Early Clinically Important Improvement (ECII) and Exacerbation Outcomes in COPD Patients

Konstantinos Kostikas,1 Alexander J Mackay,2 Claus F Vogelmeier,3 Stefan-Marian Frent,4 Pritam Gupta,5 Donald Banerji,6 Francesco Patalano,7 Pascal J Pfister,7 Jadwiga A Wedzicha8 1Respiratory Medicine Department, University of Ioannina Medical School, Ioannina, Greece; 2National Heart and Lung Institute, Imperial College London, London, UK; 3Department of Medicine, Pulmonary and Critical Care Medicine, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 4Department of Pulmonology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania; 5Novartis Healthcare Pvt. Ltd., Hyderabad, India; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 7Novartis Pharma AG, Basel, Switzerland; 8Respiratory Clinical Science Section, National Heart and Lung Institute, Imperial College London, London, UKCorrespondence: Konstantinos KostikasRespiratory Medicine Department, University of Ioannina Medical School, Ioannina 45110, GreeceTel +30-6944780616Email ktkostikas@gmail.comBackground: 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.Keywords: exacerbations, ECII, indacaterol/glycopyrronium, lung function, PROs