Abstract
Rationale
There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD).
Objectives
To evaluate the efficacy of losartan, an angiotensin receptor blocker, to reduce emphysema progression.
Methods
The trial was a multicenter, randomized, placebo-controlled trial conducted between May 2017 and January 2021. Eligible participants were aged ⩾40 years, had moderate to severe airflow obstruction, ⩾10 pack-years of smoking, mild-moderate emphysema on high-resolution computed tomography, and no medical indication for or intolerance of angiotensin receptor blockers. Treatment with losartan 100 mg daily or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on high-resolution computed tomography over 48 weeks. Secondary outcomes included the St George’s Respiratory Questionnaire, the modified Medical Research Council dyspnea scale, the COPD Assessment Test, and the Physical Function–Short Form 20a.
Measurements and Main Results
A total of 220 participants were enrolled; 58% were men, 19% were African American, and 24% were current smokers. The medians (interquartile ranges) for age were 65 (61–73) years and 48 (36–59) for percent predicted FEV1 after bronchodilator use. The mean (95% confidence interval) percentage emphysema progression was 1.35% (0.67–2.03) in the losartan group versus 0.66% (0.09–1.23) in the placebo group (P = NS).
Conclusions
Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema.
Clinical trial registered with www.clinicaltrials.gov (NCT02696564).
Keywords: emphysema, angiotensin receptor blocker, clinical trial, losartan, quantitative image analysis
At a Glance Commentary
Scientific Knowledge on the Subject
Human observational and pilot studies have suggested that angiotensin receptor blockers may prevent progression of emphysema in cigarette smokers with chronic obstructive pulmonary disease. Experimental studies have shown that angiotensin receptor blockers prevent emphysema in smoke-exposed mice. Accordingly, we conducted a randomized clinical trial of losartan in people with emphysema to determine if it prevented emphysema progression over 1 year.
What This Study Adds to the Field
We did not find a significant reduction in emphysema progression in patients treated with losartan compared with placebo. Losartan did not prevent the progression of emphysema. Losartan was well tolerated but is not an effective treatment in patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease comprising chronic bronchitis and emphysema and is a major cause of morbidity and mortality (1). Smoking cessation slows the progression of the disease, and bronchodilators can provide sustained improvement in lung function, but there are no pharmacologic agents that clearly modify emphysema progression (2–5).
Angiotensin receptor blockers (ARBs) have been suggested as potential drugs to slow the progression of COPD. Mancini and colleagues found reduced mortality and hospitalization in ARB-treated patients with COPD (6, 7). Andreas and colleagues found that 4 months of ARB treatment tended to improve airflow limitation, hyperinflation, and air trapping on pulmonary function testing (8). The COPDGene (COPD Genetic Epidemiology) study found that patients treated with ARBs had slower progression of radiographic emphysema and lower rates of lung function decline (9).
Evidence suggests that ARBs have pharmacologic effects that may explain these findings. Angiotensin-1 receptors in lung tissue are involved in the apoptosis of alveolar epithelial cells, which is a mechanism proposed to lead to the progression of emphysema (10, 11). The effect on lung remodeling by angiotensin-1 receptor activation is mediated by transforming growth factor-β (TGF-β). Fibrillin-deficient mice develop emphysema because of TGF-β signaling, which can be prevented or reversed by the ARB losartan (12, 13). Moreover, mice exposed to cigarette smoke develop TGF-β–mediated emphysema that can be inhibited and reversed by ARBs (14). In a pilot study of losartan, the subgroup of participants with COPD with emphysema randomly assigned to receive losartan had less radiographic progression at 1 year than participants assigned to placebos (P = 0.06) (www.clinicaltrials.gov identifier NCT00720226) (15).
Accordingly, we conducted a placebo-controlled, randomized clinical trial to test the hypothesis that the ARB losartan would reduce the progression of emphysema in patients with COPD with mild to moderate emphysema assessed by high-resolution computed tomography (HRCT). Secondary outcomes included symptoms and quality of life. Adverse events that were monitored included acute exacerbations of COPD.
Methods
The study design has been published, and the protocol is included as an online supplement (16). The trial was registered with www.clinicaltrials.gov (NCT02696564), approved by local institutional review boards, and monitored by an independent data monitoring board. The study was a collaboration between the American Lung Association Airways Clinical Research Centers and the NIH-NHLBI Pulmonary Trials Cooperative.
The study was a two-group, parallel, randomized, placebo-controlled trial (see Figure E1 in the online supplement). Participants had visits every 12 weeks (Table E1). The study was conducted between May 2017 and January 2021.
The primary outcome measure was the change in quantitative whole-lung emphysema score after 48 weeks measured by the percentage of lung voxels less than −950 Hounsfield units (PCT950) on full inspiratory HRCT (17).
Secondary outcome measures included the St. George’s Respiratory Questionnaire (0–100, full scale; minimal important difference [MID], 4) (18, 19), the modified Medical Research Council dyspnea scale (0–4 full scale; MID, 1) (20, 21), the COPD Assessment Test (0–40 full scale; MID, 2) (22, 23), and the Physical Function– Short Form 20a (0–100 full scale; MID, 2.5) (24, 25). FEV1 and FVC were measured (26).
Safety assessments included measurement of blood pressure and blood tests for electrolytes and renal function. COPD exacerbations were defined as two or more new or worse symptoms for ⩾3 days and classified by treatment as mild (neither antibiotics nor oral steroids), moderate (an antibiotic or oral steroid), or severe (hospitalization).
The main inclusion criteria were age ⩾40 years; stable moderate to severe COPD, defined by FEV1/FVC ratio ⩽0.70 and FEV1 20–80% of predicted; current or former smoker with ⩾10 pack-years of exposure; and an inspiratory HRCT scan with mild to moderate emphysema (PCT950, 5–35%). The main exclusion criteria were current therapy with, an indication for or known intolerance of angiotensin-converting enzyme inhibitors or ARBs, history of angioedema, or renal insufficiency.
Participants were randomly assigned (1:1) to receive losartan or placebo according to a randomization schedule stratified by clinical center. Treatments were blinded and distributed in bottles containing capsules with losartan 50 mg or matching placebo. The dose was one capsule daily for 2 weeks, and, if well tolerated and the systolic blood pressure was >90 mm Hg, it was increased to two capsules (100 mg or placebo). Participants and site investigators were masked to treatment assignment.
Baseline characteristics were described with medians and interquartile ranges (IQRs), or proportions. Analyses were performed according to treatment assignment (intention to treat). Generalized linear mixed models (GLMMs) with covariates including site, baseline value, and treatment group were used to evaluate primary and secondary outcomes. The primary analysis of the difference between treatment groups was estimated by comparing the between-group least-squares means of changes in PCT950. Statistical differences were inferred if the 95% confidence intervals (CIs) did not include zero. A multivariate GLMM with Bonferroni correction for multiplicity was used to compare change in PCT950 across the five lung lobes.
Treatment effects in protocol-defined subgroups were evaluated using GLMMs with interaction terms with treatment. Rates of COPD exacerbations were analyzed by negative binomial regression (27). Analyses were performed using SAS 9.4 and R 4.1.1 software. The sample size of 220 participants provided 90% power with a two-sided type I error of 5% for a minimum detectable difference in the change in PCT950 of 2%, assuming an SD of 4% and 20% loss of data (15, 28).
Results
The LEEP (Losartan Effects on Emphysema Progression) trial was conducted between May 2017 and January 2021 at 17 clinical sites in the United States; 2,799 individuals were evaluated, and 220 participants were enrolled (16). Disposition of potential participants and follow-up are shown in Figure 1. HRCT scans were obtained at baseline and at the 48-week visit for 202 participants. Nine participants were excluded from the analysis because of technical problems with the acquisition or measurement of their 48-week scan. Patient-reported outcomes were obtained in 92% of participants at the final visit. Because of coronavirus disease (COVID-19) pandemic restrictions, final visit spirometry was obtained in only 71% of participants, and in-person HRCT scans were delayed at some sites.
Figure 1.
Participant flow diagram. HRCT = high-resolution computed tomography.
Participant characteristics were similar between treatment groups (Table 1). Overall, the median (IQR) age was 65 (61–73) years; 58% were male, 19% were Black/African American, and 24% were current smokers. The median (IQR) post-bronchodilator FEV1 percent predicted was 47% (36–59).
Table 1.
Participant Characteristics at Baseline
| Characteristic | Total (N = 220) |
Placebo (n = 112) |
Losartan (n = 108) |
|---|---|---|---|
| Age, yr, median (IQR) | 65 (61–73) | 65 (61–71) | 66 (63–74) |
| BMI, kg/m2, median (IQR) | 26 (23–29) | 26 (23–28) | 27 (22–31) |
| Male sex, n (%) | 127 (58%) | 66 (59%) | 61 (56%) |
| Race, n (%)* | |||
| Black or African American | 42 (19%) | 23 (21%) | 19 (18%) |
| White | 176 (80%) | 88 (79%) | 88 (81%) |
| Smoking status, n (%) | |||
| Current (past mo) | 52 (24%) | 26 (23%) | 26 (24%) |
| Pack-years | 44 (34–58) | 42 (34–57) | 46 (35–60) |
| PCT950, median (IQR) | 15 (10–25) | 15 (10–25) | 17 (10–26) |
| Spirometry, median (IQR) | |||
| Pre-BD not available, n (%) | 19 (9%) | 8 (7%) | 11 (10%) |
| Pre-BD % predicted FEV1 | 43 (33–55) | 43 (31–54) | 43 (33–57) |
| Pre-BD FEV1 (L) | 1.1 (0.9–1.5) | 1.1 (0.8–1.5) | 1.1 (0.9–1.5) |
| Post-BD % predicted FEV1 | 48 (36–59) | 48 (35–59) | 48 (37–61) |
| Sitting blood pressure, mm Hg, median (IQR) | |||
| Systolic | 124 (113–133) | 123 (111–134) | 125 (116–133) |
| Diastolic | 76 (70–81) | 75 (68–81) | 77 (72–81) |
| SGRQ score (⬇ 0–100)†, median (IQR) | |||
| Total | 42 (28–55) | 40 (26–61) | 42 (30–52) |
| Symptoms | 55 (39–72) | 56 (37–73) | 55 (39–71) |
| Activity | 59 (46–72) | 59 (43–79) | 59 (46–66) |
| Impact | 27 (14–42) | 26 (14–45) | 28 (14–41) |
| CAT score (⬇ 0–40)†, median (IQR) | 17 (12–23) | 16 (11–25) | 17 (13–22) |
| Impact level, n (%) | |||
| Low | 47 (21%) | 26 (23%) | 21 (19%) |
| Medium | 97 (44%) | 45 (40%) | 52 (48%) |
| High | 68 (31%) | 33 (29%) | 35 (32%) |
| Very high | 8 (4%) | 8 (7%) | 0 (0%) |
| mMRC dyspnea scale (⬇ 0–4)†, median (IQR) | 1 (1–2) | 1 (1–2) | 1 (1–2) |
| PROMIS Physical Function–20a T-score (⬆)‡, median (IQR) | 40 (37–44) | 40 (36–44) | 40 (38–44) |
Definition of abbreviations: BD = bronchodilator; BMI = body mass index; CAT = COPD Assessment Test; IQR = interquartile range; mMRC = modified Medical Research Council; PCT950 = percentage of voxels less than −950 Hounsfield units; PROMIS = Patient-reported Outcomes Measurement Information System; SGRQ = St. George’s Respiratory Questionnaire.
Race was reported by the participants, who could choose more than one category.
Range of possible score and direction of improvement; ⬇= lower score indicates fewer symptoms.
Total raw scores on the PROMIS Physical Function–20a were converted to T-scores; ⬆= higher T-scores indicate better function.
At 48 weeks, the least-squares mean (95% CI) for the difference (losartan − placebo) in change in emphysema assessed by PCT950 was 0.69 (−0.21, 1.58) (i.e., slightly more progression in the losartan group (Figure 2, Table 2). The treatment effects were similar across the five lobes of the lung (Table E2). Subgroup analysis showed no significant interaction for subgroups defined by sex, race, severity of COPD, airflow limitations, or adherence. Former smokers assigned to losartan had more emphysema progression than current smokers assigned to placebo (Figure 2) (P value for interaction = 0.032). There were no treatment effects on measures of lung function, COPD Assessment Test score, or dyspnea score (Table 2). Participants assigned to losartan had more favorable changes in the St. George’s Respiratory Questionnaire and Physical Function–Short Form 20a during follow-up, but the magnitude of improvement was small, and the results of post hoc responder analyses were negative.
Figure 2.
Treatment effects on emphysema progression, overall and by subgroup. Treatment effects (difference in the change in PCT950) estimates are represented by squares and 95% confidence interval by the whiskers overall and by predefined subgroups: sex, smoking status, airflow limitation, and percentage emphysema at baseline. P values are for tests of interactions of subgroups with treatment assignment. CI = confidence interval; HU = Hounsfield units; LS = least squares; PCT950 = percentage of voxels less than −950 Hounsfield units.
Table 2.
Primary and Secondary Outcomes at 48 Weeks
| Placebo |
Losartan |
Losartan vs. Placebo | ||||
|---|---|---|---|---|---|---|
| No. | LS Mean (95% CI) | No. | LS Mean (95% CI) | Mean Difference (95% CI) | P Value* | |
| Primary outcome | ||||||
| Change from baseline in PCT950 | 99 | 0.66 (0.09, 1.23) | 94 | 1.35 (0.67, 2.02) | 0.69 (−0.21, 1.58) | 0.133 |
| Secondary outcomes | ||||||
| Change from baseline in pre-BD FEV1 % predicted | 56 | −0.54 (−2.47, 1.38) | 51 | −0.99 (−3.18, 1.20) | −0.45 (−3.37, 2.47) | 0.762 |
| Change from baseline in post-BD FEV1 % predicted | 73 | −2.37 (−3.71, −1.03) | 73 | −2.60 (−4.22, −0.98) | −0.23 (−2.38, 1.92) | 0.834 |
| Change from baseline in CAT score | 104 | 0.03 (−1.04, 1.09) | 99 | −0.18 (−1.21, 0.85) | −0.21 (−1.73, 1.30) | 0.783 |
| Change from baseline in SGRQ score | ||||||
| Total | 103 | 1.20 (−0.68, 3.08) | 99 | −1.31 (−3.15, 0.52) | −2.51 (−5.05, 0.03) | 0.053 |
| Symptoms | 103 | −1.78 (−4.04, 0.49) | 99 | −6.19 (−8.76, −3.62) | −4.41 (−8.00, −0.83) | 0.016 |
| Activity | 103 | 2.45 (−0.10, 5.00) | 99 | −0.66 (−3.22, 1.91) | −3.11 (−6.41, 0.20) | 0.065 |
| Impact | 103 | 1.35 (−0.67, 3.38) | 99 | −0.25 (−2.46, 1.96) | −1.60 (−4.59, 1.38) | 0.293 |
| Change from baseline in mMRC dyspnea scale | 103 | 0.11 (−0.03, 0.26) | 99 | 0.01 (−0.15, 0.16) | −0.11 (−0.33, 0.12) | 0.356 |
| Change from baseline in PROMIS-20a T-score | 102 | −1.04 (−1.62, −0.45) | 99 | 0.00 (−0.59, 0.59) | 1.04 (0.26, 1.82) | 0.009 |
Definition of abbreviations: BD = bronchodilator; CAT = COPD Assessment Test; CI = confidence interval; LS = least squares; mMRC = modified Medical Research Council; PCT950 = percentage of lung voxels less than −950 Hounsfield units; PROMIS = Patient-reported Outcomes Measurement Information System; SGRQ = St. George’s Respiratory Questionnaire.
P value based on generalized linear mixed models with covariates for site, baseline value, and treatment group.
The number of severe COPD exacerbations associated with a hospitalization was numerically lower in the losartan group than in the placebo group (7 vs. 21; incidence rate ratio [95% CI], 0.36 [0.02–6.51]) (Table 3). However, the difference was not statistically significant.
Table 3.
Chronic Obstructive Pulmonary Disease Exacerbations, by Severity and Treatment Assignment
| Treatment Assignment |
||||
|---|---|---|---|---|
| Placebo | Losartan | RR* (Los/Plb) (95% CI) | P Value* | |
| No. | 112 | 106 | ||
| Follow-up d, median (IQR) | 336 (329–344) | 336 (329–343) | ||
| Moderate exacerbation | ||||
| No. of events | 47 | 41 | ||
| Rate, events/100 person-years | 48.2 | 43.7 | 0.91 (0.05–14.97) | 0.946 |
| Participants with ⩾1 event, n (%) | 30 (27%) | 26 (25%) | ||
| Severe exacerbation | ||||
| No. of events | 21 | 7 | ||
| Rate, events/100 person-years | 21.4 | 7.7 | 0.36 (0.02–6.51) | 0.487 |
| Participants with ⩾1 event, n (%) | 15 (13%) | 7 (7%) | ||
Definition of abbreviations: CI = confidence interval; IQR = interquartile range; Los = losartan; Plb = placebo; RR = relative rate.
Relative rates and P values are based on negative binomial model.
Serious adverse events were reported for 18 participants assigned to losartan compared with 25 in the placebo group (Table E3). The most common events were hospitalizations for a pulmonary problem, most frequently a COPD exacerbation: 13 pulmonary events involving 13 participants in the losartan group and 30 pulmonary events among 21 participants in the placebo group. There were three deaths during the treatment period: one in the losartan group and two in the placebo group.
Seventeen participants could not tolerate titration of study drug up to two capsules because of low blood pressure: 11 in the losartan group and 6 in the placebo group. Six participants assigned to losartan who initially had their dose increased to 100 mg subsequently had the dose reduced to 50 mg because of low blood pressure (n = 2) or dizziness (n = 4). One participant in the placebo group had the dose reduced because of low blood pressure.
Most participants terminated the study treatment at the end of the study: 90 (83%) in the losartan arm and 102 (91%) in the placebo group. More participants assigned to losartan stopped the study drug early (16 vs. 9); however, adverse effects leading to drug discontinuation were similar between groups (9 vs. 7) (Table E4). Adherence, defined as consumption of 80% or more of the prescribed dose by pill counts, was 75% of participants in both groups.
Discussion
The main finding of this randomized controlled trial is that losartan does not prevent progression of emphysema in patients with COPD who have mild to moderate pulmonary emphysema. Nonadherence was unlikely to explain the negative result insofar as a sensitivity analysis of participants who consumed >80% of prescribed treatment also showed no benefit.
The null primary study outcome may be the result of a slower progression of emphysema than we found in our pilot study (2.18% in the placebo group vs. 0.32% in the losartan group; P = 0.06), so there was little opportunity for a substantial reduction in emphysema progression with losartan. Regardless of this, the greater progression of emphysema in the active treatment arm does not suggest a beneficial treatment effect, and an emphysema trial limited to current smokers or a larger or longer-duration trial does not seem warranted.
There may, however, be other treatment effects of losartan that this study was not designed to detect. Of note, the losartan group had significant improvements in patient-reported outcomes measuring health-related quality of life as compared with the placebo group (Table 2). Moreover, there was a reduction in hospitalized COPD exacerbations in the losartan group that did not reach statistical significance (Table 3). This is consistent with the findings of Mancini and colleagues, who found a 14% reduction in hospitalizations for patients with COPD with low cardiac risk (6). However, there were no differences in the rate of moderate exacerbations. Thus, these findings are of uncertain clinical relevance but raise the question whether there might be an effect of ARBs on COPD exacerbations. Database studies have demonstrated that use of ARBs and angiotensin-converting enzyme inhibitors are associated with lower risk of viral infection, but a recent trial indicates that losartan is not effective in the treatment of hospitalized patients with COVID-19 (29, 30). It is puzzling why there would be an effect only on severe exacerbations and not those of less severity. One explanation for this paradox, as well as the improvement in quality of life, might be related to prevention or amelioration of cardiovascular complications associated with COPD exacerbations.
There was a qualitative treatment interaction for smoking status. In former smokers, losartan was associated with more emphysema progression than in current smokers. Because no subgroup showed a clear benefit from losartan and because there are no practical therapeutic implications for this finding, these subgroup differences should be interpreted with caution.
Strengths and Limitations
This trial has several strengths. It was a rigorously designed, double-masked trial conducted at multiple sites under the joint sponsorship of the American Lung Association and the NIH/NHLBI and with the support of the Pulmonary Trials Cooperative Network Coordinating Center. The primary outcome measure was objective and was evaluated by an independent masked image analysis core. The overall quality of the scans was high, and only nine (4%) of the scans did not meet quality standards for inclusion in the primary analysis. There was a substantial degree of adherence to treatment, as evidenced by pill counts in returned drug containers, with 75% of participants taking 80% or more of prescribed doses.
Despite the occurrence of the COVID-19 pandemic in the final year of the study, we had a high level of data completion for patient-reported outcomes (92%) as well as HRCT scans (92%). Because of the COVID-19 prohibition of research-related aerosol-generating procedures at some sites, we were not able to conduct spirometry during the final study year and had only 71% completion of that outcome measure.
In summary, on the basis of evidence acquired during the LEEP trial, there is no rationale to prescribe losartan to prevent progression of emphysema. Our results raise the possibility that losartan may be beneficial for some patients with COPD in terms of health-related quality of life and severe exacerbations, but these findings are not convincing.
Acknowledgments
American Lung Association Airways Clinical Research Centers and Pulmonary Trials Cooperative members:
Baylor College of Medicine, Houston, TX: Nicola Hanania, M.D. (principal investigator); Marianna Sockrider, M.D., Dr.P.H. (co–principal investigator); Laura Bertrand, R.N., R.P.F.T. (lead clinic coordinator); Mustafa Atik, M.D. (coordinator)
Columbia University, New York, NY: Emily DiMango, M.D. (principal investigator); Tarnjot Saroya (lead clinic coordinator)
New York University, New York, NY: Joan Reibman, M.D. (principal investigator); Karen Carapetyan, M.A. (lead clinic coordinator)
Weill Cornell Medicine, New York, NY: Robert J. Kaner, M.D. (principal investigator); Fernando J. Martinez, M.D., M.S.; Xiaoping Wu, M.D., M.S. (coinvestigators); Alicia J. Morris (lead clinic coordinator); Elizabeth M. Peters, B.S.N., R.N.; Matthew Marcelino (coordinators)
Duke University Health System, Durham, NC: Loretta G. Que, M.D. (principal investigator); Anne Mathews, M.D.; Devon Paul, M.D., M.Sc.-G.H.; Isaretta Riley, M.D., M.P.H.; Timothy Scialla, M.D. (coinvestigators); Catherine Foss, B.S., R.R.T., R.P.F.T., C.C.R.C. (lead clinic coordinator); Antoinette Santoro, M.S., R.R.T.; Eli Morgan; Erika Coleman (coordinators); Duke Early Phase Research Unit
Northwestern University, Chicago, IL: Ravi Kalhan, M.D. (principal investigator); Sharon Rosenberg, M.D., Lewis Smith, M.D. (coinvestigators); Jenny Hixon, B.S., C.C.R.C. (lead clinic coordinator)
University of Chicago, Chicago, IL: Edward Naureckas, M.D. (principal investigator); Virginia Zagaja (lead clinic coordinator)
University of Illinois at Chicago, Chicago, IL: Jerry Krishnan, M.D., Ph.D. (principal investigator); Valentin Prieto-Centurion, M.D. (coinvestigator); Lourdes Norwick, B.S.N., R.N. (lead clinic coordinator); Aileen Baker; Lauren Castro, M.S.N., A.P.N.; Julie DeLisa; Wendy Hasse; Sai Illendula (coordinators)
Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL: James Moy, M.D. (principal investigator); Christopher Codispoti, M.S., M.D.; Byung Yu, M.D. (coinvestigators); Ben Xu, B.S., C.C.R.C. (lead clinic coordinator)
Louisiana State University Health Sciences Center–New Orleans, Section of Pulmonary & Critical Care/Allergy & Immunology, New Orleans, LA: Kyle Happel, M.D. (principal investigator); Matthew Lammi, M.D.; Richard Tejedor, M.D.; Sarah Jolley, M.D., M.Sc. (coinvestigators); Connie Romaine (lead clinic coordinator)
National Jewish Health, Denver, CO: Barry J. Make, M.D. (principal investigator); Flavia Hoyte, M.D. (coinvestigator); Jennifer Underwood, C.C.R.C. (lead clinic coordinator)
Mount Sinai Health System, New York, NY: Linda Rogers, M.D. (principal investigator); Sonali Bose, M.D., M.P.H.; Sidney Braman, M.D.; Jessica Harris, N.P.; Gwen Skloot, M.D. (coinvestigators); Chelsea Chung (lead clinic coordinator); Deelan Ayhan (clinic coordinator)
Former member: Diana Valerio, B.S., C.C.R.C.
University of Florida Health Jacksonville, Jacksonville, FL: James Cury, M.D. (principal investigator); Vandana Seeram, M.D. (coinvestigator); Fallon Wainwright, B.S. (lead clinic coordinator); Katrina Maloney (clinic coordinator)
St. Louis Asthma Clinical Research Center: Washington University, St. Louis, MO: Kaharu Sumino, M.D. (principal investigator); Brenda Patterson, M.S.N., R.N. (lead clinic coordinator)
Former members: Mario Castro, M.D., M.P.H.; Leonard B. Bacharier, M.D.; Jaime J. Tarsi, R.N., M.P.H.
University of Kansas Medical Center, Kansas City, KS: Mario Castro, M.D., M.P.H. (principal investigator); Vanessa Curtis (lead clinic coordinator)
St. Vincent Hospital and Health Care Center, Inc., Indianapolis, IN: Michael Busk, M.D., M.P.H. (principal investigator); Ellen Looney, B.S. (lead clinic coordinator)
Vermont Lung Center at the University of Vermont, Colchester, VT: David A. Kaminsky, M.D. (principal investigator); Anne E. Dixon, M.D.; Charles Irvin, Ph.D. (coinvestigators); Erika Gonyaw (lead clinic coordinator)
Former members: Stephanie Burns, Kathy Meehan
Western Connecticut Health Network/Nuvance Health, Danbury, CT: Douglas Kahn, D.O., John Chronakos, M.D. (co–principal investigators); Guillermo Ballarino, M.D.; Loren Inigo-Santiago, M.D.; Sakshi Sethi, M.D.; Thomas Botta, M.D. (coinvestigators); Margaret Mukwaya (lead clinic coordinator)
Pacific Northwest Airways, Seattle, WA: Laura Feemster, M.D. (principal investigator); David Au, M.D., M.S.; Lucas Donovan, M.D., M.S. (coinvestigators); Amber Lane (lead clinic coordinator)
Former members: Ed Udris
Temple Lung Center, Philadelphia, PA: Gerard J. Criner, M.D. (principal investigator); Helga Criner (lead clinic coordinator)
University of Pittsburgh, Pittsburgh, PA: Divay Chandra, M.D. (principal investigator); Craig Riley, M.D.; Jessica Bon Field, M.D. (coinvestigators); Elizabeth Stempkowski, C.C.R.C. (lead clinic coordinator)
University of Alabama at Birmingham, Birmingham, AL: Mark T. Dransfield, M.D. (principal investigator); Surya Bhatt, M.D.; Anand Iyer, M.D., M.S.P.H.; Taku Mkorombindo, M.D.; James Wells, M.D. (coinvestigators); Necole Harris (lead clinic coordinator)
University of Arizona, Tucson, AZ: Lynn B. Gerald, Ph.D., M.S.P.H. (principal investigator); Monica Kraft, M.D.; Afshin Sam, M.D. (coinvestigators); Michele Simon (lead clinic coordinator)
Former members: Natalie S. Provencio-Dean
University of California, San Diego, San Diego, CA: Amber J. Martineau (lead clinic coordinator)
Former members: Joe Ramsdell, M.D.; Xavier Soler, M.D.
University of California, San Francisco, San Francisco, CA: Stephen C. Lazarus, M.D. (principal investigator); Prescott Woodruff, M.D., M.P.H. (coinvestigator); Julian Silva (lead clinic coordinator)
University of Michigan, Ann Arbor, MI: MeiLan Han, M.D., M.S. (principal investigator); Catherine Meldrum, R.N., Ph.D.; Wassim Labaki, M.D. (coinvestigators); Gretchen Bautista (lead clinic coordinator); Kelly Rysso; Crystal Cutlip (clinic coordinators)
University of South Florida, Tampa, FL: Thomas B. Casale, M.D. (principal investigator); Juan Carlos Cardet, M.D.; Claudia Gaefke, M.D.; Dennis Ledford, M.D.; Richard Lockey, M.D.; Amber Pepper, M.D.; Shiven Patel, M.D.; Tara Saco, M.D.; Kirk Shepard, M.D.; Raul Villarreal, M.D.; Emma Westerman, M.D. (coinvestigators); Catherine Renee Smith (lead clinic coordinator)
Chairman’s Office, University of Alabama at Birmingham, Birmingham, AL: William C. Bailey, M.D.
Data Coordinating Center, Johns Hopkins University Center for Clinical Trials, Baltimore, MD: Robert A. Wise, M.D. (center director); Janet T. Holbrook, Ph.D., M.P.H. (deputy director); Alexis Rea, M.P.H. (lead coordinator); Anne Shanklin Casper, M.A.; Jiaxin He, M.S.; Robert J. Henderson, M.S.; Andrea Lears, B.S.; Jill Meinert; David Shade J.D.; Emily Szilágyi
Former members: Joy Saams, R.N.; Ashley McCook, M.S.; Robert J. Henderson, M.S.
NHLBI Representative: Dong-Yun Kim, Ph.D.
Data Safety and Monitoring Board: Andrew H. Limper, M.D. (chair); Gordon Bernard, M.D. (chair); Joao A. de Andrade, M.D.; Deborah R. Barnbaum, Ph.D.; Daren L. Knoell, Pharm.D.; Peter Lindenauer, M.D., M.Sc.; Irina Petrache, M.D.; Andre Rogatko, Ph.D.; Marinella Temprosa, Ph.D.
Footnotes
A complete list of American Lung Association Airways Clinical Research Centers and Pulmonary Trials Cooperative members may be found before the beginning of the References.
Supported by grants from the American Lung Association and the National Heart, Lung, and Blood Institute (U01HL128951 and U01HL128954).
Author Contributions: R.A.W., and J.T.H. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: E.R.N., R.A.W., and J.T.H., with advice from all authors. Acquisition, analysis, or interpretation of data: all of the authors and contributors. Initial drafting of the manuscript: R.A.W., and J.T.H. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: J.T.H., J.H., and R.J.H. Administrative, technical, or material support: R.H.B. Supervision: R.A.W., and J.T.H.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.202201-0206OC on April 30, 2022
Author disclosures are available with the text of this article at www.atsjournals.org.
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