Autor:innen:
C. Vogelmeier (Marburg, DE)
E. Kerwin (Medford, US)
I. Naya (Brentford, GB)
L. Tombs (Stockley Park West, Uxbridge, Middlesex, GB)
L. Bjermer (Lund, SE)
F. Maltais (Québec, CA)
P. Jones (Brentford, GB)
D. Lipson (Collegeville, US)
C. Compton (Brentford, GB)
I. Boucot (Brentford, GB)
Rationale: The clinically important deterioration composite endpoint has become a recognized
marker of disease stability in COPD clinical trials. This analysis investigated its corollary, the clinically
important improvement (CII), which is a composite endpoint that requires concordant minimum
clinically important differences (MCID) in ≥ 2 patient-reported outcomes (PROs).
Methods: The 24-week, double-blind, parallel-group Early MAXimization of bronchodilation for
improving COPD stability (EMAX) trial randomized patients with symptomatic COPD and low
exacerbation risk not receiving inhaled corticosteroids to umeclidinium/vilanterol (UMEC/VI)
62.5/25 mcg once daily, UMEC 62.5 mcg once daily, or salmeterol (SAL) 50 mcg twice daily.
Responders to PROs were assessed a priori at Weeks 4 and 24 and were defined as: ≥ 1-point
improvement in Transition Dyspnea Index (TDI) focal score, ≥ 4-point change from baseline (CFB) in
St George’s Respiratory Questionnaire (SGRQ) total score, ≥ 2-point CFB in COPD Assessment Test
(CAT) score, and ≥2-point CFB in Evaluating Respiratory Symptoms-COPD (E-RS) total score (assessed
at Weeks 1─4 and 21─24). Global Assessment of Disease Severity (GADS) was assessed at Weeks 4
and 24. Odds ratios (OR) of patients having a CII, defined as an MCID in ≥2 PROs, at Weeks 4 and 24,
and ordered OR of patients with a better response category in GADS at Weeks 4 and 24 were
obtained post hoc using generalized linear mixed models.
Results: The odds of a patient achieving CII were significantly greater with UMEC/VI versus UMEC
and SAL at both Weeks 4 and 24 . Among patients with 2, 3, and 4 PRO responses at Week 4
(ie, achieving CII), 67%, 87%, and 96%, respectively, had GADS improvement (ie, a better GADS
response category) at Week 4, whereas among patients with 0 and 1 PRO response (ie, not achieving
CII), 23% and 47%, respectively, had GADs improvement . The OR (compared with 0 positive
PROs) of GADS improvement at Weeks 4 and 24 increased with the number of PRO responses at
Week 4, and all ordered OR were significant versus patients with 0 PRO responses.
Conclusion: CII was experienced by more patients treated with UMEC/VI versus UMEC or SAL as
early as Week 4. Compared with patients without CII, greater proportions of patients with CII at
Week 4 had improvements in GADS at Weeks 4 and 24, suggesting that early assessment of
concordant clinical responses to treatment may be predictive of longer-term response.
Funding: GlaxoSmithKline (study 201749; NCT03034915).