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      The impact of indacaterol/glycopyrronium fixed-dose combination versus tiotropium monotherapy on lung function and treatment preference: a randomized crossover study – the FAVOR study

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          Abstract

          Background

          The objective of the FAVOR study was to evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus tiotropium on peak forced expiratory volume in 1 s (FEV 1) and also to investigate patient satisfaction and treatment preference.

          Methods

          Patients with moderate-to-severe airflow limitation (FEV 1/forced vital capacity ratio of <0.70), those with a COPD assessment test score of ≥10, and those who were maintained on tiotropium HandiHaler ® therapy prior to enrollment were recruited for the study, and randomized (1:1) to receive either 4 weeks open-label IND/GLY (110/50 μg) once daily followed by 4 weeks of tiotropium (18 μg) once daily or vice versa. The primary endpoint was FEV 1 1 h post-inhalation after 4 weeks of treatment. Other endpoints included patient’s and physician’s preference for treatment, patient’s satisfaction evaluated using a study-specific questionnaire and the abbreviated Treatment Satisfaction Questionnaire for Medication, and safety and tolerability.

          Results

          Eighty-seven out of 88 randomized patients completed the study and showed significantly higher FEV 1 1 h post-inhalation after 4 weeks of treatment with IND/GLY versus tiotropium (treatment difference =0.081 L; p=0.0017). IND/GLY was preferred over tiotropium among the patients (69.4% versus 30.6%, p=0.0004) and the physicians (81.6% versus 18.4%, p<0.0001). A higher proportion of the patients stated they were very satisfied or satisfied with IND/GLY versus tiotropium with regard to dyspnea reduction (79.3% versus 58.0%, respectively) and reduction of dyspnea on exertion (72.4% versus 43.2%, respectively). Patients treated with IND/GLY showed significant improvement in Treatment Satisfaction Questionnaire for Medication domain scores versus tiotropium. IND/GLY demonstrated a good safety and tolerability profile.

          Conclusion

          This study indicated that, beyond FEV 1, important patient-reported outcomes improved with the open-label dual bronchodilator IND/GLY when compared with tiotropium. This study suggests that individual patients felt the lung function benefits with IND/GLY compared with tiotropium, which, in turn, may also have contributed to the preference for IND/GLY.

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          Most cited references 11

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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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            Medication adherence issues in patients treated for COPD

            Although medical treatment of COPD has advanced, nonadherence to medication regimens poses a significant barrier to optimal management. Underuse, overuse, and improper use continue to be the most common causes of poor adherence to therapy. An average of 40%–60% of patients with COPD adheres to the prescribed regimen and only 1 out of 10 patients with a metered dose inhaler performs all essential steps correctly. Adherence to therapy is multifactorial and involves both the patient and the primary care provider. The effect of patient instruction on inhaler adherence and rescue medication utilization in patients with COPD does not seem to parallel the good results reported in patients with asthma. While use of a combined inhaler may facilitate adherence to medications and improve efficacy, pharmacoeconomic factors may influence patient’s selection of both the device and the regimen. Patient’s health beliefs, experiences, and behaviors play a significant role in adherence to pharmacological therapy. This manuscript reviews important aspects associated with medication adherence in patients with COPD and identifies some predictors of poor adherence.
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              Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease

              Chronic obstructive pulmonary disease (COPD) represents a significant cause of global morbidity and mortality, with a substantial economic impact. Recent changes in the Global initiative for chronic Obstructive Lung Disease (GOLD) guidance refined the classification of patients for treatment using a combination of spirometry, assessment of symptoms, and/or frequency of exacerbations. The aim of treatment remains to reduce existing symptoms while decreasing the risk of future adverse health events. Long-acting bronchodilators are the mainstay of therapy due to their proven efficacy. GOLD guidelines recommend combining long-acting bronchodilators with differing mechanisms of action if the control of COPD is insufficient with monotherapy, and recent years have seen growing interest in the additional benefits that combination of long-acting muscarinic antagonists (LAMAs), typified by tiotropium, with long-acting β2-agonists (LABAs), such as formoterol and salmeterol. Most studies have examined free combinations of currently available LAMAs and LABAs, broadly showing a benefit in terms of lung function and other patient-reported outcomes, although evidence is limited at present. Several once- or twice-daily fixed-dose LAMA/LABA combinations are under development, most involving newly developed monotherapy components. This review outlines the existing data for LAMA/LABA combinations in the treatment of COPD, summarizes the ongoing trials, and considers the evidence required to inform the role of LAMA/LABA combinations in treatment of this disease.
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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
                2018
                22 December 2017
                : 13
                : 69-77
                Affiliations
                [1 ]Pulmonary Department, Respiratory and Sleep Medicine at Red Cross Maingau Hospital, Group Practice Allergy, Frankfurt, Germany
                [2 ]Novartis Pharma GmbH, Nuremberg, Germany
                Author notes
                Correspondence: Peter Kardos, Pulmonary Department, Respiratory and Sleep Medicine at Red Cross Maingau Hospital, Group Practice Allergy, Scheffelstrasse 33, 60318 Frankfurt am Main, Germany, Tel +49 691 505 3976, Email kardos@ 123456lungenpraxis-maingau.de
                Article
                copd-13-069
                10.2147/COPD.S146189
                5744738
                © 2018 Kardos and Hagedorn-Peinz. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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