Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial.

RATIONALE: The long-acting ß2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY. OBJECTIVES: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured. METHODS: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days. MEASUREMENTS AND MAIN RESULTS: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial. CONCLUSIONS: IND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983).

Two cases of chronic obstructive pulmonary disease evaluated by dynamic-ventilatory digital radiography for pulmonary function and assessment of treatment efficacy.

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Population Pharmacokinetic Analysis of Indacaterol/Glycopyrronium/Mometasone Furoate After Administration of Combination Therapies Using the Breezhaler® Device in Patients with Asthma.

BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.

Comparative Effectiveness and Safety of Different Types of Inhaled Long-Acting ß2-Agonist Plus Inhaled Long-Acting Muscarinic Antagonist vs Inhaled Long-Acting ß2-Agonist Plus Inhaled Corticosteroid Fixed-Dose Combinations in COPD A Propensity Score-Inverse Probability of Treatment Weighting Cohort Study.

BACKGROUND: Despite multiple available fixed-dose combinations (FDCs) of inhaled long-acting ß2-agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) and LABAs plus inhaled corticosteroids (ICS) for COPD, uncertainty remains regarding their comparative effects. RESEARCH QUESTION: Can comparative effectiveness and safety of LABA plus LAMA (LABA/LAMA) and LABA plus ICS (LABA/ICS) FDCs vary by different individual components of the dual combinations in COPD? STUDY DESIGN AND METHODS: We conducted a new user, propensity score-inverse probability of treatment weighting cohort study to compare the effectiveness and safety of two frequently used LABA/LAMA FDCs (indacaterol plus glycopyrronium [IND/GLY] and vilanterol plus umeclidinium [VI/UMEC]) vs three commonly prescribed LABA/ICS FDCs (salmeterol plus fluticasone propionate [SAL/FP], formoterol fumarate plus budesonide [FF/BUD], and formoterol fumarate plus beclomethasone dipropionate [FF/BDP]) using the Taiwanese nationwide health care claims from 2014 through 2017. The primary effectiveness outcome was the annual moderate to severe exacerbation rate, and safety outcomes included risks of severe pneumonia and cardiovascular disease requiring hospitalization. Weighted generalized linear mixed models and Cox proportional hazard models were used to assess the effectiveness and safety outcomes, respectively. RESULTS: Patients with COPD initiating IND/GLY and VI/UMEC showed an 11% (incidence rate ratio [IRR], 0.89; 95% CI, 0.80-0.98) and 20% (IRR, 0.80; 95% CI, 0.71-0.90) reduced annual rate of moderate to severe exacerbations, respectively, than those initiating SAL/FP, but showed a similar rate as those initiating FF/BUD or FF/BDP. Both LABA/LAMA FDCs, compared with SAL/FP and VI/UMEC vs FF/BDP, were associated with a 27% (hazard ratio [HR], 0.73; 95% CI, 0.59-0.90) to 42% (HR, 0.58; 95% CI, 0.48-0.70) reduced pneumonia risk. Cardiovascular risk was comparable in five groups. An intraclass difference existed in rates of moderate to severe COPD exacerbation and risks of pneumonia among LABA/ICS FDCs, but not between LABA/LAMA FDCs. INTERPRETATION: Both LABA/LAMAs vs SAL/FP are associated with a lower exacerbation rate and pneumonia risk, but exhibit similar effectiveness and safety outcomes compared with FF/BDP or FF/BUD, suggesting that comparative effects may differ by individual components of the dual therapies in COPD.

Long-acting dual bronchodilator therapy (indacaterol/glycopyrronium) versus nebulized short-acting dual bronchodilator (salbutamol/ipratropium) in chronic obstructive pulmonary disease: A double-blind, randomized, placebo-controlled trial.

INTRODUCTION: Most guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. METHODS: This was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 µg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. RESULTS: A total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0-6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. CONCLUSION: Among patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

Relieving exertional dyspnea during the 3-min constant speed shuttle test in patients with COPD with indacaterol/glycopyrronium versus tiotropium: the RED trial.

BACKGROUND: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea. METHODS: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements. RESULTS: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean -1.00, 95% confidence interval (CI) -1.49 to -0.52] but not with tiotropium alone (mean -0.36, 95% CI -0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of -0.64, 95% CI -1.11 to -0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI -0.44 to 0.61). CONCLUSION: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation.The reviews of this paper are available via the supplemental material section.

Impact of baseline symptoms and health status on COPD exacerbations in the FLAME study.

BACKGROUND: COPD is a heterogeneous disease and patients may respond differently to therapies depending on baseline symptom burden. METHODS: This post-hoc analysis from the 52-week FLAME study investigated the impact of baseline symptom burden in terms of health status, dyspnoea, bronchitis status, eosinophil levels and smoking status on the subsequent risk of moderate or severe exacerbations. Health status was measured by St. George's Respiratory Questionnaire (SGRQ) score (higher ≥46.6 and lower < 46.6) and COPD Assessment Test (CAT) score (higher ≥17 and lower < 17); dyspnoea and bronchitis were assessed via an electronic diary (eDiary). Differential response to once-daily indacaterol/glycopyrronium (IND/GLY) 110/50 µg versus twice-daily salmeterol/fluticasone (SFC) 50/500 µg was assessed. RESULTS: Data from 3354 patients was analysed. The risk of exacerbations was lower in patients who had less severe health impairment (rate ratio [RR] [95% CI]): SGRQ-C, (0.88 [0.78, 0.99]); CAT, 0.85 [0.75, 0.96]) and lower dyspnoea (0.79 [0.69, 0.90]) at baseline versus those with more severe health impairment and higher dyspnoea, respectively. Compared with SFC, IND/GLY led to better prevention of moderate-to-severe exacerbations in the majority of groups studied. CONCLUSION: Patients with more severe health status impairment and greater symptom burden at baseline subsequently experienced more exacerbations in the FLAME study. IND/GLY was overall more effective in preventing exacerbations versus SFC, regardless of baseline symptom burden. Our results suggest that future studies on novel exacerbation therapies should consider targeting patients with higher symptom burden at baseline. CLINICAL TRIAL IDENTIFIER: NCT01782326.

Efficacy and safety of topical sofpironium bromide gel for the treatment of axillary hyperhidrosis: A phase II, randomized, controlled, double-blinded trial.

BACKGROUND: Primary axillary hyperhidrosis has limited noninvasive, effective, and well-tolerated treatment options. OBJECTIVE: To evaluate the topical treatment of axillary hyperhidrosis with the novel anticholinergic sofpironium bromide. METHODS: A phase II, multicenter, randomized, controlled, double-blinded study. Participants were randomized to 1 of 3 dosages or vehicle, with daily treatment for 42 days. Coprimary end points were the percentage of participants exhibiting ≥1-point improvement in the Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) score by logistic regression, and change in HDSM-Ax as a continuous measure by analysis of covariance. Pair-wise comparisons were 1-sided with α = 0.10. RESULTS: At the end of therapy, 70%, 79%, 76%, and 54% of participants in the 5%, 10%, 15%, and vehicle groups exhibited ≥1-point improvement in HDSM-Ax (P < .05). Least-square mean (SE) changes in HDSM-Ax were -2.02 (0.14), -2.09 (0.14), 2.10 (0.14), and -1.30 (0.14) (all P ≤ .0001). Most treatment-related adverse events were mild or moderate. LIMITATIONS: Not powered to detect changes in gravimetric sweat production. CONCLUSION: Sofpironium bromide gel produced meaningful reductions in hyperhidrosis severity and had an acceptable safety profile.

Conduta terapêutica em pacientes com doença pulmonar obstrutiva crônica: monoterapia ou terapia cominada? / Therapy for chronic obstructive pulmonary disease patients: monotherapy or combination therapy?

Objetivo: Comparar a dupla terapia broncodilatadora com glicopirrônio mais indacaterol à monoterapia com glicopirrônio em pacientes portadores de doença pulmonar obstrutiva crônica. Métodos: Estudo clínico prospectivo, unicêntrico, controlado, cruzado, randomizado e duplo-cego realizado com 14 pacientes com diagnóstico de doença pulmonar obstrutiva crônica grau II. Os participantes receberam cada um dos tratamentos durante 30 dias. Antes de cada terapia, realizou-se período de wash-out por 7 dias, com broncodilador de curta ação. Antes e após cada intervenção, os pacientes passaram por exame de espirometria e responderam ao questionário COPD Assessment Test. Resultados: Observou-se melhora na função pulmonar medida por meio do volume expiratório forçado no primeiro segundo de 19mL (±36) para a monoterapia e 87mL (±33) para a terapia dupla. O ganho foi de 67mL (p=0,042) da associação dos medicamentos em relação ao glicopirrônio isolado. A melhora na qualidade de vida, medida a partir das pontuações do questionário, foi de 4,7 (±8,9) pontos para a monoterapia e 5,2 (±11) pontos para a dupla terapia (p=0,08). Conclusão: Ambos os tratamentos demonstram melhora na função pulmonar dos pacientes.

Objective: To compare dual bronchodilator therapy (Glycopyrronium with Indacaterol) versus Glycopyrronium monotherapy in patients with chronic obstructive pulmonary disease. Methods: This was a prospective, unicentric, controlled, crossover, randomized, and double-blind clinical trial with 14 patients diagnosed with grade II chronic obstructive pulmonary disease. The participants received each treatment during the period of 30 days. Before each therapy, a 7-day wash-out period with a short-acting bronchodilator was instituted. Before and after each intervention, the patients underwent spirometry and answered the COPD Assessment Test questionnaire. Results: An improvement in pulmonary function measured by forced expiratory volume during the first second of 19mL (±36) for monotherapy, and 87mL (±33) for dual therapy was observed. The gain was of 67mL (p=0.042) in the association of the drugs in relation to Glycopyrronium alone. The mean improvement in quality of life measured from the questionnaire scores was 4.7 (±8.9) points for monotherapy and 5.2 (± 11) points for dual therapy (p=0.08). Conclusion: Both treatments show improvement in the patients' pulmonary function.

Identification of Major Esterase Involved in Hydrolysis of Soft Anticholinergic (2R3'R-SGM) Designed From Glycopyrrolate in Human and Rat Tissues.

The glycopyrrolate soft analog, SGM, designed to be easily hydrolyzed into the significantly less active zwitterionic metabolite, SGa, typifies soft drug that reduces systemic side effects (a problem often seen with traditional anticholinergics) following local administration. In this study, hydrolysis of 2R3'R-SGM, the highest pharmacologically active stereoisomer of SGM, was investigated in human and rat tissues. In both species, 2R3'R-SGM was metabolized to 2R3'R-SGa in plasma but was stable in liver and intestine. The half-life of 2R3'R-SGM was found to be 16.9 min and 9.8 min in human and rat plasma, respectively. The enzyme inhibition and stimulation experiments showed that plasma paraoxonase 1 (PON1) is responsible for the hydrolysis of 2R3'R-SGM in humans and rats. The PON1-mediated hydrolysis of 2R3'R-SGM was confirmed in the lipoprotein-rich fractions of human plasma. As PON1 is naturally attached to high-density lipoprotein, it might be absent in topical tissues where 2R3'R-SGM is applied, supporting its local stability and efficacy. The metabolic behavior of 2R3'R-SGM indicates that it is an ideal soft drug to be detoxified as soon as it moves into systemic circulation. Furthermore, the similarity of 2R3'R-SGM metabolism in humans and rats showed that the rat is a suitable animal for preclinical study.

Effects of indacaterol/glycopyrronium (QVA149) on lung hyperinflation and physical activity in patients with moderate to severe COPD: a randomised, placebo-controlled, crossover study (The MOVE Study).

BACKGROUND: Physical activity limitation is common in chronic obstructive pulmonary disease (COPD), and is associated with worse health status, and increased hospitalisation and mortality. Long-acting bronchodilators, either alone or in combination, have been shown to improve exercise intolerance. However, none of these studies were designed with physical activity as primary outcome. This study assessed the effect of indacaterol/glycopyrronium fixed dose combination (IND/GLY) 110/50 µg once daily (OD) versus placebo on lung hyperinflation (inspiratory capacity [IC]) and physical activity in patients with moderate-to-severe COPD. METHODS: In this multicentre, randomised, double-blind, placebo-controlled crossover study, patients received IND/GLY or placebo OD in two 21-day treatment periods (14-day washout between periods). Eligible patients were ≥40 years of age, current or ex-smokers (smoking history ≥10 pack-years), with post-salbutamol forced expiratory volume in 1 s (FEV1) 40-80 % predicted, and FEV1:forced vital capacity <0.70. The co-primary endpoints were peak IC after 21 days and average daily activity-related energy expenditure. Key secondary endpoints were average number of steps per day and the duration of at least moderate activity per day. Peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days were other secondary endpoints. RESULTS: A total of 194 patients were randomised (65.5 % male, mean age 62.8 years, mean FEV1 61.6 % predicted), with 183 (94.3 %) completing the study. Compared with placebo, IND/GLY significantly increased peak IC after 21 days (difference 202 mL, p < 0.0001), activity-related energy expenditure (difference 36.7 kcal/day, p = 0.040), and the average number of steps per day (difference 358, p = 0.029), with a trend towards an improvement in the duration of at least moderate activity (difference 4.4 min, p = 0.264). IND/GLY was associated with statistically significant improvements versus placebo in peak IC and FEV1 on Day 1, and trough IC and FEV1 after 21 days. The incidence of treatment-emergent adverse events was 22.8 % with IND/GLY and 22.9 % with placebo. CONCLUSIONS: In this study, compared with placebo, IND/GLY reduced hyperinflation, and, despite no patient education or lifestyle advice, improved daily physical activity levels. This suggests that IND/GLY has the potential to impact two of the main clinical concerns in the care of patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01996319 .

Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis.

BACKGROUND: Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable. This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers. METHODS: A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers. Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework. RESULTS: A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 µg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks. The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: -14.2, 42.3]), SGRQ total score (0.18 [-1.28, 1.63]), TDI focal score (-0.30 [-0.73, 0.13]), and rescue medication use (0.02 [-0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [-25.3, 159.4]), SGRQ total score (-0.11 [-1.84, 1.61]), and TDI focal score (0.58 [-0.33, 1.50]); and compared with formoterol plus TIO 18 µg on SGRQ total score (-0.68 [-1.77, 0.39]). Results at week 12 were consistent with week 24 outcomes. Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks. CONCLUSION: UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints.

FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease (COPD) if symptoms are not adequately controlled by a single bronchodilator. OBJECTIVES: The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 (indacaterol/glycopyrrolate), a fixed-dose combination of a long-acting ß2-agonist (indacaterol) and a long-acting muscarinic antagonist (glycopyrrolate), compared with its monocomponents and placebo in patients with moderate-to-severe COPD. METHODS: FLIGHT1 and FLIGHT2 were 12-week, identical, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled studies. Patients were randomized (1:1:1:1) to indacaterol/glycopyrrolate (27.5/15.6 µg twice daily), indacaterol (27.5 µg twice daily), glycopyrrolate (15.6 µg twice daily), or placebo, all delivered via the Neohaler device. The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for standardized area under the curve from 0-12 hours for FEV1 at Week 12. Secondary objectives included St. George's Respiratory Questionnaire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo. MEASUREMENTS AND MAIN RESULTS: In total, 2,038 patients were included in the pooled analysis. Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0-12 hours compared with its monocomponents (P < 0.001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P < 0.001). The safety profile was comparable across the treatment groups. CONCLUSIONS: Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01727141 and NCT 0171251).

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

BACKGROUND: The current Global initiative for chronic Obstructive Lung Disease (GOLD) treatment strategy recommends the use of one or more bronchodilators according to the patient's airflow limitation, their history of exacerbations, and symptoms. The LANTERN study evaluated the effect of the long-acting ß2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) dual bronchodilator, QVA149 (indacaterol/glycopyrronium), as compared with the LABA/inhaled corticosteroid, salmeterol/fluticasone (SFC), in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year. METHODS: In this double-blind, double-dummy, parallel-group study, 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were randomized (1:1) to QVA149 110/50 µg once daily or SFC 50/500 µg twice daily for 26 weeks. The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second (FEV1) at week 26. RESULTS: Overall, 676 patients completed the study. The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met. QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 (treatment difference [Δ]=75 mL; P<0.001). QVA149 demonstrated a statistically significant improvement in standardized area under the curve (AUC) from 0 hours to 4 hours for FEV1 (FEV1 AUC0-4h) at week 26 versus SFC (Δ=122 mL; P<0.001). QVA149 and SFC had similar improvements in transition dyspnea index focal score, St George Respiratory Questionnaire total score, and rescue medication use. However, QVA149 significantly reduced the rate of moderate or severe exacerbations by 31% (P=0.048) over SFC. Overall, the incidence of adverse events was comparable between QVA149 (40.1%) and SFC (47.4%). The incidence of pneumonia was threefold lower with QVA149 (0.8%) versus SFC (2.7%). CONCLUSION: These findings support the use of the LABA/LAMA, QVA149 as an alternative treatment, over LABA/inhaled corticosteroid, in the management of moderate-to-severe COPD patients (GOLD B and GOLD D) with a history of ≤1 exacerbation in the previous year.

Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan.

Once-daily dual-bronchodilator therapy with combined indacaterol and glycopyrronium bromide in one device (Ultibro, Breezhaler), often called QVA149, was first approved in 2013 in Japan and Europe. As of November 2014, more than 40 countries had approved this medication except for the USA. This is the first dual bronchodilator in one device. Now, the Breezhaler is the only device that can provide long-acting muscarinic antagonist (glycopyrronium bromide), long-acting beta agonist (indacaterol), and a combination of the two medications (QVA149). The choice among the three medications allows a patient to use the same inhalation device even when the regimen is changed from single-bronchodilator therapy to dual-bronchodilator therapy. In addition, the quick bronchodilation effect and once-daily administration can improve patient adherence to medical treatment for chronic obstructive pulmonary disease (COPD). To our knowledge, as of November 2014, the safety and the efficacy of QVA149 have been evaluated in 14 randomized controlled trials. The 14 trials generally showed good safety profiles, and there were better or not-inferior bronchodilator effects of QVA149 when compared with placebo, or other inhaled medication. According to the Japanese Respiratory Society guidelines, QVA149 is a combination of the two first-line bronchodilators. Our meta-analysis indicated that QVA149 is superior to the salmeterol-fluticasone combination to treat COPD in respect of the frequency of adverse effects, exacerbation, pneumonia, and improvement of trough forced expiratory volume in 1 second (FEV1). Thus, we believe that QVA149 can be a key medication for COPD treatments.

QVA149 (indacaterol/glycopyrronium) for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: The combination of two bronchodilators with different mechanisms of action to treat patients with chronic obstructive pulmonary disease (COPD) is an established medical practice, but the dissimilarities in the onset and duration of action of long-acting ß2-agonists (LABA) and long-acting muscarinic agents (LAMA) and differences in the devices used for the delivery of these drugs make free combinations uncomfortable and unpredictable, especially if focused on adherence to prescribed treatment. Therefore, there is the need for fixed-dose combinations (FDCs) of bronchodilators in a single inhaler. AREAS COVERED: The results of the pivotal Phase III IGNITE and EXPEDITION programs show that QVA149 (indacaterol/glycopyrronium FDC) is able to elicit a significant improvement in lung function and patient-reported outcomes, including breathlessness and rescue medication use, reduced rates of COPD exacerbations and health-related quality of life when compared with current standard of care. Moreover, QVA149 is generally well tolerated, with most adverse events being of mild-to-moderate severity. EXPERT OPINION: Given that the LABA/LAMA coformulation is the most powerful bronchodilator available, QVA149, which has been the first LABA/LAMA FDC to be developed, should be considered central in the maintenance treatment of COPD, and could be a potential option for improving lung function and health status in maintenance-naïve patients.

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.

BACKGROUND: QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting ß2-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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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. TRIAL REGISTRATION NUMBER: NCT01120717.

Indacaterol for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: The need for a rapid onset of action and a long duration of the broncholytic effect is the likely reason for the development of new long-acting ß2-agonists (LABAs) that are fast acting and have true 24 h duration of action. Indacaterol is the archetype of once-daily LABAs and already marketed as a maintenance therapy in patients with moderate to severe chronic obstructive pulmonary disease (COPD). AREAS COVERED: Meta-analyses of published data or pooled analyses of primary data provide good insight into the clinical role of indacaterol in COPD. EXPERT OPINION: The choice of the once-daily bronchodilator to start treatment in a patient with COPD mainly depends on the outcome of interest. Indacaterol is more effective than tiotropium if we consider symptoms or health-related quality of life as the primary outcome. Moreover, in symptomatic patient indacaterol should be preferred to tiotropium because of its rapid onset of action. By contrast, tiotropium appears to be more effective than indacaterol if exacerbations are the expected primary outcome. However, as indacaterol/glycopyrronium fixed-dose combination (QVA149) shows superior efficacy compared to glycopyrronium and tiotropium in patients with moderate to severe COPD, a fundamental question regarding the use of indacaterol that requires clarification is whether it is preferable to start immediately with QVA149 rather than using indacaterol alone.

Pooled safety analysis of the fixed-dose combination of indacaterol and glycopyrronium (QVA149), its monocomponents, and tiotropium versus placebo in COPD patients.

BACKGROUND: To further assess the safety profile of the fixed-dose combination of indacaterol and glycopyrronium (QVA149) and its monocomponents; we investigated the impact of individual patient-level factors and time by integrating the patient-level safety data from the QVA149 clinical programme with relevant information from the independent indacaterol and glycopyrronium safety databases. METHODS: Data from 11,404 patients with chronic obstructive pulmonary disease (COPD) were pooled from 14 clinical studies of QVA149, indacaterol and glycopyrronium of ≥3 month's duration with at least two of the treatment groups: QVA149 110/50 µg, glycopyrronium 50 µg, indacaterol 150 µg, placebo or tiotropium 18 µg. Overall hazard ratio (HR) was assessed between the active treatments and placebo and in various subgroups related to severity of airways obstruction, inhaled corticosteroid use, cardiovascular risk factors, sex, age and body mass index for death, serious cases of cardio- and cerebrovascular (CCV) events, major adverse cardiovascular events (MACEs), pneumonia, COPD exacerbations requiring hospitalisation or atrial flutter/fibrillation (AF/F). RESULTS: The HR for QVA149 versus placebo showed no significant increase in the overall risk for death (HR [95% confidence interval]: 0.93 [0.34-2.54]); CCV events (0.60 [0.29-1.24]); MACE (1.04 [0.45-2.42]); pneumonia (1.10 [0.54-2.25]); COPD exacerbations (0.60 [0.40-0.91]); and AF/F (1.03 [0.49-2.18]). Similar results were observed for indacaterol, glycopyrronium and tiotropium versus placebo for overall risk and in analysed subgroups. CONCLUSIONS: There was no increase in the risk for the investigated safety endpoints for the fixed-dose combination QVA149, and it had a comparable safety profile as its monocomponents and tiotropium versus placebo.