Background: Chronic obstructive pulmonary disease (COPD) exacerbations are difficult outcomes to measure in clinical trials. It would be valuable to be able to predict which patients are likely to benefit in terms of exacerbation prevention based on their early response in lung function and symptoms. Methods: This was a post-hoc analysis from the 52-week, randomized, double-blind, double-dummy, non-inferiority FLAME trial. Early clinically important improvement (ECII) was defined as achievement of minimal clinically important difference in trough forced expiratory volume in 1 second (FEV1; >/=100 mL increase) and one patient-reported outcome (PRO): either St. George's Respiratory Questionnaire for COPD (>/=4-unit reduction; D1), or COPD assessment test (>/=2-point reduction; D2) at Week 4 or 12. Results: Approximately 18-20% of patients achieved ECII at Week 4 or 12 post-randomization according to any of the two definitions. The rate of subsequent exacerbations was lower in patients who achieved ECII at Week 4 (D1: ratio of rates [95% CI], 0.85 [0.74 to 0.98]; D2, 0.88 [0.77 to 1.00]) or at Week 12 (D1, 0.85 [0.74 to 0.98]; D2, 0.86 [0.75 to 1.00]) versus patients not achieving ECII. Patients who achieved ECII experienced longer time-to-first exacerbation between Week 4 or 12 to end of study. More patients achieved ECII with indacaterol/glycopyrronium versus salmeterol/fluticasone according to both definitions at Week 4 (D1, odds ratio [95% CI], 1.69 [1.40 to 2.04]; D2, 1.61 [1.34 to 1.93]), and 12 (D1, 2.01 [1.66 to 2.44]; D2, 1.80 [1.48 to 2.18]). Conclusion: ECII is a novel composite endpoint, based on clinically relevant improvement in lung function and PROs in the early phase of treatment intervention that may predict subsequent exacerbation risk and may be used in clinical trials.
- Kostikas, K.
- Mackay, A. J.
- Vogelmeier, C. F.
- Frent, S. M.
- Gupta, P.
- Banerji, D.
- Patalano, F.
- Pfister, P. J.
- Wedzicha, J. A.
Keywords
- *ecii
- *PROs
- *exacerbations
- *indacaterol/glycopyrronium
- *lung function
- analysis and has received honoraria for presentations and/or consulting services
- and reports grants and/or personal fees from AstraZeneca, Boehringer Ingelheim,
- Chiesi, ELPEN, GlaxoSmithKline, Menarini, Novartis, Nuvoair, and Sanofi, not
- related to this work. AJM was a European Respiratory Society Fellow in Industry
- at Novartis Pharma AG at the time of conduct of this study and is currently
- employed and hold shares of AstraZeneca. CV reports grants and personal fees from
- AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Mundipharma,
- Novartis, personal fees from Cipla, Berlin Chemie/Menarini, CSL Behring, Teva,
- German Federal Ministry of Education and Research (BMBF) Competence Network
- Asthma and COPD (ASCONET), and grants from Bayer Schering Pharma AG, MSD, Pfizer,
- outside the submitted work. SF was an ERS Fellow at Novartis Pharma AG during
- this project and reports personal fees from Astra Zeneca and Novartis, outside
- the submitted work. PG is an employee of Novartis. DB, FP and PP are employees
- and shareholders of Novartis. JAW reports grants from GlaxoSmithKline, Johnson
- and Johnson, AstraZeneca, Boehringer Ingelheim, Chiesi, and Novartis, outside the
- submitted work.