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 R Anzueto, Vijay K T Alagappan, Shahid Siddiqui, Ludmyla Rekeda, Christopher J. Miller, Sofia Zetterstrand, Colin Reisner, Stephen I. Rennard

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

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 b2-agonist with or without a long-acting muscarinic antagonist (LAMA). Methods: In this 52-week, phase 4, double-blind, placebocontrolled 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 mg (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
Volume194
Issue number5
DOIs
StatePublished - Sep 1 2016

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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