title: Effects of roflumilast in COPD patients receiving inhaled corticosteroid/long-acting β2-agonist fixed-dose combination: RE(2)SPOND rationale and study design.
abstract: BACKGROUND
  Roflumilast, a once-daily, selective phosphodiesterase-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. The RE(2)SPOND study is examining whether roflumilast, when added to an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) fixed-dose combination (FDC), further reduces exacerbations. The methodology is described herein.
  
  
  METHODS
  In this Phase IV, multicenter, double-blind, placebo-controlled, parallel-group trial, participants were randomized 1:1 (stratified by long-acting muscarinic antagonist use) to receive roflumilast or placebo, plus ICS/LABA FDC, for 52 weeks. Eligible participants had severe COPD associated with chronic bronchitis, had two or more moderate-severe exacerbations within 12 months, and were receiving ICS/LABA FDC for ≥3 months. The primary efficacy measure is the rate of moderate or severe COPD exacerbations per participant per year. The secondary efficacy outcomes include mean change in prebronchodilator forced expiratory volume in 1 second (FEV1) over 52 weeks, rate of severe exacerbations, and rate of moderate, severe, or antibiotic-treated exacerbations. Additional assessments include spirometry, rescue medication use, the COPD assessment test, daily symptoms using the EXACT-Respiratory symptoms (E-RS) questionnaire, all-cause and COPD-related hospitalizations, and safety and pharmacokinetic measures.
  
  
  RESULTS
  Across 17 countries, 2,354 participants were randomized from September 2011 to October 2014. Enrollment goal was met in October 2014, and study completion occurred in June 2016.
  
  
  CONCLUSIONS
  This study will further characterize the effects of roflumilast added to ICS/LABA on exacerbation rates, lung function, and health of severe-very severe COPD participants at risk of further exacerbations. The results will determine the clinical benefits of roflumilast combined with standard-of-care inhaled COPD treatment.
authors: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; AstraZeneca, Cambridge, UK.
authors: Stephen I
authors: SI
authors: Rennard
authors: Joan and Sanford I Weill Department of Medicine, Weill Cornell University, New York, NY; Department of Internal Medicine, Michigan Health System, Ann Arbor, MI, USA.
authors: Fernando J
authors: FJ
authors: Martinez
authors: LungenClinic Grosshansdorf, Großhansdorf; Department of Medicine, University Kiel, Kiel; Airway Research Center North, German Center for Lung Research, Großhansdorf, Germany.
authors: Klaus F
authors: KF
authors: Rabe
authors: Department of Medicine, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors: Sanjay
authors: S
authors: Sethi
authors: Department of Medicine, Universidade Federal de Santa Catarina, Santa Catarina, Brazil.
authors: Emilio
authors: E
authors: Pizzichini
authors: Firestone Institute of Respiratory Health, St Joseph's Healthcare, McMaster University, Hamilton, ON, Canada.
authors: Andrew
authors: A
authors: McIvor
authors: AstraZeneca, Gaithersburg, MD.
authors: Shahid
authors: S
authors: Siddiqui
authors: South Texas Veterans Health Care System at San Antonio, University of Texas Health Science Center, San Antonio, TX.
authors: Antonio
authors: A
authors: Anzueto
authors: Allergan plc, Jersey City, NJ, USA.
authors: Haiyuan
authors: H
authors: Zhu
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage* / Q000009:adverse effects; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D029481:Bronchitis, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000069502:Budesonide, Formoterol Fumarate Drug Combination / Q000008:administration & dosage* / Q000009:adverse effects; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D000068297:Fluticasone-Salmeterol Drug Combination / Q000008:administration & dosage* / Q000009:adverse effects; D005541:Forced Expiratory Volume; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D012107:Research Design; D012720:Severity of Illness Index; D013147:Spirometry; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D014797:Vital Capacity
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D000631:Aminopyridines; D001549:Benzamides; D001993:Bronchodilator Agents; D000069502:Budesonide, Formoterol Fumarate Drug Combination; D003521:Cyclopropanes; D000068297:Fluticasone-Salmeterol Drug Combination; D058988:Phosphodiesterase 4 Inhibitors; C424423:Roflumilast
keywords: ICS/LABA; RE2SPOND; exacerbation; methodology; phosphodiesterase-4; study design