Phenotyping Mechanistic Pathways for Adverse Health Outcomes in Sleep Apnea

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").

Study Overview

• Status: Recruiting
• Conditions: Sleep Apnea
• Intervention / Treatment: Device: PAP

• Study Type: Interventional
• Enrollment (Anticipated): 158
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nkiru G Ujomu; Phone Number: 617-732-8976; Email: nujomu@bwh.harvard.edu
• Study Contact Backup: Name: Kiley E Blodgett; Phone Number: 617-732-8976; Email: keblodgett@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Contact: Nkiru G Ujomu; Phone Number: 617-732-8976; Email: nujomu@bwh.harvard.edu
      • Contact: Kiley Blodgett; Email: keblodgett@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Positive Airway Pressure Device; All participants will receive PAP therapy	Device: PAP; Positive airway pressure to treat sleep apnea

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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Ali Azarbarzin, PhD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2020
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): June 30, 2024

Study Registration Dates

• First Submitted: September 16, 2020
• First Submitted That Met QC Criteria: September 29, 2020
• First Posted (Actual): October 5, 2020

Study Record Updates

• Last Update Posted (Actual): December 14, 2021
• Last Update Submitted That Met QC Criteria: December 13, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Positive airway pressure; Sleep apnea; Apnea hypopnea index; Hypoxic burden; Arousal intensity; Post-event tachycardia
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Signs and Symptoms, Respiratory; Sleep Apnea Syndromes; Apnea
• Other Study ID Numbers: PhenOSA; 1R01HL153874 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes