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.

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. 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. 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). 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. Novartis Pharma AG.

Vogelmeier CF ，Bateman ED ，Pallante J ，Alagappan VK ，D'Andrea P ，Chen H ，Banerji D ... -  《-》

LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD.

Zhong N ，Wang C ，Zhou X ，Zhang N ，Humphries M ，Wang L ，Thach C ，Patalano F ，Banerji D ，LANTERN Investigators ... -  《International Journal of Chronic Obstructive Pulmonary Disease》

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.

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

Wedzicha JA ，Decramer M ，Ficker JH ，Niewoehner DE ，Sandström T ，Taylor AF ，D'Andrea P ，Arrasate C ，Chen H ，Banerji D ... -  《-》

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

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. 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). 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. 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.

Dahl R ，Chapman KR ，Rudolf M ，Mehta R ，Kho P ，Alagappan VK ，Chen H ，Banerji D ... -  《-》

Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study.

QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% to <80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George's Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV1, forced vital capacity (FVC) and safety. Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: -0.69 units; 95% CI -2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV1 (+68 mL, 95% CI 37 mL to 100 mL; p<0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. NCT01120717.

Buhl R ，Gessner C ，Schuermann W ，Foerster K ，Sieder C ，Hiltl S ，Korn S ... -  《-》