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Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial.
Am J Respir Crit Care Med. 2016 09 01; 194(5):559-67.AJ

Abstract

RATIONALE

Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease.

OBJECTIVES

To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting β2-agonist with or without a long-acting muscarinic antagonist (LAMA).

METHODS

In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting β2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 μg (n = 1,178), or placebo (n = 1,176). Stratification was based on LAMA use.

MEASUREMENTS AND MAIN RESULTS

Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; P = 0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants.

CONCLUSIONS

Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).

Authors+Show Affiliations

1 Weill Cornell University, New York, New York.2 LungenClinic Grosshansdorf, Groβhansdorf, Germany. 3 Department of Medicine of University Kiel, Kiel, Germany. 4 Airway Research Center North of the German Center for Lung Research, Groβhansdorf, Germany.5 University at Buffalo, State University of New York, Buffalo, New York.6 Universidade Federal de Santa Catarina, Santa Catarina, Brazil.7 McMaster University, Firestone Institute of Respiratory Health, St. Joseph's Healthcare, Ontario, Canada.8 University of Texas Health Science Center, San Antonio, Texas. 9 South Texas Veterans Health Care System at San Antonio, San Antonio, Texas.10 AstraZeneca, Gaithersburg, Maryland.10 AstraZeneca, Gaithersburg, Maryland.11 Allergan plc, Jersey City, New Jersey.10 AstraZeneca, Gaithersburg, Maryland.12 AstraZeneca, Gothenburg, Sweden.13 AstraZeneca, Morristown, New Jersey.14 University of Nebraska Medical Center, Omaha, Nebraska; and. 15 AstraZeneca, Cambridge, United Kingdom.

Pub Type(s)

Clinical Trial, Phase IV
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27585384

Citation

Martinez, Fernando J., et al. "Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist On Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). a Randomized Clinical Trial." American Journal of Respiratory and Critical Care Medicine, vol. 194, no. 5, 2016, pp. 559-67.
Martinez FJ, Rabe KF, Sethi S, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. Am J Respir Crit Care Med. 2016;194(5):559-67.
Martinez, F. J., Rabe, K. F., Sethi, S., Pizzichini, E., McIvor, A., Anzueto, A., Alagappan, V. K., Siddiqui, S., Rekeda, L., Miller, C. J., Zetterstrand, S., Reisner, C., & Rennard, S. I. (2016). Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. American Journal of Respiratory and Critical Care Medicine, 194(5), 559-67. https://doi.org/10.1164/rccm.201607-1349OC
Martinez FJ, et al. Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist On Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). a Randomized Clinical Trial. Am J Respir Crit Care Med. 2016 09 1;194(5):559-67. PubMed PMID: 27585384.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial. AU - Martinez,Fernando J, AU - Rabe,Klaus F, AU - Sethi,Sanjay, AU - Pizzichini,Emilio, AU - McIvor,Andrew, AU - Anzueto,Antonio, AU - Alagappan,Vijay K T, AU - Siddiqui,Shahid, AU - Rekeda,Ludmyla, AU - Miller,Christopher J, AU - Zetterstrand,Sofia, AU - Reisner,Colin, AU - Rennard,Stephen I, PY - 2016/9/2/entrez PY - 2016/9/2/pubmed PY - 2017/7/20/medline KW - bronchodilators KW - clinical trial KW - hospitalization KW - phosphodiesterase-4 inhibitor SP - 559 EP - 67 JF - American journal of respiratory and critical care medicine JO - Am J Respir Crit Care Med VL - 194 IS - 5 N2 - RATIONALE: Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease. OBJECTIVES: To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting β2-agonist with or without a long-acting muscarinic antagonist (LAMA). METHODS: In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting β2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 μg (n = 1,178), or placebo (n = 1,176). Stratification was based on LAMA use. MEASUREMENTS AND MAIN RESULTS: Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; P = 0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants. CONCLUSIONS: Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845). SN - 1535-4970 UR - https://www.unboundmedicine.com/medline/citation/27585384/Effect_of_Roflumilast_and_Inhaled_Corticosteroid/Long_Acting_β2_Agonist_on_Chronic_Obstructive_Pulmonary_Disease_Exacerbations__RE_2_SPOND___A_Randomized_Clinical_Trial_ L2 - https://www.atsjournals.org/doi/10.1164/rccm.201607-1349OC?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -