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Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials

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Summary

Background

Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β2 agonist is more protective than a once-daily longacting β2 agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone.

Methods

We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV1 of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952).

Findings

1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7–1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group.

Interpretation

Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.

Funding

GlaxoSmithKline.

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.

Section snippets

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

    L Sanford no longer works for GlaxoSmithKline but was an employee of the company at the time of this work

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