1. Lancet Respir Med 2013; 1: 199–209 R4.신재령 / Prof. 박명재
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
Jadwiga A Wedzicha, Marc Decramer, Joachim H Ficker
Dennis E Niewoehner, Thomas Sandstrom, Angel Fowler Taylor Peter D’Andrea, Christie Arrasate, Hungta Chen, Donald Banerji
Lancet Respir Med 2013; 1: 199–209
R4.신재령 / Prof. 박명재

2. Introduction
Prevention of COPD exacerbations is an important management strategy and a key objective for new drug treatments for COPD
Both long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have shown efficacy in preventing exacerbations of COPD
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

3. Introduction
The SPARK study was designed to evaluate the effect of once-daily QVA149 on exacerbations of COPD
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
The effect of QVA149 was compared with the once-daily LAMAs glycopyrronium and tiotropium

4. Methods- Study design
SPARK was a multicentre study (362 centres across 27 countries)
pre-randomisation period
double blind, parallel-group treatment period (64 weeks)
After prescreening, patients were given an electronic diary, to record symptoms and use of rescue salbutamol
Eligible patients were randomly assigned in a 1:1:1 ratio to receive
QVA149, glycopyrronium, or tiotropium for the next 64 weeks
Spirometry, Health status, St George’s Respiratory Questionnaire (SGRQ) was assessed at baseline and at clinic visits
Patients were contacted every 2 weeks by telephone to check whether their COPD symptoms had worsened or needed treatment and that the e-diary was completed

6. Methods- Patients
This study enrolled patients (men and women; aged≥40 years) at risk of exacerbations, defined as patients with severe to very severe airflow limitation (Stage III or IV according to [GOLD] criteria)
Patients were excluded if they had a COPD exacerbation
Needed treatment with antibiotics, systemic corticosteroids or hospitalisation in the 6 weeks before prescreening or during screening
Developed a COPD exacerbation during prescreening or screening,
Had a respiratory tract infection within 4 weeks before prescreening

7. Methods- Treatments Patients received once-daily treatment
QVA149 (indacaterol 110 μg and glycopyrronium 50 μg) or
Glycopyrronium 50 μg, both double-blinded and administered via a single-dose dry powder inhaler or
Open-label, once-daily tiotropium 18 μg via a single-dose dry powder inhaler
Patients randomly allocated to open-label tiotropium were not assigned a medication number because this treatment was supplied locally

8. Methods - Objectives, assessments, and outcome measures
The primary objective was to demonstrate superiority of QVA149 compared with glycopyrronium for the rate of moderate or severe COPD exacerbations during the treatment period
The key secondary objective was to demonstrate superiority of QVA149 compared with tiotropium with respect to the rate of moderate to severe COPD exacerbations during the treatment period
Additional secondary objectives also compared the effect of QVA149 versus glycopyrronium and tiotropium on bronchodilator effect (predose or trough FEV1), health status (SGRQ total score), and use of rescue salbutamol during the treatment period

9. Methods - Objectives, assessments, and outcome measures
COPD exacerbations were defined in terms of worsening symptoms (recorded on e-diaries) and categorised by severity according to the need for additional treatment
Two major symptoms (dyspnea, sputum volume, sputum purulence) / one major + any one minor symptom (sore throat, cold, fever without other cause, cough, wheeze)
They could be self-managed by the patient (mild), treated with systemic corticosteroids or antibiotics or both (moderate), or require hospital admission or emergency treatment (severe)

10. Statistical analysis Data were analysed with SAS version 9.1.
Exacerbation rates during treatment were analysed with the negative binomial model
FEV1 was analysed with a mixed-model analysis of covariance with treatment as a fixed effect and baseline FEV1 and FEV1 reversibility as covariates
Efficacy variables were analysed for all patients randomly assigned to treatment groups
Sensitivity analyses of the primary variable are reported for all patients randomly assigned to treatment groups; without imputation, and per protocol (excluding protocol deviations)
Pearson’s χ² test was used to test for any between-treatment group differences in adverse events

11. Results

20. Conclusion
The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single long-acting 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