Fernando J Martinez1, Klaus F Rabe2, Peter M A Calverley3, Leonardo M Fabbri4,5, Sanjay Sethi6, Emilio Pizzichini7, Andrew McIvor8, Antonio Anzueto9, Vijay K T Alagappan10, Shahid Siddiqui10, Colin Reisner10, Sofia Zetterstrand11, Jonas Román11, Debasree Purkayastha12, Nitin Bagul13, Stephen I Rennard14,15. 1. 1 Weill Cornell Medicine, New York, New York. 2. 2 LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany. 3. 3 Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom. 4. 4 Department of Clinical Medicine, University of Ferrara, Ferrara, Italy. 5. 5 COPD Center, Sahlgrenska University Hospital, Gothenburg, Sweden. 6. 6 University at Buffalo, State University of New York, Buffalo, New York. 7. 7 Universidade Federal de Santa Catarina, Santa Catarina, Brazil. 8. 8 McMaster University, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, Hamilton, Ontario, Canada. 9. 9 University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, Texas. 10. 10 AstraZeneca, Gaithersburg, Maryland. 11. 11 AstraZeneca, Gothenburg, Sweden. 12. 12 PHASTAR Corporation, Manchester, United Kingdom. 13. 13 Takeda Development Centre Europe Ltd., London, United Kingdom. 14. 14 University of Nebraska Medical Center, Omaha, Nebraska; and. 15. 15 Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
Abstract
RATIONALE: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted. OBJECTIVES: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast. METHODS: Predefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE2SPOND (Roflumilast Effect on Exacerbations in Patients onDual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year. MEASUREMENTS AND MAIN RESULTS: In the overall intention-to-treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils ≥150 cells/μl (0.81; 0.71-0.93; P = 0.0020), ≥150 to <300 cells/μl (0.84; 0.71-0.98; P = 0.0282), or ≥300 cells/μl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at ≥150 cells/μl (0.65; 0.52-0.82; P = 0.0003) and 42.7% at ≥300 cells/μl (0.57; 0.37-0.88; P = 0.0111) versus placebo. CONCLUSIONS: This prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (≥150 cells/μl, ≥150 to <300 cells/μl, or ≥300 cells/μl) baseline blood eosinophil count.
RCT Entities:
RATIONALE: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted. OBJECTIVES: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast. METHODS: Predefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE2SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year. MEASUREMENTS AND MAIN RESULTS: In the overall intention-to-treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils ≥150 cells/μl (0.81; 0.71-0.93; P = 0.0020), ≥150 to <300 cells/μl (0.84; 0.71-0.98; P = 0.0282), or ≥300 cells/μl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at ≥150 cells/μl (0.65; 0.52-0.82; P = 0.0003) and 42.7% at ≥300 cells/μl (0.57; 0.37-0.88; P = 0.0111) versus placebo. CONCLUSIONS: This prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (≥150 cells/μl, ≥150 to <300 cells/μl, or ≥300 cells/μl) baseline blood eosinophil count.
Authors: Wassim W Labaki; Lucas M Kimmig; Gökhan M Mutlu; MeiLan K Han; Surya P Bhatt Journal: Am J Respir Crit Care Med Date: 2019-06-15 Impact factor: 21.405
Authors: Graham Devereux; Seonaidh Cotton; Shona Fielding; Nicola McMeekin; Peter J Barnes; Andrew Briggs; Graham Burns; Rekha Chaudhuri; Henry Chrystyn; Lisa Davies; Anthony De Soyza; Simon Gompertz; John Haughney; Karen Innes; Joanna Kaniewska; Amanda Lee; Alyn Morice; John Norrie; Anita Sullivan; Andrew Wilson; David Price Journal: JAMA Date: 2018-10-16 Impact factor: 56.272
Authors: Fernando J Martinez; Alvar Agusti; Bartolome R Celli; MeiLan K Han; James P Allinson; Surya P Bhatt; Peter Calverley; Sanjay H Chotirmall; Badrul Chowdhury; Patrick Darken; Carla A Da Silva; Gavin Donaldson; Paul Dorinsky; Mark Dransfield; Rosa Faner; David M Halpin; Paul Jones; Jerry A Krishnan; Nicholas Locantore; Fernando D Martinez; Hana Mullerova; David Price; Klaus F Rabe; Colin Reisner; Dave Singh; Jørgen Vestbo; Claus F Vogelmeier; Robert A Wise; Ruth Tal-Singer; Jadwiga A Wedzicha Journal: Am J Respir Crit Care Med Date: 2022-02-01 Impact factor: 21.405