Study of COPD Subgroups and Biomarkers

Study Overview
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Brief Summary
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SPIROMICS I and SPIROMICS II are observational studies of Chronic Obstructive Pulmonary Disease (COPD). SPIROMICS I had two main 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 so provide new ways of testing whether a new treatment is working. SPIROMICS II has three primary aims. Aim 1 is to define the natural history of Smokers with symptoms despite preserved spirometry and characterize the airway mucus abnormalities underlying this condition. Aim 2 is to determine the radiographic precursor lesion(s) for emphysema, and identify the molecular phenotypes underlying airway disease and emphysema. Aim 3 is to advance understanding of the biology of COPD exacerbations through analysis of predisposing baseline phenotypes, exacerbation triggers and host inflammatory response.

Detailed Description
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SPIROMICS was initially funded through contracts from the NIH. That phase of SPIROMICS is now referred to as SPIROMICS I. SPIROMICS is now funded as a grant from the NIH. The current phase is referred to as SPIROMICS II. Brief summary of SPIROMICS I: The purpose of SPIROMICS is 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 has two main goals. The first is to find groups of patients with COPD who share certain characteristics. Certain groups may respond differently to certain treatments. The second is 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 has three substudies and two ancillary studies. Substudies: Repeatability Substudy: The entire baseline clinic visit will be repeated on 100 volunteers. The goal of this substudy is to determine reliability of measurement procedures. Bronchoscopy Substudy: 300 participants will be enrolled for two additional study visits, including a bronchoscopy. The goal of this substudy is to collect and assess biological specimens and relate those results to clinical measurements. Exacerbation Substudy: Up to 400 participants will be enrolled in this substudy. A daily symptom diary will be collected on all participants. Participants will also be seen in the clinic during a pulmonary exacerbation. The goals of this substudy are to 1) better understand the relationship between symptoms and exacerbations and 2) obtain clinical data and specimens during a pulmonary exacerbation. Ancillary Studies: Air Pollution Ancillary Study: The SPIROMICS Air Pollution ancillary study uses state-of-the art air pollution exposure assessments to determine individual-level outdoor and indoor air pollution exposure. The goals of this substudy are 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. Parametric Response Mapping in COPD: The Parametric Response Mapping (PRM) in COPD ancillary study collects an additional CT scan during the final study visit and uses a new analysis technique (PRM) to assess the functional small airways of the lung and emphysema. Brief summary of SPIROMICS II: Aim 1 is to define the natural history of Smokers with symptoms despite preserved spirometry and characterize the airway mucus abnormalities underlying this condition. Aim 2 is to determine the radiographic precursor lesion(s) for emphysema, and identify the molecular phenotypes underlying airway disease and emphysema. Aim 3 is to advance understanding of the biology of COPD exacerbations through analysis of predisposing baseline phenotypes, exacerbation triggers and host inflammatory response. SPIROMICS II will continue follow-up of current participants, with no new enrollment. Each participant will have one clinic visit and will be contacted by telephone every 4 months.

Official Title
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Subpopulations and Intermediate Outcome Measures in COPD Study

Conditions
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COPD, Chronic Obstructive Pulmonary Disease, Chronic Bronchitis, Emphysema

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Smokers without COPD<br>Current or former smokers with at least a 20 pack-year history with normal lung function based on post-bronchodilator spirometry (n=944). | |
| Severe COPD<br>Current and former smokers with at least a 20 pack-year history with severe COPD based on post-bronchodilator spirometry (n=625). | |
| Mild/Moderate COPD<br>Current and former smokers with at least a 20 pack-year history with mild to moderate COPD based on post-bronchodilator spirometry (n=1210). | |
| Non-smokers<br>Never-smokers with normal lung function on spirometry without use of bronchodilators (n=201). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morbidity | Morbidity in SPIROMICS will primarily be measured by assessing acute exacerbations in the SPIROMICS cohort. | Up to end of follow-up (data presented up to month 36) | 
| 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. | Up to end of follow-up (data presented up to month 36) | 
| 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. | Up to end of follow-up (data presented up to month 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to end of recruitment (2-6 week measurement repeatability) | 
| Exacerbation Substudy: Assess clinical and biological data in relation to an acute exacerbation | The exacerbation substudy will collect clinical and biological measurements during an acute exacerbation in a subset of participants. These will be used to better understand the biological processes underlying an acute exacerbation. | Up to end of follow-up (data presented up to month 15) | 
| Exacerbation Substudy: Assess symptomatic changes in COPD in relation to acute exacerbation | The exacerbation substudy will collect a daily symptom diary. Data from this daily diary will be used to characterize the stable versus exacerbative state in a subset of participants. | Up to end of follow-up (data presented up to month 15) | 
| Parametric Response Mapping in COPD: Structural assessment of the lung | In the PRM ancillary study, 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. | Up to end of follow-up (data presented up to month 36) |