ArticlesOnce-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials
Introduction
Chronic obstructive pulmonary disease (COPD) is a leading cause of death, and mortality associated with the disease continues to increase worldwide. Exacerbations are important events that are associated with accelerated loss of lung function and poor health status;1 mortality 1 year after an exacerbation-related hospital admission exceeds 20%.2 People with frequent exacerbations (ie, ≥2 events in a year) might form a distinct subtype of patient,3 and guidelines have identified exacerbation frequency as a key target for preventive treatment.4
Twice-daily use of combinations of inhaled corticosteroids (ICSs) and longacting β2 agonists (LABAs) reduce the frequency of exacerbations.5 Unlike that of tiotropium6 and roflumilast,7 which also reduce these events, the effect of once-daily treatment with ICS–LABA combinations on exacerbation frequency has not been studied. Few data are available for the dose-responsiveness of ICSs in exacerbation protection.8 Once-daily dosing is attractive for inhaled treatments because such regimens could improve adherence.9 Poor adherence (<80%) to the twice daily combination of fluticasone propionate (an ICS) and salmeterol (a LABA), has been linked to increased hospital admissions and death.10 Additionally, the combination of fluticasone propionate and salmeterol is associated with an increased risk of pneumonia.11
Fluticasone furoate has better in-vitro anti-inflammatory effects than does fluticasone propionate12 and can be given once daily.13 Vilanterol is an analogue of salmeterol14 that is more than 1000 times more selective for β2 than for β1 or for β3 receptors15 and can also be given once daily.16
Studies in COPD have shown that vilanterol alone16 or in combination with fluticasone furoate17 improves short-term lung function. We postulated that treatment with fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol monotherapy. We did replicate 1 year studies comparing vilanterol alone with vilanterol in combination with fluticasone furoate.
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Study design and patients
We did two replicate multicentre, randomised, double-blind, parallel-group studies comparing three strengths of fluticasone furoate–vilanterol combinations with one strength of vilanterol. The studies—HZC102871 (study 1) and HZC102970 (study 2)—were identically designed, done, and analysed. The appendix contains a detailed description of all methods. Study 1 was at 167 sites in 15 countries and study 2 at 183 sites in 15 countries (appendix). The start date (ie, the date of enrolment of the
Results
2631 people were screened for participation and 1622 randomly assigned in study 1, and 2635 people screened and 1633 randomly assigned in study 2 (figure 1A, 1B). Withdrawals from the trials were mainly associated with adverse events, lack of efficacy, and withdrawal of consent (Figure 1, Figure 2). At screening, participants' characteristics were well matched between all groups (table 1). The study population had clinically significant COPD, with mean predicted post-bronchodilator FEV1 ranging
Discussion
Our replicate double-blind, parallel-group, randomised controlled trials showed that, in the pooled analysis, once-daily fluticasone furoate and vilanterol significantly reduced the yearly rate of moderate and severe exacerbations compared with vilanterol alone. Fluticasone furoate and vilanterol also improved lung function (as measured by trough FEV1) throughout the study compared with vilanterol alone.
Our data are consistent with previous studies of twice-daily ICS–LABA combinations that
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These authors contributed equally
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L Sanford no longer works for GlaxoSmithKline but was an employee of the company at the time of this work