Hungta Chen

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

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.

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

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.

Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study

We evaluated the effect of QVA149, a dual bronchodilator combining indacaterol and glycopyrronium, on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease. In this multicentre, blinded, double-dummy, three-period crossover study, 247 patients were randomised to once-daily QVA149 110/50 μg, placebo or tiotropium 18 μg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised (SAC) version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function, rescue medication use and safety. After 6 weeks, the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37, p<0.001) and tiotropium (LSM treatment difference 0.49, p=0.021). QVA149 provided significant improvements in lung function, with higher forced expiratory volume in 1 s area under the curve from 0–4 h post-dose versus placebo and tiotropium at day 1 and week 6 (all p<0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p<0.001) and tiotropium (p=0.002). All treatments were well tolerated. Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium. These benefits were associated with improvements in other symptoms and reduced use of rescue medication. Two different bronchodilators in a single inhaler were effective in relieving patient-reported dyspnoea in COPD http://ow.ly/qjIpe

Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: The ENLIGHTEN study

BACKGROUND QVA149 is an inhaled, once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium (NVA237) for the treatment of chronic obstructive pulmonary disease (COPD). We investigated the safety and efficacy of QVA149 over 52 weeks. METHODS This 52-week, multicenter, double-blind, parallel-group, placebo-controlled study randomized (2:1) patients with moderate-to-severe COPD to once-daily QVA149 (110 μg indacaterol/50 μg glycopyrronium) or placebo delivered via the Breezhaler device. Primary endpoint was safety and tolerability for treatment-emergent adverse events (AEs). Secondary endpoints included safety based on vital signs, electrocardiograms (ECGs), laboratory evaluations, and pre-dose forced expiratory volume in 1 s (FEV1). RESULTS Of 339 patients randomized, QVA149 [n = 226], placebo [n = 113]; 76.9% male, mean age: 62.6 years, post-bronchodilator FEV1: 57.4% predicted, 83.5% completed study. A smaller percentage of patients discontinued in the QVA149 group (14.2%) compared with placebo (21.2%). Overall incidence of AEs was similar in the QVA149 (57.8%) and placebo (56.6%) groups, with most AEs being mild to moderate in severity. The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics. No clinically relevant differences were observed between treatment groups for vital signs or ECG parameters. The five deaths reported were unrelated to study medication (QVA149, n = 4 [1.8%]; placebo, n = 1 [0.9%]). QVA149 demonstrated rapid and clinically meaningful bronchodilation sustained over 52 weeks versus placebo. CONCLUSION QVA149 demonstrated a good safety and tolerability profile, providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD. ClinicalTrials.gov identifier: NCT01120717.

Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study.

Introduction The BEACON study evaluated the efficacy and safety of QVA149, a once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist (LABA) indacaterol and long-acting muscarinic antagonist (LAMA) glycopyrronium (NVA237), in development for the treatment of patients with chronic obstructive pulmonary disease (COPD), compared with the free-dose concurrent administration of indacaterol plus glycopyrronium (IND+GLY). Methods In this multicenter, double-blind, parallel group study, patients with stage II or stage III COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] 2010) were randomized (1:1) to once-daily QVA149 (110 μg indacaterol/50 μg glycopyrronium) or concurrent administration of indacaterol (150 μg) and glycopyrronium (50 μg) via the Breezhaler® device (Novartis AG, Basel, Switzerland) for 4 weeks. The primary endpoint was to evaluate the noninferiority of QVA149 as compared with concurrent administration of IND+GLY, for trough forced expiratory volume in 1 second (FEV1) after 4 weeks of treatment. The other assessments included FEV1 area under the curve from 0 to 4 hours (AUC0–4 hours) at day 1 and week 4, symptom scores, rescue medication use, safety, and tolerability over the 4-week study period. Results Of 193 patients randomized, 187 (96.9%) completed the study. Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.46 L ± 0.02 and 1.46 L ± 0.18, respectively. The FEV1 AUC0–4 hours at day 1 and week 4 were similar between the two treatment groups. Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period. Overall, 25.6% of patients in QVA149 group and 25.2% in the IND+GLY group experienced an adverse event, with the majority being mild-to-moderate in severity. No deaths were reported during the study or during the 30 days follow-up period. Conclusion The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium.

Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study

Background Addition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) whose symptoms are insufficiently controlled by bronchodilator monotherapy. GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting β2-agonist indacaterol (IND) and the long-acting muscarinic antagonist glycopyrronium (GLY) versus IND alone in patients with moderate-to-severe COPD. Materials and methods In this randomized, double-blind, parallel group, placebo-controlled, 12-week study, patients were randomized 1:1 to IND 150 μg and GLY 50 μg daily (IND + GLY) or IND 150 μg daily and placebo (IND + PBO) (all delivered via separate Breezhaler® devices). The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO for trough forced expiratory volume in 1 second (FEV1) at week 12. Other end points included trough FEV1 at day 1, FEV1 area under the curve from 30 minutes to 4 hours (AUC30min–4h), peak FEV1, inspiratory capacity and trough forced vital capacity (FVC) at day 1 and week 12, and transition dyspnea index (TDI) focal score, COPD symptoms, and rescue medication use over 12 weeks. Results A total of 449 patients were randomized (IND + GLY, 226; IND + PBO, 223); 94% completed the study. On day 1 and at week 12, IND + GLY significantly improved trough FEV1 versus IND + PBO, with treatment differences of 74 mL (95% CI 46–101 mL) and 64 mL (95% CI 28–99 mL), respectively (both P<0.001). IND + GLY significantly improved postdose peak FEV1, FEV1 AUC30min–4h, and trough FVC at day 1 and week 12 versus IND + PBO (all P<0.01). TDI focal score and COPD symptoms (percentage of days able to perform usual daily activities and change from baseline in mean daytime respiratory score) were significantly improved with IND + GLY versus IND + PBO (P<0.05). The incidence of adverse events was similar for the two treatment groups. Conclusion In patients with moderate-to-severe COPD, once-daily coadministration of IND and GLY provides significant and sustained improvement in bronchodilation versus IND alone from day 1, with significant improvements in patient-centered outcomes.

P236 Superior lung function with once-daily QVA149 translates into improvements in patient-reported breathlessness compared with placebo and tiotropium in COPD patients: the BLAZE study

Introduction QVA149, a novel once-daily inhaled dual bronchodilator combining a fixed dose of the long-acting β2 agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium, has demonstrated improvements in dyspnoea versus its mono-components (indacaterol and glycopyrronium), tiotropium, and salmeterol/fluticasone using the interviewer-based Transition Dyspnoea Index (TDI) questionnaire.1,2 The BLAZE study evaluated the effect of once-daily QVA149 on patient-reported dyspnoea versus placebo and blinded tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Methods This was a 6 week, multicentre, randomised, blinded, double-dummy, placebo-controlled, 3-period, cross-over study. Patients aged ≥40 years with moderate-to-severe COPD, post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥30% and <80% of the predicted normal, and post-bronchodilator FEV1/ forced vital capacity <0.7 were randomised to receive QVA149 110/50 μg (via the Breezhaler® device) or placebo (via the Breezhaler®/ HandiHaler® device) or blinded tiotropium 18 μg (via the HandiHaler® device). The primary objective of the study was to evaluate the superiority of QVA149 versus placebo in the improvement of patient-reported dyspnoea as assessed by Self-Administered Computerised (SAC) version of the Baseline Dyspnoea Index (BDI)/TDI after 6 weeks of treatment. Other objectives included; standardised FEV1 area under the curve from 0 to 4 hours post-dose (AUC0–4 h); rescue medication use; safety and tolerability. Abstract P236 Figure 1. TDI total score after 6 Weeks. Results Of the 247 patients (mean age 62.8 years) randomised, 191 completed the study. The SAC TDI total score was significantly improved with QVA149 compared with placebo and tiotropium after 6 weeks (figure). FEV1 AUC 0–4 h was significantly higher for QVA149 versus placebo and tiotropium at Day 1 and Week 6 (all p < 0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p < 0.001) and tiotropium (p = 0.002). Incidence rate of adverse events was similar across all the treatment groups (QVA 149: 35.0%; tiotropium: 35.5%; placebo: 39.4%). Conclusion The BLAZE study provides evidence that the improved lung function with QVA149 translates into greater relief of breathlessness and improved patient-reported outcomes. Reference Bateman et al. Eur Respir J. 2013 May 30. Vogelmeier et al. Lancet Respir Med. 2013; 1:51–60.

P237 Comparison of COPD exacerbations with once-daily QVA149 versus twice-daily salmeterol/fluticasone combination: the ILLUMINATE study

Introduction Exacerbations are the most frequent cause of hospitalisation and death among patients with COPD. Combinations of long-acting bronchodilators maximise bronchodilation and may reduce the risk of exacerbations. QVA149, a once-daily dual bronchodilator containing the long-acting β2 agonist (LABA) indacaterol and long-acting muscarinic antagonist (LAMA) glycopyrronium, improves lung function, breathlessness and rescue medication use compared with twice-daily salmeterol/fluticasone combination (SFC), in patients with moderate-to-severe COPD.1 Methods In this 26-week, multicenter, double-blind study, patients ≥ 40 years with COPD (forced expiratory volume in 1 second [FEV1] ≥40% to <80% predicted and no history of exacerbations in the previous year) were randomised (1:1) to QVA149 110/50 µg or SFC 50/500 µg. In this post hoc analysis, we report the rate of mild, moderate or severe COPD exacerbations during 26 weeks of treatment with QVA149 or SFC. Results Of 522 patients randomised [QVA149 (n = 258), SFC (n = 264); mean age: 63.3 years; mean post-bronchodilator FEV1: 60.2% predicted], 82.6% completed. Rate ratio of QVA149 versus SFC [RR] of moderate or severe exacerbations was 0.80 (95% confidence interval [CI]: 0.41–1.56) and for all COPD exacerbations (mild, moderate, and severe), RR was 0.69 (95% CI: 0.44–1.07) (neither statistically significant). Conclusion Risk of exacerbations with once-daily QVA149 was numerically, but not statistically significantly, lower than twice-daily SFC in patients with moderate-to-severe COPD and no previous history of exacerbations. The LABA/LAMA combination QVA149 has the potential to be an alternative to LABA/ICS in preventing COPD exacerbations. Reference Vogelmeier et al. Lancet Respir Med 2013;1(1):50–60.

QVA149 Improves Lung Function, Dyspnea, and Health Status Independent of Previously Prescribed Medications and COPD Severity: A Subgroup Analysis from the SHINE and ILLUMINATE Studies

Background: QVA149 is a dual bronchodilator combining the long-acting β2-agonist(LABA) indacaterol and the long-acting muscarinic antagonist (LAMA) glycopyrronium, for maintenance treatment of COPD. This post hoc analysis evaluated the improvements in lung function, dyspnea, and health status in subgroups of patients based on prior medication use, disease severities, baseline cough score, and baseline rescue medication use, achieved with QVA149 compared with placebo and other active comparators in 2 phase III clinical studies. Methods: In both the SHINE (NCT01202188) and ILLUMINATE (NCT01315249) studies, symptomatic patients aged ≥40 years with moderate-to-severe COPD were randomized to once-daily QVA149 (110/50 µg), indacaterol (150 µg), glycopyrronium (50 µg), tiotropium (18 μg), or placebo (2:2:2:2:1) and once-daily QVA149 (110/50 µg) or twice-daily salmeterol/fluticasone ([SFC]; 50/500 µg), respectively for 26 weeks. Here, we present the improvements in lung function, transition dyspnea index (TDI) and St. Georges Respiratory Questionnaire (SGRQ) total score by prior medication use and COPD disease severity separately from both studies. Results: In total, 2144 and 523 patients were randomized in the SHINE and ILLUMINATE studies; 89.1% and 82.6%, respectively, completed the study. QVA149 showed significant improvements in lung function compared with placebo (SHINE study) and SFC (ILLUMINATE study) regardless of prior medication, disease severity, baseline cough score, and rescue medication use. TDI and SGRQ total scores were also improved with QVA149 compared with placebo and SFC in most of the analyzed subgroups. Conclusion: QVA149 showed improvements in lung function, dyspnea, and health status in both moderate and severe COPD patients independent of previous medication use and baseline cough score.

P235 DUAL-BRONCHODILATION WITH ONCE-DAILY QVA149 IN PATIENTS WITH MODERATE-TO-SEVERE COPD: OVERVIEW OF THE IGNITE PROGRAM

Introduction In patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) whose symptoms are insufficiently controlled by monotherapy, current treatment strategies recommend the addition of a second bronchodilator with a different mechanism of action. Once-daily QVA149 is a dual bronchodilator combining the long-acting β2-agonist indacaterol (IND) and long-acting muscarinic antagonist glycopyrronium (GLY). The IGNITE program comprises a series of randomised controlled trials that investigate the efficacy and safety of QVA149 in patients with moderate-to-severe COPD. Methods This overview includes data from 4 multicentre, double-bind, randomised controlled trials evaluating the effect of QVA149 110/50 μg versus IND 150 μg, GLY 50 μg, tiotropium (TIO) 18 μg (open-label in the SHINE and SPARK studies; blinded in the BLAZE study), salmeterol/fluticasone (SFC) 50/500 μg, and placebo (PBO) in patients with moderate-to-very severe COPD. Outcomes reported here are lung function, transitional dyspnoea index (TDI), health status (via the St George’s Respiratory Questionnaire [SGRQ]), and exacerbations over 6 weeks (BLAZE), 26 weeks (SHINE, ILLUMINATE), and 64 weeks (SPARK). Results Data from 5138 patients were included in this overview. QVA149 provided statistically significant and clinically meaningful bronchodilation (p < 0.001) that was sustained throughout the treatment periods versus all comparators in all studies. QVA149 provided superior benefits versus TIO, SFC, and PBO with respect to TDI score in BLAZE and ILLUMINATE studies. At Week 64, QVA149 significantly improved SGRQ score (p≤0.001) and significantly lowered the rate of all exacerbations compared with GLY and TIO in the SPARK study (Table). In addition, QVA149 reduced the rate of all exacerbations by 31% and significantly delayed the time to first exacerbation versus SFC in the ILLUMINATE trial. Conclusion The results from the IGNITE trials demonstrate that superior improvements in lung function with once-daily QVA149 translate into meaningful therapeutic outcomes for patients with COPD as demonstrated by improved lung function, dyspnoea, health status, and reduced exacerbations. Abstract P235 Table 1. IGNITE data overview Treatment differences (QVA149 vs comparator) Parameters Study (N) PBO IND GLY TIO SFC Lung function SPARK(2224) Trough FEV1, mL - - 70*** 60*** - SHINE (2144) 200*** 70*** 90*** 80*** - FEV1 AUC0−12h, mL 330*** 130*** 130*** 120*** - ILLUMINATE (523) - - - - 140*** BLAZE (247) FEV1 AUC0−4h, mL 250*** - - 90*** - Dyspnoea TDI score 1.37*** - - 0.49* - ILLUMINATE - - - - 0.76** Health status SPARK SGRQ score - - −2.07*** −2.69*** - Rate reduction of exacerbations, % Moderate-to-severe - - 12 RR 0.88* 10 RR 0.90 - All - - 15RR 0.85*** 14RR 0.86** - ILLUMINATE Moderate-to-severe - - - - 20 RR 0.80 All - - - - 31RR 0.69 * p<0.05;** p<0.01; *** p≤0.001; †free combination; GLY=glycopyrronium; IND=indacaterol; PBO=placebo; SFC=salmeterol/fluticasone; RR=rate ratio;TIO=tiotropium