Fernando J Martinez1, Klaus F Rabe2,3,4, Sanjay Sethi5, Emilio Pizzichini6, Andrew McIvor7, Antonio Anzueto8,9, Vijay K T Alagappan10, Shahid Siddiqui10, Ludmyla Rekeda11, Christopher J Miller10, Sofia Zetterstrand12, Colin Reisner13, Stephen I Rennard14,15. 1. 1 Weill Cornell University, New York, New York. 2. 2 LungenClinic Grosshansdorf, Großhansdorf, Germany. 3. 3 Department of Medicine of University Kiel, Kiel, Germany. 4. 4 Airway Research Center North of the German Center for Lung Research, Großhansdorf, Germany. 5. 5 University at Buffalo, State University of New York, Buffalo, New York. 6. 6 Universidade Federal de Santa Catarina, Santa Catarina, Brazil. 7. 7 McMaster University, Firestone Institute of Respiratory Health, St. Joseph's Healthcare, Ontario, Canada. 8. 8 University of Texas Health Science Center, San Antonio, Texas. 9. 9 South Texas Veterans Health Care System at San Antonio, San Antonio, Texas. 10. 10 AstraZeneca, Gaithersburg, Maryland. 11. 11 Allergan plc, Jersey City, New Jersey. 12. 12 AstraZeneca, Gothenburg, Sweden. 13. 13 AstraZeneca, Morristown, New Jersey. 14. 14 University of Nebraska Medical Center, Omaha, Nebraska; and. 15. 15 AstraZeneca, Cambridge, United Kingdom.
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 β2-agonist with or without a long-acting muscarinic antagonist (LAMA). METHODS: In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients onDual [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. 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. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).
RCT Entities:
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 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. 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. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).
Authors: Diego J Maselli; Megan Hardin; Stephanie A Christenson; Nicola A Hanania; Craig P Hersh; Sandra G Adams; Antonio Anzueto; Jay I Peters; MeiLan K Han; Fernando J Martinez Journal: Chest Date: 2018-08-02 Impact factor: 10.262