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Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study

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Summary

Background

We evaluated the effect of dual, longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease (COPD).

Methods

In this parallel-group study, 2224 patients (aged ≥40 years, Global Initiative for Chronic Obstructive Lung Disease stages III–IV, and one or more moderate COPD exacerbation in the past year) were randomly assigned (1:1:1; via interactive voice response or web system; stratified for smoking status) to once-daily QVA149 (fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks. Assignment to QVA149 and glycopyrronium was double-blind; tiotropium was open-label. Efficacy was assessed in all patients randomly assigned to treatment groups who received at least one dose of study drug; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group. The primary objective was to show superiority of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorised by treatment requirements) during treatment. This completed trial is registered at ClinicalTrials.gov, NCT01120691.

Findings

Between April 27, 2010, and July 11, 2012, 741 patients were randomly assigned to receive QVA149, 741 to receive glycopyrronium, and 742 to receive tiotropium (729, 739, and 737 patients, respectively, analysed for efficacy). QVA149 significantly reduced the rate of moderate to severe exacerbations versus glycopyrronium by 12% (annualised rate of exacerbations 0·84 [95% CI 0·75–0·94] vs 0·95 [0·85–1·06]; rate ratio 0·88, 95% CI 0·77–0·99, p=0·038). Adverse events (including exacerbations) were reported for 678 (93%) of 729 patients on QVA149, 694 (94%) of 740 on glycopyrronium, and 686 (93%) of 737 on tiotropium. Incidence of serious adverse events was similar between groups (167 [23%] patients on QVA149, 179 [24%] on glycopyrronium, and 165 [22%] on tiotropium); COPD worsening was the most frequent serious adverse event (107 [15%] patients on QVA149, 116 [16%] on glycopyrronium, 87 [12%] on tiotropium).

Interpretations

The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status. These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD.

Funding

Novartis Pharma AG.

Introduction

Chronic obstructive pulmonary disease (COPD) is associated with a progressive and accelerated reduction in lung function and worsening dyspnoea, punctuated by episodes of acute worsening of symptoms needing additional specific drug treatment and, possibly, emergency or hospital care. Such exacerbations are associated with a poor prognosis in terms of accelerated lung function decline;1, 2 and increased risk of death,3, 4 as well as reduced physical activity and poor health status.5, 6, 7 Prevention of exacerbations is an important management strategy8 and a key objective for new drug treatments for COPD.

Longacting inhaled bronchodilators feature prominently in the recommended management strategy for COPD.8 Both longacting β2-agonists (LABAs) and longacting muscarinic antagonists (LAMAs) have shown efficacy in preventing exacerbations of COPD.9, 10, 11, 12, 13 Although these agents are effective in the treatment of COPD, significant deterioration in health status can persist and hence a need remains for increased disease control. QVA149, a once-daily dual bronchodilator in development for treatment of patients with COPD, contains a fixed dose of the LABA indacaterol and the LAMA glycopyrronium (NVA237). Both these components provide 24-h bronchodilation with once-daily dosing and have an established profile of efficacy and safety in patients with moderate-to-severe COPD.14, 15, 16, 17, 18

The hypothesis for the present study was that the potent bronchodilator effect of a fixed-dose combination of a LABA and a LAMA would translate into better patient-reported outcomes than single bronchodilator therapy, particularly in terms of prevention of COPD exacerbations. We also expected that a greater bronchodilator effect would be associated with an improvement in health status.19 The SPARK study was designed to evaluate the effect of once-daily QVA149 on exacerbations of COPD, using rigorous methods to detect events, including mild exacerbations. The study was conducted in patients with severe or very severe airflow limitation who had experienced at least one exacerbation in the past year and who were therefore at high risk of future adverse outcomes.8 The effect of QVA149 was compared with the once-daily LAMAs glycopyrronium and tiotropium.

Section snippets

Study design

SPARK was a multicentre study (international investigators by country are listed in the appendix pp 2–3) consisting of a pre-randomisation period and a double-blind, parallel-group treatment period (64 weeks). The double-blind treatment period could be extended to a total of 76 weeks; this extension period was designed to increase the number of exacerbation events to ensure the study achieved the exacerbation rate prespecified for analysis (further details provided in statistical analysis

Results

The study was undertaken at 362 centres across 27 countries (appendix p 11). The first patient was enrolled on April 27, 2010; the last patient completed on July 11, 2012. Patient disposition is shown in figure 1. Of 3865 patients screened, 2224 were randomly assigned to treatment groups. The most frequent reasons for screening failure were unacceptable test procedure result and not meeting criteria for diagnosis or COPD severity. Overall, 75% of patients completed the study treatment period.

Discussion

To our knowledge, this is the first report of the efficacy of dual long-acting bronchodilator treatment in a population of patients with severe and very severe COPD at high risk of COPD exacerbations (panel). The study met its primary endpoint, the dual LABA/LAMA bronchodilator QVA149 significantly reduced the rate of moderate to severe exacerbations by 12% compared with the LAMA glycopyrronium, one of its components, and a 10% reduction was seen versus the LAMA tiotropium; however, this

References (46)

  • AF Connors et al.

    Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments)

    Am J Respir Crit Care Med

    (1996)
  • GC Donaldson et al.

    Exacerbations and time spent outdoors in chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (2005)
  • TA Seemungal et al.

    Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease

    Am J Respir Crit Care Med

    (1998)
  • Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease

  • DE Niewoehner et al.

    Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial

    Ann Intern Med

    (2005)
  • JA Wedzicha et al.

    The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide

    Am J Respir Crit Care Med

    (2008)
  • C Vogelmeier et al.

    Tiotropium versus salmeterol for the prevention of exacerbations of COPD

    N Engl J Med

    (2011)
  • PM Calverley et al.

    Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease

    N Engl J Med

    (2007)
  • DP Tashkin et al.

    A 4-year trial of tiotropium in chronic obstructive pulmonary disease

    N Engl J Med

    (2008)
  • JF Donohue et al.

    Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium

    Am J Respir Crit Care Med

    (2010)
  • R Buhl et al.

    Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD

    Eur Respir J

    (2011)
  • R Dahl et al.

    Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD

    Thorax

    (2010)
  • A D'Urzo et al.

    Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial

    Respir Res

    (2011)
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