Early Clinically Important Improvement (ECII) and Exacerbation Outcomes in the FLAME Study

Rationale 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 The 52-week FLAME study randomised COPD patients with ≥ 1 exacerbation in past year to indacaterol/glycopyrronium (IND/GLY 110/50 μg od) or salmeterol/fluticasone (SFC 50/500 μg bid) (Wedzicha, JA et al. N Engl J Med 2016). ECII was defined at 4 or 12 weeks as achievement of minimal

clinically important difference in trough FEV₁ (≥ 100 mL increase) AND one patient reported outcome:

reduction in e-Diary score ≥ 0.6 points; reduction in COPD Assessment Test (CAT) ≥ 2 points or reduction in Saint Georgeʼs Respiratory Questionnaire (SGRQ) ≥ 4 points.

Results Approximately 18 – 21% of patients achieved ECII at weeks 4 or 12 post randomisation according to the different definitions. Patients who achieved ECII experienced lower rates of subsequent exacerbations (annualised exacerbation rate: 0.83 – 0.91 vs. 0.99 – 1.04) and longer time to first exacerbation. More patients achieved ECII with IND/GLY vs. SFC according to the best predictor definition at week 4 (FEV₁ and SGRQ, odds ratio 1.69, 95%CI 1.40, 2.04, P < 0.001) and week 12 (FEV₁ and CAT, odds ratio 1.80, 95%CI 1.48, 2.18, P < 0.001).

Conclusion ECII is a novel composite outcome measure that could predict subsequent exacerbation risk and may be used in clinical trials.