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      Specific role of combination aclidinium: formoterol in the treatment of chronic obstructive pulmonary disease

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          Abstract

          Co-administration of a long-acting β 2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β 2-agonist fixed-dose combination that has been studied for this therapeutic indication.

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          Most cited references 47

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          Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study

          Introduction Bronchodilators are the cornerstone of symptomatic management of chronic obstructive pulmonary disease (COPD) [1]. Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate-to-very-severe COPD [1]. The use of two bronchodilators with different mechanisms of action has been shown to provide additional benefits compared with either given alone, without significantly increasing side-effects [2, 3]. Both indacaterol, a long-acting β2-agonist (LABA), and tiotropium, a long-acting muscarinic antagonist (LAMA), are effective as monotherapies and have acceptable safety profiles [4, 5]. In addition, their concurrent use has been shown to provide superior bronchodilation and improvement in air trapping compared with tiotropium alone [6]. Glycopyrronium (NVA237) is a recently approved once-daily LAMA for the treatment of moderate-to-severe COPD, and has been shown to provide rapid and sustained improvements in lung function, dyspnoea, health status, exercise endurance and exacerbation risk, with improvements similar to tiotropium and a safety profile similar to placebo [7–9]. QVA149 is a novel once-daily dual bronchodilator containing a fixed dose of the LABA indacaterol with the LAMA glycopyrronium. In patients with COPD, QVA149 has demonstrated rapid and sustained bronchodilation, which is significantly superior to that observed with indacaterol alone or placebo, and it is well tolerated, with an adverse event profile similar to placebo [10, 11]. In the current SHINE study, we sought to confirm the “rule of combination” [12] that dual bronchodilation with QVA149 will provide additional therapeutic benefits compared to the monocomponents indacaterol and glycopyrronium, as well as compared to tiotropium, the current gold standard of care, and placebo in patients with moderate-to-severe COPD. Methods Study design The study was a multicentre, randomised, double-blind, parallel-group, placebo- and active-controlled 26-week trial, and comprised a washout, run-in and the 26-week treatment period, with 30 days of follow-up after the last visit (fig. 1). The first patient’s first visit was September 21, 2010, and the last patient’s last visit was February 10, 2012. Patients receiving fixed-dose combinations of LABA/inhaled corticosteroid (ICS) were switched to an equivalent dose of ICS monotherapy. After screening, eligible patients were randomised in a 2:2:2:2:1 ratio (via interactive response technology) to treatment with double-blind QVA149 (indacaterol 110 μg/glycopyrronium 50 μg), indacaterol 150 μg, glycopyrronium 50 μg, open-label tiotropium 18 μg or placebo. All medications were administered once daily in the morning via the Breezhaler® (Novartis Pharma AG, Stein, Switzerland) device except for tiotropium, which was administered via the HandiHaler® (Boehringer Ingelheim, Ingelheim, Germany) device. A salbutamol/albuterol pressurised metered-dose inhaler was provided as rescue medication. Additional details of the study design and randomisation/blinding procedures are included in the online supplementary material. Figure 1– The SHINE study design. Patients Participants were aged ≥40 years, had moderate-to-severe stable COPD (stage II or III according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008 criteria [13]) and a smoking history of ≥10 pack-years. At screening, they were required to have a post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and 100 mL or >200 mL in trough FEV1 at week 26). Figure 3– Trough forced expiratory volume in 1 s (FEV1) a) at week 26 and b) over the entire 26-week treatment period. a) Data are presented as least squares mean±se. One-sided adjusted p-values are presented for comparisons in the statistical gatekeeping procedure and two-sided p-values are presented for all other comparisons. b) QVA149 was superior to all active treatments and placebo at all timepoints (all p 30 days after the last dose of study drug but before the end of the follow-up visit (indacaterol (n = 1): pneumonia and glycopyrronium (n = 1): colon cancer). None of the deaths were considered by the investigator to be related to the study drug. Discussion Combining two bronchodilators with different mechanisms of action has the potential to enhance efficacy compared with single agents without increasing adverse effects [2, 3]. In the SHINE study, dual bronchodilation with QVA149, administered once-daily, provided superior improvements in lung function compared with its monocomponents indacaterol and glycopyrronium given alone, as well as tiotropium and placebo. Improvement in the primary end-point, trough FEV1 was both statistically and clinically significant (considered to be ≥100 mL in COPD) over placebo, and versus active comparators it approached clinical significance. Furthermore, lung function improvements with QVA149 were superior at their peak and, in a subset of patients monitored over 24 h, throughout the day. Similar trends to the overall population were observed in subgroup analyses. Improvements in lung function versus placebo were greater in patients with moderate versus severe COPD; however, statistically and clinically significant improvements in trough FEV1 were seen for both moderate and severe patient subgroups. Improvements in lung function were not influenced by patient age, sex or concurrent use of ICS. Furthermore, they were maintained throughout the 26-week treatment period, and the onset of action of QVA149 was confirmed to be rapid, similar to that of a short-acting β2-agonist. These beneficial effects of QVA149 on lung function were paralleled by statistically significant improvements in other clinically important end-points: dyspnoea, health status and patient symptoms and reduced rescue medication use. QVA149 was significantly superior to placebo and tiotropium for both the TDI and SGRQ total score at week 26; no other active treatment achieved a significant improvement in SGRQ versus placebo. Furthermore, a significantly higher proportion of patients on QVA149 achieved a clinically meaningful improvement in TDI (≥1 unit) and SGRQ (≥4 units) versus placebo and tiotropium. QVA149 was well tolerated over the 26-week study with an adverse event profile similar to that of placebo. In addition, no actual or potential safety signals were observed with the combination compared with the single bronchodilators. Despite previous concerns that LABAs and LAMAs may present a risk of cardiovascular events [14–17], the CCV safety profile of this LABA/LAMA combination was similar to that of placebo. The results of this study are consistent with those of several published studies that have investigated the efficacy and safety of free combinations of LABAs and LAMAs in patients with COPD [6, 18–20], but this is the first to demonstrate the additive benefit of the two classes of long-acting bronchodilator in a combination device. Previous studies have been limited by different durations of actions of the LAMA and LABA components (i.e. formoterol or salmeterol having to be administered twice daily). Our study confirms that the additive benefit of indacaterol and glycopyrronium persists over 24 h, without tachyphylaxis, providing further support for the use of dual bronchodilators. The present study supports the GOLD 2013 strategy alternative choice recommendation that the addition of a second bronchodilator in patients with moderate-to-severe COPD (groups B–D) may optimise symptom benefit [1]. In “low-risk” patients who remain symptomatic on a single bronchodilator (group B), the combination of indacaterol plus glycopyrronium in a single inhaler may lead to significantly improved outcomes compared with LABA or LAMA monotherapy. In “high-risk” patients with severe or very severe COPD (high symptom level and historical exacerbation frequency; groups C and D in the GOLD management strategy [1]) a LABA plus a LAMA is recommended as an alternative to a LABA/ICS combination (group C) or ICS plus LABA and/or LAMA (group D). In comparing LABA plus LAMA and LABA/ICS combination, improvements in lung function achieved with two bronchodilators are expected to be numerically superior to the single bronchodilator in LABA/ICS combinations. In the TORCH (Towards a Revolution in COPD Health) study, combination therapy achieved 50 mL and 44 mL improvement in FEV1 versus salmeterol and fluticasone propionate alone, respectively; however, the LABA/ICS combination is selected for its demonstrated effect on COPD exacerbations [21]. A real-world analysis has indicated that a high proportion of patients at low risk for exacerbations (groups A or B) may be receiving ICS inappropriately [22]. Some patients currently receiving combined LABA/ICS may do better on a LABA/LAMA combination [23]. This would provide dual bronchodilation without the need for ICS treatment, and therefore without the inherent risks of ICS [24], as recommended by the GOLD 2013 strategy [1]. The 26-week ILLUMINATE study supports the use of QVA149 versus LABA/ICS in this population [25]. QVA149 once daily was associated with significant improvements in lung function and dyspnoea versus twice-daily salmeterol/fluticasone. Furthermore, the current SHINE study provides evidence for the additive benefit and safety of a LABA/LAMA combination, demonstrating that QVA149 is superior for most end-points over tiotropium, which is currently recommended as an alternative to LABA/ICS combination, alone or in combination with a LABA. Features of QVA149 that may help to reduce nonadherence to treatment, which remains high in COPD [26], are the convenience of once-daily dosing [27] which is generally preferred by patients [26, 28, 29] and the need for only a single inhaler. Furthermore, the rapid onset of action may be evident to patients as they wake at the nadir of their daily lung function cycle when symptoms are most prominent [30]. However, these advantages of a LABA/LAMA combination and QVA149 are speculative and need to be tested in further prospective studies. We acknowledge several limitations in our study. Firstly, with regards to the study population, we did not intend to include the full range of COPD severities that might benefit from dual long-acting bronchodilators. Since our main objective was to assess the incremental benefit of two bronchodilators in combination (versus one), we elected to recruit only patients with moderate-to-severe COPD. As in our study, results of studies involving LABA/ICS combinations (e.g. the TORCH study [21]) and tiotropium (e.g. the UPLIFT study [31]), have confirmed that patients with moderate disease showed the greatest improvements in lung function. The apparent high reversibility of FEV1 (20%) is attributable to the fact that both salbutamol and ipratropium were administered during this test, and reversibility of this magnitude is not unusual in moderate COPD. We went to lengths to exclude patients with asthma (inclusion criteria: age of onset of symptoms >40 years, absence of rhinitis and blood eosinophil count of <600 cells·mm−3 (see the online supplementary material)). Finally, unlike most COPD studies, which enrich for patients with exacerbations, in our study we excluded patients with a recent COPD exacerbation (in the previous 6 weeks) to reduce the impact of withdrawal due to exacerbations on the primary spirometric end-point. For this reason, along with the fact that patients had milder disease and the study was relatively short (6 months), the present study does not provide useful information on the effect of QVA149 on COPD exacerbations, which has been examined in studies of appropriate design (SPARK study [32]). A further limitation of our study is the difficulty in evaluating the clinical significance of spirometric and other clinical end-points (TDI and SGRQ) versus active (monocomponent) treatments. Although statistically superior to all monocomponents, QVA149 attained the MCID for only some comparisons (fig. 3 and online supplementary table S3). However, it should be noted that the MCID for a trough FEV1 of 100 mL is generally used for comparisons versus placebo, and that the mean improvements of 70, 80 and 90 mL versus indacaterol, glycopyrronium and tiotropium, respectively, approach this threshold value; comparative data for TDI and SGRQ also support this trend. In conclusion, once-daily QVA149 demonstrated superior efficacy compared with placebo, its monocomponents indacaterol and glycopyrronium, and the current standard of care (tiotropium) in patients with moderate-to-severe COPD. QVA149 was also associated with an adverse event profile that was similar to placebo with no additional safety signal compared with monotherapies. This is the first study to demonstrate the advantage of dual bronchodilation with a fixed-dose LABA/LAMA combination, compared with a single bronchodilator in patients with moderate-to-severe COPD.
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            Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.

            Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD. In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg, UMEC 62·5 μg plus VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV1) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2). 1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. In both studies, we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 μg plus VI 25 μg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 μg plus VI 25 μg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 μg plus VI 25 μg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy (UMEC 125 μg plus VI 25 μg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 μg monotherapy (UMEC 125 μg plus VI 25 μg: 0·037 L [-0·012 to 0·087; p=0·14]; UMEC 62·5 μg plus VI 25 μg: 0·022 L [-0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1-4 [<1-2%] patients across treatment groups in study 1 and 1-6 [<1-3%] patients in study 2). We recorded five to 15 (2-7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4-10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups. Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD. GlaxoSmithKline. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey.

              To determine diurnal variability of symptoms in chronic obstructive pulmonary disease (COPD) and to assess the impact of COPD upon patients' morning activities and routines. Quantitative internet interviews with 803 COPD patients from Europe and the USA, including 289 patients with severe COPD. Severe COPD was defined according to regular use of COPD medication, third level of breathlessness or above using the modified Medical Research Council (MRC) dyspnoea scale (MRC dyspnoea score > or =3) and one or more COPD exacerbations in the preceding 12 months. Morning was the worst time of day for COPD symptoms, particularly in patients with severe COPD (reported by 46% of severe patients). In these patients, shortness of breath was the most frequently reported symptom, correlating strongly with problems experienced with morning activities. Morning activities most affected by COPD were walking up and down stairs, putting on shoes and socks, making the bed, dressing, showering or bathing and drying. The majority of patients were not taking their medication in time for it to exert its optimal effect. Many patients consider the impact of COPD on morning activities to be substantial. Physicians should question patients about morning activities to assess disease impact and to advise regarding the optimal time to use therapy. This was an internet-based questionnaire survey and possible bias in patient selection and self-reported diagnosis of COPD and its severity should be taken into account.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2016
                05 January 2016
                : 11
                : 73-79
                Affiliations
                [1 ]Department of Experimental Medicine, Second University of Naples, Naples, Italy
                [2 ]Department of Respiratory Diseases, Monaldi Hospital, University Federico II, Naples, Italy
                [3 ]Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
                Author notes
                Correspondence: Maria Gabriella Matera, Department of Experimental Medicine, Second University of Naples, via Santa Maria di Costantinopoli, 16, 80138 Naples, Italy, Email mariagabriella.matera@ 123456unina2.it
                Article
                copd-11-073
                10.2147/COPD.S78000
                4708173
                © 2016 Matera et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Respiratory medicine

                symptoms, aclidinium, formoterol, fixed-dose combination, copd

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