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Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol–fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study

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Summary

Background

QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol–fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD.

Methods

In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II–III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients who received at least one dose of study drug. The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the standardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0–12h) after 26 weeks of treatment. This trial was registered at ClinicalTrial.gov, NCT01315249.

Findings

Between March 25, 2011, and March 12, 2012, 259 patients were randomly assigned to receive QVA149 and 264 to receive SFC. At week 26, FEV1 AUC0–12h was significantly higher with QVA149 than with SFC (treatment difference 0·138 L; 95% CI 0·100–0·176; p<0·0001). Overall incidence of adverse events (including COPD exacerbations) was 55·4% (143 of 258) for the QVA149 group and 60·2% (159 of 264) for the SFC group. Incidence of serious adverse events was similar between treatment groups (QVA149, 13 of 258 [5·0%]; SFC 14 of 264 [5·3%]); COPD worsening was the most frequent serious adverse event (one of 13 [0·4%] and three of 14 [1·1%], respectively).

Interpretation

Once-daily QVA149 provides significant, sustained, and clinically meaningful improvements in lung function versus twice-daily SFC, with significant symptomatic benefit. These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients.

Funding

Novartis Pharma AG.

Introduction

In 2011, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) released new recommendations for the management of chronic obstructive pulmonary disease (COPD).1 According to the GOLD 2011 strategy, drug treatment should be predicated according to the level of patient's risk, defined in terms of airflow limitation, symptoms, and history of exacerbations.1 Longacting bronchodilators are the preferred option, either alone or in combination with an inhaled corticosteroid (ICS), for maintenance treatment of patients with all but the lowest risk category of COPD. The use of ICS should be reserved for those patients at high risk (group C and D),1 defined by a history of frequent exacerbations (two or more a year) or severe airflow limitation (forced expiratory volume in 1 second [FEV1] <50% predicted1), who stand to gain the most benefit from treatment. Despite these recommendations, there is evidence of widespread and possibly inappropriate use of ICS in patients with more moderate disease2, 3, 4 (equivalent to group B).1 Whether such patients would benefit from an approach of intensive bronchodilation rather than with a combination of an ICS and a longacting β2-agonist (LABA) has not previously been explored.

The strategy of combining bronchodilators of different pharmacological classes in COPD is to provide additional benefit over the use of single agents, without significantly increasing the risk of side-effects.1, 5, 6 Concurrent treatment with LABAs and longacting muscarinic antagonists (LAMAs) have shown significant improvements in lung function compared with either type of therapy used alone.5, 7, 8

Our study compares a dual bronchodilator (QVA149; a once-daily, fixed-dose combination of the LABA indacaterol and the LAMA glycopyrronium [NVA237] in development for the treatment of COPD) and a combined LABA and ICS (salmeterol–fluticasone [SFC]; twice a day), in patients with moderate-to-severe COPD and no history of exacerbations in the previous year. Our study hopes to address the question of whether, in a largely low-risk but symptomatic population of COPD patients, intensive bronchodilator maintenance treatment alone (with two longacting bronchodilators) is safe and offers benefits compared with the common practice of using a combined LABA and ICS.

Section snippets

Study design

ILLUMINATE was a multicentre (93 centres in ten countries [appendix]), randomised, double-blind, double-dummy, parallel-group, 26-week study in patients with moderate-to-severe COPD (GOLD II or III as defined in the 2009 GOLD guidelines; figure 1).9 The first patient was enrolled on March 25, 2011, and the last patient completed on March 12, 2012.

We enrolled men and women 40 years of age or older, current or former smokers with a smoking history of at least 10 pack-years, post-bronchodilator FEV

Results

523 patients were randomised and 522 (QVA149 n=258; SFC n=264) were included in the safety and full analysis sets. One patient was randomised in error and did not receive any study medication, and was excluded. 432 patients completed the study (completion and withdrawal rates were similar between the two treatment groups: 83% completion rate for QVA149 and 82·2% for SFC); the primary reasons for discontinuation were adverse events and withdrawal of consent (figure 2; see appendix for patient

Discussion

QVA149 once a day provides significantly better and clinically relevant improvements in lung function compared with SFC administered twice a day in patients with moderate-to-severe COPD. It also provided improvements in important patient-reported outcomes such as dyspnoea and rescue medication use compared with SFC. The safety of both QVA149 and SFC were acceptable, with the overall incidence of adverse events being similar between the two groups.

The ILLLUMINATE study addresses the gap in

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