title: Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting β2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial.
abstract: Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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: 1 Weill Cornell University, New York, New York.
authors: Fernando J
authors: FJ
authors: Martinez
authors: 2 LungenClinic Grosshansdorf, Großhansdorf, Germany.|3 Department of Medicine of University Kiel, Kiel, Germany.|4 Airway Research Center North of the German Center for Lung Research, Großhansdorf, Germany.
authors: Klaus F
authors: KF
authors: Rabe
authors: 5 University at Buffalo, State University of New York, Buffalo, New York.
authors: Sanjay
authors: S
authors: Sethi
authors: 6 Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
authors: Emilio
authors: E
authors: Pizzichini
authors: 7 McMaster University, Firestone Institute of Respiratory Health, St. Joseph's Healthcare, Ontario, Canada.
authors: Andrew
authors: A
authors: McIvor
authors: 8 University of Texas Health Science Center, San Antonio, Texas.|9 South Texas Veterans Health Care System at San Antonio, San Antonio, Texas.
authors: Antonio
authors: A
authors: Anzueto
authors: 10 AstraZeneca, Gaithersburg, Maryland.
authors: Vijay K T
authors: VK
authors: Alagappan
authors: 10 AstraZeneca, Gaithersburg, Maryland.
authors: Shahid
authors: S
authors: Siddiqui
authors: 11 Allergan plc, Jersey City, New Jersey.
authors: Ludmyla
authors: L
authors: Rekeda
authors: 10 AstraZeneca, Gaithersburg, Maryland.
authors: Christopher J
authors: CJ
authors: Miller
authors: 12 AstraZeneca, Gothenburg, Sweden.
authors: Sofia
authors: S
authors: Zetterstrand
authors: 13 AstraZeneca, Morristown, New Jersey.
authors: Colin
authors: C
authors: Reisner
authors: 14 University of Nebraska Medical Center, Omaha, Nebraska; and.|15 AstraZeneca, Cambridge, United Kingdom.
authors: Stephen I
authors: SI
authors: Rennard
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000627:therapeutic use; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000627:therapeutic use; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D029481:Bronchitis, Chronic / Q000188:drug therapy* / Q000209:etiology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy*; D012138:Respiratory Therapy / Q000379:methods; D012720:Severity of Illness Index
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D000631:Aminopyridines; D001549:Benzamides; D001993:Bronchodilator Agents; D003521:Cyclopropanes; D018727:Muscarinic Antagonists; C424423:Roflumilast
keywords: bronchodilators; clinical trial; hospitalization; phosphodiesterase-4 inhibitor