Articles
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 Sandström, Angel Fowler Taylor, Peter D’Andrea, Christie Arrasate, Hungta Chen, Donald Banerji
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.5−7 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 www.thelancet.com/respiratory Vol 1 May 2013
COPD.8 Both longacting β2-agonists (LABAs) and longacting muscarinic antagonists (LAMAs) have shown efficacy in preventing exacerbations of COPD.9−13 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 oncedaily dosing and have an established profile of efficacy and safety in patients with moderate-to-severe COPD.14−18 The hypothesis for the present study was that the potent bronchodilator effect of a fixed-dose combination
Lancet Respir Med 2013; 1: 199–209 Published Online April 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70052-3 See Comment page 176 Centre for Respiratory Medicine, University College London, Royal Free Campus, London, UK (Prof J A Wedzicha MD); Respiratory Division, University Hospitals, Leuven, Belgium (Prof M Decramer MD); Paracelsus Medical University Nuremberg, Nuremberg, Germany (Prof J H Ficker MD); Klinikum Nuremberg, Department of Respiratory Medicine, Allergology, and Sleep Medicine, Nuremberg, Germany (Prof J H Ficker); University of Minnesota, Minneapolis VA Health Care Center, Pulmonary Section, Minneapolis, MN, USA (Prof D E Niewoehner MD); Umeå University, Department of Public Health and Clinical Medicine, Umeå, Sweden (Prof T Sandström MD); and Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (A Fowler Taylor RPh, P D’Andrea MD, C Arrasate BS, H Chen PhD, D Banerji MD) Correspondence to: Prof Jadwiga A Wedzicha, Centre for Respiratory Medicine, University College London, Royal Free Campus, London NW3 2PF, UK [email protected]
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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.
Methods Study design See Online for appendix
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 doubleblind, 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 section). Approvals from institutional review boards or ethics committees were obtained from each investigator site. At an initial prescreening visit, informed consent was obtained and current COPD treatments were reviewed and if necessary adjusted. Up to 7 days after prescreening, patients were given an electronic diary (e-diary; an accepted method used for exacerbation detection20,21) to record symptoms and use of rescue salbutamol and started a 14-day run-in when screening assessments were done (including spirometry for eligibility) and baseline e-diary data were collected. At the next visit, eligible patients were randomly assigned in a 1:1:1 ratio to receive QVA149, glycopyrronium, or tiotropium for the next 64 weeks. Spirometry was done according to recognised standards22 and with centralised quality control, with measurements at baseline and at clinic visits during the treatment period. Health status, measured using St George’s Respiratory Questionnaire (SGRQ),23 was assessed at baseline and at clinic visits. Patients were instructed to complete the e-diary each morning (before taking study drug) and evening. On evidence of worsening of symptoms, which met predefined criteria for COPD exacerbation (see below for definitions), the e-diary triggered an alarm and the patient was advised to contact the site. Patients were contacted every 2 weeks by telephone to check whether
3865 screened
1641 excluded*
2224 randomised
741 assigned to QVA149 736 received drug 5 did not receive drug
741 assigned to glycopyrronium 739 received drug 1 did not receive drug 1 randomised twice
171 discontinued treatment 59 adverse event 33 withdrew consent 21 death 18 unsatisfactory therapeutic effect 15 administrative problems 13 protocol deviation 5 lost to follow-up 3 abnormal laboratory test 3 inability to use inhaler 1 abnormal laboratory value
570 completed study 7 excluded from analysis† 729 analysed for safety 729 analysed for efficacy
742 assigned to tiotropium 739 received drug 3 did not receive drug
203 discontinued treatment 67 adverse event 50 withdrew consent 22 death 32 unsatisfactory therapeutic effect 8 administrative problems 12 protocol deviation 6 lost to follow-up 2 abnormal test result 1 inability to use inhaler 3 abnormal laboratory value
538 completed study 740 analysed for safety 739 analysed for efficacy
183 discontinued treatment 47 adverse event 44 withdrew consent 24 death 38 unsatisfactory therapeutic effect 9 administrative problems 12 protocol deviation 4 lost to follow-up 1 abnormal test result 4 abnormal laboratory value
559 completed study 2 excluded from analysis† 737 analysed for safety 737 analysed for efficacy
Figure 1: Disposition of patients during study *Most screening failures were due to unacceptable test procedure results (457 patients) or did not meet diagnostic or severity criteria (456 patients). †Study site terminated (Good Clinical Practice violation).
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their COPD symptoms had worsened or needed treatment and that the e-diary was completed.
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 Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2008 criteria,24 post-bronchodilator forced expiratory volume in 1 s [FEV1]
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 Sandström, Angel Fowler Taylor, Peter D’Andrea, Christie Arrasate, Hungta Chen, Donald Banerji
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.5−7 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 www.thelancet.com/respiratory Vol 1 May 2013
COPD.8 Both longacting β2-agonists (LABAs) and longacting muscarinic antagonists (LAMAs) have shown efficacy in preventing exacerbations of COPD.9−13 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 oncedaily dosing and have an established profile of efficacy and safety in patients with moderate-to-severe COPD.14−18 The hypothesis for the present study was that the potent bronchodilator effect of a fixed-dose combination
Lancet Respir Med 2013; 1: 199–209 Published Online April 23, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70052-3 See Comment page 176 Centre for Respiratory Medicine, University College London, Royal Free Campus, London, UK (Prof J A Wedzicha MD); Respiratory Division, University Hospitals, Leuven, Belgium (Prof M Decramer MD); Paracelsus Medical University Nuremberg, Nuremberg, Germany (Prof J H Ficker MD); Klinikum Nuremberg, Department of Respiratory Medicine, Allergology, and Sleep Medicine, Nuremberg, Germany (Prof J H Ficker); University of Minnesota, Minneapolis VA Health Care Center, Pulmonary Section, Minneapolis, MN, USA (Prof D E Niewoehner MD); Umeå University, Department of Public Health and Clinical Medicine, Umeå, Sweden (Prof T Sandström MD); and Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA (A Fowler Taylor RPh, P D’Andrea MD, C Arrasate BS, H Chen PhD, D Banerji MD) Correspondence to: Prof Jadwiga A Wedzicha, Centre for Respiratory Medicine, University College London, Royal Free Campus, London NW3 2PF, UK [email protected]
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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.
Methods Study design See Online for appendix
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 doubleblind, 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 section). Approvals from institutional review boards or ethics committees were obtained from each investigator site. At an initial prescreening visit, informed consent was obtained and current COPD treatments were reviewed and if necessary adjusted. Up to 7 days after prescreening, patients were given an electronic diary (e-diary; an accepted method used for exacerbation detection20,21) to record symptoms and use of rescue salbutamol and started a 14-day run-in when screening assessments were done (including spirometry for eligibility) and baseline e-diary data were collected. At the next visit, eligible patients were randomly assigned in a 1:1:1 ratio to receive QVA149, glycopyrronium, or tiotropium for the next 64 weeks. Spirometry was done according to recognised standards22 and with centralised quality control, with measurements at baseline and at clinic visits during the treatment period. Health status, measured using St George’s Respiratory Questionnaire (SGRQ),23 was assessed at baseline and at clinic visits. Patients were instructed to complete the e-diary each morning (before taking study drug) and evening. On evidence of worsening of symptoms, which met predefined criteria for COPD exacerbation (see below for definitions), the e-diary triggered an alarm and the patient was advised to contact the site. Patients were contacted every 2 weeks by telephone to check whether
3865 screened
1641 excluded*
2224 randomised
741 assigned to QVA149 736 received drug 5 did not receive drug
741 assigned to glycopyrronium 739 received drug 1 did not receive drug 1 randomised twice
171 discontinued treatment 59 adverse event 33 withdrew consent 21 death 18 unsatisfactory therapeutic effect 15 administrative problems 13 protocol deviation 5 lost to follow-up 3 abnormal laboratory test 3 inability to use inhaler 1 abnormal laboratory value
570 completed study 7 excluded from analysis† 729 analysed for safety 729 analysed for efficacy
742 assigned to tiotropium 739 received drug 3 did not receive drug
203 discontinued treatment 67 adverse event 50 withdrew consent 22 death 32 unsatisfactory therapeutic effect 8 administrative problems 12 protocol deviation 6 lost to follow-up 2 abnormal test result 1 inability to use inhaler 3 abnormal laboratory value
538 completed study 740 analysed for safety 739 analysed for efficacy
183 discontinued treatment 47 adverse event 44 withdrew consent 24 death 38 unsatisfactory therapeutic effect 9 administrative problems 12 protocol deviation 4 lost to follow-up 1 abnormal test result 4 abnormal laboratory value
559 completed study 2 excluded from analysis† 737 analysed for safety 737 analysed for efficacy
Figure 1: Disposition of patients during study *Most screening failures were due to unacceptable test procedure results (457 patients) or did not meet diagnostic or severity criteria (456 patients). †Study site terminated (Good Clinical Practice violation).
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their COPD symptoms had worsened or needed treatment and that the e-diary was completed.
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 Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2008 criteria,24 post-bronchodilator forced expiratory volume in 1 s [FEV1]
