Abstract
SPIROMICS is a multi-center observational study of chronic obstructive pulmonary disease (COPD) designed to guide future development of therapies for COPD by 1) providing robust criteria for sub-classifying COPD participants into groups most likely to benefit from a given therapy during a clinical trial, thereby improving the chances of successful outcome; and 2) identifying biomarkers/phenotypes that can be used as intermediate outcomes to reliably predict clinical benefit during therapeutic trials, thus reducing costs. The goal is to enroll 3,200 participants in four strata: severe COPD, mild/moderate COPD, smokers without airflow obstruction and non-smoking controls. Participants undergo a baseline visit including morphometric measures, spirometry, six-minute walk, an inspiratory and expiratory chest CT, and a set of standardized questionnaires. Biospecimens, including plasma, serum, DNA, urine and induced sputum, are collected and stored. There are three annual follow-up examinations, with quarterly telephone calls to assess for exacerbations, hospitalizations and mortality. Bronchoscopy is being performed in a subset of participants and a subset of COPD patients will be assessed during exacerbations. Adjudication of exacerbations and mortality will be undertaken. SPIROMICS is designed so that sub-studies and ancillary studies testing additional hypotheses can be added.
Keywords: COPD Exacerbations, Emphysema, Imaging/CT MRI etc, COPD epidemiology
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a chronic, usually progressive, lung disease characterized by incompletely reversible airflow obstruction. Both the airways (obstructive bronchiolitis/small airways disease) and the parenchyma (emphysema/parenchymal destruction) contribute to the airflow obstruction and ultimately dyspnea. Additional processes such as mucous hypersecreation (chronic bronchitis) and exacerbations contribute to the overall impact of the disease. COPD is the third leading cause of death in the US [1].
There are no proven medical therapies for COPD, other than supplemental oxygen and smoking cessation, that significantly reduce mortality [2]. No pharmacological treatments have been shown to modify meaningfully the long-term decline in lung function. Complicating the therapeutic scenario is the fact that the disease is highly heterogeneous. Obstructive bronchiolitis and emphysema are clinically distinct histological entities, but individual patients with COPD may have either or both. Moreover, each can occur in the absence of spirometrically defined COPD and likely result from a number of mechanistic pathways. The recognition of COPD as a systemic disease that affects extra-pulmonary systems, including cardiovascular, sleep and muscle function, further complicates disease classification. Because of clinical and pathological heterogeneity, individual patient subtypes may benefit from unique therapeutic regimens. Identifying meaningful subpopulations of COPD patients is a key goal of SPIROMICS. Additionally, the efficiency and cost of clinical trials could be improved considerably by validated intermediate endpoints.
OBJECTIVES OF SPIROMICS
SPIROMICS has two primary aims. Primary Aim 1 is to identify homogeneous subgroups of COPD patients for targeted enrollment in future therapeutic clinical trials. Primary Aim 2 is intermediate endpoint discovery and validation. SPIROMICS will endeavor to identify intermediate outcome measures that predict long-term clinical endpoints of morbidity. There are also three secondary aims, involving cohort building, developing a COPD controlled vocabulary, and supporting ancillary studies.
Further details of the aims and other aspects of the study are provided in the On-line Supplement.
STUDY DESIGN AND METHODS
SPIROMICS is a prospective cohort study that will enroll 3,200 participants into four strata (Non-smokers, Smokers without airflow obstruction, Mild/Moderate COPD, and Severe COPD) as shown in Table 1.
Table 1.
SPIROMICS Enrollment Strata
| Non-Smokers (Stratum 1) | Smokers (Stratum 2) | Mild/Moderate COPD (Stratum 3) | Severe COPD (Stratum 4) | |
|---|---|---|---|---|
| Smoking Status | < 1 pack-year | > 20 pack-years | > 20 pack-years | > 20 pack-years |
| Bronchodilator Status for Assessing Lung Function | Pre-bronchodilator | Post-bronchodilator | Post-bronchodilator | Post-bronchodilator |
| FEV1/FVC ratio criteria | FEV1/FVC > 0.7 | FEV1/FVC > 0.7 | FEV1/FVC < 0.7 | FEV1/FVC < 0.7 |
| Other Lung Function Criteria | FVC>LLN | FVC>LLN | FEV1 > 50% pred. | FEV1 < 50% pred. |
| Sample Size | N = 200 (6.25%) | N = 900 (28.1%) | N = 1500 (46.9%) | N = 600 (18.75%) |
FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; LLN: lower limit of normal
Participants may be enrolled in concurrent observational studies, excluding the COPDGene Study [3], which will facilitate combined analyses between SPIROMICS and COPDGene. Subjects enrolled in therapeutic clinical trials may enroll in SPIROMICS after the treatment is unmasked; those in SPIROMICS may be recruited into other interventional studies after SPIROMICS baseline values are obtained.
The Institutional Review Boards/Ethics Committees of all the cooperating institutions have approved the study protocols.
Inclusion and exclusion criteria
Participants must be 40–80 years of age at baseline, have a smoking history of ≤ 1 pack-year (Stratum 1) or ≥ 20 pack-years (Strata 2–4) and meet lung function criteria as specified in Table 1. Major exclusion criteria are non-COPD obstructive lung disease or a history of diseases or treatments likely to interfere with interpretation of study tests, BMI > 40 kg/m2 at baseline, hypersensitivity to or intolerance of the bronchodilators used in study assessments and diagnosis of unstable cardiovascular disease. Lung surgery and metal in the chest that may affect the chest CT interpretation is also exclusionary. Supplementary Table 1 contains the complete list of exclusion criteria.
Baseline and follow-up assessments
There are baseline (Visit 1) and three annual in-person follow-up visits (Visits 2–4). Participants also receive quarterly follow-up calls to assess health status and determine if an exacerbation has occurred. Visits 1, 2 and 4, include anthropometry, seated blood pressure, spirometry, 6-minute walk test, biological specimen collection, and a series of questionnaires (Supplementary Table 2). Information is collected on medical history, respiratory exposures and current medications. Visit 3 omits specimen collection. Visits 1 and 2 include a thoracic CT scan at maximum inspiration and expiration.
Clinical outcomes, including hospitalizations and deaths, will be adjudicated centrally.
Imaging
Acquisition of state-of-the-art computed tomography (CT) images is a key component in SPIROMICS for detailed phenotype identification (Supplementary Table 3). Two CT scans are performed, one at total lung capacity (TLC), and one at residual volume. The CT protocol for the TLC scan is identical to that used in other NHLBI-sponsored studies including the Multi-ethnic Study of Atherosclerosis (MESA) Lung Study and the Severe Asthma Research Program (SARP), which will facilitate comparative papers across studies.
Biospecimen collection
Fasting blood and urine specimens are collected at Visits 1, 2 and 4. Approximately 70 ml of blood is collected per visit, including plasma, and serum. DNA will be extracted from blood collected at Visit 1 and RNA from PAX-Gene™ tubes collected at Visits 1 and 2. Urine is collected into aliquots with and without preservative. One EDTA plasma specimen is assessed locally for complete blood, differential and platelet count. All other samples are sent to the SPIROMICS biospecimen repository. Additional blood and urine samples are collected from participants in the sub-studies. Induced sputum samples are collected at the baseline visit. Sputum is being processed using the “whole sputum” method.
SUB-STUDIES AND ANCILLARY STUDIES
A sub-study is a component of the protocol funded by the SPIROMICS contract and performed on a subset or the entire cohort. An ancillary study is one that contributes new data to SPIROMICS but whose aims are distinct from the parent study. Ancillary studies are not funded as part of the parent study. However, they must be approved by SPIROMICS to assure that the use of SPIROMICS resources are scientifically and practically justified and that the study does not interfere with the primary goals of SPIROMICS.
Three key sub-studies are 1) the Repeatability and Replicate Sub-study, in which 100 participants will have the entire baseline clinic visit including the CT scanning repeated in order to quantify reliability and short-term within-person variability of study procedures and assay methods; 2) the Bronchoscopy Sub-study, in which 300 participants will undergo bronchoscopy with bronchoalveolar lavage, epithelial brushings and bronchial biopsies; and 3) the Exacerbation Sub-study, in which up to 400 participants will be followed prospectively and biological samples and clinical information will be collected at the time of an acute exacerbation.
STUDY ORGANIZATION
SPIROMICS has six core clinical centers, with sub-sites and satellite clinics, and several central agencies. These are the NHLBI Project Office, a Genomics and Informatics Center (which functions as the data and statistical coordinating center and includes the biospecimen core), a Radiology Center, a Pulmonary Function Test Reading Center, and a Sputum Reading Center. An Observational Studies Monitoring Board provides annual and ad hoc evaluations of the study with recommendations to the NHLBI. An External Scientific Board that is composed of representatives from the pharmaceutical industry and the Food and Drug Administration (FDA) serves in an advisory role.
DISCUSSION
The marked clinical and mechanistic heterogeneity that characterizes COPD confounds development of novel treatments. It is likely that mechanistically-based therapy will be effective only in selected subsets of the COPD population. SPIROMICS is designed to identify meaningful subsets of the COPD population appropriate for future mechanistically-based therapeutic interventions. Furthermore, the identification and validation of meaningful intermediate outcomes would facilitate development and testing of new treatments by enabling the design of more efficient clinical trials [4]. Although a number of such measures have been suggested, the validation of these measures is limited by the lack of data in a well-characterized, longitudinal COPD cohort.
Several other studies will complement SPIROMICS to help address these questions. ECLIPSE [5] utilized a three year observation period similar to SPIROMICS and shares similar goals. COPDGene [3] was originally designed to explore the genetics of COPD in a large cohort of subjects. Longitudinal data and collection of blood biomarkers are now in progress.
While the goals for SPIROMICS are ambitious, there are limitations. Even combined with other large studies like COPDGene and ECLIPSE, SPIROMICS will not be able to fully characterize COPD heterogeneity, its natural history or to fully validate biomarkers and other intermediate outcomes. These goals will undoubtedly require additional studies. SPIROMICS is committed to sharing protocols, instruments and data with other investigators. The availability of standardized methods and datasets will facilitate the development of other large cohorts and expedite their comparison with SPIROMICS and other studies.
Strengths of SPIROMICS include the large cohort with two types of controls, detailed characterization at baseline and longitudinally, and extensive follow-up, with central adjudication of clinical outcomes.
In summary, SPIROMICS is a prospective observational study of COPD subjects and controls. It will characterize individuals with clinical, physiologic, imaging, biochemical, cellular and histologic parameters. Samples will be collected by a variety of methods. A subset of participants will be assessed at the time of an exacerbation. The rich characterization of COPD subjects will permit definition of meaningful subsets of COPD patients. By assessing the relationship of clinical measures with longitudinal outcomes, SPIROMICS will advance validation of intermediate measures to be used in COPD. Finally, the availability of a well-characterized cohort of participants that can be used in specific ancillary studies should prove to be a long-term resource for furthering understanding of COPD.
Supplementary Material
Acknowledgments
The following are also co-authors of this manuscript:
Neil Alexis, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Wayne Anderson, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Safwan Badr, Division of Pulmonary Critical Care and Sleep Medicine, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI, USA
Patricia Basta, Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Richard C. Boucher, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Elizabeth Carretta, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Christopher B Cooper, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
Jeff Curtis, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
Claire Doerschuk, Departments of Medicine and Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Jane Greenberg, School of Information and Library Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Nadia Hansel, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
Robert Kaner, Institute of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
Mehmet Kesimer, Department of Pathology and Laboratory Medicine; and Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Stephen C. Lazarus, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA
Deborah Meyers, Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, NC, USA
Wanda O’Neal, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Robert Paine, III, Department of Internal Medicine/Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA
Stephen P Peters, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
Sanjeev Raman, Department of Internal Medicine/Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA
Mary Beth Scholand, Department of Internal Medicine/Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA
Krishna Sundar, Department of Internal Medicine/Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA
Donald P. Tashkin, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
Robert A. Wise, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
Fred A. Wright, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
FUNDING
Funder: The National Heart, Lung, and Blood Institute (NHLBI) of the NIH.
Contract and grant numbers: NHLBI contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN2682009000019C, and HHSN268200900020C; NHLBI grant R01HL110906.
Role of the funder: The funder proposed the study and continues to be involved in its management.
CONTRIBUTORSHIP
David Couper takes responsibility for the overall content as guarantor. The manuscript was written primarily by Drs. Couper, Rennard, and Han. It is based on the (unpublished) SPIROMICS protocol. Dr. LaVange, as PI of the Genomics and Informatics Center at the time, and Dr. Rennard as Chair of the Steering Committee, led development of the study protocol. All authors were involved in planning various aspects of the study and all authors reviewed the manuscript and provided feedback.
COMPETING INTERESTS
Dr. Barr reports (1) Royalties from UpToDsate; (2) Reimbursement for travel to the TransAltantic Airways Conference (Boehringer Ingelheim).
Dr. Boucher reports board membership, consultancy, patents, royalties and stock/stock options, all from Parion Sciences.
Ms. Carretta reports money paid to her institution, towards her employment on studies other than SPIROMICS, from the NIH and the COPD Foundation.
Dr. Curtis reports (1) Grants (other than for SPIROMICS) from the nIH and the Department of Veterans Affairs; (2) Travel/accommodation/meeting expenses (other than for SPIROMICS) from the American Thoracic Society
Dr. Han reports (1) Consulting fees or honoraria from GSK, Pfizer, Boehringer Ingelheim, Forest, Grifols, Novartis, Medimmune and Ikaria; (2) Fees for participation in review activities from GSK; (3) Royalties from Uptodate; (4) Payment for development of educational presentations from the Office of Research on Women’s Health (ORWH) at the National Institutes of Health (NIH) and the Office of Women’s Health (OWH) at the Food and Drug Administration (FDA), from WebMD, and from the National Association for Continuing Education.
Dr. Hansel reports a consultancy with Boehringer-Ingelheim.
Dr. Hoffman is a founder and shareholder of VIDA Diagnostics, a company commercializing lung image analysis software developed, in part, at the University of Iowa.
Dr. Kleerup reports (1) A one-day consultancy with Ikaria; (2) Grants from Boehringer Ingelheim, Forest, GlaxoSmithKline, Novartis, Osiris, Pearl Therapeutics, Schering Plough, and Sunovion; (3) GlaxoSmithKline donated Ventolin HFA for spirometric testing in this study to the Foundation for the NIH. Boehringer Ingelheim donated Atrovent HFA for spirometric testing in this study to the Foundation for the NIH. (Dr. Kleerup heads the Spirometry Reading Center for SPIROMICS.)
Dr. Martinez reports (1) Board memberships of Actelion, Almirall/Forest, Nycomed/Takeda, Bayer, Ikaria, Merck, Pearl, Pfizer, Jannsen, and Vertex; (2) Consultancies with Actelion, Forest, American Institute for Research, AstraZeneca, GSK, Gilead, HCRC, Merion, Sudler and Hennessey, Carden Jennings, and Grey Healtcare; (3) Grants other than for SPIROMICS from the NIH; (4) Payment for lectures including service on speakers bureaus from Forest, Nycomeda/Takeda, AstraZeneca, Bayer, William Beaumont Hospital, Boeheringer Ingelheim, GSK, Lovelace, University of Illinois - Chicago, University of Texas - Southwestern, Wayne State University, and Spectrum Health; (5) Royalties from Informa; (6) Payment for development of educational presentations from the American College of Chest Physicians, the Center for Healthcare Education, CME Incite, France Foundation, MedEd, NACE, St. Luke’s Hospital, UpToDate, University of Virginia, American Thoracic Society, NCME, Projects in Knowledge, and MedScape/WebMD; (7) Service on a DSMB for Novartis.
Dr. O’Neal reports salary support (other than for SPIROMICS) paid to her institution by the NIH.
Dr. Paine reports research grants (other than for SPIROMICS) from NHLBI and the Department of Veterans Affairs.
Dr. Peters reports (1) Service on advisory boards for AstraZeneca, Aerocrine, Airsonett AB, GlaxoSmithKline, Merck, Targacept, and TEVA; (2) Payment for lectures from Merck, and Integrity Continuing Education; (3) Royalties from UpToDate.
Dr. Rennard reports (1) Grants to his institution from AstraZeneca, Biomarck, Centocor, Mpex, Nabi, Novartis, Otsuka; (2) Consulting fees or honoraria from AstraZeneca, Novartis, and Otsuka; (3) Board memberships for Almirall, Novartis, Nycomed, and Pfizer; (4) Consultancies with Able Associates, Adelphi Research, APT Pharma/Britnall, Aradigm, AstraZeneca, Chiesi, CommonHealth, Consult Complete, COPDForum, Data Monitor, Decision Resource, Defined Health, Dey, Dunn Group, Easton Associates, Equinox, Gerson, GlaxoSmithKline, Infomed, KOL Connection, M. Pankove, MedaCorp, MDRx Financial, Mpex, Oriel Therapeutics, Otsuka, Pennside, ParmaVentures, Pharmaxis, Price Waterouse, Propagate, Pulmatrix, Reckner Associates, Recruiting Resources, Roche, Schlesinger Medical, Scimed, Sudler and Hennessey, TargeGen, Theravance, UBC, Uptake Medical, VantagePoint Management, Forest, Nycomed, Pearl, Sankyo, and Novartis; (5) Grants from AstraZeneca, Biomarck, Centocor, Mpex, Nabi, Novartis, Otsuka, Boehringer Ingelheim, and Nycomed; (6) Payment for lectures including service on speakers bureaus from AAAAI, American College of Osteopathic Physicians, Asan Medical Center, American Thoracic Society, AstraZeneca, California Society of Allergy, Convergent Health Solutions for Reviews and Trends in COPD, COPDFoundation, Creative Educational Concepts, Dey, Duke University, France Foundation, Information TV, University of Southern California - Los Angeles, Network for Continuing Education (CHARM), Novartis (Horsham), Nycomed, Otsuka, Pfizer, Sarasota Memorial Hospital, Spanish Thoracic Society, University of Washington, University of Alabama - Birmingham, University of Pittsburgh, University of British Columbia, University of California - Davis, and Sioux Falls VA; (7) Travel, accommodation and meeting expenses otehr than for SPIROMICS, from Amirall, AstraZeneca, Boehringer Ingelheim, California Allergy Society, Creative Educational Concept, France Foundation, GlaxoSmithKline, Information TV, Network for Continuing Education, Novartis, Nycomed, and Pfizer.
Dr. Sundar reports (1) Payment for lectures including service on speakers bureaus from Forest, and Boehringer Ingelheim; (2) Travel, accommodations and meeting expenses other than for SPIROMICS from Spiriva, and Forest; (3) Serving as an investigator for Gilead.
Dr. Tashkin reports (1) Board memberships with Sunovion, AstraZeneka, Novartis, and Mylan; (2) Consultancies with Sunovion, AstraZeneka, Novartis, and Mylan; (3) Grants from Boehringer-Ingelheim, Pearl Therapeutics, Sunovion, GlaxoSmithKline, Forest, and Pfizer; (4) Payment for lectures including service on speakers bureaus from Boehringer-Ingelheim, AstraZeneca, Forest, Novartis, Pfizer.
Dr. Wise reports (1) Consultancies with BIPI, GSK, Merck, Mylan, Sunovion, Spiration, Pulmonx, and Intermune; (2) Grants from BIPI, GSK, and Merck.
Dr. Woodruff reports consultancies with Boehringer-Ingelheim, Merck, Kalobios, and Medimmune.
All other authors report only contracts/grants from NHLBI to their institution for SPIROMICS and for travel to SPIROMICS meetings.
Contributor Information
David Couper, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Lisa M. LaVange, Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA (This work was performed while Dr. LaVange was at the University of North Carolina. She is now at the U.S. Food and Drug Administration (FDA).)
MeiLan Han, Division of Pulmonary & Critical Care, University of Michigan, Ann Arbor, MI, USA.
R. Graham Barr, Department of Medicine, Columbia University, New York, NY, USA.
Eugene Bleecker, Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, NC, USA.
Eric A. Hoffman, Department of Radiology, University of Iowa, Iowa City, IA, USA
Richard Kanner, Department of Internal Medicine/Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA.
Eric Kleerup, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Fernando J. Martinez, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
Prescott G. Woodruff, Division of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of California at San Francisco, San Francisco, CA, USA
Stephen Rennard, Division of Pulmonary, Critical Care, Sleep & Allergy; Department of Internal Medicine, University of Nebraska, Omaha, NE, USA.
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