Study of COPD Subgroups and Biomarkers

N/AActive Not RecruitingNCT01969344

University of North Carolina, Chapel Hill2,981 enrolled

Overview

SPIROMICS I, SPIROMICS II, and SPIROMICS III are longitudinal observational studies of Chronic Obstructive Pulmonary Disease (COPD) cohort. SPIROMICS I had two primary aims: (1) To find groups of patients with COPD who share certain characteristics; (2) To find new ways of measuring whether or not COPD is getting worse and to provide new ways of testing whether a new treatment is working. SPIROMICS II had three primary aims: (1) To define the natural history of "smokers with symptoms despite preserved spirometry" and characterize the airway mucus abnormalities underlying this condition; (2) To determine the radiographic precursor lesion(s) for emphysema and identify the molecular phenotypes underlying airway disease and emphysema; (3) To advance understanding of the biology of COPD exacerbations through analysis of predisposing baseline phenotypes, exacerbation triggers and host inflammatory response. SPIROMICS III has three primary aims: (1) To identify the main forms of smoking-related airway disease that are caused by pathological airway mucus, their biological underpinnings, and their physiological significance; (2) To identify longitudinal trajectories in established and novel CT measures of emphysema, test how they predict COPD progression, and define their underlying biology; (3) To identify environmental and social determinants of health that impact disease severity and progression and their influence on lung structure, biology, and health disparities in COPD.

SPIROMICS was initially funded through contracts from the NIH. That phase of SPIROMICS is now referred to as SPIROMICS I. SPIROMICS II was funded as a grant from the NIH to continue the longitudinal observation of the SPIROMICS cohort recruited in SPIROMICS I. The current phase, referred to as SPIROMICS III, is funded through a contract from the NIH to continue the longitudinal observation of the SPIROMICS cohort that remain active (not withdrawn, lost to follow-up, or deceased). Description of SPIROMICS I: The purpose of SPIROMICS was to learn about chronic obstructive pulmonary disease (COPD), which is sometimes called emphysema or chronic bronchitis. Millions of Americans have COPD, and it is the fourth leading cause of death in the country. The most common cause of COPD is cigarette smoking, although not all smokers get COPD. The discovery of new treatments for COPD has been slowed by a poor understanding of different types of COPD and a lack of ways to measure whether or not COPD is getting worse. The study had two main goals. The first was to find groups of patients with COPD who share certain characteristics. Certain groups may respond differently to certain treatments. The second was to find new ways of measuring whether or not COPD is getting worse. This would provide new ways of testing whether a new treatment is working. SPIROMICS I had three sub studies and two key ancillary studies. Sub studies: 1. Repeatability Substudy: The entire baseline clinic visit was repeated on 100 participants on a volunteer basis. The goal of this substudy was to determine reliability of measurement procedures. 2. Bronchoscopy Substudy: \~300 participants were enrolled for two additional study visits, including a bronchoscopy. The goal of this substudy was to collect and assess biological specimens and relate those results to clinical measurements. 3. Exacerbation Substudy: \~400 participants were enrolled in this substudy. A daily symptom diary was collected on all participants. Participants were also seen in the clinic during a pulmonary exacerbation. The goals of this substudy were to 1) better understand the relationship between symptoms and exacerbations and 2) obtain clinical data and specimens during a pulmonary exacerbation. Ancillary Studies: 1. Air Pollution Ancillary Study: The SPIROMICS Air Pollution ancillary study used state-of-the art air pollution exposure assessments to determine individual-level outdoor and indoor air pollution exposure. The goals of this substudy were to determine the effect of long-term air pollution exposure on COPD morbidity and to determine whether short-term changes in outdoor air pollution are associated with changes in COPD morbidity. 2. Parametric Response Mapping in COPD: The Parametric Response Mapping (PRM) in COPD ancillary study collected an additional CT scan during the final study visit and used a new analysis technique (PRM) to assess the functional small airways of the lung and emphysema. Description of SPIROMICS II: Aim 1 was to define the natural history of "smokers with symptoms despite preserved spirometry" and characterize the airway mucus abnormalities underlying this condition. Aim 2 was to determine the radiographic precursor lesion(s) for emphysema and identify the molecular phenotypes underlying airway disease and emphysema. Aim 3 was to advance understanding of the biology of COPD exacerbations through analysis of predisposing baseline phenotypes, exacerbation triggers and host inflammatory response. SPIROMICS II continued follow-up of active participants, with no new enrollment. Each participant had one clinic visit at 5-7 years of follow-up from SPIROMICS I baseline and was contacted by telephone every 4 months to assess respiratory health status. Description of SPIROMICS III: Aim 1 is to identify the main forms of smoking-related airway disease that are caused by pathological airway mucus, their biological underpinnings, and their physiological significance. Aim 2 is to identify longitudinal trajectories in established and novel CT measures of emphysema, test how they predict COPD progression, and define their underlying biology. Aim 3 is to identify environmental and social determinants of health that impact disease severity and progression and their influence on lung structure, biology, and health disparities in COPD. SPIROMICS III will enroll and consent approximately 1800 participants to conduct (a) a single in-person clinic visit at approximately 11-16 years of follow-up for those originally enrolled into SPIROMICS I and approximately 5-6 years of follow-up for those originally enrolled into SOURCE (and MAP COPD) (NCT05033990), (b) follow-up telephone calls every 4 months to assess respiratory health status, and (c) to assess indoor and outdoor environmental monitoring.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 80 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Between 40 and 80 at baseline visit * Never smokers: \<1 pack-year history of smoking * Never smokers: Must meet lung function criteria based on spirometry without inhaled bronchodilators * Current or former smokers: \>20 pack-year history of smoking * Current or former smokers: Must meet lung function criteria based on spirometry with inhaled bronchodilators Exclusion Criteria: * Dementia or other cognitive dysfunction which in the opinion of the investigator would prevent the participant from consenting to the study or completing study procedures * Plans to leave the area in the next 3 years * Smoking history of \> 1 pack-year but \<21 pack-years * BMI \> 40 kg/m2 at baseline exam * Prior significant difficulties with pulmonary function testing * Hypersensitivity to or intolerance of albuterol sulfate or ipratropium bromide or propellants or excipients of the inhalers * Non-COPD obstructive lung disease, severe kyphoscoliosis, neuromuscular weakness, or other conditions, including clinically significant cardiovascular and pulmonary disease, that, limit the interpretability of the pulmonary function measures. * History of Interstitial lung disease * History of Lung volume reduction surgery or lung resection * History of lung or other organ transplant * History of endobronchial valve therapy * History of large thoracic metal implants (e.g., AICD (automatic implantable cardioverter/defibrillator) and/or pacemaker) * Currently taking \>=10mg a day/20mg every other day of prednisone or equivalent systemic corticosteroid * Currently taking any immunosuppressive agent * Current illicit substance abuse, excluding marijuana * History of or current use of IV Ritalin * History of or current use of heroin * History of illegal IV drug use within the last 10 years or more than 5 instances of illegal IV drug use ever * Known HIV/AIDS infection * History of lung cancer or any cancer that spread to multiple locations in the body * History of or current exposure to chemotherapy or radiation treatments that, in the opinion of the investigator, limits the interpretability of the pulmonary function measures. * Diagnosis of unstable cardiovascular disease including myocardial infarction in the past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia * Any illness expected to cause mortality in the next 3 years * Active pulmonary infection, including tuberculosis * History of pulmonary embolism in the past 2 years * Known diagnosis of primary bronchiectasis * Currently institutionalized (e.g., prisons, long-term care facilities) * Known to be a first degree relative of another, already enrolled participant (i.e., biological parent, biological sibling) * Never smokers only: Current diagnosis of asthma * Women only: Cannot be pregnant at baseline or plan to become pregnant during the course of the study Temporal Exclusion Criteria for SPIROMICS III: * Participants who present with a pulmonary exacerbation, either solely participant-identified or that has been clinically treated, in the last six weeks, can complete the study visit once a six-week window has passed. * Participants who present with an upper respiratory infection, either solely participant-identified or that has been clinically treated, in the last six weeks, can complete the study visit once a six-week window has passed. * Participants who present with current use of acute antibiotics or steroids can complete the study visit ≥30 days after discontinuing acute antibiotics/steroids. This does not apply to participants who are on chronic prednisone therapy of \<10 mg per day or \<20 mg every other day or participants who are currently on chronic, prophylactic, or suppressive antibiotic therapy. * Participants who present with a myocardial infarction or eye, chest or abdominal surgery within six weeks can complete the study visit after a six-week window has passed. * Female participants who present \<3 months after giving birth will be asked to schedule the visit once three months have passed post-delivery.

Outcomes

Primary Outcomes

Morbidity

Morbidity in SPIROMICS will primarily be measured by assessing acute exacerbations in the SPIROMICS cohort.

Time frame: Through study completion, an average of 18 years.

Lung Function

COPD is characterized by physiological problems, such as airflow limitations and abnormalities of gas exchange and lung hyperinflation. These features of lung function are accessed objectively in the laboratory setting using spirometry/plethysmography, which can measure such parameters as FEV1 (forced expiratory volume in one second), FVC (forced vital capacity or total volume of air exhaled after full inspiration), FRC (functional residual capacity or volume of gas remaining in the lung at the end of tidal expiration), and IC (inspiratory capacity or maximum volume of gas that can be inspired from end-tidal expiration). The FDA preferred primary endpoint for assessment of alteration in disease progression in COPD is serial measurements of FEV1 over three years.

Time frame: Through study completion, an average of 18 years.

Mortality

Deaths of SPIROMICS participants will be identified during follow-up calls and attempts to schedule clinic exams during the three-year study period, and deaths will be recorded in the clinical database. The cause of death will be determined via chart review and adjudication, and deaths attributable to COPD worsening or exacerbation will be recorded as confirmed clinical endpoints, in addition to contributing to the endpoint of all-cause mortality.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Radiology - Emphysema Volume

Percent Emphysema (percent \<-950HU)

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Radiology - Functional Small Airway Disease through Parametric Response Mapping (PRM)

PRM metrics will be used to non-invasively evaluate the regional structural heterogeneity of the lung, including small airways disease and emphysema, and its relationship to clinical measurements. The metric is PRMfSAD.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Radiology - Functional Small Airway Disease through Disease Probability Method (DPM)

Patients undergo both full-inspiration and full-expiration chest CT scans. These scans are coregistered-aligned voxel-by-voxel-to allow for direct comparison of lung tissue characteristics between breathing phases. Each voxel (3D pixel) in the lung is classified into one of three categories: Normal: No signs of disease, Emphysema: Identified by low attenuation on inspiratory CT, Gas Trapping (SAD): Identified by abnormal retention of air on expiratory CT without emphysema features. The proportion of voxels classified as emphysema, gas trapping, or normal is calculated.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Radiology - Airway Wall Thickness

Pi10 as a measure of airway wall thickness

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Physiology - Lung function (Spirometry)

Lung function will be assessed as FEV1 through spirometry using forced and slow vital capacity before and after bronchodilator (BD) administration.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Physiology - Lung function (Respiratory Oscillometry)

Assessment of lung function through respiratory oscillometry.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Biological - Mucin concentrations

Mucus samples obtained from sputum, bronchial brushings, and Bronchoalveolar Lavage (BAL) will be analyzed for total mucin concentration.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Biological - MUCQ index

The MUCQ index which integrates mucin concentration with MUC5AC/MUC5B ratios will be calculated and provide more detailed understanding of mucin composition and regulation. The formula MUCQ=\[total mucin\] x \[5AC\]/\[MUC5B\] / 100 will be used.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Biological - Mucin-interacting proteins

Mucin-interacting proteins will be identified and quantified using labeled and label free mass spectrometry.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Outdoor concentrations of particulate matter (PM) 2.5

Data on ambient air quality will be obtained from the EPA DataMart for sites nearest each participant home address. Data will be obtained at the highest temporal resolution and averaged to daily and weekly values. Outdoor concentrations of PM2.5 will be measured in micrograms per cubic meter of air (µg/m³).

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Outdoor concentrations of nitrogen dioxide (NO2)

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Outdoor concentrations of nitrogen oxides (NOx)

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Outdoor concentrations of ozone (O3)

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Outdoor concentrations of wildfire-derived particulate matter (PM) 2.5

Data on ambient air quality will be obtained from the EPA DataMart for sites nearest each participant home address. Data will be obtained at the highest temporal resolution and averaged to daily and weekly values. Outdoor concentrations of wildfire-derived PM2.5 will be measured in micrograms per cubic meter of air (µg/m³).

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Indoor concentrations of particulate matter (PM)

Indoor PM will be measured using a low-cost sensor monitor. Monitors will provide a year-long continuous in-home air monitoring and assessment. Indoor concentrations of PM2.5 will be measured in micrograms per cubic meter of air (µg/m³).

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Indoor measurements of temperature

Indoor temperature will be measured using a low-cost sensor monitor. Monitors will provide a year-long continuous in-home air monitoring and assessment.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Indoor measurements of humidity

Indoor humidity will be measured using a low-cost sensor monitor. Monitors will provide a year-long continuous in-home air monitoring and assessment.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Indoor measurements of NO2

Airborne NO2 will be monitored with passive samplers for approximately one week or seven days in the home. Temperature and humidity measurements will be used to adjust the NO2 analytical results as appropriate. Indoor concentrations of NO2 will be measured in parts per billion (ppb).

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Indoor measurements of air nicotine

Air nicotine will be monitored using passive sampling badges for one week or seven days in the home. Nicotine is collected by passive diffusion onto glass fiber filters treated with a 4% sodium bisulfate solution. The cassette is sealed and returned to the clinic laboratory for extraction and analysis. Indoor concentrations of airborne nicotine will be measured in micrograms per cubic meter (µg/m³).

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Indoor measurements of settled dust

Settled dust samples will be collected from the home to ascertain exposure to common household allergens. The presence of indoor allergens will be assessed by extracting protein from the settled dust samples and quantifying them using enzyme-linked immunosorbent assay (ELISA).

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Environmental and Social Determinants of Health - Geocoding

Geocoding will assess residential mobility and neighborhood characteristics including area deprivation, food access, and segregation.

Time frame: Through study completion, an average of 18 years.

SPIROMICS III: Epigenetic

Illumina EPIC Methylation Arrays

Time frame: Through study completion, an average of 18 years.

Secondary Outcomes

Repeatability Substudy: Repeatability of clinic visit measurements

The repeatability of clinic visit measurements will be assessed at the end of this substudy. In this substudy all clinic procedures and samples are repeated/recollected 2-6 weeks after the baseline clinic visit in a subset of participants. This provides a measurement of short-term repeatability of these assessments.

Time frame: Up to end of recruitment (2-6 week measurement repeatability)

Exacerbation Substudy: Nasal swab analyses

Self-administered nasal swabs will be collected during an acute exacerbation in a subset of participants. These will be used to better understand the biological processes underlying an acute exacerbation, including providing information about viral triggers and the host inflammatory response. Analyses will include measurements for RNA and DNA.

Time frame: Through study completion, an average of 18 years.

Exacerbation Substudy: Sputum analyses for ribonucleic acid (RNA)

Spontaneous sputum will be collected during an acute exacerbation in a subset of participants. It will be used to better understand the biological processes underlying an acute exacerbation, including initial characterization of the host response. Sputum will be analyzed for RNA and host gene expression.

Time frame: Through study completion, an average of 18 years.

Exacerbation Substudy: Sputum analyses for mucins

Time frame: Through study completion, an average of 18 years.

Exacerbation Substudy: Sputum analyses for proteins

Study of COPD Subgroups and Biomarkers

Overview

Conditions

Eligibility

Locations (14)

Outcomes

Primary Outcomes

Secondary Outcomes