Triple Versus Dual Combination Therapy in Chronic Obstructive Pulmonary Disease in Asian Countries: Analysis of the IMPACT Trial

David M G Halpin, Gerard J Criner, Mark T Dransfield, MeiLan K Han, Benjamin Hartley, Catherine Harvey, C Elaine Jones, Motokazu Kato, Peter Lange, Sally Lettis, David A Lomas, Fernando J Martinez, Neil Martin, Dave Singh, Robert Wise, Jinping Zheng, David A Lipson, David M G Halpin, Gerard J Criner, Mark T Dransfield, MeiLan K Han, Benjamin Hartley, Catherine Harvey, C Elaine Jones, Motokazu Kato, Peter Lange, Sally Lettis, David A Lomas, Fernando J Martinez, Neil Martin, Dave Singh, Robert Wise, Jinping Zheng, David A Lipson

Abstract

Introduction: In the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI or UMEC/VI dual therapy in patients with chronic obstructive pulmonary disease (COPD); however, pneumonia incidence was higher in FF-containing arms. As COPD is a growing problem in Asia, we compared the efficacy and safety of FF/UMEC/VI in Asia versus non-Asia regions.

Methods: IMPACT was a double-blind, 52-week trial in symptomatic COPD patients with ≥ 1 moderate/severe exacerbation in the prior year. This pre-specified analysis evaluated the annual rate of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score, mortality, and safety (including pneumonia) in Asia versus non-Asia regions.

Results: The intent-to-treat population comprised 10,355 patients (Asia n = 1644 [16%]). Rate ratios (95% confidence intervals) for moderate/severe exacerbations with FF/UMEC/VI were 0.89 (0.76-1.05) versus FF/VI and 0.86 (0.71-1.04) versus UMEC/VI in Asia, and 0.84 (0.79-0.90) and 0.74 (0.68-0.80) in non-Asia. Efficacy of FF/UMEC/VI on other endpoints was similar in both regions. There was an increased incidence of investigator-reported pneumonia in patients in Asia (FF/UMEC/VI: 13%; FF/VI: 14%; UMEC/VI: 6%) compared with non-Asia (FF/UMEC/VI: 6%; FF/VI: 5%; UMEC/VI: 4%). The increased risk of pneumonia in patients in Asia was most marked in patients with lower body mass index, lower lung function, and taking inhaled corticosteroids. In post hoc analysis of adjudicated on-treatment all-cause mortality, probabilities of death were numerically lower in both regions with FF/UMEC/VI (Asia: 1.16%; non-Asia: 1.35%) and FF/VI (Asia: 1.77%; non-Asia: 1.21%) versus UMEC/VI (Asia: 1.91%; non-Asia: 2.23%).

Conclusions: FF/UMEC/VI provides similar benefits in COPD patients in Asia and non-Asia regions. Clinical benefits of treatment, including reduction in mortality risk, should be weighed against risk of pneumonia, taking account of all known risk factors.

Trial registration: ClinicalTrials.gov identification, NCT02164513.

Keywords: Asia; Chronic obstructive; Drug therapy; Mortality; Pneumonia; Pulmonary disease.

Figures

Fig. 1
Fig. 1
Rate of on-treatment moderate and severe exacerbations by regional subgroup. a FF/UMEC/VI vs. FF/VI; b FF/UMEC/VI vs. UMEC/VI; c UMEC/VI vs. FF/VI. n is the number of subjects included in the analysis for the two treatment groups of interest. Rate of exacerbations (generalized linear models assuming a negative binomial distribution) included covariates of treatment group, sex, exacerbation history (≤ 1, ≥ 2 moderate/severe), smoking status (screening), post-bronchodilator percent predicted FEV1 (screening) [1] and geographical region [2] and region (Asia/non-Asia) and treatment group by visit by region interactions. CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, UMEC umeclidinium, VI vilanterol
Fig. 2
Fig. 2
Change from baseline in trough FEV1 (l) and SGRQ total score at week 52. a Change from baseline in trough FEV1 with FF/UMEC/VI vs. FF/VI, FF/UMEC/VI vs. UMEC/VI and UMEC/VI vs. FF/VI; b change from baseline in SGRQ total score at week 52 with FF/UMEC/VI vs. FF/VI, FF/UMEC/VI vs. UMEC/VI and UMEC/VI vs. FF/VI. n is the number of subjects included in the analysis for the two treatment groups of interest. Trough FEV1 and SGRQ total score (repeated measures models) included covariates of treatment group, smoking status (screening), visit, baselines, baseline by visit, treatment group by visit interactions [1] and geographical region [2] and region (Asia/non-Asia), treatment group by region, visit by region and treatment group by visit by region interactions. CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, LS least squares, SGRQ St George’s Respiratory Questionnaire, UMEC umeclidinium, VI vilanterol
Fig. 3
Fig. 3
Time-to-first on-treatment pneumonia reported as an AESI in regional subgroups. Kaplan–Meier plot of time-to-first on-treatment event in the pneumonia AESI group in a Asia and b non-Asia regions. AESI adverse event of special interest, FF fluticasone furoate, UMEC umeclidinium, VI vilanterol

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