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Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33

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Pulmonary Pharmacology & Therapeutics

journal homepage: www.elsevier .com/locate/ypupt

Role of dual bronchodilators in COPD: A review of the currentevidence for indacaterol/glycopyrronium

Joachim H. Ficker a, b, *, Klaus F. Rabe c, Tobias Welte d

a Department for Respiratory Medicine, Allergology and Sleep Medicine, Nuernberg General Hospital, Nuremberg, Germanyb Department for Respiratory Medicine, Allergology and Sleep Medicine, Paracelsus Medical University Nuernberg, Nuremberg, Germanyc Lung Clinic Grosshansdorf, and Department of Medicine Christian Albrecht University Kiel, Kiel, Germanyd Department of Pulmonary and Infectious Diseases at Hannover University School of Medicine, Hannover, Germany

a r t i c l e i n f o

Article history:Received 27 January 2017Received in revised form29 March 2017Accepted 1 April 2017Available online 4 April 2017

Keywords:COPDDual bronchodilationGlycopyrroniumHumanIndacaterolQVA149

* Corresponding author. Medical Department for RNathan-Str. 1, 90419 Nürnberg, Germany.

E-mail address: ficker@klinikum-nuernberg.de (J.H

http://dx.doi.org/10.1016/j.pupt.2017.04.0021094-5539/© 2017 The Authors. Published by Elsevie

a b s t r a c t

In this review, we summarize the rationale for combining long-acting bronchodilators in the manage-ment of chronic obstructive pulmonary disease (COPD), and the evidence for the long-acting broncho-dilator combination indacaterol/glycopyrronium (IND/GLY). Clinical practice guidelines generallyrecommend the use of long-acting bronchodilators in the treatment of patients with all severities ofCOPD, either as a first-choice or alternative-choice therapy. Combining classes of long-acting broncho-dilators can result in superior improvements in lung function and clinical outcomes compared withbronchodilator monotherapy, as observed in studies of free combinations of long-acting b2-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 exacer-bations and rescue medication use versus an inhaled corticosteroid/LABA, with a comparable safetyprofile and lower incidence of pneumonia. The LABA/LAMA FDC of IND/GLY is approved for use in themanagement of COPD. This review summarizes the evidence for IND/GLY, including its pharmacody-namic and pharmacokinetic profile, and published efficacy and safety data from clinical trials in patientswith COPD. We also explore the unmet needs in COPD and discuss the potential future of COPDmanagement.© 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license

(http://creativecommons.org/licenses/by/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202. Why combine a LABA and LAMA? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

2.1. Mechanistic rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.2. Clinical evidence with free combinations of a LABA and a LAMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.3. The rationale for LABA/LAMA FDCs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

3. IND/GLY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.1. Pharmacodynamic and pharmacokinetic profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3.1.1. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.1.2. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3.2. Dosing and administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.3. Clinical trial evidence of the efficacy of IND/GLY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

3.3.1. Lung function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.3.2. Dyspnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223.3.3. Health status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243.3.4. Patient symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

espiratory Medicine, Allergology and Sleep Medicine, Klinikum Nuernberg/Paracelsus Medical University, Prof. Ernst-

. Ficker).

r Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e3320

3.3.5. Rescue medication use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253.3.6. COPD exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273.3.7. Exercise tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

3.4. Clinical trial evidence of the safety and tolerability of IND/GLY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294. Expert opinion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Author disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

1. Introduction

The core aims of pharmacologic management of chronicobstructive pulmonary disease (COPD), as stated in global recom-mendations, are to reduce symptoms and risk [1,2]. Bronchodila-tors, which are central to COPD management, provideimprovements in lung function and reductions in symptoms andexacerbations [1e3]. The purpose of this review is to discuss therationale for combining two classes of bronchodilators (a long-acting b2-agonist [LABA] and a long-acting muscarinic antagonist[LAMA]), in a fixed-dose combination (FDC) and to discuss theavailable efficacy and safety data. Specifically, we will provide acomprehensive summary of data for the once-daily LABA/LAMAcombination indacaterol maleate (IND)/glycopyrronium bromide(GLY), which is administered via a single inhaler device. Lastly, wewill discuss future possibilities related to combined bronchodilatortherapy for COPD, and the unmet needs in COPD management.

2. Why combine a LABA and LAMA?

Bronchodilator monotherapy may not provide adequate symp-tom control in COPD [2]. Guidance from local and global bodiesacknowledges that combining bronchodilator treatments withdifferent mechanisms may be clinically beneficial, and thereforerecommend the use of combination treatments based on anassessment of symptoms, spirometry, risk of exacerbations, orphenotype [2e5].

2.1. Mechanistic rationale

b2-agonists and muscarinic antagonists target different molec-ular pathways to achieve bronchodilation [6,7]. Bronchodilationmay be induced at the pre-and post-synaptic level either directly(through stimulation of b2-receptors with b2-agonists) or indirectly(by inhibiting the action of acetylcholine [ACh] at muscarinic re-ceptors with muscarinic antagonists; Fig. 1) [8]. LABAs act on b2-adrenergic receptors, which are expressed abundantly on humanairways smooth muscle [6]. Activation of b2-adrenergic receptorsresults in increased levels of cyclic adenosine monophosphate(cAMP), leading to the conversion of protein kinase A (PK-A) froman inactive to an active form. PK-A then promotes smooth musclerelaxation and bronchodilation [6]. LAMAs prevent the binding ofthe neurotransmitter ACh (released by post-ganglionic, para-sympathetic cholinergic nerves) to muscarinic receptors. Bron-choconstriction is mediated by the activation of muscarinic type 1(M1) and type 3 (M3) receptors; the activation of inhibitory type 2(M2) receptors triggers feedback inhibition of ACh release [9]. Thebinding of ACh to M3 receptors results in the formation of diac-ylglycerol, which activates protein kinase C (PK-C) [10]. ACh bindingalso leads to an increase in intracellular calcium; both activated PK-C and increased intracellular calcium lead to airway smooth musclecontraction [10].

b2-adrenergic receptors appear abundant in the small airways[11], whereas historically, M3 receptors have been described topredominate in the lower trachea and bronchi [12]. Althoughstudies employing more advanced techniques are needed toexplore such findings, it is possible that by predominantly actingat different sites of the respiratory tract, a combination of a b2-agonist and a muscarinic antagonist could maximize the bron-chodilator response [6]. Additionally, a complementary interac-tion between cholinergic and adrenergic pathways in airwaysmooth muscle has been suggested by in vitro studies. Addition ofa b2-agonist to a muscarinic antagonist decreased the release ofACh via modulation of cholinergic neurotransmission by pre-junctional b2-adrenergic receptors [13], amplifying bronchialsmooth muscle relaxation induced by a muscarinic antagonist[14]. Moreover, ACh may control adenylyl cyclase via post-junctional M2-receptors on airway smooth muscle, resulting in adecrease in cAMP and smooth muscle contraction [15]. Thebinding of muscarinic antagonist to the M2-receptor would pre-vent this cascade, allowing the increase of cAMP levels via b2-agonist binding to b2-adrenergic receptors [15].

The potential interaction between cholinergic and adrenergicpathways in airway smooth muscle has been explored ex vivo onisolated human bronchi and in vivo in patients with COPD [16,17].The results indicated an improvement in relaxation of both me-dium and small airways following concomitant administration ofa LAMA and LABA versus either agent alone [16,17]. The interac-tion between IND and GLY has also been studied in human iso-lated bronchi, small airways and bronchial epithelial cells [18]. Inthis study, co-administration of the two medications was shownto produce a synergistic improvement in bronchodilation byinhibiting release of non-neuronal ACh from the bronchialepithelium, and by increasing cAMP concentrations in the airwaysmooth muscle and bronchial epithelium [18]. Further studiescharacterizing the pharmacologic interaction between LAMAs andLABAs on human bronchi are required to evaluate the potential forsynergism. There is also a requirement for clinical studies toconfirm or refute preclinical evidence of synergy at clinicallyrelevant doses; however, post-hoc analysis of data from clinicaltrials indicates that an additive effect exists with regards tobronchodilation [15].

2.2. Clinical evidence with free combinations of a LABA and a LAMA

An FDC of short-acting bronchodilators is well established foreffective short-term relief and has been a standard in manycountries for approximately 20 years [19]. Clinical data demon-strating the efficacy and tolerability of free LABA plus LAMAcombinations in patients with COPD also support the rationale foran FDC of long-acting bronchodilators [20]. Tiotropium in freecombination with formoterol, salmeterol or IND provided supe-rior outcomes in lung function, dyspnea and rescue medicationuse compared with tiotropiummonotherapy [21e27]. In addition,

Fig. 1. Mechanisms of bronchodilatory action of b2-adrenergic receptor agonists and muscarinic antagonists [8].The mechanism of action of b2-adrenergic receptor agonists and muscarinic antagonists is complex involving the reciprocal influences of cholinergic and adrenergic systems at boththe pre- and post-synaptic level. At the post-synaptic level, this includes: (1) activation of b2-AR; (2) block of the M3 muscarinic receptor; and (3) inhibition of Gi-coupled M2muscarinic receptors. At the pre-synaptic level, this includes: (4) inhibition of the M2 muscarinic receptor which may increase ACh release into the pre-synaptic space; and (5) b2-agonist-modulated reduction in cholinergic neurotransmission via KCaþþ channels. These combined mechanisms inhibit smooth muscle cell contraction and promote smoothmuscle relaxation and bronchodilation.AC ¼ adenylyl cyclase; ACh ¼ acetylcholine; ATP ¼ adenosine triphosphate; AMP ¼ adenosine monophosphate; b2-AR ¼ b2-adrenergic receptor; cAMP ¼ cyclic adenosinemonophosphate; CNS ¼ central nervous system; DAG ¼ diacylglycerol; Gs ¼ stimulatory G-protein; IP3 ¼ inositol triphosphate; KCaþþ ¼ calcium-activated potassium;M ¼ muscarinic receptor type; PK-(A) ¼ protein kinase (A); PK-(C) ¼ protein kinase C; PLC ¼ phospholipase C. Reprinted from European Journal of Pharmacology 761; Calzetta L,Gabriella Matera M, Cazzola M. Pharmacological interaction between LABAs and LAMAs in the airways: optimizing synergy, Copyright (2015), with permission from Elsevier.

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33 21

a free combination of IND and GLY significantly improved lungfunction and dyspnea compared with IND monotherapy, withoutany additional safety concerns [28]. Indeed it was demonstratedthat combining IND and GLY in an FDC was non-inferior to a freecombination of IND and GLY in improving lung function andsymptomatic endpoints [29], and was non-inferior to a freecombination of tiotropium and formoterol in improving healthstatus, with significant improvements observed in lung functionand dyspnea [30].

2.3. The rationale for LABA/LAMA FDCs

A LABA/LAMA FDC, delivered via a single inhaler, may be moreconvenient for patients compared with a free combination fromtwo different inhalers and could potentially improve treatmentadherence [31]. There are a number of LABA/LAMA FDCs availablefor COPD management, including IND/GLY, vilanterol/umeclidi-nium, formoterol/aclidinium and olodaterol/tiotropium. In addi-tion, a formoterol/GLY FDC is in Phase III development [32].

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e3322

3. IND/GLY

A combination of IND (110 mg) and GLY (50 mg), delivered via asingle inhaler device, was the first once-daily LABA/LAMA FDC to beapproved in the EU for COPD management [33].

3.1. Pharmacodynamic and pharmacokinetic profiles

The pharmacodynamic and pharmacokinetic profiles of IND/GLYreflect those of its component agents.

3.1.1. PharmacodynamicsIND and GLY each have a rapid onset and sustained duration of

action in vitro and in animal models [34e37]. In patients withCOPD, both IND and GLY monotherapy provided improvements inlung function five minutes after the first dose that were signifi-cantly superior to placebo and tiotropium [38e40]. A Phase II studyof IND/GLY 300/50 mg demonstrated that IND/GLY provided a sig-nificant increase in FEV1 5 min post-dose and at all post-dosetimepoints compared with IND monotherapy and placebo [41].IND/GLY 110/50 mg also provided significant improvements in lungfunction at 5 min post-dose compared with placebo, GLY and tio-tropium [42] and the LABA/inhaled corticosteroid (ICS) salmeterol/fluticasone propionate combination (SFC) [43]. Significant im-provements in lung function were sustained over the majority oftimepoints in a 24-h dosing interval with IND/GLY versus placebo,the monocomponents and tiotropium [42].

3.1.2. PharmacokineticsThe pharmacokinetic properties of IND and GLY are displayed in

Table 1 [44].Co-administration of IND and GLY has no effect on the

pharmacokinetics of either drug at steady state [44]. Warningsagainst contraindications include co-administration with otheranticholinergic medicinal products, other sympathomimetic agentsor hypokalemic treatment [44].

3.2. Dosing and administration

The recommended dose of IND/GLY is the contents of onecapsule, once daily, inhaled via the Breezhaler® device [44]. TheBreezhaler® device has a low airflow resistance and can be used bypatients with a range of airflow limitation severities [45]. Eachcapsule of IND/GLY contains 110 mg IND and 50 mg GLY (themeteredor measured dose), which delivers a dose of 85 mg IND and 43 mgGLY [44]. The metered dose of IND monotherapy is higher (150 mg)than in the FDC due to the use of magnesium stearate in the IND/GLY Breezhaler® but not in the IND Breezhaler® [46]. Magnesiumstearate improves dispersion such that the fine particle massdelivered with 110 mg IND in IND/GLY is equivalent to that achievedwith 150 mg IND monotherapy [46,47]. The equivalence of the twodose formulations was confirmed in a randomized, double-blind,parallel-group study (BEACON), in which trough forced expiratory

Table 1Summary of pharmacokinetic parameters of IND/GLY monocomponents [

Pharmacokinetic parameter

Median time to reach peak plasma concentrations (min)Absolute bioavailability (% of delivered dose)Time taken to reach steady state following dosing (days)Volume of distribution during the terminal elimination phase (L)Renal clearance (%)Average terminal half-life (hours)

GLY ¼ glycopyrronium.IND ¼ indacaterol.

volume in 1 s (FEV1) differed by only 5 mL with the free combi-nation (IND 150 mg plus GLY 50 mg) versus IND/GLY FDC (110/50 mg)[29].

3.3. Clinical trial evidence of the efficacy of IND/GLY

The efficacy and safety of IND/GLY 110/50 mg were evaluated inthe IGNITE clinical trial program (Table 2). The following sectionprovides a summary of data from ten IGNITE trials that have beencompleted and published so far (SHINE [42], ILLUMINATE [43],BEACON [29], BRIGHT [48], ENLIGHTEN [49], SPARK [50], ARISE[51], BLAZE [52], LANTERN [53], and FLAME [54]) as well as anothertrial outside of the IGNITE program, a health-status study (QUAN-TIFY) that compared the effects of IND/GLY (110/50 mg) versus tio-tropium (18 mg) plus formoterol (12 mg twice daily) on health status[30].

3.3.1. Lung functionImprovements were observed across a range of lung function

measures with IND/GLY compared with placebo, the mono-components, tiotropium (blinded and open label [OL]), SFC andblinded tiotropium plus formoterol (Table 3A and B). Significantimprovements in trough FEV1 were observed with IND/GLYcompared with placebo, the monocomponents and tiotropium(Fig. 2), as well as SFC and tiotropium plus formoterol, all of whichwere sustained throughout the studies [30,42,43,49,50,53,54].Significant improvements were also observed in peak FEV1 andFEV1 area under the curve from 0 to 12 h (AUC0e12h) with IND/GLYcompared with placebo, the monocomponents, tiotropium and SFC(Fig. 3) [42,43,52e54]. IND/GLY provided 24-h bronchodilationcomparedwith placebo, themonocomponents, tiotropium and SFC,with a rapid onset of action [42,43,52].

IND/GLY was also associated with significant improvements inbody plethysmography measurements compared with placebo andtiotropium, indicating a reduction in hyperinflation and airwayresistance [48]. IND/GLY significantly and consistently improvedstatic and dynamic inspiratory capacity comparedwith placebo andtiotropium [48].

3.3.2. DyspneaIND/GLY demonstrated beneficial effects on dyspnea, reflecting

improvements seen in lung function (Table 4A and B). IND/GLYsignificantly improved Transition Dyspnea Index (TDI) total scoreand increased the proportion of patients achieving the clinicallyimportant difference of �1-unit improvement [55] compared withplacebo, OL tiotropium (Fig. 4) and SFC [42,43]. A significantlyhigher proportion of patients receiving IND/GLYachieved a�1-unitimprovement in TDI total score than those receiving tiotropiumplus formoterol [30]. IND/GLY also provided significant and clini-cally meaningful improvements in self-administered computerizedTDI compared with placebo and blinded tiotropium (the primaryendpoint in BLAZE) [52].

44].

IND GLY

15 561e85% ~47%12e15 72557 3762e5 60e7045.5e126 33e57

Table 2Overview of completed IND/GLY Phase III clinical studies.

Study title Study design Patient population N Treatment arms Duration Primary endpoint Key finding(Primary endpoint)

SHINE [42](A2303)

NCT01202188

MC, R, DB, OL(TIO), PG, PC,AC

Moderate-to-severe COPD(FEV1 �30% and <80%predicted) and symptomatic(total daily symptom score �1on �4 of the 7 days prior torandomization)

475477475483234(Total2144)

IND/GLY 110/50 mg q.d.IND 150 mg q.d.GLY 50 mg q.d.OL TIO 18 mg q.d.Placebo(2:2:2:2:1)

26 weeks Mean trough FEV1 at Week 26 vsmonocomponents

Trough FEV1 wassignificantly improvedwith IND/GLY vsmonocomponents atWeek 26

ILLUMINATE[43](A2313)

NCT01315249

MC, R, DB, DD,PG, AC

Moderate-to-severe COPD(FEV1 �40% and <80%predicted) and symptomatic(total daily symptom score �1on �4 of the 7 days prior torandomization); no COPDexacerbation requiringtreatment with antibiotics,systemic corticosteroids and/orhospitalization in the previousyear

259264(Total523)

IND/GLY 110/50 mg q.d.SFC 50/500 mg b.i.d.(1:1)

26 weeks FEV1 AUC0e12h at Week 26 vs SFC IND/GLY providedsignificantly superiorimprovements in FEV1

AUC0e12h vs SFC atWeek 26

BRIGHT [48](A2305)

NCT01294787

MC, R, DB*,DD, 3-period,XO, PC, AC

Moderate-to-severe COPD(FEV1 �40% and <70%predicted)

Total85

IND/GLY 110/50 mg q.d.TIO 18 mg q.d.Placebo

15 weeks (3weeks perperiod)

Exercise endurance time (SMETT) atWeek 3 vs placebo

IND/GLY significantlyimproved exerciseendurance time(SMETT) vs placebo atWeek 3

ENLIGHTEN[49](A2307)

NCT01120717

MC, R, DB, PG,PC

Moderate-to-severe COPD(FEV1 �30% and <80%predicted) and symptomatic(total daily symptom score �1on �4 of the 7 days prior torandomization)

226113(Total339)

IND/GLY 110/50 mg q.d.Placebo(2:1)

52 weeks Frequency of treatment-emergentAEs vs placebo

Overall incidence of AEswas similar with IND/GLY and placebo

SPARK [50](A2304)

NCT01120691

MC, R, DB, OL(TIO), PG, AC

Severe-to-very severe COPD(FEV1 <50% predicted) with �1COPD exacerbation requiringtreatment with systemiccorticosteroids and/orantibiotics in the previous year

741741742(Total2224)

IND/GLY 110/50 mg q.d.GLY 50 mg q.d.OL TIO 18 mg q.d.(1:1:1)

64e76weeks

Rate of moderate or severeexacerbations vs GLY

IND/GLY reduced therate of moderate orsevere exacerbations vsGLY

ARISE [51,97](A1301)

NCT01285492

MC, R, OL, PG,AC

Japanese patients withmoderate-to-severe COPD(FEV1 �30% and <80%predicted)

12139(Total160)

IND/GLY 110/50 mg q.d.OL TIO 18 mg q.d.(3:1)

52 weeks AEs, SAEs or death IND/GLY was welltolerated over 52weeks

BLAZE [52](A2322)

NCT01490125

MC, R, DB*,DD, 3-period,XO, PC, AC

Moderate-to-severe COPD(FEV1 �30% and <80%predicted) with mMRC grade�2

Total247

IND/GLY 110/50 mg q.d.TIO 18 mg q.d.Placebo

6 weeks perperiod

Patient-reported dyspnea (SAC BDI/TDI) at Week 6 vs placebo

IND/GLY providedsuperior improvementspatient-reporteddyspnea (SAC BDI/TDI)vs placebo at Week 6

BEACON [29](A2326)

NCT01529632

MC, R, DB, PG,AC

Moderate-to-severe COPD(FEV1 �30% and <80%predicted) and symptomatic(total daily symptom score �1on �3 days prior torandomization)

90103

(Total193)

IND/GLY 110/50 mg q.d.IND 150 mg q.d. andGLY 50 mg q.d. (freecombination)(1:1)

4 weeks Trough FEV1 at Week 4 (non-inferiority of IND/GLY to IND þ GLY[free combination])

IND/GLY was non-inferior to IND þ GLY interms of trough FEV1 atWeek 4

LANTERN[53](A2331)

NCT01709903

MC, R, DB, DD,PG, AC

Moderate-to-severe COPD(FEV1 �30% and <80%predicted) with mMRC grade�2

372372(Total744)

IND/GLY 110/50 mg q.d.SFC 50/500 mg b.i.d.(1:1)

26 weeks Trough FEV1 at Week 26 (non-inferiority of IND/GLY to SFC)

IND/GLY was non-inferior to SFC in termsof trough FEV1 at Week26

QUANTIFY[30]

(ADE01)NCT01574651

MC, R, DB, TD,PG, AC

Moderate-to-severe COPD(FEV1 �30% and <80%predicted)

476458

(Total934)

IND/GLY 110/50 mg q.d.TIO 18 mg q.d. plusformoterol 12 mg q.d.(free combination)

26 weeks SGRQ at Week 26 (non-inferiority ofIND/GLY to TIO þ formoterol)

IND/GLY was non-inferior toTIO þ formoterol inimproving SGRQ atWeek 26

FLAME [54](A2318)NCT01782326

MC, R, DB, DD,PG, NI

Moderate-to-very severe COPD(FEV1 �25 and < 60% predicted)with mMRC grade �2 and adocumented history of �1COPD exacerbation requiringtreatment with systemiccorticosteroids and/orantibiotics) in the previous 1year

16801682(Total3362)

IND/GLY 110/50 mg q.d.SFC 50/500 mg b.i.d.(1:1)

52 weeks Rate of COPD exacerbations during52 weeks of treatment (non-inferiority of IND/GLY to SFC)

IND/GLY was non-inferior to SFC in rate ofCOPD exacerbationsduring 52 weeks oftreatment; additionally,IND/GLY was superiorto SFC in reducingannual rate ofexacerbations

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33 23

Table 3Summary of treatment differences in lung function parameters with IND/GLY versus (A) placebo and monocomponents [29,42,48e50,52], and (B) standards of care[30,42,43,48,50,52e54].

A)

Study(No. of patients)

LSM treatment differencea IND/GLY 110/50 mg q.d.b vs

Placebo Monocomponents

IND 150 mg q.d. GLY 50 mg q.d. IND 150 mg þ GLY 50 mg q.d. (free combination)

SHINE(n ¼ 232)

BLAZE(n ¼ 218)

BRIGHT(n ¼ 77)

ENLIGHTEN(n ¼ 113)

SHINE(n ¼ 476)

SHINE(n ¼ 473)

SPARK(n ¼ 739)

BEACON(n ¼ 97)

FEV1

Trough (mL)c 200* e 200* 189* 70* 90* 70e80* �5d

Peak (mL)c 330* e e e 120* 130* e �12NS

AUC0e12h (mL)c 330*e e e e 130*e 130*e e e

AUC0e4h (mL)c 340* 330* e e 110* 140* e �12NS

At 5 min, Day 1 (mL) 130* 126* e e 10NS 40* e e

At 30 min, Day 1 (mL) 200* 182* e e e e e e

At 5 min, study end (mL)c 290* e e e 80* 130* e e

At 30 min, study end (mL)c 320* e e e e e e e

B)

Study(No. of patients)

LSM treatment differencea IND/GLY 110/50 mg q.d.b vs

Standards of care

TIO 18 mg q.d.f TIO 18 mg þ formoterol 12 mg q.d. (free combination) SFC 50/500 mg b.i.d.

SHINE(n ¼ 480)

BLAZE(n ¼ 220)

BRIGHT(n ¼ 83)

SPARK(n ¼ 737)

QUANTIFY(n ¼ 458)

ILLUMINATE(n ¼ 264)

LANTERN(n ¼ 369)

FLAME(n ¼ 1682)

FEV1

Trough (mL)g 80* e 100* 60e80* 68* 103* 75* 62*Peak (mL)g 130* e e e e 155* 121* e

AUC0e12h (mL)g 120*e e e e e 138* e 110*e

AUC0e4h (mL)g 130* 110* e e e e 122* e

At 5 min, Day 1 (mL) 70* 70* e e e 81* e e

At 30 min, Day 1 (mL) e 68* e e e 75* e e

At 5 min, study end (mL)g 120* 94* e e e 150* e e

At 30 min, study end (mL)g e 93* e e 21NS 161* e e

e¼ analysis was not performed or data have not been published; AUC¼ area under curve; b.i.d.¼ twice daily; FEV1¼ forced expiratory volume in 1 s; GLY¼ glycopyrronium;IND ¼ indacaterol; LSM ¼ least-squares mean; NS ¼ not statistically significant; q.d. ¼ once daily; TIO ¼ tiotropium; SFC ¼ salmeterol/fluticasone propionate combination.*p < 0.001.

a Treatment differences are calculated from absolute LSM values.b IND/GLY patient no.¼ 474 (SHINE), 223 (BLAZE), 77 (BRIGHT), 225 (ENLIGHTEN), 729 (SPARK) 84 (BEACON), 476 (QUANTIFY), 258 (ILLUMINATE), 372 (LANTERN) and 1680

(FLAME).c At Week 26 in SHINE, at Week 6 in BLAZE, at Week 3 in BRIGHT, at Week 52 in ENLIGHTEN, at multiple timepoints over 64 weeks in SPARK and at Week 4 in BEACON.d Non-inferiority demonstrated.e Analysis was performed in the serial spirometry subset (SHINE: placebo: n ¼ 31, IND: n ¼ 64, GLY: n ¼ 63, TIO: n ¼ 70, IND/GLY: n ¼ 66; FLAME: IND/GLY: n ¼ 279, SFC:

n ¼ 277).f Open label in SHINE and SPARK, blinded in BLAZE and BRIGHT.g At Week 52 in FLAME, Week 26 in SHINE, ILLUMINATE, and LANTERN, at Week 6 in BLAZE, at Week 3 in BRIGHT and at multiple timepoints over 64 weeks in SPARK.

*Investigator-blinded only for tiotropium. AC ¼ active controlled; AE ¼ adverse event; AUC0 ¼ area under the plasma concentration-time curve; B ¼ blinded; BDI ¼ BaselineDyspnea Index; b.i.d. ¼ twice daily; COPD ¼ chronic obstructive pulmonary disease; DB ¼ double blind; DD ¼ double dummy; FEV1 ¼ forced expiratory volume in 1 s;GLY ¼ glycopyrronium; IND ¼ indacaterol; MC ¼ multicenter; mMRC ¼ modified Medical Research Council; NI ¼ non-inferiority; OL ¼ open label; PC ¼ placebo controlled;PG ¼ parallel group; q.d. ¼ once daily; R ¼ randomized; SAC ¼ self-administered computerized; SAE ¼ serious adverse event; SFC ¼ salmeterol/fluticasone propionatecombination; SGRQ ¼ St George's Respiratory Questionnaire; SMETT ¼ sub-maximal exercise tolerance test; TD ¼ triple dummy; TDI ¼ Transition Dyspnea Index;TIO ¼ tiotropium; XO ¼ crossover.

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e3324

3.3.3. Health statusIND/GLY demonstrated beneficial effects on patient health sta-

tus, as assessed by St George's Respiratory Questionnaire (SGRQ;Table 4A and B). IND/GLY significantly improved SGRQ total scoreand the proportion of patients achieving the clinically importantdifference of a �4-unit reduction [56] compared with placebo, GLYand OL tiotropium [42,50]. While improvements in SGRQ totalscore with IND/GLY were similar to SFC in ILLUMINATE and LAN-TERN [43,53], IND/GLY significantly improved SGRQ total score andthe proportion of patients achieving a clinically important differ-ence compared with SFC in FLAME [54]. IND/GLY was non-inferiorto tiotropium plus formoterol for improvement in SGRQ total score(the primary endpoint in QUANTIFY) and the percentage of patients

achieving a �4-unit improvement in SGRQ total score was similarbetween treatment groups [30].

3.3.4. Patient symptomsIND/GLY provided significant improvements in symptom scores

compared with placebo, the monocomponents, tiotropium and SFC(Table 4A and B). IND/GLY significantly improved the percentage ofnights with no night-time awakenings (compared with placebo,GLYand tiotropium) [42,52,57], percentage of days with no daytimesymptoms (compared with placebo, GLY, tiotropium and SFC)[42,43,49,52,57], percentage of ‘days able to perform usual dailyactivities’ (compared with placebo, IND, GLY and tiotropium)[42,49,52,57], and daily total symptom score (compared with

Fig. 2. SHINE: trough FEV1 at Week 26 [42].Data are least-squares mean ± standard error. One-sided adjusted p-values are presented for comparisons in the statistical gate-keeping procedure and two-sided p-values arepresented for all other comparisons.FEV1 ¼ forced expiratory volume in 1 s; GLY ¼ glycopyrronium; IND ¼ indacaterol; n ¼ number per treatment group in the full analysis set; TIO ¼ tiotropium; q.d. ¼ once daily.Reproduced with permission of the European Respiratory Society ©. European Respiratory Journal Dec 2013, 42 (6) 1484‒1494; DOI: 10.1183/09031936.00200212.

Fig. 3. Effect of IND/GLY on FEV1AUC0e12h at Week 26 in the ILLUMINATE study [43].Data are least-squares mean ± standard error.AUC0e12h ¼ area under the plasma concentration-time curve from 0 to 12 h; b.i.d. ¼ twice daily; FEV1 ¼ forced expiratory volume in 1 s; q.d. ¼ once daily; SFC ¼ salmeterol/fluticasone propionate combination. Reprinted from Lancet Respiratory Medicine, 1(1); Vogelmeier CF, Bateman ED, Pallante J, Alagappan VK, D'Andrea P, Chen H, Banerji D. Efficacy andsafety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomized, double-blind, parallelgroup study, 51e60, Copyright (2013), with permission from Elsevier.

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33 25

placebo, GLY and tiotropium) [42,49,52,58].

3.3.5. Rescue medication useIND/GLY significantly reduced daily rescue medication use

compared with placebo, the monocomponents, tiotropium and SFC

(Table 4A and B) [42,43,48e50,52,54]. In addition, IND/GLY signif-icantly increased the percentage of days without rescue medicationuse compared with placebo, GLY, tiotropium and SFC[42,50,52,54,57].

Table 4Summary of treatment differences in patient-reported outcomes with IND/GLY versus (A) placebo and monocomponents [29,42,48e50,52], and (B) standards of care[30,42,43,48,50,52e54,57,58].

A)

Study(No. of patients)

Treatment differencea IND/GLY 110/50 mg q.d.b vs

Placebo Monocomponents

IND 150 mg q.d. GLY 50 mg q.d. IND 150 mg þ GLY 50 mg q.d.(free combination)

SHINE(n ¼ 232)

BLAZE(n ¼ 218)

BRIGHT(n ¼ 77)

ENLIGHTEN(n ¼ 113)

SHINE(n ¼ 476)

SHINE(n ¼ 473)

SPARK(n ¼ 739)

BEACON(n ¼ 97)

Dyspnea (TDI)c

TDI total score 1.09* 1.37*d e e 0.26NS 0.21NS e e

Proportion of patients achieving MCID(odds ratio)e

1.86y 2.78* e e þ þ e e

Health status (SGRQ)c

SGRQ total score �3.01y e e e �1.09NS �1.18NS �1.9 to �2.8y e

Proportion of patients achieving MCID (odds ratio)f 1.39NS e e e þ þ 1.28 to 1.62zg e

Patient symptomsh

% of nights with ‘no night-time awakenings’ 10.01* 5.6* e 6.32NS 1.20NS 5.05y 4.67y e

% of days with ‘no daytime symptoms’ 3.05z 3.5y e 5.29z �1.68NS 1.09NS 2.94* e

% of ‘days able to perform usual daily activities’ 11.48* 8.8* e 8.13z 5.04z 5.87y 1.87NS e

Daily total symptom score e �0.72* e �0.57z e e 0.37z 0.07NS

Rescue medication useh

Daily no. of puffs �0.96* �1.43* �1.23* �0.73y �0.30z �0.66* �0.81* �0.04NS

% of days with no rescue medication use 12.33* 19.9* e e 2.28NS 9.35* 7.71* e

B)

Study(No. of patients)

Treatment differencea IND/GLY 110/50 mg q.d.b vs

Standards of care

TIO 18 mg q.d.i TIO 18 mg þ formoterol 12 mg q.d.(free combination)

SFC 50/500 mg b.i.d.

SHINE(n ¼ 480)

BLAZE(n ¼ 220)

BRIGHT(n ¼ 83)

SPARK(n ¼ 737)

QUANTIFY(n ¼ 458)

ILLUMINATE(n ¼ 264)

LANTERN(n ¼ 369)

FLAME(n ¼ 1682)

Dyspnea (TDI)j

TDI score 0.51y 0.49zd e e 0.38NS 0.76y 0.13NS e

Proportion of patients achievingMCID (odds ratio)e

* 1.78z e e [1.17#] 1.56z e e

Health status (SGRQ)j

SGRQ total score �2.13y e e �1.7 to �3.1z �0.69NS �1.24NS �0.69NS �1.3yProportion of patients achieving

MCID (odds ratio)f* e e 1.28 to 1.48zk e 1.32NS e 1.30*

Patient symptomsl

% of nights with ‘no night-time awakenings’ 3.68NSx 2.6NS e 6.16* e e �0.29NS e

% of days with ‘no daytime symptoms’ 1.95NS 1.5NS e 3.26* e 2.50z �2.90NS e

% of ‘days able to perform usual daily activities’ 8.45* �0.4NS e 4.95y e e 1.85NS e

Daily total symptom score e �0.03NS e 0.44z e e 0.21NS e

Rescue medication usel

Daily no. of puffs �0.54* �0.45y �1.08* �0.76* e �0.39z �0.03NS �0.25*% of days with no rescue medication use 10.58* 9.1* e 5.50* e e 0.96NS 4.7*

e¼ analysis was not performed or data have not been published; b.i.d.¼ twice daily; GLY¼ glycopyrronium; IND¼ indacaterol; LSM¼ least-squares mean;MCID¼minimumclinically important difference; NS ¼ not statistically significant; q.d. ¼ once daily; SFC ¼ salmeterol/fluticasone propionate combination; SGRQ ¼ St George's RespiratoryQuestionnaire; TDI ¼ Transition Dyspnea Index; TIO ¼ tiotropium.*p < 0.001; yp < 0.01; zp < 0.05; xp ¼ 0.052; #p ¼ 0.033 (odds ratio not reported; value shown is risk ratio). þ ¼ numerical improvement.

a Treatment differences are calculated from absolute LSM values for TDI score, SGRQ score and percentages of nights with no awakenings, days with no daytime symptoms,days able to perform usual daily activities and days with no rescue medication use. Treatment differences are calculated from LSM changes from baseline for daily rescuemedication use and daily total symptom score.

b IND/GLY patient no. ¼ 474 (SHINE), 223 (BLAZE), 77 (BRIGHT), 225 (ENLIGHTEN), 729 (SPARK), 84 (BEACON), 436 (QUANTIFY), 258 (ILLUMINATE), 372 (LANTERN) and1680 (FLAME).

c At Week 26 in SHINE, at Week 6 in BLAZE and at multiple timepoints over 64 weeks in SPARK.d Self-administered computerized total score.e Change in TDI total score �1 unit from baseline.f Change in SGRQ total score �4 units from baseline.g Differences were statistically significant at all timepoints up to Week 52 (at Week 64, p ¼ 0.055).h Over treatment period (26 weeks in SHINE, 6 weeks in BLAZE, 3 weeks in BRIGHT, 52 weeks in ENLIGHTEN, 64e76 weeks in SPARK. and 4 weeks in BEACON).i Open label in SHINE and SPARK, blinded in BLAZE and BRIGHT.j At Week 52 in FLAME, Week 26 in SHINE, QUANTIFY, ILLUMINATE and LANTERN at Week 6 in BLAZE, at multiple timepoints over 64 weeks in SPARK.k Differences were statistically significant at all timepoints up to Week 52 (at Week 64; p ¼ 0.051).l Over treatment period (52 weeks in FLAME, 26 weeks in SHINE and ILLUMINATE, 6 weeks in BLAZE, 3 weeks in BRIGHT and 64e76 weeks in SPARK).

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e3326

Fig. 4. SHINE: TDI total score at Week 26 [42].Data are least-squares mean ± standard error.GLY ¼ glycopyrronium; IND ¼ indacaterol; n ¼ number per treatment group in the full analysis set; TDI ¼ Transition Dyspnea Index; TIO ¼ tiotropium; q.d. ¼ once daily. Reproducedwith permission of the European Respiratory Society ©. European Respiratory Journal Dec 2013, 42 (6) 1484‒1494; DOI: 10.1183/09031936.00200212.

Table 5Summary of treatment differences in exacerbations with IND/GLY versus placebo, GLY and standards of care [30,50,53,54,59].

Study(No. of patients)

Treatment difference IND/GLY 110/50 mg q.d.a vs

Placebo GLY 50 mg q.d. Standards of care

TIO 18 mg q.d.b TIO 18 mg þ formoterol 12 mg q.d.(free combination)

SFC 50/500 mg b.i.d.

SHINE(n ¼ 232)

SPARK(n ¼ 739)

SPARK(n ¼ 737)

QUANTIFY(n ¼ 458)

LANTERN(n ¼ 372)

FLAME(n ¼ 1682)

Annualized rate (rate ratio [95% CI])c

All exacerbations e 0.85 [0.77, 0.94]y 0.86 [0.78, 0.94]y e 0.79 [0.58, 1.07]NS 0.89 [0.83, 0.96]yd

Moderate or severe exacerbations 0.57 [0.41, 0.79]* 0.88 [0.77, 0.99]z 0.90 [0.79, 1.02]NS 0.85 [0.62, 1.17]NS 0.69 [0.48, 1.00]z 0.83 [0.75, 0.91]*

Severe exacerbations e e e e e 0.87 [0.69, 1.09]NS

Time to first exacerbation (hazard ratio [95% CI])d

All exacerbations e e e e e 0.84 [0.78, 0.91]*

Moderate or severe exacerbations e e e e 0.65 [0.44, 0.95]z 0.78 [0.70, 0.86]*

Severe exacerbations e 0.79 [0.60, 1.05]NS 1.13 [0.83, 1.53]NS e 0.32 [0.12, 0.88]z 0.81 [0.66, 1.00]z

e¼ analysis was not performed or data have not been published; b.i.d.¼ twice daily; CI¼ confidence interval; GLY¼ glycopyrronium; IND¼ indacaterol; NS¼ not statisticallysignificant; q.d. ¼ once daily; TIO ¼ tiotropium; SFC ¼ salmeterol/fluticasone propionate combination.*p < 0.001; yp < 0.01; zp < 0.05.

a IND/GLY patient no. ¼ 474 (SHINE), 729 (SPARK), 436 (QUANTIFY), 369 (LANTERN) and 1680 (FLAME).b Open label.c Over treatment period (26 weeks in SHINE, QUANTIFY and LANTERN, 52 weeks in FLAME and 64e76 weeks in SPARK).d Analysis of the per protocol set (primary objective).

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33 27

3.3.6. COPD exacerbationsIND/GLY provided significant reductions in the rate of COPD

exacerbations compared with placebo [59], GLY and OL tiotropium[50], and SFC [53,54] (Table 5).

IND/GLY significantly reduced the rate of exacerbations classi-fied as moderate (treated with systemic corticosteroids or antibi-otics or both) or severe (requiring hospital admission or emergencytreatment) by 43%, versus placebo [59].

In patients with severe-to-very severe airflow limitation and�1

exacerbations in the previous year (SPARK), IND/GLY significantlyreduced the rate of moderate or severe exacerbations by 12%compared with GLY (primary endpoint) [50]. A 10% reduction thatdid not reach statistical significance (p ¼ 0.096) in the rate ofmoderate or severe exacerbations was seenwith IND/GLY versus OLtiotropium [50]. In the same population, IND/GLY significantlyreduced the rate of all exacerbations (mild [self-managed by thepatient], moderate, or severe) compared with both GLY and OLtiotropium [50].

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e3328

In patients with moderate-to-severe COPD and �1 exacerba-tions in the previous 12 months (LANTERN), IND/GLY significantlyreduced the rate of moderate or severe exacerbations by 31%compared with SFC [53]. In the same study population, IND/GLYsignificantly prolonged the time to first moderate or severe exac-erbation compared with SFC, with a 35% reduction in the risk ofmoderate or severe exacerbation [53].

In patients with moderate-to-very severe COPD and �1 exac-erbation in the previous year requiring treatment with systemiccorticosteroids and/or antibiotics (FLAME), IND/GLY significantlyreduced the rate of all (11%) (Fig. 5A) and moderate or severe (17%)exacerbations compared with SFC [54]. Furthermore, IND/GLYsignificantly prolonged the time to first exacerbation, first

Fig. 5. A) Rate ratio for all exacerbations (mild, moderate, and severe) in the IND/GLY grointervals. The modified intention-to-treat population included all patients who underwent radid not have major violations of compliance with Good Clinical Practice guidelines before uintention-to-treat population who did not have any major protocol deviations (definitionsB) Time to first exacerbation (all, moderate or severe, and severe) during 52 weeks of treatmmodified intention-to-treat population. Patients at risk are patients who were still receivinb.i.d. ¼ twice daily; CI ¼ confidence interval; GLY ¼ glycopyrronium; HR ¼ hazard ratio; INDReproduced from New England Journal of Medicine, Wedzicha JA, Banerji D, Chapman KR, VestIndacaterol-glycopyrronium versus salmeterol-fluticasone for COPD, 374(23); 2222‒34. CopyrigMedical Society.

moderate or severe exacerbation and first severe exacerbationrelative to SFC, with respective risk reductions of 16%, 22% and 19%(Fig. 5B). A prospective examination of exacerbation rates accord-ing to baseline blood eosinophil levels indicated no impact on re-sults, with rates of all and moderate or severe exacerbationsremaining significantly lower with IND/GLY compared with SFC inboth the <2% and �2% blood eosinophil subgroups [54].

In patients with moderate-to-severe airflow limitation and nohistory of exacerbations in the 6 weeks prior to screening (QUAN-TIFY), the proportion of patients who had �1 moderate or severeexacerbations and the time to first moderate or severe exacerbationwere comparable between IND/GLYand tiotropium plus formoterol[30].

up versus the SFC group in the FLAME study [54]. The bars indicate 95% confidencendomization, received at least one dose of a trial drug during the treatment period, andnblinding occurred. The per-protocol population included all patients in the modifiedof major protocol deviations were specified before unblinding occurred).ent with IND/GLY or SFC in the FLAME study [54]. The analyses were performed in theg treatment and had not had an event.¼ indacaterol; q.d. ¼ once daily; SFC ¼ salmeterol/fluticasone propionate combination.bo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF; FLAME Investigators,ht © (2016) Massachusetts Medical Society. Reprinted with permission from Massachusetts

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33 29

3.3.7. Exercise toleranceIND/GLY significantly improved exercise endurance time versus

placebo after 3 weeks of treatment, with a treatment difference of59.5 s during a sub-maximal, constant-load, cycle ergometry ex-ercise tolerance test (SMETT) [48]. The improvement observedwithIND/GLY was comparable to that reported with tiotropium [48]. Inaddition to the significant improvements seen with IND/GLY interms of exercise endurance time and markers of dynamic hyper-inflation (see 3.3.1 Lung function), IND/GLY was associated with asignificant improvement in dynamic inspiratory capacity (isotime,during exercise, post exercise) after 3weeks of treatment comparedwith placebo and tiotropium [48]. Extra-pulmonary factors, such asleg fatigue, may have contributed to a ‘ceiling effect’ of improve-ment in exercise endurance observed with the active treatments,preventing a distinct treatment difference between the broncho-dilators [48].

3.4. Clinical trial evidence of the safety and tolerability of IND/GLY

The individual LABA and LAMA components of IND/GLY havewell-characterized safety profiles [60,61]. To date, IND/GLY hasdemonstrated a favorable overall safety and tolerability profile instudies up to 64 weeks' in duration [29,30,42,43,48e50,52,54]. Theincidence of adverse events (AEs) with IND/GLY was similar to thatwith placebo, the monocomponents, concurrent administration ofIND and GLY, tiotropium (blinded and OL), SFC and tiotropium plusformoterol [30,42,43,48e50,52e54]. Similarly, frequency of seriousAEs (SAEs) with IND/GLY was comparable to that with placebo, themonocomponents, and SFC [42,43,49,50,52e54]. The most com-mon AEs overall were COPD worsening, nasopharyngitis, cough,and headache [29,30,42,43,48e50,52,53]. Incidence of pneumoniawas lower with IND/GLY than SFC [43,53,54]. In an analysis ofpooled safety data from 14 IND/GLY clinical studies (12e76 weekstreatment duration), the hazard ratio for IND/GLY versus placeboindicated no significant increase in the overall risk of death, cardio-cerebrovascular events, major adverse cardiovascular events, ex-acerbations, pneumonia or atrial flutter/fibrillation (Table 6) [62].Cardiovascular events were uncommon in all treatment groups[42,50,54], with no clinically relevant between-treatment differ-ences in QTc interval (Fridericia's formula) [42]. In addition, theincidence of cardio-cerebrovascular SAEs was not significantlydifferent between IND/GLY and placebo in a 52-week safety study[49]. Mortality rates were similar with IND/GLY, GLYand tiotropiumin the 64-week SPARK study [50] and similar to SFC in the 52-weekFLAME study [54]. The majority of observed deaths were consid-ered to be unrelated to treatment [42,43,49].

Table 6Pooled safety analysis of IND/GLY, monocomponents and tiotropium versus placebo [62]

HR (95% CI) INDversus placebo

GLYversus

Death 0.55 (0.16, 1.91) 0.85 (0

Serious CCV event 0.84 (0.42, 1.71) 0.56 (0

MACE 0.62 (0.34, 1.14) 1.37 (0

Pneumonia 0.81 (0.32, 2.04) 0.67 (0

COPD exacerbation 0.82 (0.47, 1.42) 0.61 (0

Atrial flutter/fibrillation 1.46 (0.53, 4.05) 1.45 (0

Patient numbers: IND (n ¼ 2528), GLY (n ¼ 2411), TIO (n ¼ 2777), IND/GLY (n ¼ 1547GLY ¼ glycopyrronium; IND ¼ indacaterol; HR ¼ hazard ratio; MACE ¼ major adverse c

4. Expert opinion

A considerable amount of evidence is available for the efficacyand safety of the FDC of IND/GLY compared with placebo and activecomparators, with data obtained from ten clinical trials in theIGNITE program, and the QUANTIFY study.

In brief, IND/GLY provided significant improvements in lungfunction and patient-reported outcomes compared with placebo[42,48,49,52]. IND/GLY was superior to the individual mono-components for improvements in lung function and rescue medi-cation use, with additional significant improvements observedversus GLY in health status and exacerbations [42,50]. IND/GLY alsoprovided significant improvements in measures such as lungfunction, dyspnea, rescue medication use and exacerbationscompared with the most established therapies for COPD, tio-tropium and SFC [42,43,50,52e54]. In addition, IND/GLY signifi-cantly improved health status compared with tiotropium, and wasnon-inferior to tiotropium plus formoterol in health status im-provements [30,42,52]. There were no additional safety concernsobserved with IND/GLY compared with the monocomponents [42].The pharmacodynamic and pharmacokinetic profiles of IND/GLYreflect those of the individual component agents [44], and IND andGLY have the same fine particle mass when administered as a FDCas when administered as monotherapy via separate inhalers[44,46].

Other FDC LABA/LAMAs available for use in COPD managementinclude vilanterol/umeclidinium, formoterol/aclidinium and olo-daterol/tiotropium. Until recently, evidence for the efficacy ofLABA/LAMAs as a class has been limited. There is now a plethora ofdata evaluating the bronchodilatory effects of LABA/LAMA versusmono-bronchodilator therapy in patients with COPD. In general,these data are in agreement that LABA/LAMAs provide improve-ments in lung function compared with one or both mono-bronchodilators [42,63e65]. Evidence is also accumulating for theefficacy of LABA/LAMA FDCs versus LABA/ICS, with consistent im-provements observed in lung function [43,53,54,66e68]. LABA/LAMAs are also at least as effective as LABA/ICS in improvingpatient-reported outcomes [43,53,54,66,67], with significant im-provements in dyspnea, health status and rescue medication useobserved with IND/GLY versus SFC [50,53]. To date, SPARK andFLAME are the only published studies that specifically investigatethe effect of LABA/LAMAs on exacerbations. The published vilan-terol/umeclidinium, formoterol/aclidinium and olodaterol/tio-tropium studies have not prospectively collected exacerbations asefficacy endpoints and have not been powered to assess the impactof treatment on exacerbations, therefore additional data areneeded to evaluate the role of these combinations in the reductionof exacerbations [64,65,69]. Exactly how bronchodilators prevent

.

placeboTIOversus placebo

IND/GLYversus placebo

.33, 2.16) 1.10 (0.43, 2.86) 0.93 (0.34, 2.54)

.29, 1.09) 0.61 (0.32, 1.17) 0.60 (0.29, 1.24)

.71, 2.63) 1.19 (0.62, 2.26) 1.04 (0.45, 2.42)

.34, 1.32) 0.83 (0.42, 1.62) 1.10 (0.54, 2.25)

.41, 0.89) 0.49 (0.32, 0.74) 0.60 (0.40, 0.91)

.77, 2.70) 1.64 (0.83, 3.27) 1.03 (0.49, 2.18)

), placebo (n ¼ 2141); CCV ¼ cardio- or cerebrovascular; CI ¼ confidence interval;ardiovascular event; TIO ¼ tiotropium.

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e3330

exacerbations is unclear, yet potential mechanisms include reducedhyperinflation and mechanical stress, reduced mucus productionand enhanced mucociliary clearance, improvement in symptomseverity and fluctuation, and potential anti-inflammatory proper-ties [70]. This latter anti-inflammatory phenomenon may be due toreduced release of non-neuronal ACh from the bronchial epithe-lium, but not from the bronchi [71]. In addition, exacerbation pre-vention by LABA/LAMAs is thought to be driven by the resetting oflung function dynamics, which is thought to produce a synergisticinhibition of the entire airway smooth muscle tone via modulationof the cAMP-dependent pathway [71].

In the studies reviewed here, an improvement in lung functiondid not always translate into a significant or clinically meaningfulimprovement in symptoms or health status. However, the lack ofsignificant improvements in patient-reported outcomes may bedue in part to a lack of sensitivity in the tools used to analyze theseendpoints [72]. In addition, the concept of minimal clinicallyimportant differences (MCIDs) is founded on experiences inplacebo-controlled trials, in which the observed treatment differ-ences may be large [73]. While small differences between activetreatments may not achieve the MCID, patients may still perceive abenefit [73]. Instead, identifying the additional proportion of pa-tients that benefit from one active treatment over another or whentwo drugs are combined (termed ‘minimum worthwhile incre-mental advantage’) may be a more appropriate measure of clini-cally important differences [73].

Several studies of patients receiving bronchodilator mono-therapy have reported that patients remain symptomatic in spite ofreceiving treatment [74,75]. While the present studies suggest thatdual bronchodilation can provide benefits beyond monotherapy interms of lung function, patient-reported outcomes, exercise ca-pacity and exacerbation risk [42,50,63e65,69,76], there is currentlyno guidance as towhen patients should be re-examined after initialassessment and when therapies should be switched or stepped up.As such, studies that evaluate initiation of bronchodilator mono-therapy versus dual bronchodilation would be highly informative.

For most patients with COPD, initial treatment is with LABA orLAMA monotherapy and for the vast majority of patients whoremain symptomatic on monotherapy, the most rational next stepis to initiate LAMA/LABA combination therapy. However, for pa-tients who initially present with a very high symptom burden orwith a history of exacerbations, dual bronchodilationwith a LAMA/LABA is the most reasonable initial treatment.

LABA/ICS are currently recommended for patients at high risk ofexacerbation [2]. However, patients at high risk of exacerbationmay differ in clinical phenotype, with some at risk due to airflowlimitation, some due to prior exacerbation history, and some due toboth risk factors. Indeed, in an analysis of three different cohorts,63e79% of patients categorized as high risk (and symptomatic;GOLD Group D) were categorized as such based on airflow limita-tion alone, compared with 9e14% based on exacerbation historyalone and 9e28% based on both risk factors [77]. It is possible thatthese different clinical phenotypes may benefit from differenttherapeutic approaches. For example, patients at high risk based onairflow limitation alone may benefit from a more effective bron-chodilation strategy (i.e. a LABA/LAMA) than an anti-inflammatorystrategy (LABA/ICS). In general, there is emerging evidence for theefficacy of dual bronchodilation compared with LABA/ICS not onlyin patients at high risk of exacerbation [54], but also in patients whoare at low risk of exacerbation and symptomatic, with superiorimprovements observed in lung function and similar symptomaticbenefits [43,53]. But what about triple FDCs? Studies comparing theeffects of a dual LABA/LAMAversus a triple FDC on an exacerbation-specific endpoint would be insightful, to determine whether an ICSconfers any additional benefits beyond those provided by dual

bronchodilation.The use of ICS in the broad treatment of COPD is questioned

owing to a lack of consistent benefit and evidence of safety con-cerns, including an elevated risk of pneumonia [3,78e80]. Evidencefrom studies indicate that ICS may be withdrawn in patients at lowrisk of exacerbationwithout adverse effects if patients are receivingadequate bronchodilation [81,82]. Available data for withdrawingICS, while maintaining dual bronchodilation, are limited, thusfurther studies examining this issue would be of interest. However,in the WISDOM study, the withdrawal of patients with severe-to-very severe COPD and �1 exacerbation in the past year from tri-ple therapy to a LABA plus LAMA did not increase the risk ofmoderate or severe exacerbations and was associated with a sig-nificant but small reduction in FEV1 versus ICS continuation [83]. Asdiscussed in this review, an efficacious LABA/LAMA can even pro-vide superior improvements in lung function versus LABA/ICS, withsimilar or superior symptomatic benefits, and significant im-provements in exacerbation risk in patients with an exacerbationhistory.

The identification of patients who will benefit most from ICS isan important area for future research, so that patients who are lesslikely to benefit are not exposed to an increased risk of pneumoniaand other potential side effects of long-term use of ICS unneces-sarily. One such group may be patients with asthma-COPD overlapsyndrome, where ICS may be used to treat the asthma componentof the disease. However, the evidence base for the diagnosis andtreatment of the asthma-COPD overlap syndrome is limited due tothe exclusion of patients with symptoms of both asthma and COPDfrom clinical trials [84]. It is also thought that blood eosinophilsmay provide an indication of which patients would respond to ICStreatment [85e87]. Indeed, post-hoc analyses comparing the effi-cacy of an ICS/LABA with LABA or LAMA monotherapy have shownthat patients with elevated blood eosinophil counts (�2% or�279.8/mL) are more likely to benefit e in terms of reduced exac-erbation rates e from an ICS-containing regimen than patients whohave a lower blood eosinophil count (<2% or <279.8/mL) [86e88].

These post-hoc analyses compared the effects of blood eosino-phil count on ICS/LABA FDC versus LABA or LAMA monotherapy,but what about the effects on ICS/LABA therapy versus LABA/LAMAFDC, a treatment which provides superior bronchodilation tomonotherapy? In the recently-published prospective FLAME study,IND/GLY as LABA/LAMA therapy consistently resulted in signifi-cantly lower exacerbation rates than ICS/LABA therapy, regardlessof baseline blood eosinophil level (<2% or �2%). This was true forthe analyses of ‘all exacerbations’ as well as ‘moderate and severeexacerbations’, and there was no cut-off point at which ICS/LABAperformed better than LABA/LAMA [54].

Blood eosinophils may potentially identify patients inwhom ICSwithdrawal would be deleterious (in terms of exacerbation risk). Ina recent analysis of the WISDOM study, exacerbation rate wasincreased following ICS withdrawal versus ICS continuation in asubgroup of patients with eosinophil counts�300 cells/mL (or�4%)[89]. Finally, eosinophil count may also be used to potentiallyidentify patients who are at greater risk of pneumonia; in a post-hoc meta-analysis (N ¼ 10,861), patients who had blood eosino-phil counts <2% had more pneumonia events than patients withhigher eosinophil counts, i.e. �2%. Collectively, these data suggestthat patients with lower eosinophil counts derive the least benefitfrom ICS treatment [90].

Further studies are needed to determine whether blood eosin-ophils are a potential biomarker and if so, what the most appro-priate eosinophil threshold for ICS use is. Furthermore, bloodeosinophils as a single biomarker may not be sufficient, and, giventhe poor association between eosinophil level and exacerbationrisk [91], may only be useful in patients who have a history of

J.H. Ficker et al. / Pulmonary Pharmacology & Therapeutics 45 (2017) 19e33 31

exacerbations.In addition to identification of underlying genetic factors and

biomarkers in COPD [92,93], individualized treatment and patientphenotyping are increasingly recognized as important areas forfurther research and consideration [5]. Furthermore, choice oftherapy is dictated not only by effectiveness and safety/tolerabilityprofile, as discussed above, but also by factors linked to inhalerdevice, such as ease of use and convenience [94]. Indeed, a treat-ment is only effective if patients take their medication as directed,and the importance of device use in the management of COPD isrecognized as a valid patient-reported outcome [94,95]. Factorsthat affect a patient's attitude to therapy and preferences for aspecific inhaler device include [94]: ability to actuate a device (e.g.important for patients affected by arthritis); ability to generatesufficient inspiratory flow rate, which can be a problem withbreath-actuated devices for patients with more severe disease; theneed for actuation/inhalation coordination, an inherent challengeassociated with pressurized metered dose inhalers; dose and refillfrequency (e.g. single-dose, multi-dose, once-daily and twice-dailydevices are available); size, weight and appearance of device mayalso affect a patient's preference, as well as cleaning issues. Treat-ment individualization is therefore crucial in deciding which of theavailable LABA/LAMA combinations is appropriate.

Other further desirable areas of research in COPD include theeffect of LABA/LAMA FDCs on exacerbation rates, hospitalizations,mortality and comorbidities such as cardiovascular disease/risk.Also, further studies examining whether LABA/LAMA FDCs canimprove exercise tolerance to a greater degree than LAMA mono-therapywould be of interest. Although one study has shown similarimprovements in exercise endurance time with a LABA/LAMAversus LAMA monotherapy, the study was not powered to detectdifferences between the two treatment arms and patients were notselected specifically for exercise limitation (indeed, they had onlymoderately severe airflow obstruction) [48]. A recent studydemonstrated that a LABA/LAMA significantly improved exerciseendurance time versus placebo, with a greater increase in endur-ance time observed when a concurrent exercise training pro-gramme was administered [96]. As observed in the BRIGHT study,extra-pulmonary factors such as leg fatigue may impact on themaximum effect on exercise endurance observable with improvedbronchodilation [48]. Thus, it could be hypothesized that exercisetrainingwould be needed to optimize the efficacy of LABA/LAMA onexercise tolerance.

In summary, a paradigm shift is occurring with regard to how tomanage patients with COPD. While LABA/ICS combinations areused frequently in COPD, recent clinical trial data from WISDOMand FLAME have meant that the ICS use is now under discussion.However, the question remains regarding which patients withCOPD should receive treatment with a LABA/LAMA. Is there aspecific phenotype, and who would benefit most? To our knowl-edge and based on current evidence, it is not clear whether patientswith lung emphysema would benefit more from dual bronchodi-lator therapy than patients who have chronic bronchitis. Nor it ispossible to establish whether patients with co-morbidities such ascardiovascular disease/heart failure would benefit from such ther-apy, and therefore further research is needed in this field.

5. Conclusions

IND/GLY is an effective and well-tolerated LABA/LAMA combi-nation, which demonstrates positive effects on lung function,patient-reported outcomes and exacerbations compared with pla-cebo, the monocomponents and well-established COPD therapies.The FDC of IND and GLY provides the benefits of dual bronchodi-lation in a single, simple-to-use device, thus making it a valuable

treatment option for patients with COPD.

Author disclosures

JH Ficker reports non-financial support fromNovartis during thepreparation of the manuscript; personal fees and non-financialsupport from Almirall, AstraZeneca, Boehringer, Berlin Chemie,CSL Behring, GlaxoSmithKline, Grifols, Novartis, Takeda and Teva,outside the submitted work.

KF Rabe reports personal fees and non-financial support fromAstraZeneca, Boehringer, Berlin Chemie, Chiesi, Novartis, Roche,Sanofi Regeneron, Takeda and Teva, outside the submitted work.

T Welte received fees for lectures/advisory boards from Astra-Zeneca, Bayer, Boehringer, Berlin-Chemie, GSK, Grifols, Insmed,Mundipharma, MSD, Novartis and Pfizer. T Welte's institution re-ceives grants from Novartis, Bayer, Insmed and Grifols.

Acknowledgments

The authors were assisted in the preparation of the manuscriptby Elizabeth Andrew and Sharon Smalley, professional medicalwriters at CircleScience, an Ashfield company, part of UDGHealthcare plc (Tytherington, UK). Medical writing support wasfunded by Novartis Pharma GmbH (Nuernberg, Germany).

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