{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:33:49Z","timestamp":1790094829888,"version":"4.0.1"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100005632","name":"Forest Laboratories","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>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 \u03b22-agonist with or without a long-acting muscarinic antagonist (LAMA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this 52-week, phase 4, double-blind, placebo-controlled RE2SPOND (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 \u03b22-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 \u03bcg (n\u2009=\u20091,178), or placebo (n\u2009=\u20091,176). Stratification was based on LAMA use.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>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\u20131.04; P\u2009=\u20090.163). 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\u2013related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT01443845).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201607-1349oc","type":"journal-article","created":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T11:18:33Z","timestamp":1472728713000},"page":"559-567","source":"Crossref","is-referenced-by-count":110,"title":["Effect of Roflumilast and Inhaled Corticosteroid\/Long-Acting \u03b22-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE2SPOND): A Randomized Clinical Trial"],"prefix":"10.1093","volume":"194","author":[{"given":"Fernando J.","family":"Martinez","sequence":"first","affiliation":[{"name":"Weill Cornell University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus F.","family":"Rabe","sequence":"additional","affiliation":[{"name":"LungenClinic Grosshansdorf, Gro\u00dfhansdorf, Germany"},{"name":"Department of Medicine of University Kiel, Kiel, Germany"},{"name":"Airway Research Center North of the German Center for Lung Research, Gro\u00dfhansdorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Sethi","sequence":"additional","affiliation":[{"name":"University at Buffalo, State University of New York, Buffalo, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Pizzichini","sequence":"additional","affiliation":[{"name":"Universidade Federal de Santa Catarina, Santa Catarina, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McIvor","sequence":"additional","affiliation":[{"name":"McMaster University, Firestone Institute of Respiratory Health, St. Joseph\u2019s Healthcare, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Anzueto","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center, San Antonio, Texas"},{"name":"South Texas Veterans Health Care System at San Antonio, San Antonio, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K. 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