretic peptide (NT-proBNP) at 12 weeks | N-terminal pro b-type natriuretic peptide (NT-proBNP) measurements are calculated through fasting phlebotomy. | 12 weeks | 
| Change from baseline Hemoglobin A1c (HbA1c) at 12 weeks | Hemoglobin A1c (HbA1c) measurements are calculated through fasting phlebotomy. | 12 weeks | 
| Change from baseline Plasminogen Activator Inhibitor-1 at 12 weeks | Plasminogen activator inhibitor type 1 (PAI-1) measurements are calculated through fasting phlebotomy. | 12 weeks | 
| Change from baseline Fibrinogen Antigen at 12 weeks | Fibrinogen Antigen measurements are calculated through fasting phlebotomy. High values indicate inflammation and increased risk of atherosclerosis. | 12 weeks | 
| Change from baseline Glucose at 12 weeks | Blood glucose measurements are calculated through fasting phlebotomy | 12 weeks | 
| Change from baseline high sensitivity C-Reactive Protein (hs-CRP) at 12 weeks | C-reactive protein measurements are calculated from blood samples collected through fasting phlebotomy. | 12 weeks | 
| Change from baseline Interleukin-6 (IL-6) at 12 weeks | IL-6 is calculated from blood samples collected through fasting phlebotomy | 12 weeks | 
| Change from baseline Creatinine at 12 weeks | Creatinine is calculated from blood samples collected through fasting phlebotomy | 12 weeks | 
| Change from baseline Cystanin C with eGFR at 12 weeks | Cystanin C with eGFR is calculated from blood samples collected through fasting phlebotomy | 12 weeks | 
| Change from baseline lipid panel at 12 weeks | Lipid panel measurements are calculated from blood samples collected through fasting phlebotomy. | 12 weeks | 
| Change from baseline 24-hour mean diastolic blood pressure at 12 weeks | Mean diastolic blood pressure over a 24-hour period is measured using an ambulatory blood pressure monitor. | 12 weeks | 
| Change from baseline 24-hour mean blood pressure at 12 weeks | Mean arterial blood pressure over a 24-hour period is measured using an ambulatory blood pressure monitor. | 12 weeks | 
| Change from baseline nocturnal mean systolic blood pressure at 12 weeks | Mean systolic blood pressure during sleep is measured using an ambulatory blood pressure monitor. | 12 weeks | 
| Change from baseline nocturnal mean diastolic blood pressure at 12 weeks | Mean diastolic blood pressure during sleep is measured using an ambulatory blood pressure monitor. | 12 weeks | 
| Change from baseline nocturnal mean blood pressure at 12 weeks | Mean arterial blood pressure during sleep is measured using an ambulatory blood pressure monitor. | 12 weeks | 
| Change from baseline Psychomotor Vigilance Task reaction time at 12 weeks | 3-minute Psychomotor Vigilance Tasks will be done to quantify the speed with which subjects respond to a visual stimulus. | 12 weeks | 
| Change from baseline Psychomotor Vigilance Task lapses per test at 12 weeks | 3-minute Psychomotor Vigilance Tasks will be done to quantify the speed with which subjects respond to a visual stimulus. | 12 weeks | 
| Change from baseline Functional Outcome of Sleep Questionnaire (FOSQ) at 12 weeks | This test will be used to assess the impact of excessive sleepiness on functional outcomes relevant to daily behaviors and sleep-related quality of life. | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sleep apnea, Hypoxic burden, Arousal intensity, Post-event tachycardia, Positive airway pressure, Apnea hypopnea index