Blood Eosinophils and Response to Maintenance Chronic Obstructive Pulmonary Disease Treatment. Data from the FLAME Trial.

RATIONALE: Post hoc analyses suggest that blood eosinophils have potential as a predictive biomarker of inhaled corticosteroid efficacy in the management of chronic obstructive pulmonary disease (COPD). OBJECTIVES: We prospectively investigated the value of blood eosinophils as a predictor of responsiveness to an inhaled corticosteroid/long-acting ß2-agonist combination versus a long-acting ß2-agonist/long-acting muscarinic antagonist combination for exacerbation prevention. METHODS: We conducted prespecified analyses of data from the FLAME (Effect of Indacaterol Glycopyronium vs Fluticasone Salmeterol on COPD Exacerbations) study, which compared once-daily long-acting ß2-agonist/long-acting muscarinic antagonist indacaterol/glycopyrronium 110/50 µg with twice-daily long-acting ß2-agonist/inhaled corticosteroid salmeterol/fluticasone combination 50/500 µg in patients with one or more exacerbations in the preceding year. Subsequent post hoc analyses were conducted to address further cutoffs and endpoints. MEASUREMENTS AND MAIN RESULTS: We compared treatment efficacy according to blood eosinophil percentage (<2% and ≥2%, <3% and ≥3%, and <5% and ≥5%) and absolute blood eosinophil count (<150 cells/µl, 150 to <300 cells/µl, and ≥300 cells/µl). Indacaterol/glycopyrronium was significantly superior to salmeterol/fluticasone for the prevention of exacerbations (all severities, or moderate or severe) in the <2%, ≥2%, <3%, <5%, and <150 cells/µl subgroups, and at no cutoff was salmeterol/fluticasone superior to indacaterol/glycopyrronium. Furthermore, the rate of moderate or severe exacerbations did not increase with increasing blood eosinophils. The incidence of pneumonia was higher in patients receiving salmeterol/fluticasone than indacaterol/glycopyrronium in both the <2% and ≥2% subgroups. CONCLUSIONS: Our prospective analyses indicate that indacaterol/glycopyrronium provides superior or similar benefits over salmeterol/fluticasone regardless of blood eosinophil levels in patients with COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01782326).

Role of dual bronchodilators in COPD: A review of the current evidence for indacaterol/glycopyrronium.

In this review, we summarize the rationale for combining long-acting bronchodilators in the management of chronic obstructive pulmonary disease (COPD), and the evidence for the long-acting bronchodilator combination indacaterol/glycopyrronium (IND/GLY). Clinical practice guidelines generally recommend the use of long-acting bronchodilators in the treatment of patients with all severities of COPD, either as a first-choice or alternative-choice therapy. Combining classes of long-acting bronchodilators can result in superior improvements in lung function and clinical outcomes compared with bronchodilator monotherapy, as observed in studies of free combinations of long-acting ß2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). LABA/LAMA fixed-dose combinations (FDCs) can also significantly improve lung function, dyspnea, symptoms and health status and reduce exacerbations and rescue medication use versus an inhaled corticosteroid/LABA, with a comparable safety profile and lower incidence of pneumonia. The LABA/LAMA FDC of IND/GLY is approved for use in the management of COPD. This review summarizes the evidence for IND/GLY, including its pharmacodynamic and pharmacokinetic profile, and published efficacy and safety data from clinical trials in patients with COPD. We also explore the unmet needs in COPD and discuss the potential future of COPD management.

New combination bronchodilators for chronic obstructive pulmonary disease: current evidence and future perspectives.

Fixed dose combination (FDC) dual bronchodilators that co-administer a long acting ß2 -adrenoceptor agonist (LABA) and a long acting muscarinic antagonist (LAMA) are a new class of inhaled treatment for chronic obstructive pulmonary disease (COPD). This review focuses on the clinical evidence for the benefit of LABA/LAMA FDCs compared with monocomponent treatments, and also compared with active comparators that are widely used for the treatment of COPD, namely tiotropium and salmeterol-fluticasone. Novel FDC dual bronchodilators include QVA149 and umeclidinium/vilanterol (UMEC/VI). Long term clinical trials show that QVA149 and UMEC/VI are superior to monocomponent therapy in terms of trough forced expiratory volume in 1 s (FEV1), although the FEV1 improvement was limited to approximately 80-90% of the added monocomponent values. This suggests that the effect of combining a LABA and a LAMA is not fully additive. LABA/LAMA FDC were associated with the largest mean changes in symptoms and health status that were above the minimal clinically important difference, in contrast to the monocomponents. Furthermore, these LABA/LAMA FDCs demonstrated superiority over the active comparators tiotropium and salmeterol-fluticasone in terms of trough FEV1 and patient-reported outcomes. LABA/LAMA FDCs offer a simplified means of maximizing bronchodilation for COPD patients, with the improvements in lung function being mirrored by benefits in terms of symptoms and exacerbations. The use of LABA/LAMA FDCs in clinical practice is set to grow and further studies are needed to define their optimal place in treatment guidelines.

Efficacy of Indacaterol/Glycopyrronium in Patients with COPD Who Have Increased Dyspnea with Daily Activities.

Introduction: The Global initiative for chronic Obstructive Lung Disease (GOLD) recommends treating patients with chronic obstructive pulmonary disease (COPD) based on a combined assessment of symptom severity and airflow limitation and/or exacerbation risk. According to GOLD, patients with mild-to-moderate airflow limitation and distressing symptoms such as dyspnea should be treated with a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). If symptoms persist on monotherapy, GOLD recommends a combination of bronchodilators (LABA/LAMA). Methods: We performed a post-hoc analysis of data from two 26-week, prospective clinical trials to investigate the effect of treating patients with moderate-to-severe dyspnea with the once-daily LABA/LAMA combination indacaterol/glycopyrronium (IND/GLY) 110/50 µg compared with placebo, once-daily tiotropium 18 µg, and twice-daily salmeterol/fluticasone propionate (SFC) 50/500 µg. In this analysis, a Baseline Dyspnea Index (BDI) score ≤7 was used to identify dyspneic patients. Results: In dyspneic patients, IND/GLY significantly improved Transition Dyspnea Index (TDI) total scores compared with tiotropium (0.59 units; p<0.05) and SFC (0.97 units; p<0.05), and significantly increased the likelihood of a patient achieving a 1-unit improvement in TDI compared with tiotropium (odds ratio [OR] 1.87; p<0.05). IND/GLY also significantly improved trough forced expiratory volume in 1 second (FEV1) compared with tiotropium and SFC (p<0.001 and p<0.0001, respectively), and significantly reduced rescue medication use compared with tiotropium (p<0.001). Conclusions: Our analysis indicates that IND/GLY provides additional improvements in dyspnea and lung function compared with tiotropium and SFC in dyspneic patients.

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.

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 ß2-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. George's 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.

Symptoms and impact of COPD assessed by an electronic diary in patients with moderate-to-severe COPD: psychometric results from the SHINE study.

BACKGROUND: Symptoms, particularly dyspnea, and activity limitation, have an impact on the health status and the ability to function normally in patients with chronic obstructive pulmonary disease (COPD). METHODS: To develop an electronic patient diary (eDiary), qualitative patient interviews were conducted from 2009 to 2010 to identify relevant symptoms and degree of bother due to symptoms. The eDiary was completed by a subset of 209 patients with moderate-to-severe COPD in the 26-week QVA149 SHINE study. Two morning assessments (since awakening and since the last assessment) and one evening assessment were made each day. Assessments covered five symptoms ("shortness of breath," "phlegm/mucus," "chest tightness," "wheezing," and "coughing") and two impact items ("bothered by COPD" and "difficulty with activities") and were scored on a 10-point numeric scale. RESULTS: Patient compliance with the eDiary was 90.4% at baseline and 81.3% at week 26. Correlations between shortness of breath and impact items were >0.95. Regression analysis showed that shortness of breath was a highly significant (P<0.0001) predictor of impact items. Exploratory factor analysis gave a single factor comprising all eDiary items, including both symptoms and impact items. Shortness of breath, the total score (including five symptoms and two impact items), and the five-item symptom score from the eDiary performed well, with good consistency and reliability. The eDiary showed good sensitivity to change, with a 0.6 points reduction in the symptoms scores (on a 0-10 point scale) representing a meaningful change. CONCLUSION: The eDiary was found to be valid, reliable, and responsive. The high correlations obtained between "shortness of breath" and the ratings of "bother" and "difficulty with activities" confirmed the relevance of this symptom in patients with COPD. Future studies will be required to explore further psychometric properties and their ability to differentiate between 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.

Profile of inhaled glycopyrronium bromide as monotherapy and in fixed-dose combination with indacaterol maleate for the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. The cornerstone of pharmacological treatment for COPD is bronchodilation. Inhaled glycopyrronium bromide is a long-acting muscarinic antagonist developed as a maintenance treatment for patients with COPD. Phase III trials have shown that glycopyrronium produces rapid and sustained bronchodilation with an efficacy similar to tiotropium and is well tolerated, with a low incidence of muscarinic side effects in patients with moderate to severe COPD. A combination of glycopyrronium bromide with indacaterol maleate (QVA149) has recently been approved as a once-daily maintenance therapy in adult patients with COPD. Phase III trials (the IGNITE program) with QVA149 have demonstrated significant improvements in lung function versus placebo, glycopyrronium, and tiotropium in patients with moderate to severe COPD, with no safety concerns of note. Hence QVA149 is a safe treatment option for moderate to severe COPD patients in whom long-acting muscarinic antagonist monotherapy is inadequate.

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.

Pharmacologic rationale, efficacy and safety of the fixed-dose co-formulation of indacaterol and glycopyrronium.

Chronic obstructive pulmonary disease (COPD) is a widespread respiratory disorder, usually characterized by progressive and poorly reversible airflow limitation. Inhaled long-acting bronchodilators, namely LABA (long-acting ß2-adrenergic agonists) and LAMA (long-acting muscarinic receptor antagonists) are the mainstay of COPD treatment. Because the symptoms of many patients with COPD do not satisfactorily improve by using a single, either LABA or LAMA bronchodilator, the synergism of action resulting from the combination of the different bronchodilating mechanisms activated by LABA and LAMA, respectively, can significantly contribute to a better disease control. Based on these clinical and pharmacological considerations, several LABA/LAMA fixed-dose combinations have been developed and experimentally evaluated. Within such a context, the drug co-formulation containing indacaterol and glycopyrronium is probably the LABA/LAMA association which has been most extensively studied during the last few years.

Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study.

INTRODUCTION: QVA149 is a novel, inhaled, once-daily dual bronchodilator containing a fixed-dose combination of the long-acting ß2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium (NVA237), for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the effects of QVA149 on exercise tolerance, hyperinflation, lung function and lung volumes versus placebo and tiotropium. METHODS: Patients with moderate-to-severe COPD were randomized to QVA149 110/50 µg, placebo or tiotropium 18 µg once daily in a blinded, 3-period crossover study for 3 weeks. The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo. RESULTS: Eighty-five patients were randomized; 86% completed the study. QVA149 significantly improved exercise endurance time at Day 21 compared with placebo (least squares mean treatment difference 60 s [p = 0.006]). No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found. Dynamic inspiratory capacity (IC) at exercise isotime, trough forced expiratory volume in 1 s, residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study. The safety profiles were similar across groups. CONCLUSIONS: In patients with moderate-to-severe COPD, once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise. TRIAL REGISTRATION: ClinicalTrials.gov NCT01294787. TAKE HOME MESSAGE: Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD.

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 ß2-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.

Indacaterol/glycopyrronium bromide fixed-dose combination for the treatment of COPD.

Chronic obstructive pulmonary disease (COPD) is a worldwide problem causing prolonged and progressive morbidity as well as premature mortality. Pharmacologic treatment consists primarily in the relief of symptoms and preventing or minimizing the consequences of exacerbations. Central to the pharmacologic management of COPD is the use of bronchodilator therapy. Two major classes of agents are frequently used: ß-adrenoceptor agonists and antimuscarinic agents. These drugs are used mainly in the inhalational form, primarily as rescue medication, but occasionally for maintenance in combination therapy. The availability of "ultra-long"-acting ß-adrenoceptor agonists and long-acting antimuscarinic agents opens the way for combinations of these agents to be used in maintenance therapy. Such a combination offers the potential of enhanced efficacy due to additive effects and better compliance as the result of once-daily treatment. This article reviews the rationale for current bronchodilator therapy of COPD as well as the current status of a fixed-dose combined inhaler using two novel long-acting agents: glycopyrronium bromide and indacaterol maleate.