Assessment of Continuous Positive Airway Pressure Therapy in OSA and ILD (ACT-IPF)

The purpose of this study is to evaluate whether biomarkers of lung epithelial and endothelial injury are associated with obstructive sleep apnea (OSA) and interstitial lung disease (ILD).

Study Overview

• Status: Terminated
• Conditions: Obstructive Sleep Apnea; Interstitial Lung Disease
• Intervention / Treatment: Device: Continuous positive airway pressure (CPAP) therapy; Device: Nox A1 Recorder

Detailed Description

This study is comprised of 3 aims:

Aim 1: Determine whether the greater OSA severity is associated with higher levels of serum biomarkers of AEC and endothelial injury and ECM remodeling in community-dwelling adults. This is a retrospective study that will analyze biospecimens from those who participated in the MESA sleep study [Chen et al].

Aim 2: Determine whether CPAP use is associated with reductions in alveolar epithelial cell (AEC) injury and endothelial injury, and extracellular matrix (ECM) remodeling biomarkers in adults with moderate-to-severe OSA. This is a retrospective study that will analyze biospecimens from those who participated in either the HeartBEAT [Gottlieb et al] and BestAIR [Bakker et al] studies.

Revised Aim 3: a) Determine whether untreated OSA promotes AEC and endothelial injury and ECM remodeling biomarkers in adults with ILD and OSA compared with those without OSA; b) Determine prospectively whether clinically-initiated 4-week PAP therapy increases markers of alveolar endothelial lung injury in OSA. Participants will be recruited at Columbia University and be assigned CPAP therapy as an intervention.

• Study Type: Interventional
• Enrollment (Actual): 2021
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for Patients with ILD:

1. Ability to provide informed consent.
2. Age 18 years or greater

3. Diagnosis of any of the following fibrotic interstitial lung diseases as defined by ATS/ERS/JRS/ALAT guidelines and research statements and Delphi surveys:

   • Idiopathic pulmonary fibrosis
   • Idiopathic non-specific interstitial pneumonia (NSIP) with fibrosis
   • Chronic hypersensitivity pneumonitis with fibrosis
   • Connective tissue disease related interstitial lung disease (CTD-ILD)
   • Unclassifiable idiopathic interstitial pneumonia with fibrosis

Exclusion criteria for Patients with ILD:

1. Clinically significant lung disease other than fibrotic interstitial lung disease
2. Planned change to the IPF treatment during the study period
3. Current cigarette smoking (past 4 weeks)
4. Lower respiratory tract infection in past 60 days. (Upper respiratory tract infection is not a contraindication)
5. History of life-threatening cardiac arrhythmias
6. Known chronic heart failure (LVEF < 45% or echo evidence of RV dysfunction or PH)
7. Chronic opiate analgesic use
8. History of sleepiness-related automobile accident within past year of enrollment
9. Expected survival time in the opinion of the investigator of less than 6 months
10. History of stroke or spinal cord injury

Inclusion criteria for OSA patients:

1. Age 18 years or greater
2. Clinical diagnosis of untreated OSA documented by nocturnal polysomnography

Exclusion criteria for OSA patients:

1. Current treatment with CPAP or oral appliance
2. Identical exclusion criteria as for ILD patients

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Community based Multi-Ethnic Study of Atherosclerosis (MESA); This cohort includes biospecimens collected from 1852 participants in the MESA sleep study [Chen et al]. Serum biomarkers were measured by immunoassay in the Laboratory for Clinical Biochemistry Research at the University of Vermont. All participants in this cohort will be analyzed for only the Aim 1 outcome measures.
No Intervention: HeartBEAT and BestAir; The cohort includes 62 men and 20 women with newly diagnosed moderate-to-severe OSA and without known severe lung disease, who had participated in either of two randomized trials of PAP therapy, the HeartBEAT [Gottlieb et al] and BestAIR [Bakker et al] studies. Participants were selected for this analysis based on mean PAP adherence of ≥4 hours daily over a follow-up period of 3 months in the HeartBEAT study and 6 months in the BestAIR study. Morning serum samples drawn at baseline and at the end of the PAP treatment period were assayed using commercially available ELISA for each biomarker in the Laboratory for Clinical Biochemistry Research at the University of Vermont Larner College of Medicine. All participants in this cohort will be analyzed for only the Aim 2 outcome measures.
Experimental: CPAP treatment of OSA; Participants with obstructive sleep apnea (OSA) will be treated with continuous positive airway pressure therapy (CPAP). All participants in this cohort will be analyzed for only the Aim 3a outcome measures.	Device: Continuous positive airway pressure (CPAP) therapy; Standard, clinically used CPAP therapy. CPAP will be prescribed by the participants' clinician provider and not by the study investigators.
Experimental: ILD screening for OSA; Participants with interstitial lung disease (ILD) will be screened for OSA by polysomnography. All participants in this cohort will be analyzed for only the Aim 3b outcome measures.	Device: Nox A1 Recorder; Non-invasive, body-worn, sleep recording device for nocturnal polysomnography.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surfactant Protein D (SP-D) [Aim 1]	SP-D is a marker of alveolar epithelial cell injury. This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study.	1 day
E-selectin [Aim 1]	This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study.	1 day
Angiopoietin-2 [Aim 1]	This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study.	1 day
Vascular Endothelial Growth Factor-A (VEGF-A) [Aim 1]	This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study.	1 day
Angiopoietin-interacting Soluble Tie-2 (sTie2) [Aim 1]	This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study.	1 day
Change in Serum Matrix Metalloproteinase-7 (MMP-7) Following CPAP [Aim 2]	The differences between-arms in the longitudinal changes of MMP-7 will be measured. For the purpose of this analysis, all individuals receiving active CPAP in the experimental arm will be compared to all individuals receiving sham CPAP device in the control arm. This Outcome is specific to Aim 2 and will only be measured on participants in the Aim 2 phase of the study.	Baseline and post-CPAP follow-up, up to 24 Weeks
Change in Serum Surfactant Protein-D (SP-D) Following CPAP [Aim 2]	The between-arm difference in the longitudinal changes of SP-D will be measured. For the purpose of this analysis, all individuals receiving active CPAP in the experimental arm will be compared to all individuals receiving sham CPAP device in the control arm. This Outcome is specific to Aim 2 and will only be measured on participants in the Aim 2 phase of the study.	Baseline and post-CPAP follow-up, up to 24 Weeks
Change in Serum Angiopoietin-2 (Ang-2) Following CPAP [Aim 2]	The between-arm difference in the longitudinal changes of Ang-2 will be measured. For the purpose of this analysis, all individuals receiving active CPAP in the experimental arm will be compared to all individuals receiving sham CPAP device in the control arm. This Outcome is specific to Aim 2 and will only be measured on participants in the Aim 2 phase of the study.	Baseline and post-CPAP follow-up, up to 24 Weeks
Change in Serum Osteopontin Following CPAP [Aim 2]	The differences between-arms in the longitudinal changes of Osteopontin will be measured. For the purpose of this analysis, all individuals receiving active CPAP in the experimental arm will be compared to all individuals receiving sham CPAP device in the control arm. This Outcome is specific to Aim 2 and will only be measured on participants in the Aim 2 phase of the study.	Baseline and post-CPAP follow-up, up to 24 Weeks
Serum Angiopoietin-2 (Ang-2, ng/mL) [Aim 3a]	Participants will be treated with CPAP for 4 weeks. Serum Ang-2 levels will be measured at baseline and after CPAP therapy. This Outcome is specific to Aim 3a and will only be measured on participants in the Aim 3a phase of the study.	Baseline and 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Forced vital capacity (FVC)	Forced vital capacity, or FVC, is defined as the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible.	24 and 48 weeks
Diffusing capacity of the lung for carbon monoxide (DLCO)	Diffusing capacity of the lungs for carbon monoxide (DLCO) is a medical test that determines how much oxygen travels from the alveoli of the lungs to the blood stream.	24 and 48 weeks
Score on St. George's Respiratory Questionnaire (SGRQ)	The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction. Scores range from 0 to 100, with higher scores indicating more limitations.	24 and 48 weeks
Score on University of California San Diego (USCD) Shortness of Breath Questionnaire (SOBQ)	The SOBQ is a a 24-item questionnaire that assesses self-reported shortness of breath while performing a variety of activities of daily living. Items are assessed on a 6-point scale (0 = "not at all" to 5 = "maximal or unable to do because of breathlessness") for a total score ranging from 0 to 120.	24 and 48 weeks
Score on Epworth Sleepiness Scale (ESS)	The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight different activities. The ESS score (the sum of 8 item scores, 0-3) can range from 0 to 24. The higher the ESS score, the higher that person's average sleep propensity in daily life (ASP), or their 'daytime sleepiness'.	24 and 48 weeks
Sleep Apnea Quality of Life Index (SAQLI)	The SAQLI is a 35-item questionnaire is used to assess obstructive sleep apnea-related quality of life (QOL). Items are assessed on a 7-point scale with 0 indicating "all the time" to 7 indicating "not at all".	24 and 48 weeks
Assess Quality of life in Idiopathic Pulmonary Fibrosis (ATAQ-IPF)	ATAQ-IPF is a 74-item questionnaire used to assess quality of life among adults with idiopathic pulmonary fibrosis.	24 and 48 weeks
Gastroesophageal Reflux Disease Questionnaire (GERD-Q)	GerdQ is a 6-item questionnaire to assess gastroesophageal reflux symptoms.	24 and 48 weeks
Cough Visual Analog Scale	Cough visual analog scale, a standardized scale ranging from 0 (no cough) to 100 (severe cough) on a continuous scale.	24 and 48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Surfactant Protein-A (SP-A, ng/mL)	The between-arm difference in the longitudinal changes of SP-A will be measured.	Up to 24 weeks

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Sanja Jelic, MD, Columbia University; Study Chair: Daniel J Gottlieb, MD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Gottlieb DJ, Punjabi NM, Mehra R, Patel SR, Quan SF, Babineau DC, Tracy RP, Rueschman M, Blumenthal RS, Lewis EF, Bhatt DL, Redline S. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med. 2014 Jun 12;370(24):2276-85. doi: 10.1056/NEJMoa1306766.
• Bakker JP, Wang R, Weng J, Aloia MS, Toth C, Morrical MG, Gleason KJ, Rueschman M, Dorsey C, Patel SR, Ware JH, Mittleman MA, Redline S. Motivational Enhancement for Increasing Adherence to CPAP: A Randomized Controlled Trial. Chest. 2016 Aug;150(2):337-45. doi: 10.1016/j.chest.2016.03.019. Epub 2016 Mar 24.
• Chen X, Wang R, Zee P, Lutsey PL, Javaheri S, Alcantara C, Jackson CL, Williams MA, Redline S. Racial/Ethnic Differences in Sleep Disturbances: The Multi-Ethnic Study of Atherosclerosis (MESA). Sleep. 2015 Jun 1;38(6):877-88. doi: 10.5665/sleep.4732.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Actual): October 16, 2023
• Study Completion (Actual): October 16, 2023

Study Registration Dates

• First Submitted: April 2, 2019
• First Submitted That Met QC Criteria: April 2, 2019
• First Posted (Actual): April 3, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 13, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: CPAP; Obstructive Sleep Apnea (OSA); Interstitial Lung Disease (ILD)
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Sleep Wake Disorders; Apnea; Sleep Disorders, Intrinsic; Dyssomnias; Lung Diseases; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Lung Diseases, Interstitial
• Other Study ID Numbers: AAAR6902; 1R01HL137234-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Researchers will be required to submit a written request to the Study Principal Investigator (PI) describing the use of the specimens. The researcher must also document institutional review board (IRB) approval and sign a material transfer agreement. The Study PI will make all decisions about use of the specimens. No identifiable information will be released, only coded anonymized samples and non-identifiable clinical/demographic information. For genomic data generated from whole-exome sequencing, the genotype and relevant phenotype data for participants who consented to share data will be registered and shared through the database of Genotypes and Phenotypes (dbGaP), a controlled access database, once the sequencing data have been cleaned and quality control procedures are completed.
• IPD Sharing Time Frame: Data will be available no later than 3 years after last research subject is enrolled in the study.
• IPD Sharing Access Criteria: Researchers will be required to submit a written request to the Study PI describing the use of the specimens. The researcher must also document IRB approval and sign a material transfer agreement. The Study PI will make all decisions about use of the specimens. No identifiable information will be released, only coded samples and non-identifiable clinical/demographic information.
• 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
• product manufactured in and exported from the U.S.: No