The clinical trial of Towards a Revolution in COPD Health (TORCH) has previously compared salmeterol (long acting beta-2 selective adrenergic agonist [LABA] bronchodilator) plus fluticasone (steroid), administered as a single inhaler, with placebo over a 3-year period in 6,112 participants with a mean age of 65 years and moderate-to-severe chronic obstructive pulmonary disease (COPD). The primary outcome was all-cause mortality, but the treatment effect did not meet the predetermined level of statistical significance. We note, however, that the TORCH trial established COPD and its severity based on spirometric criteria from the Global initiative for chronic Obstructive Lung Disease (GOLD). The latter criteria increasingly misidentify COPD in aging populations, starting at ages >45-50 years. As an alternative approach, spirometric Z-scores that are calculated from reference equations by the Global Lung Initiative (GLI) rigorously account for age- related changes in lung function and are associated with important health outcomes. Hence, using existing high-quality data, we propose to reclassify lung function in the TORCH trial by using (GLI-calculated) spirometric Z-scores. We will then evaluate the consequence of the misidentification of moderate-to-severe COPD, as an additional covariate, on the primary outcome of all-cause mortality, as well as on the secondary outcomes of exacerbations, health status, lung function, and adverse events, comparing salmeterol plus fluticasone to placebo over a 3-year period (study population and randomization is maintained). We will also redefine the TORCH study population as including only those participants with spirometric Z-score defined moderate-to-severe COPD. Although this latter approach loses the benefits of randomization, it will evaluate the associations of salmeterol plus fluticasone with the same outcomes, relative to placebo, but with results specific to spirometric Z-score defined moderate-to-severe COPD. Lastly, to further assess bronchodilator therapy, we propose to additionally evaluate tiotropium, a long acting muscarinic antagonist [LAMA] bronchodilator, using existing data from the UPLIFT trial (N=5993, mean age 65 years, GOLD defined moderate-to-severe COPD, 4-year study) and including similar analyses as above.

Public Health Relevance

Clinical trials of pharmacotherapy in chronic obstructive pulmonary disease (COPD) often include aging populations and diagnostic algorithms that are based on spirometric criteria from the Global initiative for chronic Obstructive Lung Disease (GOLD). Because GOLD criteria increasingly misidentify COPD starting at ages >45-50 years, we propose to reclassify lung function in two major trials of COPD pharmacotherapy (mean age 65 years) by using age-appropriate spirometric criteria from the Global Lung Initiative. Our research may show that that COPD pharmacotherapy will have greater efficacy and less adverse events, as well as a more definitive indication across the spectrum of patient care, after accounting for the age-related misidentification of moderate-to-severe COPD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Research Grants (R03)
Project #
5R03AG057450-02
Application #
9601617
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Salive, Marcel
Project Start
2017-12-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Fragoso, Carlos A Vaz; Gill, Thomas M; Leo-Summers, Linda S et al. (2018) Spirometric Criteria for Chronic Obstructive Pulmonary Disease in Clinical Trials of Pharmacotherapy. COPD 15:17-20