Effect of roflumilast and inhaledcorticosteroid/long-acting b2-agonist on chronic obstructive pulmonary disease exacerbations (RE2SPOND): A randomized clinical trial

Fernando J. Martinez, Klaus F. Rabe, Sanjay Sethi, Emilio Pizzichini, Andrew McIvor, Antonio Anzueto, Vijay K.T. Alagappan, Shahid Siddiqui, Ludmyla Rekeda, Christopher J. Miller, Sofia Zetterstrand, Colin Reisner, Stephen I. Rennard

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98 Scopus citations


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 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 b2-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.

Original languageEnglish (US)
Pages (from-to)559-567
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number5
StatePublished - Sep 1 2016


  • Bronchodilators
  • Clinical trial
  • Hospitalization
  • Phosphodiesterase-4 inhibitor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine


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