Randomized trial of zileuton for treatment of COPD exacerbations requiring hospitalization
Prescott G Woodruff, Richard K Albert, William C Bailey, Richard Casaburi, John E Connett, John A D Cooper Jr, Gerard J Criner, Jeffrey L Curtis, Mark T Dransfield, Meilan K Han, Sarah M Harnden, Victor Kim, Nathaniel Marchetti, Fernando J Martinez, Charlene E McEvoy, Dennis E Niewoehner, John J Reilly, Kathryn Rice, Paul D Scanlon, Steven M Scharf, Frank C Sciurba, George R Washko, Stephen C Lazarus, Copd Clinical Research Network, Prescott G Woodruff, Richard K Albert, William C Bailey, Richard Casaburi, John E Connett, John A D Cooper Jr, Gerard J Criner, Jeffrey L Curtis, Mark T Dransfield, Meilan K Han, Sarah M Harnden, Victor Kim, Nathaniel Marchetti, Fernando J Martinez, Charlene E McEvoy, Dennis E Niewoehner, John J Reilly, Kathryn Rice, Paul D Scanlon, Steven M Scharf, Frank C Sciurba, George R Washko, Stephen C Lazarus, Copd Clinical Research Network
Abstract
Rationale: Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations.
Objective: We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization.
Methods: Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production.
Main findings: Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75 +/- 2.19 vs. 3.86 +/- 3.06 days for zileuton vs. placebo, p = 0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p = 0.63) despite a decline in urinary LTE(4) levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine -1.38 +/- 1.19 vs. 0.14 +/- 1.51, p < 0.0001) and 72 hours (-1.32 +/- 2.08 vs. 0.26 +/- 1.93, p<0.006). Adverse events were similar in both groups.
Principal conclusions: While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE(4) levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.
Trial registration: ClinicalTrials.gov NCT00493974.
Conflict of interest statement
DECLARATION OF INTEREST
SMS received a grant of $90,000 from Forrest Laboratories; JLC $10,001–$50,001 in capitation for a clinical trial from Boehringer Ingelheim; DEN received honoraria or advisory fees from Boehringer Ingelheim, Pfizer, AstraZeneca, GlaxoSmithKline, Nycomed, Forest Research Institute, Adams Respiratory Therapeutics, and Sepracor within the past 3 years. MTD has served on advisory boards and as a speaker for GlaxoSmithKline (<$10,000 in 2009) and Boehringer Ingelheim (<$5000 in 2009). He has received contracted research support from Aeris, Allegro, Altana/Nycomed/Forest, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Pfizer, and Roche. GJC Grant support: GlaxoSmithKline, Boehringer Ingelheim, Novartis, Respironics, Forest. Advisory groups: Dey, Boehringer Ingelheim, GlaxoSmithKline; MKH received Lecture Fees: GlaxoSmithKline, CSL Behring, Boehringer Ingelheim, Pfizer. Consulting: Novartis, Nycomed.
FJM has received speaking, consultancy and steering committee fees from GlaxoSmithKline and Nycomed. He has received speaking and consulting fees from Medimmune/Astra Zeneca, Boehringer Ingelheim (BI) and Schering. He has received consulting and steering committee fees from Actelion. He has received consulting and DSMB fees from Novartis. He has received consulting fees from Forest/Almirall, Roche, Bayer and HLS. He has received advisory board fees from Merck, Pearl, UBC, Mpex, Talecris, Comgenix, and Boom-Comm. He has received lecture fees from France Foundation, NACE, MedEd, Potomac, fb Communications, Pfizer, Vox Medic, the American Lung Association, WebMD, epocrates and HIT Global. He has received royalities from Associates in Medical Marketing, and Castle Connolly. He has received sponsored grants from the NIH. His institution has received sponsored grants from BI.
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Source: PubMed