Interstitial Lung Disease, Obstructive Sleep Apnea
Conditions
Keywords
Interstitial Lung Disease (ILD), Obstructive Sleep Apnea (OSA), CPAP
Brief summary
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).
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.
Interventions
Standard, clinically used CPAP therapy. CPAP will be prescribed by the participants' clinician provider and not by the study investigators.
DEVICENox A1 Recorder
Non-invasive, body-worn, sleep recording device for nocturnal polysomnography.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (Open Label)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serum Angiopoietin-2 (Ang-2, ng/mL) [Aim 3a] | Baseline and 4 weeks | 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. |
| Surfactant Protein D (SP-D) [Aim 1] | 1 day | 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. |
| E-selectin [Aim 1] | 1 day | This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study. |
| Angiopoietin-2 [Aim 1] | 1 day | This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study. |
| Vascular Endothelial Growth Factor-A (VEGF-A) [Aim 1] | 1 day | This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study. |
| Angiopoietin-interacting Soluble Tie-2 (sTie2) [Aim 1] | 1 day | This Outcome is specific to Aim 1 and will only be measured on participants in the Aim 1 phase of the study. |
| Change in Serum Matrix Metalloproteinase-7 (MMP-7) Following CPAP [Aim 2] | Baseline and post-CPAP follow-up, up to 24 Weeks | 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. |
| Change in Serum Surfactant Protein-D (SP-D) Following CPAP [Aim 2] | Baseline and post-CPAP follow-up, up to 24 Weeks | 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. |
| Change in Serum Angiopoietin-2 (Ang-2) Following CPAP [Aim 2] | Baseline and post-CPAP follow-up, up to 24 Weeks | 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. |
| Change in Serum Osteopontin Following CPAP [Aim 2] | Baseline and post-CPAP follow-up, up to 24 Weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Serum Surfactant Protein-A (SP-A, ng/mL) | Up to 24 weeks | The between-arm difference in the longitudinal changes of SP-A will be measured. |
Countries
United States
Participant flow
Recruitment details
Recruitment for Aim 3b of the study was terminated before any prospective participants could be enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Aim 1 Cohort: 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. | 1,852 |
| Aim 2 Cohort: HeartBEAT and BestAir This 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. | 82 |
| Aim 3a Cohort: CPAP Treatment of OSA Participants with OSA will be treated with CPAP. | 87 |
| Aim 3b Cohort: ILD Screening for OSA Participants with ILD will be screened for OSA by polysomnography. | 0 |
| Total | 2,021 |
Baseline characteristics
| Characteristic | Aim 2 Cohort: HeartBEAT and BestAir | Aim 3a Cohort: CPAP Treatment of OSA | Total | Aim 1 Cohort: MESA |
|---|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 7 | 46 years STANDARD_DEVIATION 13 | 60 years STANDARD_DEVIATION 10 | 68 years STANDARD_DEVIATION 9 |
| Race and Ethnicity Not Collected | — | — | 0 Participants | — |
| Region of Enrollment United States | 82 Participants | 87 Participants | 2021 Participants | 1852 Participants |
| Sex: Female, Male Female | 20 Participants | 41 Participants | 1040 Participants | 979 Participants |
| Sex: Female, Male Male | 62 Participants | 46 Participants | 981 Participants | 873 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1,852 | 0 / 82 | 0 / 87 | 0 / 0 |
| other Total, other adverse events | 0 / 1,852 | 0 / 82 | 0 / 87 | 0 / 0 |
| serious Total, serious adverse events | 0 / 1,852 | 0 / 82 | 0 / 87 | 0 / 0 |
Outcome results
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MESA | Angiopoietin-2 [Aim 1] | 1785 pg/mL | Standard Deviation 1082 |
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MESA | Angiopoietin-interacting Soluble Tie-2 (sTie2) [Aim 1] | 83496 pg/mL | Standard Deviation 15417 |
Primary
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.
Time frame: Baseline and post-CPAP follow-up, up to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MESA | Change in Serum Angiopoietin-2 (Ang-2) Following CPAP [Aim 2] | 0.28 ng/mL |
Primary
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.
Time frame: Baseline and post-CPAP follow-up, up to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MESA | Change in Serum Matrix Metalloproteinase-7 (MMP-7) Following CPAP [Aim 2] | 0.004 ng/mL |
Primary
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.
Time frame: Baseline and post-CPAP follow-up, up to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MESA | Change in Serum Osteopontin Following CPAP [Aim 2] | -0.80 ng/mL |
Primary
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.
Time frame: Baseline and post-CPAP follow-up, up to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MESA | Change in Serum Surfactant Protein-D (SP-D) Following CPAP [Aim 2] | 0.68 ng/mL |
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MESA | E-selectin [Aim 1] | 20438 pg/mL | Standard Deviation 10558 |
Primary
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.
Time frame: Baseline and 4 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MESA | Serum Angiopoietin-2 (Ang-2, ng/mL) [Aim 3a] | Baseline | 1889 pg/mL | Standard Deviation 903 |
| MESA | Serum Angiopoietin-2 (Ang-2, ng/mL) [Aim 3a] | 4 weeks | 2153 pg/mL | Standard Deviation 926 |
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MESA | Surfactant Protein D (SP-D) [Aim 1] | 8 pg/mL | Standard Deviation 6 |
Primary
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.
Time frame: 1 day
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MESA | Vascular Endothelial Growth Factor-A (VEGF-A) [Aim 1] | 156 pg/mL | Standard Deviation 125 |
Other Pre-specified
Serum Surfactant Protein-A (SP-A, ng/mL)
The between-arm difference in the longitudinal changes of SP-A will be measured.
Time frame: Up to 24 weeks
Population: Data was not collected thus cannot be analyzed.