glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease.

Drugs (2014) 74:465–488 DOI 10.1007/s40265-014-0194-8

ADIS DRUG EVALUATION

QVA149 (Indacaterol/Glycopyrronium Fixed-Dose Combination): A Review of Its Use in Patients with Chronic Obstructive Pulmonary Disease James E. Frampton

Published online: 7 March 2014 Ó Springer International Publishing Switzerland 2014

Abstract QVA149 (indacaterol/glycopyrronium) [XoternaÒ BreezhalerÒ, UltibroÒ BreezhalerÒ] is an inhaled fixed-dose combination of indacaterol (a long-acting selective b2-adrenergic receptor agonist [LABA]) and glycopyrronium (a long-acting muscarinic receptor antagonist [LAMA]) that has been approved in the EU and Japan for the symptomatic control of chronic obstructive pulmonary disease (COPD) in adults. In phase III studies, QVA149 significantly improved bronchodilation versus indacaterol, glycopyrronium or tiotropium alone and the LABA/inhaled corticosteroid fixed-dose combination salmeterol/fluticasone. These improvements in lung function, which were rapid in onset and maintained during long-term treatment, were generally associated with significant improvements in dyspnoea, health status, COPD exacerbation risk, patient symptoms, and rescue medication use. The SHINE and ILLUMINATE studies in low (exacerbation) risk patients with moderate to severe disease The manuscript was reviewed by: R. Buhl, Pulmonary Department, Mainz University Hospital, Mainz, Germany; M. Cazzola, Unit of Respiratory Clinical Pharmacology, Department of System Medicine, University of Rome ‘‘Tor Vergata’’, Rome, Italy; R. Dahl, Allergy Centre, Odense University Hospital, Odense, Denmark; A.D. D’Urzo, Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; P.P. Montuschi, Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy; L.J. Nannini, Hospital de G Baigorria, Universidad Nacional Rosario, Rosario, Argentina; D.D. Spina, Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, School of Biomedical and Health Sciences, King’s College London, London, England; A.M. Turner, QEHB Research Labs, University of Birmingham, Birmingham, England. J. E. Frampton (&) Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand e-mail: [email protected]

suggest that QVA149 may offer more symptomatic relief than tiotropium and salmeterol/fluticasone. Similarly, the SPARK study in high (exacerbation) risk patients with severe or very severe disease showed that QVA149 was more effective than glycopyrronium in preventing moderate to severe exacerbations, and suggests that QVA149 may offer more symptomatic relief than LAMA monotherapy. Another phase III study comparing QVA149 with salmeterol/fluticasone in high-risk patients with moderate to very severe disease (FLAME) is ongoing. QVA149 is generally well tolerated, with no new safety signals identified compared with its monocomponents. Bronchodilators remain central to the symptomatic management of COPD. When dual bronchodilation is indicated, QVA149 offers the convenience of two bronchodilators in a single inhaler coupled with a simple, once-daily dosing regimen that may encourage better treatment adherence. Therefore, it is a valuable option in the treatment of COPD.

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J. E. Frampton

2 Pharmacological Properties QVA149 (indacaterol/glycopyrronium) in chronic obstructive pulmonary disease (COPD): a summary Inhaled fixed-dose combination of two approved bronchodilators with different mechanisms of action: indacaterol (a long-acting selective b2-adrenergic receptor agonist) and glycopyrronium (a long-acting muscarinic receptor antagonist) Simple and convenient once-daily dosing regimen Efficacy and tolerability/safety being assessed in the IGNITE phase III clinical trial programme in [10,000 patients worldwide Provides rapid and sustained improvements in bronchodilation that are generally accompanied by symptomatic benefits compared with its monocomponents and the standard-of-care treatments tiotropium and salmeterol/fluticasone Generally well tolerated, with no new safety signals identified compared with its monocomponents, tiotropium and salmeterol/fluticasone

1 Introduction QVA149 (indacaterol/glycopyrronium) [XoternaÒ BreezhalerÒ, UltibroÒ BreezhalerÒ] is a fixed-dose combination formulation of indacaterol, an inhaled, long-acting selective b2-adrenergic receptor agonist (LABA) [1], and glycopyrronium, an inhaled, long-acting muscarinic receptor antagonist (LAMA) [2]. Like its monotherapy components, QVA149 administered once daily has been approved in the EU (and also Japan [3, 4]) as a maintenance bronchodilator treatment for the symptomatic control of chronic obstructive pulmonary disease (COPD) in adult patients [5]. This article summarizes the pharmacological properties of QVA149 (and/or those of its monocomponents) and reviews the therapeutic efficacy and tolerability of indacaterol/glycopyrronium in the treatment of COPD in adult patients. Each QVA149 inhalation powder hard capsule contains 143 lg of indacaterol maleate equivalent to 110 lg of indacaterol (in turn equivalent to 150 lg of indacaterol as a monotherapy [6]) and 63 lg of glycopyrronium bromide equivalent to 50 lg of glycopyrronium. Each delivered dose (i.e. the amount of drug that leaves the inhaler) contains 110 lg of indacaterol maleate equivalent to 85 lg indacaterol and 54 lg of glycopyrronium bromide equivalent to 43 lg of glycopyrronium [5]. Dosages of inhaled QVA149 in this article are for the equivalent administered (not delivered) dose of indacaterol/glycopyrronium.

2.1 Pharmacodynamic Properties This section includes a brief overview of the mechanism of action and bronchodilator effects of the QVA149 monocomponents, indacaterol and glycopyrronium, which have been reviewed previously [1, 2]. When given in combination (as in QVA149), these agents provide additive bronchodilator effects through the targeting of different receptors and pathways to achieve smooth muscle relaxation [5] (see Sect. 6). 2.1.1 Indacaterol Indacaterol is a nearly full agonist at human b2-adrenergic receptors (mean maximal effect [Emax] 73 % of that of isoprenaline); it has around two-fold higher intrinsic activity than salmeterol and salbutamol (Emax 38 and 47 %, respectively). In comparison, it is a very weak agonist at b1-adrenergic receptors (Emax 16 %) and a full agonist at b3-adrenergic receptors (Emax 116 %). Indacaterol produces bronchodilation, at least in part, by increasing cyclic adenosine monophosphate levels in, and thereby causing the relaxation of, airway smooth muscle cells. In vitro, the agonist activity of indacaterol at b2-adrenergic receptors is [24-fold greater than that at b1-adrenergic receptors and 20-fold greater than that at b3-adrenergic receptors. b2Adrenergic receptors predominate in the lung and comprise 10–50 % of the total adrenergic receptors in the heart (where b1-adrenergic receptors predominate) [1, 5]. The bronchodilator efficacy of therapeutic dosages of inhaled indacaterol has been demonstrated in several randomized, double-blind, multicentre trials of 12–52 weeks’ duration in patients with COPD (see review by McKeage [1]). For example, indacaterol 150 or 300 lg once daily significantly (p \ 0.01) improved lung function in terms of the trough forced expiratory volume in 1 s (FEV1) at week 12 compared with placebo in the INHANCE (stage 2) [7], INVOLVE [8], INLIGHT-1 [9] and INLIGHT-2 [10] studies, compared with the LAMA tiotropium 18 lg once daily in the INHANCE (stage 2) study [7], compared with the LABA formoterol 12 lg twice daily in the INVOLVE study [8], and compared with the LABA salmeterol 50 lg twice daily in the INLIGHT-2 [10] and INSIST [11] studies. In two other trials, namely INTENSITY [12] and INVIGORATE [13], indacaterol 150 lg once daily was (at least) noninferior to tiotropium 18 lg once daily with regard to this endpoint. Significant (p \ 0.001) improvements in trough FEV1 versus placebo were observed at all assessed timepoints in the 12-week INLIGHT-1 and 26-week INLIGHT-2 and INHANCE (stage 2) studies, including after the first dose of indacaterol on day 2.

Indacaterol/Glycopyrronium Fixed-Dose Combination: A Review

Moreover, the efficacy of indacaterol was maintained over a 1-year period in INDORSE [14], a 26-week extension of INLIGHT-2. Single indacaterol doses of up to 3,000 lg (i.e. 10 times the maximum recommended daily dose) had minimal systemic effects in patients with COPD [15]. Moreover, 2 weeks’ treatment with indacaterol at dosages up to 600 lg once daily (i.e. two to four times the therapeutic dosage) was not associated with any clinically relevant effects on Fridericia’s-corrected QT interval (QTcF) in healthy volunteers. At dosages of 150 or 300 lg once daily, it was associated with a low incidence of notable increases ([60 ms) in QTcF interval in patients with COPD; changes in heart rate and blood pressure in indacaterol recipients did not differ significantly from those in placebo recipients [1].

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observed at all assessed timepoints in the GLOW1 and 2 studies, including at the end of day 1 (first assessment) [17, 18]. Tiotropium 18 lg once daily was included as a reference comparator in GLOW2; a significant (p \ 0.01) improvement in trough FEV1 favouring glycopyrronium over tiotropium was observed at week 26, but not at the end of day 1 or at weeks 12 and 52 [18]. A single supratherapeutic dose of glycopyrronium 400 lg (i.e. eight times the recommended therapeutic dose) had no relevant effect on the QTcF interval in a QTc study. Furthermore, there were no consistent, clinically relevant differences between glycopyrronium and placebo recipients with respect to the proportions of patients with COPD experiencing high QTcF values or large increases in QTcF interval [2]. 2.1.3 QVA149

2.1.2 Glycopyrronium Glycopyrronium is a competitive muscarinic receptor antagonist; it bronchodilates the airways by inhibiting acetylcholine-induced bronchoconstriction in bronchial smooth muscle cells. In vitro, glycopyrronium binds with high affinity to the three muscarinic receptor subtypes detected in human airways (M1, M2 and M3) and has a 4- to 5-fold higher selectivity for human M3 and M1 receptors than for the human M2 receptor (equilibrium binding affinity constants of 9.60–9.81 and 9.47–9.64 vs. 8.70–9.25). The M3 receptor is thought to be the prime mediator of cholinergic bronchoconstriction, while the M2 receptor protects against bronchoconstriction (and, in the heart, mediates muscarinic receptor-induced bradycardia). Therefore, ideal bronchodilator agents have high affinity for the M3 (and M1) receptor, but low affinity for the M2 receptor [2, 5]. Glycopyrronium has demonstrated a faster onset of action than tiotropium, both in vitro and in vivo [2]. Essentially, this observation can be explained by differences in kinetic parameters (of these LAMAs) at the M3 receptor, which suggest that glycopyrronium will reach equilibrium faster than tiotropium. Glycopyrronium also displays greater binding selectivity and kinetic selectivityfor M3 over M2 receptors than tiotropium in vitro, indicating the potential for an improved therapeutic index [16]. The bronchodilator efficacy of the recommended dosage of inhaled glycopyrronium has been demonstrated in several randomized, double-blind, multicentre trials in patients with COPD (see review by Carter [2]). For example, glycopyrronium 50 lg once daily significantly (p \ 0.001) improved lung function in terms of the trough FEV1 at week 12 versus placebo in the 26-week GLOW1 [17] and 52-week GLOW2 [18] studies. Significant (p \ 0.001) improvements in trough FEV1 compared with placebo were

Once-daily QVA149 110/50 lg produced significantly greater bronchodilation compared with one or other of its monocomponents administered alone in phase III studies in patients with COPD (Sect. 3.1.2.1). A single supratherapeutic dose of QVA149 440/200 lg (i.e. four times the recommended therapeutic dose; see Sect. 5) had no clinically relevant effect on heart rate and QTcF in a randomized, double-blind, placebo-controlled, cross-over study in 50 healthy volunteers [19]. Moreover, QVA149 had no effect on heart rate and QTcF relative to supratherapeutic doses of its monocomponents, indacaterol and glycopyrronium, administered alone, and less of an effect on heart rate and QTcF than salmeterol alone. For QVA149, the largest positive time-matched mean difference in heart rate versus placebo, indacaterol 600 lg, glycopyrronium 200 lg and salmeterol 200 lg was 5.69, -0.19, 5.20 and -2.07 beats per minute, respectively; the corresponding largest negative timematched mean difference in heart rate was -2.51, -5.76, -1.56 and -11.34 beats per minute, respectively. The largest increase in time-matched mean QTcF difference for QVA149 versus placebo, indacaterol, glycopyrronium and salmeterol was 4.62, 4.88, 6.42 and 2.12 ms, respectively; the corresponding largest decrease in timematched mean QTcF difference was -2.71, -2.66, -1.37 and -5.86 ms, respectively [19]. Similarly, 2 weeks’ treatment with supratherapeutic dosages of QVA149 once daily had no clinically relevant effect on heart rate and QTcF in a five-arm, randomized, double-blind, placebo-controlled, parallel-group study in 257 patients with moderate to severe COPD [20]. A maximum QTcF increase of between 30 and 60 ms was experienced by 16.0, 21.6 and 20.4 % of QVA149 150/100, 300/100 and 600/100 lg once daily recipients (n = 51, 51 and 49), respectively, compared with 1.9 % of placebo

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recipients (n = 53); however, no QVA149 recipient and only one placebo recipient experienced a QTcF increase [60 ms. In the fifth arm of this trial, 19.6 % of indacaterol 300 lg recipients (n = 51) experienced a maximum QTcF increase of between 30 and 60 ms; however, none experienced a QTcF increase [60 ms [20]. The cardiovascular safety of QVA149 in phase III studies in patients with COPD is discussed in Sect. 4. 2.2 Pharmacokinetic Properties The pharmacokinetic properties of QVA149 (indacaterol/ glycopyrronium 110/50 lg) in healthy volunteers and patients with COPD essentially reflect those of its monocomponents, indacaterol and glycopyrronium, which have been reviewed previously [1, 2, 21] and are summarized in Table 1. In this regard, coadministration of indacaterol and glycopyrronium has no effect on the pharmacokinetics of either drug at steady state [2]. Following inhalation of QVA149 via the BreezhalerÒ device, the median time to reach the peak plasma concentration of indacaterol and glycopyrronium was &15 and 5 min, respectively [5] (see Table 1). Steady-state exposure to indacaterol was similar or slightly lower than that following inhalation of indacaterol 150 lg via the BreezhalerÒ device, while steady-state exposure to glycopyrronium was similar to that following inhalation of glycopyrronium 50 lg via the BreezhalerÒ device [5]. Estimates of the absolute bioavailability of indacaterol and glycopyrronium from inhaled QVA149 are 61–85 and &47 % of the delivered dose, respectively [5]. Systemic exposure to indacaterol and glycopyrronium was not significantly affected by age, gender and (lean) bodyweight, according to a population pharmacokinetic analysis of QVA149 in patients with COPD [5]. Moreover, QVA149 can be used at the recommended dose (see Sect. 5) in patients with mild to moderate hepatic or renal impairment, based on the pharmacokinetic characteristics of its monocomponents [5] (see Table 1). However, QVA149 should be used cautiously in patients with severe hepatic impairment (due to a lack of relevant data); it should only be used in patients with severe renal impairment or end-stage renal disease requiring dialysis if the expected benefit outweighs the potential risk [22]. Drug–drug interactions studies have not been performed with QVA149; therefore, the potential for such interactions is based on that with the monocomponents [5]. As such, concomitant use of QVA149 and b-adrenergic antagonists, anticholinergics and sympathomimetic agents is not recommended; caution is required when QVA149 is used concomitantly with drugs that can cause hypokalaemia, for example, methylxanthine derivatives and corticosteroids (CS) [5].

J. E. Frampton

3 Therapeutic Efficacy Data regarding the efficacy of inhaled QVA149 in the treatment of COPD are available from the IGNITE (Indacaterol and GlycopyrroNium bromide clInical sTudiEs) international clinical trial programme, which consists of a total of 11 randomized, multicentre, phase III studies (ARISE [23, 24], BEACON [6], BLAZE [25, 26], BRIGHT [27, 28], ENLIGHTEN [29, 30], FLAME [31], ILLUMINATE [30, 32–38], LANTERN [39], RADIATE [40], SHINE [30, 34–38, 41–43] and SPARK [30, 35, 37, 44, 45]). This section discusses the eight trials that have been completed to date (see Table 2 for key design details, including treatment groups/dosages and primary endpoints). Some of the data described herein are derived solely from abstracts/oral presentation [23, 26, 33, 42, 43], posters [30, 34–38, 45] and/or an on-line clinical trial registry [28]. Findings from a pooled analysis of three completed studies (ARISE, ENLIGHTEN and SPARK) have also been reported in preliminary form [46]. The three ongoing studies, namely FLAME [31, 47], LANTERN [39] and RADIATE [40], are described briefly in Sect. 6. Six completed trials were primarily designed to assess the efficacy of QVA149 with respect to bronchodilation (the 26-week SHINE and ILLUMINATE studies), dyspnoea (the 6-week BLAZE study), exercise endurance (the 3-week BRIGHT study) and COPD exacerbations (the 64-week SPARK study) (Table 2). The efficacy of QVA149 with regard to health status was assessed as a secondary objective in three of these studies (SHINE [41], ILLUMINATE [32] and SPARK [44]). Active comparators included the monocomponents of QVA149 (indacaterol [in SHINE] and glycopyrronium [in SHINE and SPARK]), tiotropium (in SHINE, SPARK, BLAZE and BRIGHT) and the LABA/inhaled CS (ICS) fixed-dose combination of salmeterol/fluticasone (in ILLUMINATE) (Table 2). A sixth efficacy study, namely the 4-week BEACON trial, was primarily designed to assess the bronchodilatory effect of QVA149 relative to that of concurrent administration of its monocomponents (Table 2). The 52-week ARISE and ENLIGHTEN studies were primarily designed as longterm safety trials. In contrast to the placebo-controlled ENLIGHTEN study, ARISE included an active comparator (tiotropium); unlike all other efficacy and safety studies, ARISE was an open-label (as opposed to double-blind) trial and only enrolled Japanese patients (Table 2). These trials all enrolled patients with moderate to severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II or III), with the exception of SPARK, which enrolled patients with severe to very severe COPD (GOLD stage IV) (Table 2). As noted earlier, SPARK was primarily designed to assess the impact of


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Table 1 Summary of the key pharmacokinetic properties of the monocomponents of QVA149 (indacaterol/glycopyrronium fixed-dose combination)a IND [1, 5]

GLY [2, 5]

Pulmonary/GI absorption (%)

&75/25

&90/10

Median time to Cmax (mins)

&15

&5

Time to Css (days)

12–15

B7

Mean AR for AUC24

2.9–3.8

1.4–1.7

2,557c

376c (7,310b)

&95

&38–41

Primarily metabolized to a hydroxylated derivative of IND (mainly by CYP3A4)

Primarily hydrolysed to a carboxylic acid derivative of GLY

Other prominent metabolites include phenolic O-glucuronides of IND and hydroxylated IND

Other metabolites include mono- and bis-hydroxylated metabolites of GLYd and glucuronide and/or sulphate conjugates of GLY

Absorption

b

Distribution Vd [terminal elimination phase] (L) d

Serum/plasma protein binding (%) Metabolism Metabolic pathway(s)

Low affinity substrate for P-gpd

Several CYP enzymes contribute to the oxidative biotransformation of GLY, in particular CYP2D6 Elimination Elimination route (s)

Renal clearance has a minor role in elimination of systemically available IND (2–5 %) Urinary excretion of unchanged parent drug accounts for \2 % of the dosee Faecal excretion of unchanged parent drug accounts for 54 % of the dose; faecal excretion of hydroxylated IND metabolites accounts for 23 % of the dosee

Renal clearance plays the predominant role in the elimination of systemically available GLY (60–70 %) Non-renal clearance mainly reflects metabolism and, to a lesser extent, biliary excretion (B5 %) Urinary excretion of unchanged parent drug accounts for up to 23 % of the delivered dose; urinary excretion of glucuronide and/or sulphate conjugates of GLY accounts for &3 % of the delivered doseb 85 % of radioactivity from [3H]-labelled GLY is recovered in the urine within 48 hc

Mean renal clearance (L/h)

17.4–24.4b

0.46–1.2 f

33–57b

Mean terminal half-life (h)

45.5–126; 40–52

In special pt populations

No clinically relevant effects on IND PK

Either no clinically relevant effects on GLY PK or GLY dose adjustments not necessary

Hepatic impairment

IND systemic exposure unaltered by mild or moderate hepatic impairment (effect of severe hepatic impairment not studied)

Not studied (GLY elimination is predominantly via the urinary pathway); dose adjustment not necessary

Renal impairment

Not studied (due to the very low contribution of the urinary pathway to IND elimination)

GLY systemic exposure increased by up to 1.4-fold in pts with mild or moderate renal impairmentg (dose adjustment not necessary) and by up to 2.2-fold in pts with severe renal impairmentg or ESRD (use only if expected benefit outweighs potential risk)

IND systemic exposure increased by &1–2-fold in the presence of ketoconazole and erythromycin (CYP3A4 inhibitors), verapamil (P-gp inhibitor) and ritonavir (dual inhibitor of CYP3A4 and P-gp)

Low potential for drug-drug interactions (GLY does not inhibit or induce drug transporters or any enzymes involved in drug metabolism to a clinically significant extent)

GLY has no effect on steady-state PK of IND

IND has no effect on steady-state PK of GLY

Age, gender, bodyweight, race

Drug-drug interactions

AR accumulation ratio, AUC24 area under the plasma concentration-time curve from time zero to 24 hours, COPD chronic obstructive pulmonary disease, Cmax maximum plasma concentration, Css steady-state concentration, CYP cytochrome P450, eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, GI gastrointestinal, GLY glycopyrronium bromide, IND indacaterol maleate, P-gp P-glycoprotein (efflux transporter), pt(s) patient(s), Vd volume of distribution a

In studies in healthy volunteers or patients with COPD, except where indicated. Both IND and GLY are inhaled once daily

b

After inhalation

c

After intravenous administration

d

In vitro

e

After oral administration

f

Effective half-life, as calculated from IND accumulation after repeated dosing

g

eGFR of C30 mL/min/1.73 m2 (mild to moderate impairment) or \30 mL/min/1.73 m2 (severe impairment)

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J. E. Frampton

Table 2 Key design details of completed phase III studies of QVA149 in patients with chronic obstructive pulmonary disease (SHINE [41], ILLUMINATE [32], BEACON [6], SPARK [44], BLAZE [25, 26], BRIGHT [27, 28], ENLIGHTEN [29] and ARISE [23, 24])a Study (duration [weeks])

Treatment groupsb (no. of pts randomized to study drugc,d)

Primary endpoint

SHINE (26)

QVA (475), IND (477), GLY (475) TIO (483), PL (234)

Trough FEV1 at week 26 for QVA vs. IND and GLY

ILLUMINATE (26)

QVA (259), S/FC (264)

FEV1 AUC0–12h at week 26 for QVA vs. S/FC

BEACON (4)e

QVA (90), IND ? GLY(103)

Trough FEV1 at week 4 for QVA vs. IND ? GLY

SPARK (64f)

QVA (741), GLY (741), TIO (742)

Rate of moderate or severe COPD exacerbations during treatment period for QVA vs. GLY

BLAZE (6)

QVA (223), TIO (220), PL (218)

Improvement in patient-reported dyspnoea (i.e. SAC BDI/TDI score) at week 6 for QVA vs. PL

BRIGHT (3) ENLIGHTEN (52)g

QVA (77), TIO (83), PL (77) QVA (226), PL (113)

Exercise tolerance at week 3 for QVA vs. PL Frequency of TEAEs during study period for QVA vs. PL

ARISE (52)g,h

QVA (121), TIO (39)

Frequency of TEAEs during study period for QVA vs. TIO

Key inclusion criteria Age C40 years; smoking history C10 pack-years; FEV1/FVC post-BD \0.70 (all studies) Moderate to severe (stage II or IIIi) stable COPD (all studies except SPARK) or severe to very severe (stage III or IVi) stable COPD (SPARK) FEV1 post-BD C30 or 40 % and \70 or 80 % predicted (all studies, except SPARK) or \50 % predicted (SPARK) At least one COPD exacerbation requiring treatment with ABs and/or systemic CS within previous 12 months (SPARK) Total daily symptom score of C1 on C3 days prior to (BEACON) or 4 of the last 7 days prior to (SHINE, ILLUMINATE and ENLIGHTEN) randomization Grade C2 on modified MRC dyspnoea scale (BLAZE) Key exclusion crit[eria COPD exacerbation requiring treatment with ABs and/or systemic CS and/or hospitalization within 6 weeks before or during screening (all studies, where knownj, except ILLUMINATE) or within 12 months before randomization (ILLUMINATE) Chronic hypoxemia requiring daily long-term oxygen therapy; RTI within 4 weeks before or during screening; concomitant pulmonary disease; history of asthma; history of a-1 antitrypsin deficiency (all studies) History of long QT syndrome (or prolonged corrected QT interval [450 ms during screening); clinically significant ECG abnormality (all studies, where knownj) ABs antibiotics, BD bronchodilator, BDI baseline dyspnoea index, COPD chronic obstructive pulmonary disease, CS corticosteroids, FC fluticasone, FVC forced vital capacity, FEV1 forced expiratory volume in one second, FEV1 AUC0–12h area under the curve from time zero to 12 h post-dose for FEV1, GLY glycopyrronium bromide, GOLD Global Initiative for Chronic Obstructive Lung Disease, IND indacaterol maleate, MRC Medical Research Council, PL placebo, pts patients, QVA149 (IND/GLY fixed-dose combination), RTI respiratory tract infection, S salmeterol, SAC self-administered computerized, TIO tiotropium bromide, TDI transition dyspnoea index, TEAE treatment-emergent adverse event a

All trials were randomized, double-blind (ILLUMINATE, BEACON, BLAZE and BRIGHT were also double-dummy) or open-label (ARISE), and conducted at multiple centres. SHINE, ILLUMINATE, BEACON, SPARK, ENLIGHTEN and ARISE were parallel-group studies; BLAZE and BRIGHT were cross-over studies

b

Treatment doses were as follows: QVA (IND/GLY) 110/50; IND 150; GLY 50; TIO 18; and S/FC 50/500 (all lg). Active treatments were administered as follows: once daily in the morning via the BreezehalerÒ (QVA, IND, GLY) or HandihalerÒ (TIO) devices, or twice daily in the morning and evening via the AccuhalerÒ device (S/FC). TIO was administered blinded (BLAZE, BRIGHT) or open-label (SHINE, SPARK and ARISE)

c

Except for the cross-over studies, BLAZE and BRIGHT (no. of pts exposed to study drug)

d

The total no. of pts randomized in each study was as follows: ARISE, n = 160; BEACON, n = 193; BLAZE, n = 247; BRIGHT, n = 85; ENLIGHTEN, n = 339; ILLUMINATE, n = 259; SHINE, n = 2,144; and SPARK, n = 2,224

e

Noninferiority study

f

Extended to 76 weeks, if required

g

Safety study

h

Japanese pts

i

GOLD 2008 (SHINE, SPARK, ENLIGHTEN and ARISE), 2009 (ILLUMINATE, BLAZE and BRIGHT) or 2010 (BEACON) criteria

j

Relevant information for ARISE not available


QVA149 on the rate of COPD exacerbations; in contrast to all the other studies, a history of at least one COPD exacerbation requiring treatment with antibiotics and/or systemic corticosteroids within the previous year was necessary for participation in this study [44] (Table 2). Notably, a self-administered computerized (SAC) version of the Baseline Dyspnoea Index (BDI)/Transition Dyspnoea Index (TDI) questionnaires, as opposed to the standard interviewer-based method, was used to assess dyspnoea in BLAZE [25]. The design of each study included a pre-randomization period (consisting of a 7-day pre-screening/washout phase followed by a 7- [23], 14- [6, 26, 29, 32, 41, 45] or 21- [27] day screening/run-in phase) during which all patients, with the exception of those in BEACON, discontinued their maintenance (long-acting) bronchodilator therapy. In BEACON, open-label indacaterol 150 lg once daily and glycopyrronium 50 lg once daily were administered during the 14-day run-in phase in order to stabilize patients and standardize baseline lung function [6]. Existing ICS therapy was maintained; patients receiving ICS via a LABA/ICS combination inhaler were switched to an equivalent dose of ICS monotherapy [41]. Two trials employed a cross-over design (BLAZE and BRIGHT) (Table 2); the treatment periods were separated by a 14and 21-day washout period in BLAZE [25] and BRIGHT [27], respectively. Throughout all trials, salbutamol (albuterol), a short-acting selective b2-adrenergic receptor agonist, was permitted for use as a rescue medication [6, 23, 26, 27, 29, 32, 41, 45]. Key baseline patient characteristics in the studies are summarized in Table 3. The majority of patients had moderate COPD (between &60 and 80 % in all trials, except SPARK, which only enrolled patients with severe or very severe COPD); the duration of COPD ranged from &5.6 to 7.6 years in all trials, except ARISE (&3 years) and BRIGHT (&9 years) (Table 3). Patient demographics and other baseline characteristics were reportedly similar across the treatment groups in the four parallel-group efficacy studies (SHINE [41], ILLUMINATE [32], SPARK [45] and BEACON [6]). Likewise, the treatment groups in the two parallel-group safety studies (ENLIGHTEN [29] and ARISE [23]) were well matched, with the notable exceptions that numerically more QVA149 recipients than placebo recipients in ENLIGHTEN (31.1 vs 18.6 %) [29] and numerically more QVA149 recipients than tiotropium recipients in ARISE (40.3 vs 25.6 %) [23] had severe COPD. Efficacy analyses were conducted on participants from the full analysis set (i.e. all randomized patients who received at least one dose of study drug, with data available for analysis); patients were analysed according to treatment assignment at randomization, i.e. intent-to-treat (all trials,

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except BEACON). In BEACON, efficacy was assessed in the per protocol set, i.e. all randomized patients in the full analysis set without any major protocol deviations [6]. 3.1 Effect on Lung Function 3.1.1 Versus Placebo In several IGNITE trials in patients with moderate to severe COPD (SHINE, BLAZE, BRIGHT and ENLIGHTEN), QVA149 provided significant improvements in bronchodilation compared with placebo that were rapid in onset (i.e. apparent 5 minutes after the first dose on day 1), clinically meaningful in magnitude (i.e. exceeded the minimal clinically important difference [MCID] for FEV1 of C100 mL [48–50]) and maintained over treatment periods of up to 1 year [25, 27, 29, 41]. FEV1 5, 30, and 60 minutes post-dose, FEV1 AUC from time zero to 4 hours (FEV1AUC0–4h), FEV1 AUC0–12h, peak FEV1, trough FEV1 and peak forced vital capacity (FVC) were among the spirometric parameters variously measured in the afore-mentioned studies; these particular parameters were significantly (p \ 0.001) improved with QVA149 versus placebo at all assessed timepoints, including on day 1 in both SHINE and BLAZE, and at weeks 26 and 52 in SHINE and ENLIGHTEN, respectively (Tables 4, 5). In addition, serial spirometry showed that FEV1 values were significantly (p \ 0.001) higher with QVA149 than with placebo at all assessed timepoints on day 1 and at week 6 in BLAZE [25], and at all assessed timepoints on day 1 and at week 26 in SHINE [41]. 3.1.2 Versus Active Comparators 3.1.2.1 Indacaterol and/or Glycopyrronium QVA149 provided bronchodilation that was noninferior to its monocomponents administered concurrently (in BEACON [6]), but significantly better than one or other of its monocomponents administered alone (in SHINE [41] and SPARK [44]). In BEACON [6], QVA149 was noninferior to indacaterol and glycopyrronium administered concurrently with respect to the primary endpoint of trough FEV1 (i.e. mean of the FEV1 values taken at 23 h 15 min and 23 h 45 min postdose) at week 4. At this timepoint, the trough FEV1 value in the QVA149 group was 5 mL less than that in concomitant indacaterol and glycopyrronium group; noninferiority was achieved, since the lower bound of the 95 % confidence interval (CI) for the treatment difference, i.e. -5.1, was greater than the noninferiority limit of -100 mL [6]. In SHINE [41], the significant improvement in bronchodilation with QVA149 over that with indacaterol or glycopyrronium alone was rapid in onset and sustained

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J. E. Frampton

Table 3 Baseline patient characteristics in studies of QVA149 in patients with chronic obstructive pulmonary disease (SHINE [35, 41], ILLUMINATE [32, 35], BEACON [6], SPARK [35, 44], BLAZE [25, 26], BRIGHT [27, 28], ENLIGHTEN [29] and ARISE [23, 24]) Study

SHINEa

ILLUMINATEa

BEACONa

SPARKa

BLAZEb

BRIGHTb

ENLIGHTENa

ARISEa

Age (years)c

63.5–64.4

63.2–63.4

64.2–65.6

63.1–63.6

62.8

62.1

62.5–62.9

69.3–69.4

Male (% of pts)

72.8–77.2

70.2–71.6

57.3–64.4

73.2–76.3

70.3

63.1

76.1–77.3

94.9–95.8

COPD duration (years)c

6.0–6.5

6.4–7.5

6.8–7.3

7.1–7.2

7.6

8.9

5.46–5.82

2.9–3.3

COPD severity (% of pts) Moderate

61.7–67.7

80.2–80.3

58.3–61.1

0–0.1

68.3

72.6

68.4–80.5

59.7–71.8

Severe

32.3–38.3

19.7–19.8

41.7–38.9

78.8–79.3

31.7

27.4

18.6–31.1

25.6–40.3

0 56.5–58.8

0 32.9–37.1

62.1–67.8

20.6–21.2 74.9–75.8

0 54.9

31.0

0–0.9 38.9–45.8

0–2.6 26.1–28.2

Very severe Inhaled CS use (% of pts) Smoking status (% of pts) Former

59.5–61.3

51.9–52.3

58.9–60.2

61.8–63.4

54.5

46.4

54.7–54.9

72.3–74.4

Current

38.7–40.5

47.7–48.1

39.8–41.1

36.6–38.2

45.5

53.6

45.1–45.3

25.6–27.7

No. of COPD exacerbations in the previous year (% of pts) 0

73.1–79.3

99.6–100

1.1–1.8

69.9

83.3

63.7–68.4

79.5–84.0

1

15.9–22.3

0–0.4

74.9–77.3

23.2

14.3

24.9–28.3

12.6–17.9

C2

4.6–7.6

0

20.9–23.6

6.9

2.4

6.7–8.0

2.6–3.4

1.3

1.4–1.5

0.89–0.91

1.35

1.5

1.7

1.04

1.6

FEV1 pre-BD (L)c FEV1 post-BD (L)c FEV1 post-BD (% predicted)

c

1.4–1.5 1.6

1.6–1.7

54.9–55.7

60.0–60.5

53.8–54.1

37.0–37.4

56.1

55.9

56.4–59.4

53.8–58.3

FEV1 post-BD reversibility (%)c

19.3–20.6

20.3–20.5

22.7–24.4d

17.2–18.9d

20.6d

22.6

15.6–15.7

15.8–16.0

FEV1/FVC post-BD (%)c

48.2–49.2

50.0–50.3

39.3

48.0

48.5

53.4–55.0

48.3–49.9

BD bronchodilator, COPD chronic obstructive pulmonary disease, CS corticosteroids, FC fluticasone, FVC forced vital capacity, FEV1 forced expiratory volume in one second, GLY glycopyrronium bromide, IND indacaterol maleate, PL placebo, pts patients, QVA QVA149 (IND/GLY fixed-dose combination), S salmeterol, TIO tiotropium bromide a

Data presented are the range of values across the treatment groups for the safety set (n = 474, 476, 473, 480 and 232 for QVA, IND, GLY, TIO and PL, respectively, in SHINE; n = 90 and 103 for QVA and IND ? GLY, respectively, in BEACON; n = 258 and 264 for QVA and S/FC, respectively, in ILLUMINATE; n = 729, 740 and 737 for QVA, GLY and TIO, respectively, in SPARK; n = 225 and 113 for QVA and PL, respectively, in ENLIGHTEN; and n = 119 and 39 for QVA and TIO, respectively, in ARISE) b

Data presented are the values for the full analysis set (n = 246 in BLAZE and n = 84 in BRIGHT)

c

Mean value

d

Reported as FEV1 pre-/post-BD reversibility (SPARK) or not stated whether FEV1 pre- or post-BD reversibility (BEACON and BLAZE)

throughout a treatment period of 26 weeks. FEV1 5 and 30 min post-dose, FEV1AUC0–4h, FEV1AUC0–12h, peak FEV1, trough FEV1 and peak FVC were among the spirometric parameters measured in this study; these particular parameters were significantly (p \ 0.001) improved with QVA149 versus indacaterol and glycopyrronium at all assessed timepoints, with the exception of FEV1 5 min post-dose on day 1 (not significantly improved versus indacaterol) and peak FVC on day 1 (not significantly improved versus glycopyrronium) (Table 4). Similarly, serial spirometry showed that FEV1 values were significantly (p \ 0.05) higher with QVA149 than with indacaterol or glycopyrronium at almost all assessed timepoints on day 1 and at week 26 [41]. SHINE therefore met its primary endpoint by demonstrating that trough FEV1 at week 26 was significantly higher with QVA149 compared with indacaterol alone and

glycopyrronium alone (treatment differences of 70 and 90 mL, respectively) (Table 4). For different subgroups of patients defined according to age (\65 or C65 years), gender (male or female), COPD severity (moderate or severe) and concurrent ICS use (yes or no), the improvements in trough FEV1 at week 26 with QVA149 relative to indacaterol and glycopyrronium were similar to those seen in the overall study population [41]. In post hoc analyses, the proportions of patients with increases of [100 and [200 mL from baseline in trough FEV1 at week 26 were significantly (p \ 0.001) higher with QVA149 (64.3 and 39.8 %, respectively) than with indacaterol (46.2 and 26.2 %, respectively) or glycopyrronium (43.2 and 23.8 %, respectively) [41]. The SPARK study in patients with severe or very severe COPD was the only other trial to compare QVA149 with one of its monocomponents [44]. At all assessed timepoints


473

Table 4 Efficacy of QVA149 in patients with moderate to severe chronic obstructive pulmonary disease. Summary of selected lung function (spirometry) results in the SHINE [34, 36, 37, 41, 43] and ILLUMINATE [32, 34, 36, 37] studiesa Parameter (treatment differenceb)

SHINEc QVA vs. IND

ILLUMINATEd QVA vs. GLY

QVA vs. TIO

QVA vs. PL

QVA vs. S/FC

FEV1 5 mins post-dose (mL) at: Day 1

10

40**

70**

130**

81**

Week 12 Week 26

90** 80**

130** 130**

120** 120**

270** 290**

129** 150**

FEV1 30 min post-dose (mL) at: Day 1

50**

40**

90**

200**

75**

Week 12

100**

140**

140**

300**

157**

Week 26

100**

140**

140**

320**

161**

FEV1 AUC0–4h (mL) at: Day 1

60**

30**

80**

220**

Week 12

120**

140**

140**

310**

Week 26

110**

140**

130**

340**

100**

80**

130**

260**

FEV1 AUC0–12h (mL) at: Day 1 Week 12

73** 123**

130**

130**

120**

330**

138**e

Day 1 Week 12

70** 120**

30** 130**

80** 130**

210** 310**

70** 150**

Week 26

120**

130**

130**

330**

150**

Week 26 Peak FEV1 (mL) at:

Trough FEV1f (mL) at: End of day 1

80**

80**

80**

190**

Week 12

80**

100**

90**

230**

90**

Week 26

70**e

90**e

80**

200**

100**

Peak FVC (mL) at: Day 1

70**

30

110**

320**

60*

Week 12

140**

140**

160**

430**

210**

Week 26

130**

110**

140**

410**

220**

FC fluticasone, FEV1 forced expiratory volume in one second, FEV1 AUC0–x area under the curve from time zero to x h post-dose for FEV1, FVC forced vital capacity, GLY glycopyrronium bromide, IND indacaterol maleate, LSM least squares mean, PL placebo, QVA QVA149 (IND/GLY fixed-dose combination), S salmeterol, TIO tiotropium bromide, *p \ 0.05, **p \ 0.001 for comparison a

See Table 2 for study design details, including study medication dosages

b

Data presented are the LSM treatment difference in LSM values for each parameter

c

Known LSM values for parameters in the QVA group are: FEV1 5 (30) mins post-dose = 1.4 (1.48) L on day 1, and 1.52 (1.56) and 1.49 (1.55) L at weeks 12 and 26; FEV1 AUC0–4h = 1.52 L on day 1, and 1.59 and 1.57 L at weeks 12 and 26 (week 12 value estimated from a graph); FEV1 AUC0–12h = 1.5 L on day 1, and 1.51 L at week 26; peak FEV1 = 1.59 L on day 1, and 1.66 and 1.64 L at weeks 12 and 26; and trough FEV1 = 1.46 L at end of day 1, and 1.47 and 1.45 L at weeks 12 and 26 d

Known LSM values for parameters in the QVA group are: FEV1 5 (30) mins post-dose = 1.56 (1.63) L on day 1, and 1.67 (1.74) and 1.67 (1.73) L at weeks 12 and 26 (all values estimated from a graph); FEV1 AUC0–12h = 1.675 L on day 1, and 1.708 and 1.695 L at weeks 12 and 26; peak FEV1 = 1.76 L on day 1, and 1.82 and 1.82 L at weeks 12 and 26; and trough FEV1 = 1.612 and 1.601 L at weeks 12 and 26

e

Primary endpoint

f

Mean of the FEV1 values taken at 23 h 15 min and 23 h 45 min post-dose (SHINE) or 45 and 15 min pre-dose (ILLUMINATE)

in this trial (i.e. from week 4 through 64), trough FEV1 was significantly (p \ 0.0001) higher in QVA149 recipients than in glycopyrronium recipients, with treatment differences in the range 70–80 mL [44].

Additional data demonstrating that improvements in bronchodilation with QVA149 versus glycopyrronium are sustained during long-term treatment are available from a pooled analysis of patients with severe COPD who were

474

J. E. Frampton

Table 5 Efficacy of QVA149 in patients with moderate to very severe chronic obstructive pulmonary disease. Summary of selected lung function (spirometry) results in the SPARK [37, 44, 45], BLAZE [25, 26], BRIGHT [27] and ENLIGHTEN [29] studiesa Parameter (treatment differenceb)

SPARKc QVA vs. GLY

BLAZEd QVA vs. TIO

BRIGHTe

QVA vs. TIO

QVA vs. PL

70*

126*

62*

182*

QVA vs TIO

ENLIGHTENf QVA vs. PL

QVA vs. PL

FEV1 5 min post-dose (mL) at: Day 1 FEV1 30 mins post-dose (mL) at: Day 1

200*g

Week 12

260*g

Week 26

269*g

Week 52

255*g

FEV1 AUC0–4h (mL) at: Day 1

70*/70*/ 60*h

210*/230*/ 170*h

Week 6

110*/110*/ 90*h

330*/370*/ 250*h

Trough FEV1i (mL) at: Week 3

100*

200*

187*

Week 12

70*

70*

Week 26

70*

70*

163* 152*

Week 52

70*j

60*j

189*

Week 64

70*

60*

Peak FVC (mL) at: Day 1

255*g

Week 12

294*g

Week 26

331*g

Week 52

316*g

FEV1 forced expiratory volume in 1 s, FEV1 AUC0–4h area under the curve from time zero to 4 h post-dose for FEV1, FVC forced vital capacity, GLY glycopyrronium bromide, LSM least squares mean, PL placebo, QVA QVA149 (indacaterol/glycopyrronium fixed-dose combination), TIO tiotropium bromide, * p \ 0.001 for comparison a


b


c

LSM values for trough FEV1 in the QVA group are 1.08, 1.07, 1.06 and 1.06 L at weeks 12, 26, 52 and 64, respectively (all values estimated from a graph) d Known LSM values for parameters in the QVA group are FEV1 AUC0–4h = 1.56/1.57/1.56 L for all pts/subgroup of pts with moderate COPD/subgroup of pts with severe COPD on day 1, and 1.64/1.65/1.61 L all pts/subgroup of pts with moderate COPD/subgroup of pts with severe COPD at week 6 e

LSM value for trough FEV1 in the QVA group is 1.53 L at week 3

f

LSM values for parameters in the QVA group are: FEV1 60 mins post-dose = 1.67 L on day 1, and 1.75, 1.70 and 1.71 L at weeks 12, 26 and 52, respectively; trough FEV1 = 1.61, 1.59 and 1.61 L at weeks 12, 26 and 52, respectively; and peak FVC = 3.05 on day 1, and 3.10, 3.08 and 3.10 L at weeks 12, 26 and 52, respectively g

Assessed 60 min post-dose

h

For all pts/subgroup of pts with moderate COPD/subgroup of pts with severe COPD

i

Mean of the FEV1 values taken at 45 and 15 min pre-dose (SPARK, ENLIGHTEN) or 60 min pre-dose (BRIGHT)

j

Value estimated from a graph

enrolled in either SPARK, ARISE or ENLIGHTEN [46]. Compared with glycopyrronium, QVA149 significantly (p \ 0.001) improved all spirometry parameters measured at all assessed timepoints, including pre-dose (trough) FEV1 at weeks 12, 26, 39 and 52, FVC 30 and 60 min postdose on day 1 and at weeks 12, 26, 39 and 52, and pre-dose (trough) FVC at week 52. A total of 696 and 584 QVA149

and glycopyrronium recipients, respectively, were included in this analysis [46]. 3.1.2.2 Tiotropium or Salmeterol/Fluticasone In various IGNITE trials, QVA149 provided significantly greater bronchodilation compared with salmeterol/fluticasone (in ILLUMINATE [32]) or tiotropium (in SHINE [41],


SPARK [44], BLAZE [25] and BRIGHT [27]). The improvements in bronchodilation with QVA149 over that with salmeterol/fluticasone or tiotropium were rapid in onset and maintained throughout treatment periods of, for example, 26 weeks in ILLUMINATE and SHINE, and 64 weeks in SPARK. FEV1 5 and 30 min post-dose, FEV1AUC0–4h, FEV1AUC0–12h, peak FEV1, trough FEV1 and peak FVC were among the spirometric parameters measured in the aforementioned studies; these particular parameters were significantly (p \ 0.05) improved with QVA149 versus salmeterol/fluticasone (in ILLUMINATE) or tiotropium (in SHINE, SPARK, BLAZE and BRIGHT) at all timepoints assessed (see Tables 4, 5). Serial spirometry showed that FEV1 values were significantly (p \ 0.001) higher with QVA149 versus salmeterol/fluticasone at all assessed timepoints on day 1 and at weeks 12 and 26 in ILLUMINATE [32], and significantly (p \ 0.05) higher with QVA149 versus tiotropium at all assessed timepoints on day 1 in BLAZE and SHINE and at weeks 6 and 26 in BLAZE and SHINE, respectively [25, 41]. The ILLUMINATE study [32] thus met its primary endpoint by demonstrating that FEV1AUC0–12h at week 26 was significantly higher with QVA149 compared with salmeterol/fluticasone; the treatment difference of 138 mL was large enough to be considered clinically meaningful (Table 4). For different subgroups of patients defined according to age (\65 or C65 years), gender (male or female), COPD severity (moderate or severe), smoking status (current or ex-smoker) and concurrent ICS use (yes or no), the improvements in FEV1AUC0–12h at week 26 with QVA149 relative to salmeterol/fluticasone were similar to those seen in the overall study population [32]. A statistically significant and clinically meaningful difference in FEV1AUC0–12h favouring QVA149 over salmeterol/fluticasone was also observed at week 12 in this study (Table 4). Additional long-term data demonstrating sustained improvements in bronchodilation with QVA149 versus tiotropium in patients with severe COPD are available from the pooled analysis of the SPARK, ARISE and ENLIGHTEN trials [46]. Compared with tiotropium, QVA149 significantly (p \ 0.001) improved all spirometry parameters measured at all assessed timepoints, including pre-dose (trough) FEV1 at weeks 12, 26, 39 and 52, FVC 30 and 60 minutes post-dose on day 1 and at weeks 12, 26, 39 and 52, and pre-dose (trough) FVC at week 52. A total of 696 and 591 QVA149 and tiotropium recipients, respectively, were included in this analysis [46]. 3.2 Effect on Dyspnoea Compared with placebo, QVA149 provided statistically significant and clinically meaningful improvements in

475

symptoms of dyspnoea, as measured using the BDI/TDI, at all assessed timepoints in BLAZE [25] and SHINE [41] (Table 6). At week 6 in the former and week 26 in the latter, the TDI responder rate (i.e. proportion of patients achieving a clinically significant improvement [C1-unit increase] in TDI focal score) was significantly (p \ 0.001) higher in QVA149 recipients than placebo recipients (Table 6). The BLAZE study [25] therefore met its primary endpoint by demonstrating that the SAC TDI focal score at week 6 was significantly (p \ 0.001) improved with QVA149 versus placebo; as noted earlier, the treatment difference of 1.37 U (see Table 6) exceeded the MCID for the TDI of 1 U [50, 51]. In a subgroup analysis by COPD severity, QVA149 provided statistically significant (p \ 0.001) and clinically meaningful improvements in SAC TDI focal score at week 6 relative to placebo, both in patients with moderate COPD (n = 168) and in those with severe COPD (n = 78) (Table 6). The SAC TDI responder rate was significantly (p \ 0.01) higher in QVA149 recipients than placebo recipients, not only in the overall study population, but also in the subgroups of patients with moderate or severe COPD (Table 6). In general, QVA149 did not significantly improve breathlessness compared with one or other of its monocomponents administered alone (in SHINE [41]); however, it did significantly relieve shortness of breath compared with both tiotropium (in BLAZE [25] and SHINE [41]) and salmeterol/fluticasone (in ILLUMINATE [32]). In SHINE [41], the TDI focal score did not differ significantly between the QVA149 and indacaterol arms at weeks 12 and 26, and between the QVA149 and glycopyrronium arms at week 26 (Table 6). In contrast, the TDI focal score was significantly (p \ 0.05) improved with QVA149 compared with tiotropium at week 6 in BLAZE and at weeks 12 and 26 in SHINE, and compared with salmeterol/fluticasone at weeks 12 and 26 in ILLUMINATE (Table 6). The TDI responder rate was also significantly (p \ 0.05) higher in QVA149 recipients versus tiotropium recipients (at weeks 6 and 26 in BLAZE and SHINE, respectively) and salmeterol/fluticasone recipients (at weeks 12 and 26 in ILLUMINATE) (Table 6). 3.3 Effect on Health Status Compared with placebo, QVA149 provided a statistically significant improvement in health status, as assessed using the St George’s Respiratory Questionnaire (SGRQ), in SHINE [41] (Table 7). At week 12, the improvement in the SGRQ total score with QVA149 versus placebo equalled the MCID of 4 U [50, 52]) (Table 7). At week 26, however, the improvement was below the MCID and, moreover, the SGRQ responder rate (i.e. proportion of patients

476

J. E. Frampton

Table 6 Efficacy of QVA149 in patients with moderate to severe chronic obstructive pulmonary disease. Summary of results for dyspnoea in the SHINE [30, 35, 41], ILLUMINATE [30, 32, 33, 35] and BLAZE [25, 26] studiesa Parameter

SHINEb QVA vs. IND

QVA vs. GLY

QVA vs. TIO

QVA vs. PL

ILLUMINATEc

BLAZEd

QVA vs. S/FC

QVA vs. TIO

QVA vs. PL

0.49* (0.36g) [0.76*h]

1.37***i (1.11***g) [1.92***h]

35.9 vs. 24.4* (33.1 vs. 21.8*g) [41.7 vs. 30.0h]

35.9 vs. 18.1*** (33.1 vs. 16.3***g) [41.7 vs. 21.7**h]

TDI focal scoree,f at: Week 6 Week 12

0.26

0.41*

0.63***

1.22***

0.58*

Week 26

0.26

0.21

0.51***

1.09***

0.76**

TDI respondersj (%) at: Week 6 Week 12 Week 26

65.2 vs. 53.8* 68.1 vs. 64.6

68.1 vs. 63.7

68.1 vs. 59.2*

68.1 vs. 57.5**

67.5 vs. 56.8*

BDI baseline dyspnoea index, BL baseline, COPD chronic obstructive pulmonary disease, FC fluticasone, GLY glycopyrronium bromide, IND indacaterol maleate, LSM least squares mean, MCID minimal clinically important difference, PL placebo, pts patients, QVA QVA149 (IND/GLY fixed-dose combination), S salmeterol, SAC self-administered computerized, TDI transition dyspnoea index, TIO tiotropium bromide, *p \ 0.05, **p \ 0.01, ***p \ 0.001 for comparison a


b

LSM values for TDI focal scores in the QVA group are 2.44 and 2.72 at weeks 12 and 26

c

LSM values for TDI focal scores in the QVA group are 2.03 and 2.36 at weeks 12 and 26

d

LSM value for SAC TDI focal score in the QVA group is 0.88 (0.62 for subgroup of pts with moderate COPD) [1.48 for subgroup of pts with severe COPD] at week 6

e

TDI focal scores range from -9 to ?9, with increasing negative scores indicating increasing deterioration and increasing positive scores indicating increasing improvement in dyspnoea from BL, as established by the BDI. 0 = no change in dyspnoea from BL

f g

Data presented are the LSM treatment difference in LSM values for TDI focal score For subgroup of pts with moderate COPD

h

For subgroup of pts with severe COPD

i

Primary endpoint

j

Pts achieving a clinically significant improvement (increase of C1 U) in TDI focal score (1 unit is the MCID of the TDI [51])

achieving a clinically significant improvement [C4-U decrease] in SGRQ total score) did not differ significantly between the two groups (Table 7). That noted, the proportion of patients achieving a larger, C8-U decrease in SGRQ total score at week 26 was significantly higher among QVA149 recipients than placebo recipients (51.3 vs. 37.8 %; p \ 0.002) [41]. QVA149 did not significantly improve health status compared with indacaterol alone at either of the assessed timepoints in SHINE [41] (Table 7; week 12 data not reported). In comparison, QVA149 significantly improved the SGRQ total score compared with glycopyrronium alone at week 12 (but not week 26) in SHINE and at weeks 12, 26, 38, 52 and 64 in SPARK [44] (Table 7). Additionally, the SGRQ responder rate was significantly higher in QVA149 recipients than glycopyrronium recipients at all assessed timepoints in SPARK, with the exception of week 64 (Table 7).

QVA149 also significantly improved the SGRQ total score compared with tiotropium at all assessed timepoints in both SHINE and SPARK; the SGRQ responder rate was significantly higher in QVA149 recipients than tiotropium recipients at all assessed timepoints in these studies, with the exception of week 64 in SPARK (Table 7). In contrast, QVA149 did not significantly improve health status compared with salmeterol/fluticasone at either of the assessed timepoints in ILLUMINATE [32] (Table 7). 3.4 Effect on COPD Exacerbations The 26-week SHINE study was not designed to assess the effect of QVA149 on COPD exacerbations, in part because the study population was not enriched with patients who were at high risk of COPD exacerbations [41]. Nonetheless, exacerbations [defined as either the presence of two


477

Table 7 Efficacy of inhaled QVA149 in patients with moderate to severe chronic obstructive pulmonary disease. Summary of results for health status in the SHINE [30, 35, 41], ILLUMINATE [30, 32, 33, 35] and SPARK [30, 35, 44] studiesa Parameter

SHINEb QVA vs. IND

ILLUMINATEc

SPARKd

QVA vs. GLY

QVA vs. TIO

QVA vs. PL

QVA vs. S/FC

QVA vs. GLY

QVA vs. TIO

-1.84*

-2.37**

-3.99***

0.71

-2.45***

-2.94***

-1.18

-2.13**

-3.01**

-1.24

-1.88** -2.81***

-1.71* -3.14***

Week 52

-2.58***

-2.83***

Week 64

-2.07**

-2.69***

50.4 vs. 50.0

58.6 vs. 52.0**

58.6 vs. 50.4**

55.5 vs. 49.1

59.6 vs. 53.5*

59.6 vs. 53.3*

Week 38

63.3 vs. 55.1**

63.3 vs. 55.9**

Week 52

62.1 vs. 51.6***

62.1 vs. 52.4**

Week 64

57.3 vs. 51.8

57.3 vs. 50.8

SGRQ total scoree,f at: Week 12 Week 26 Week 38

-1.09

SGRQ respondersg (%) at: Week 12 Week 26

63.7 vs. 63.0

63.7 vs. 60.5

63.7 vs. 56.4*

63.7 vs. 56.6

BL baseline, FC fluticasone, GLY glycopyrronium bromide, IND indacaterol maleate, LSM least squares mean, MCID minimal clinically important difference, PL placebo, pts, patients, QVA QVA149 (IND/GLY fixed-dose combination), S salmeterol, SGRQ St George’s Respiratory Questionnaire, TIO tiotropium bromide; *p \ 0.05, **p \ 0.01, ***p \ 0.001 for comparison a


b

Where known, LSM values for SGRQ total score in the QVA group are: 37.01 at week 26

c

Where known, LSM values for SGRQ total score in the QVA group are: 42.01 at BL, and 35.45 at week 26

d

LSM values for SGRQ total scores in the QVA group are: 52.82 at BL, and 44.69, 44.06, 42.72, 43.38 and 43.39 at weeks 12, 26, 38, 52 and 64, respectively e SGRQ total scores range from 0 to 100, with a lower score indicating a better health status f

Data presented are the LSM treatment difference in LSM values for SGRQ total score

g

Pts achieving a clinically significant improvement (decrease of C4 U) in SGRQ total score (4 U is the MCID of the SGRQ [52])

major symptoms [dyspnoea, sputum volume, sputum purulence] for C2 consecutive days or a worsening of one major symptom together with an increase in any one minor symptom [sore throat, cold, fever without other cause, cough, wheeze] for C2 consecutive days) that occurred were recorded and categorized as being mild (could be selfmanaged by the patient), moderate (could be treated with systemic CS or antibiotics, or both) or severe (required hospital admission or emergency treatment) [37, 41]. Interestingly, QVA149 significantly reduced the annualized rate of moderate or severe exacerbations by 43 % compared with placebo (0.46 vs. 0.75; rate ratio [RR] 0.57 [95 % CI 0.41, 0.79]; p \ 0.001). Moderate or severe exacerbations were experienced by &18 and 26 % of QVA149 and placebo recipients, respectively [37]. The SPARK trial [44] met its primary endpoint by demonstrating that, over a 64-week period, QVA149 was more effective than glycopyrronium alone in preventing moderate to severe COPD exacerbations in patients with severe or very severe COPD who were at high risk of COPD exacerbations. Specifically, the annualized rate of moderate or severe exacerbations was 12 % lower among

QVA149 recipients than glycopyrronium recipients (0.84 vs. 0.95; RR 0.88 [95 % CI 0.77, 0.99]; p = 0.038). Similarly, the annualized rate of moderate or severe exacerbations was 10 % lower among QVA149 recipients than tiotropium recipients; however, this between-group difference was not statistically significant (0.84 vs. 0.93; RR 0.90 [95 % CI 0.79, 1.02]; p = 0.096) [44]. QVA149 also significantly reduced the annualized rate of mild exacerbations by 15 % versus glycopyrronium (2.51 vs. 2.96; RR 0.85 [95 % CI 0.75, 0.96]; p = 0.007) and 16 % versus tiotropium (2.51 vs. 2.98; RR 0.84 [95 % CI 0.75, 0.95]; p = 0.005), as well as the annualized rate of all (mild, moderate and severe) exacerbations by 15 % compared with glycopyrronium (3.44 vs. 4.04; RR 0.85 [95 % CI 0.77, 0.94]; p = 0.001) and 14 % compared with tiotropium (3.44 vs. 4.02; RR 0.86 [95 % CI 0.78, 0.94]; p = 0.002). In contrast, the rates of severe exacerbations were uniformly low; no significant differences noted when the QVA149 treatment group was compared with either the glycopyrronium treatment group (0.09 vs. 0.12; RR 0.81 [95 % CI 0.60, 1.10]; p = 0.18) or the tiotropium treatment group (0.09 vs. 0.08; RR 1.16 [95 % CI 0.84, 1.61]; p = 0.36) [44].

478

3.5 Effect on Exercise Tolerance The BRIGHT study met its primary endpoint by demonstrating that QVA149 significantly improved exercise tolerance, as measured by exercise endurance time during a sub-maximal constant load cycle ergometry test, compared with placebo [27]. Specifically, the exercise endurance time after 3 weeks of treatment was 508 s with QVA149 versus 448 s with placebo (p = 0.006); the between group difference of 60 s reached the MCID for constant load cycling endurance tests (46–105 s [49, 50]). In the QVA149 and placebo groups, 46 and 38 % of patients, respectively, stopped exercise due to leg fatigue [27]. QVA149 also significantly (p \ 0.05) improved all spirometry endpoints assessed at week 3, including dynamic inspiratory capacity at isotime during exercise, and all body plethysmography measurements assessed post-dose on day 1 and at week 3 (functional residual capacity, residual volume, slow vital capacity [SVC] and specific airways conductance [SGaw]), compared with placebo [27]. Compared with tiotropium, QVA149 significantly (p \ 0.05) improved all spirometry endpoints assessed at week 3 and some body plethysmography measurements assessed post-dose on day 1 and/or at week 3, in particular SVC and SGaw. This notwithstanding, the improvement in exercise tolerance with tiotropium over placebo (66 s) was of a similar magnitude to that seen with QVA149 (between-group statistical comparison not reported) [27]. In the tiotropium group, 44 % of the patients stopped exercise due to leg fatigue [27]. 3.6 Effect on Symptoms and Rescue Medication Use Compared with placebo, QVA149 significantly (p \ 0.05) improved all patient symptoms assessed in the SHINE [41], BLAZE [25] and ENLIGHTEN [29] studies, with the exception of the percentage of nights with no night-time awakenings in ENLIGHTEN (Table 8). Mean daily total symptom scores were also significantly (p \ 0.05) improved (i.e. reduced) with QVA149 versus placebo (Table 8). Additionally, compared with placebo recipients, QVA149 recipients used significantly (p \ 0.01) less rescue medication and had a significantly (p \ 0.001) higher percentage of days with no rescue medication use (Table 8). QVA149 provided significant (p \ 0.05) improvements in some patient symptoms relative to other active therapies, including the percentage of days able to perform usual daily activities (versus indacaterol, glycopyrronium and tiotropium in SHINE), the percentage of days with no daytime symptoms (versus salmeterol/fluticasone in ILLUMINATE) and the percentage of nights with no night-time awakenings (versus glycopyrronium in SHINE) (Table 8).

J. E. Frampton

Mean daily total symptom scores were also significantly (p \ 0.05) improved with QVA149 versus glycopyrronium and tiotropium (in SHINE and SPARK) (Table 8). In addition, QVA149 recipients used significantly (p \ 0.05) less rescue medication compared with indacaterol recipients (in SHINE), glycopyrronium recipients (in SHINE and SPARK), tiotropium recipients (in SHINE, SPARK and BLAZE) and salmeterol/fluticasone recipients (in ILLUMINATE) (Table 8). QVA149 recipients also had a significantly (p \ 0.001) higher percentage of days with no rescue medication use compared with glycopyrronium recipients (in SHINE) and tiotropium recipients (in SHINE and BLAZE) (Table 8).

4 Tolerability Data regarding the tolerability of inhaled QVA149 are available from the QVA149 clinical trial programme (IGNITE), which includes four studies of 26 (SHINE [41] and ILLUMINATE [32]) or 52 (ENLIGHTEN [29] and ARISE [23, 24]) weeks’ duration in patients with moderate to severe COPD, and one study of 64 weeks’ duration in patients with severe or very severe COPD (SPARK [44]) [see Sect. 3 for further study design details]. Pooled 6-month data from SHINE, ILLUMINATE, ENLIGHTEN and ARISE have been reported in preliminary form (as posters [53, 54]) and/or presented in the European Public Assessment Report (EPAR) for QVA149 [22]; key findings from this analysis—which is considered to be the main safety database—are summarized in Table 9. SHINE, ENLIGHTEN, ARISE and SPARK have also been included in a network meta-analysis of 14 studies from across the individual QVA149, indacaterol and glycopyrronium clinical trial programmes, which has provided additional information on infrequently occurring safety endpoints [55]. 4.1 General Profile QVA149 was generally well tolerated in patients with moderate to severe COPD, with most adverse events (AEs) being of mild to moderate severity and, moreover, no treatment-related deaths being reported [23, 29, 32, 41, 53]. COPD worsening was both the most common treatmentemergent AE and the most common treatment-emergent serious AE (SAE), based on an assessment period of 6 months (in the pooled analysis [53]) and 1 year (in ENLIGHTEN [29]). According to the pooled analysis [53], COPD worsening was reported as an AE by nearly onequarter (23.0 %) of QVA149 recipients; it was reported as an SAE by 1.6 % of patients (Table 9). Other common (incidence C2 %) treatment-emergent AEs in the pooled

QVA vs. PL

2.28

-0.30*

-0.13

-0.01

5.04*

-1.68

1.2

9.35***

-0.66***

-0.26*

-0.06

5.87**

1.09

5.05**

10.58***

-0.54***

-0.24*

-0.09**

8.45***

1.95

3.68

12.33***

-0.96***

-0.67***

-0.11**

11.48***

3.05*

10.01***

NRf

-0.39*

-0.05

-0.09**

-1.24

2.5*

-1.38

QVA vs. S/FC

QVA vs. TIO

QVA vs. IND

QVA vs. GLY

ILLUMINATE

SHINE

-0.81***e

-0.37***

QVA vs. GLY

SPARK

-0.76***e

-0.44***

QVA vs. TIO

9.1***

-0.45**

-0.03

-0.4

1.04

2.6

QVA vs. TIO

BLAZE

19.9***

-1.43***

-0.72***

8.8***

1.06***

5.6***

QVA vs. PL

-0.726**

-0.57*

8.13*

5.29*

6.32

QVA vs. PL

ENLIGHTEN

Assessed over 6 (BLAZE), 26 (SHINE, ILLUMINATE and SPARK) or 52 (ENLIGHTEN) weeks, unless indicated otherwise



f

e

51 % for QVA vs. 46.5 % for S/FC

Assessed over 64 weeks

Where known, LSM values for change from BL in daily total symptom score in the QVA group are: -1.65 at week 26 in SHINE; -1.28 at week 26 in ILLUMINATE; -1.67 at week 26 in SPARK; and -2.34 at week 52 in ENLIGHTEN

d

c

b

a

BL baseline, FC fluticasone, GLY glycopyrronium bromide, IND indacaterol maleate, LSM least squares mean, NR not reported, PL placebo, QVA QVA149 (IND/GLY fixed-dose combination), RM rescue medication, S salmeterol, TIO tiotropium bromide; *p \ 0.05, **p \ 0.01, ***p B 0.001 for comparison

RM use (%)

Days with no

RM use (puffs/day)

Change from BL in

RM use

symptom scored

Change from BL in mean daily total

lessness score

mean daily breath-

Change from BL in

daily activities (%)

perform usual

Days able to

symptoms’ (%)

day-time

Days with ‘no

awakenings’ (%)

night-time

Nights with ‘no

Patient symptoms

Endpoint (treatment differenceb,c)

Table 8 Efficacy of inhaled QVA149 in patients with moderate to very severe chronic obstructive pulmonary disease. Summary of results regarding patient symptoms and rescue medication use in the SHINE [30, 38, 41, 42], ILLUMINATE [30, 32, 33, 38], SPARK [30, 44], BLAZE [25] and ENLIGHTEN [29, 38] studiesa

Indacaterol/Glycopyrronium Fixed-Dose Combination: A Review 479

480

J. E. Frampton

Table 9 Comparative tolerability of inhaled QVA149 and other chronic obstructive pulmonary disease therapies. Summary of pooled 6-month data from the SHINE, ILLUMINATE, ENLIGHTEN and ARISE studiesa [53, 54] Eventb (% of pts)

QVA (n = 1,076)

IND (n = 476)

GLY (n = 473)

TIO (n = 519)

S/FC (n = 264)

PL (n = 345)

55.1 23.0 8.5 4.0 3.7 2.8 2.5 2.5 2.4 2.1 2.0

61.1 32.1 7.4 8.0 6.7 2.7 1.5 2.3 2.7 2.3 3.2

61.3 31.7 9.7 3.8 4.2 2.1 2.1 2.7 3.2 3.6 1.5

56.8 27.6 9.1 4.2 5.4 2.3 1.9 2.3 4.2 1.5 2.3

60.2 23.5 11.0 1.9 1.1 3.8 1.5 1.1 0.8 1.1 0.8

55.1 32.5 6.7 2.6 5.2 1.4 2.0 5.5 5.2 1.4 2.3

5.5 1.6

5.5 3.2

6.1 1.9

3.9 1.3

5.3 1.1

5.5 2.6

1.8 0.3 0.3 0.3 0.2 0.8

2.5 0.6 0 0.2 0 1.5

3.0 0.6 0 0.4 0.2 2.1

1.7 0 0.4 0.4 0.2 1.3

2.3 0.4 0.4 0 0 2.7

2.6 0 0 0 0.3 0.6

0.6

0.8

1.3

0.6

1.1

0.3

0.3 0.2 0.1 0.1 0 0.3

0.4 0.2 0 0 0.2 0.4

0.6 0 0.2 0.2 0.2 0.2

0.6 0.4 0.4 0 0 0.6

0.4 0.4 0 0 0.4 0.4

0 0 0 0 0 0

c

AEs Any AE COPD worsening Nasopharyngitis Cough URTI Headache Oropharyngeal pain Viral URTI Bacterial URTI Back pain LRTI SAEsd Any SAE COPD worsening CCV AEse Any CCV AE AF Angina pectoris Ventricular extrasystoles Supraventricular extrasystoles AF/flutter eventsf,g CCV SAEsg Any CCV SAE MACE Any MACE Non-fatal stroke Coronary revascularization Non-fatal MI HF requiring hospitalization Deaths

AE adverse event, AF atrial fibrillation, CCV cardio- and cerebrovascular, COPD chronic obstructive pulmonary disease, FC fluticasone, GLY glycopyrronium bromide, HF heart failure, IND indacaterol maleate, LRTI lower respiratory tract infection, MACE major adverse cardiovascular events, MI myocardial infarction, PL placebo, pts patients, QVA QVA149 (IND/GLY fixed-dose combination), S salmeterol, SAE serious AE, TIO tiotropium bromide, URTI upper respiratory tract infection a See Table 2 for study design details, including study medication dosages b Regardless of causality c Only AEs reported in C 2 % of pts in the QVA treatment group are presented d Only SAEs reported in C 1 % of pts in any treatment group are presented e Only CCV AEs reported in C 2 pts in the QVA treatment group are presented f New-onset or recurrent/persistent events identified by either AE reporting or ECG findings g Adjudicated

analysis included nasopharyngitis, cough, upper respiratory tract infection (URTI), headache, oropharyngeal pain, viral URTI, bacterial URTI, back pain and lower respiratory tract infection (LRTI) (Table 9) [53]. One-third (33 %) of the 1,076 QVA149 recipients in the pooled analysis had three or more cardiovascular risk factors at baseline [54]; 19 patients (1.8 %) reported at least one cardio- and cerebrovascular (CCV) AE and six

(0.6 %) reported at least one adjudicated CCV SAE (Table 9). However, only four types of CCV AE were recorded in more than one QVA149-treated patient (angina pectoris [n = 3], atrial fibrillation [n = 3], ventricular extrasystoles [n = 3] and supraventricular extrasystoles [n = 2]); no type of CCV SAE was recorded in more than one QVA149-treated patient [54]. Three patients (0.3 %) reported at least one adjudicated major adverse


cardiovascular event (MACE) and nine (0.8 %) reported an adjudicated new onset or recurrent atrial fibrillation/flutter event (see Table 9). The rates of treatment-related AEs/SAEs in the pooled analysis have not been reported. Over a 1-year period in the ARISE study [23], the most common suspected treatmentrelated AEs in Japanese patients were dry mouth and dysphonia (each 2.5 %), followed by COPD worsening, headache, pneumonia and ventricular extrasystoles (each 1.7 %). Inhaled QVA149 was also generally well tolerated in patients with severe to very severe COPD at high risk of COPD exacerbations [44]. The most common (incidence C5 %) treatment-related AEs in SPARK were COPD (87 %), bacterial URTI (18 %), nasopharyngitis (13 %), viral URTI (10 %), LRTI (18 %), cough (6%), bronchitis (5%) and pneumonia (5 %); the most common (incidence C3 %) SAEs were COPD worsening (15 %), pneumonia (3 %) and LRTI (2 %) [44]. Nearly one-third (30 %) of the 729 QVA149 recipients in this study had three or more cardiovascular risk factors at baseline; 3.7 % of patients reported at least one adjudicated CCV SAE, 1.4 % reported an adjudicated MACE, 2.6 % reported an adjudicated nonMACE, and 2.0 % reported an adjudicated new onset or recurrent atrial fibrillation/flutter event [44]. 4.2 Versus Placebo Overall, the AE and CCV AE profiles of QVA149 were similar to those of placebo, as assessed over a period of 6 or 12 months in patients with moderate to severe COPD [29, 41, 53, 54]. In the pooled analysis [53], for example, the proportions of patients experiencing any treatmentemergent AE or SAE were the same in the QVA149 and placebo groups (Table 9). Observed numerical differences in some AEs and SAEs between the QVA149 and placebo groups in ENLIGHTEN could be accounted for, at least in part, by differences in baseline characteristics (i.e. more patients in the QVA149 group versus the placebo group had severe COPD; see Sect. 3) [29]. Moreover, differences between the groups with respect to vital signs and ECG parameters were not clinically relevant; these findings were consistent with those of a 2-week study in 257 patients with moderate to severe COPD, which showed that QVA149 (even at supratherapeutic dosages) had minimal effect on these assessments, as did placebo [20] (see Sect. 2). Notably, QVA149 did not increase the risk of death (hazard ratio [HR] 0.922, 95 % CI 0.338, 2.511), serious pneumonia (HR 1.076, 95 % CI 0.526, 2.203), CCV SAEs (HR 0.597, 95 % CI 0.287, 1.241), MACEs (HR 0.984, 95 % CI 0.417, 2.319) or atrial fibrillation/flutter events (HR 1.017, 95 % CI 0.479, 2.157) compared with placebo in the network meta-analysis, which included 1,547 and

481

2,141 QVA149 and placebo recipients, respectively [55]. QVA149 did, however, decrease the risk of serious COPD exacerbations slightly (HR 0.598, 95 % CI 0.395, 0.906). Some differences in patient baseline characteristics were apparent; compared with those receiving placebo, patients receiving QVA149 were more likely to have severe or very severe COPD (39.8 vs. 65.1 %) or use ICS (42.9 vs. 61.3 %), but less likely to have three or more cardiovascular risk factors (55.1 vs. 30.7 %) [55]. Discontinuation rates due to AEs (or due to SAEs) were 4.3 (1.3) and 1.3 (0.6) % in the QVA149 and placebo groups, respectively, in the 6-month SHINE study [41], and 5.8 (5.3) and 6.2 (2.7) % in the QVA149 and placebo groups, respectively, in the 1-year ENLIGHTEN study [29]. 4.3 Versus Active Comparators Overall, the AE profile of QVA149 was similar to that of the active comparators in the IGNITE trials, which included the monocomponents indacaterol and glycopyrronium administered concomitantly or separately, as well as tiotropium and salmeterol/fluticasone [6, 44, 53, 54]. In the 4-week BEACON study [6], for example, AEs were reported by 25.6 % of patients receiving QVA149 (n = 90) versus 25.2 % of patients receiving concomitant indacaterol plus glycopyrronium (n = 103). COPD worsening (7.8 vs 5.8 %), nasopharyngitis (4.4 vs. 1.9 %) and cough (4.4 vs. 1.9 %) were the most frequently occurring AEs in both treatment groups. SAEs were reported by 5.8 and 4.4 % of QVA149 and concomitant indacaterol plus glycopyrronium recipients, respectively; however, there were no CCV SAEs in either treatment group. One QVA149 recipient, as opposed to four concomitant indacaterol plus glycopyrronium recipients, had a prolonged QTc interval ([450 ms) [6]. No new safety signals were observed for QVA149 relative to indacaterol, glycopyrronium, tiotropium and salmeterol/ fluticasone in the pooled analysis of patients with moderate to severe COPD [53]. In general, the frequencies of AEs and SAEs, including COPD worsening, were similar to, or lower than, those for the active comparators [53] (Table 9). Furthermore, there was no evidence of an increased risk of CCV events with QVA149; the frequencies of CCV AEs, adjudicated CCV SAEs (including MACEs) and adjudicated atrial fibrillation/flutter events with QVA149 were similar to, or numerically lower than, those with the active comparators (Table 9) [53, 54]. Similarly, there was no observable increase in AEs, including MACEs, with QVA149 versus glycopyrronium and tiotropium in the SPARK study in patients with severe to very severe COPD [44]. AEs (including COPD exacerbations) were reported by 93, 94 and 93 % of QVA149 (n = 729), glycopyrronium (n = 740) and tiotropium

482

(n = 737) recipients, respectively; there were no statistically significant differences between the groups for any individual AE. SAEs, CCV SAEs and MACEs were reported by 23, 3.7 and 1.4 % of QVA149 recipients, respectively, 24, 3.4 and 2.0 % of glycopyrronium recipients, respectively, and 22, 3.5 and 1.1 % of tiotropium recipients, respectively [44]. In SHINE [41], discontinuation rates due to AEs and SAEs in the QVA149 group (4.3 and 1.3 %, respectively; see Sect. 4.1) were numerically lower than, or equal to, those in the indacaterol (5.0 and 2.3 %, respectively) and glycopyrronium (3.0 and 1.3 %, respectively) groups, but numerically higher than those in the tiotropium group (2.1 and 1.0 %, respectively). In ILLUMINATE [32], discontinuation rates due to AEs and SAEs in the QVA149 group (8.5 and 1.9 %, respectively) were numerically lower than those in the salmeterol/fluticasone group (10.2 and 3.4 %, respectively).

5 Dosage and Administration In the EU, QVA149 is approved for use as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD [5]. The recommended dosage is inhalation of the contents of one capsule once daily, via the UltibroÒ BreezhalerÒ inhaler. It is also recommended to inhale QVA149 at the same time each day; if a dose is missed, it should be taken as soon as possible on the same day [5]. In Japan, QVA149 is approved for the relief of various symptoms due to airway obstruction in COPD [4]. Local prescribing information should be consulted for details of contraindications, special warnings and precautions relating to the use of QVA149.

6 Place of Indacaterol/Glycopyrronium Fixed-Dose Combination (QVA149) in the Management of Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease, a leading cause of morbidity and mortality worldwide, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases, such as cigarette smoke. This chronic inflammation leads to a mixture of small airway fibrosis (obstructive bronchitis) and parenchymal tissue destruction (emphysema); the most common symptoms of COPD are dyspnoea, cough and sputum production. Infections (bacterial and/or viral) and air pollutants are among the known factors that can trigger exacerbations of respiratory symptoms in patients with COPD; the frequency (and severity) of exacerbations tends to increase as the severity

J. E. Frampton

of the underlying COPD increases. COPD places a substantial economic burden on healthcare systems; exacerbations account for the greatest proportion of this burden [56]. Smoking cessation (if applicable) continues to be the most important intervention for COPD, as it has been shown to be effective in slowing disease progression [57]; a wide array of effective pharmacological and nonpharmacological smoking cessation therapies are available [58]. However, none of the other specific or non-specific pharmacotherapies used in the management of stable COPD, including bronchodilators, CS, phosphodiesterase-4 inhibitors, methylxanthines, oxygen, (influenza and pneumococcal) vaccines, mucolytics and opiates, have been conclusively shown to modify the longterm deterioration in lung function; thus, they are primarily aimed at relieving symptoms, reducing the frequency and severity of exacerbations, and improving health status and exercise tolerance [56, 59]. Bronchodilators remain the cornerstone of symptom management in stable COPD [56, 60–64]. Inhaled bronchodilators (i.e. b2-adrenergic receptor agonists and anticholinergics) are preferred over oral bronchodilators (i.e. methylxanthines), based on considerations of efficacy and tolerability; long-acting formulations of inhaled bronchodilators (i.e. LABAs and LAMAs) are preferred over shortacting formulations for maintenance therapy, based on considerations of efficacy and convenience [56]. Inhaled LABAs approved in the EU for the maintenance treatment of COPD include formoterol and salmeterol, both of which have a 12-h duration of action and require twice-daily administration, and the so-called ‘ultra-LABAs’ indacaterol [1] and olodaterol [65], both of which have a 24-h duration of action and a oncedaily dosing regimen. Additionally, a LABA/ICS fixed-dose combination containing the ultra-LABA vilanterol has recently been approved [66]. Other ultra-LABAs still in clinical development include milveterol [67], carmoterol [68] and abediterol [69, 70]. Inhaled LAMAs approved in the EU for the maintenance treatment of COPD include aclidinium [71], which requires twice-daily administration, and tiotropium [72] and glycopyrronium [2], both of which are administered once daily. Another once-daily LAMA, namely umeclidinium [73], is currently undergoing regulatory review (as monotherapy [74] and, together with vilanterol, as a LABA/LAMA fixed-dose combination [75]). Combining bronchodilators of different pharmacological classes may improve efficacy and decrease the risk of side effects compared with increasing the dose of a single bronchodilator; the combined use of (short- or long-acting) b2adrenergic receptor agonists and anticholinergics may be considered if symptoms are not improved with single agents [56]. The scientific rationale for combining LABAs and LAMAs in COPD has been reviewed in detail elsewhere [76]. Briefly, the mechanistic details of the interaction remain to be fully elucidated; however, b2-agonists can amplify the


bronchial smooth muscle relaxation directly induced by a muscarinic antagonist by decreasing the release of acetylcholine via modulation of cholinergic neurotransmission. Additionally, muscarinic antagonists can augment b2-agonist-stimulated bronchodilation by reducing the bronchoconstrictor effects of acetylcholine in preclinical models [76]. In clinical trials, concurrent treatment with a LABA and a LAMA significantly improved lung function compared with the LABA (and, in some studies also, the LAMA) given as monotherapy [76]. Moreover, the LAMA component per se may have effects beyond bronchodilation, as exemplified by tiotropium inhibiting pulmonary inflammation and airway remodelling in an animal model of COPD [77, 78]. When dual bronchodilation is required, fixed-dose combination therapy offers a potential advantage over separate agent administration in terms of improved adherence to treatment through the use of a single inhaler. Patient adherence may be further enhanced through the use of fixed-dose combinations with more convenient dosing regimens, e.g. those that require once-daily as opposed to twice-daily administration [63, 76, 79–81]. To date, once-daily indacaterol/glycopyrronium (QVA149) [82] is the only LABA/LAMA fixed-dose combination to have gained regulatory approval in the EU [3]. Other LABA/LAMA fixed-dose combination products currently undergoing regulatory review or still in clinical development include once-daily vilanterol/umeclidinium [75] and olodaterol/tiotropium [65], and twice-daily formoterol/glycopyrronium [83] and formoterol/aclidinium [84] (see also review by Cazzola et al. [85]). According to the most recent UK (National Institute for Health and Clinical Excellence [NICE]) guidelines [61], a LABA or a LAMA can be considered for the maintenance treatment of patients with FEV1 C50 % predicted who remain breathless or have exacerbations despite the use of short-acting b2-adrenergic receptor agonists or anticholinergics. Thereafter, a LABA/ICS fixed-dose combination can be considered for those who remain breathless or have exacerbations despite maintenance treatment with a LABA; LABA/LAMA combination therapy can be considered if ICS therapy is declined or not tolerated. In comparison, a LABA/ICS fixed-dose combination or a LAMA can be considered for the maintenance treatment of patients with FEV1 \50 % predicted who remain breathless or have exacerbations despite the use of short-acting b2-adrenergic receptor agonists or anticholinergics; LABA/ LAMA combination therapy can be considered if ICS therapy is declined or not tolerated. ‘Triple therapy’ (i.e. a LABA/ICS fixed-dose combination plus a LAMA) can be considered for patients who remain breathless or have exacerbations despite maintenance treatment with a LABA/ICS fixed-dose combination or a LAMA, irrespective of their FEV1 [61]. LABA/ICS fixed-dose combinations are more effective in reducing exacerbations than either LABA or ICS monotherapy [86, 87]; three such combination have now been

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approved in the EU for the treatment of COPD, namely oncedaily vilanterol/fluticasone [66] and twice-daily salmeterol/ fluticasone [88] and formoterol/budesonide [89]. Phase III studies investigating a fourth combination for this indication – twice-daily formoterol/mometasone—have also been completed [90]. The use of ICS in COPD does, however, remain somewhat controversial, for while they seemingly reduce the risk of exacerbations, they also appear to increase the risk of pneumonia [59, 70, 91–94]. Furthermore, overprescribing of ICS (e.g. in patients with mild or moderate disease) is widespread—a practice that has considerable potential for harm in terms of the side effects associated with the use of these agents [95]. Unlike the NICE guidance [61], the current GOLD ‘strategy document’ [56] does not really propose a progressive stepwise (first- then second-line) strategy for COPD management [81]. Briefly, according to the GOLD schema, patients are categorized (A–D) on the basis of their severity of spirometric impairment, their level of symptoms and their future risk of exacerbations. LABA/LAMA combination therapy is posited as an alternative choice to the recommended first choice of a LABA or a LAMA in category B patients, i.e. those with mild (FEV1 C80 % predicted) or moderate (50 % B FEV1 \ 80 % predicted) airflow limitation and more (rather than less) symptoms, but a low risk of exacerbation (either no event/year or 1 event/year not leading to hospital admission). LABA/LAMA combination therapy is also posited as an alternative choice to the recommended first choice of a LABA/ICS fixed-dose combination and/or a LAMA in category C and D patients, i.e. those with severe (30 % B FEV1 \ 50 % predicted) or very severe (FEV1 \30 % predicted) airflow limitation, more or less symptoms and a high risk of exacerbation (either two or more events/ year not leading to hospitalization or one or more events/year leading to hospitalization) [56]. The efficacy and tolerability/safety of QVA149 in the treatment [9, 17, 68, 76, 95] of COPD is being investigated in the phase III IGNITE clinical trial programme, in which [10,000 patients from across 52 countries have been/are being enrolled in a total of 11 studies [96] (see Sect. 3; Tables 2, 10). Eight trials have been completed to date (SHINE, ILLUMINATE, SPARK, BEACON, BLAZE, BRIGHT, ENLIGHTEN and ARISE) (Sect. 3). In several IGNITE trials in patients with moderate to severe COPD, QVA149 provided significant improvements in bronchodilation compared with placebo that were rapid in onset, clinically meaningful in magnitude and maintained over treatment periods of up to 1 year (Sect. 3.1.1). These improvements in lung function were accompanied by significant and clinically meaningful improvements in dyspnoea (including improvements in patient-assessed dyspnoea that were more pronounced in patients with more severe disease) (Sect. 3.2), statistically significant improvements in health

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Table 10 Key design details of ongoing phase III studies of QVA149 in patients with chronic obstructive pulmonary disease (FLAME [31, 47], LANTERN [39] and RADIATE [40]) Study (duration [weeks])

Estimated enrollment (no. of pts)

Treatment groups

Primary endpoint

FLAME (52)a

3332

QVA, S/FC

Rate of COPD exacerbations during treatment period

Q3 2015

LANTERN (26)a

736

QVA, S/FC

Trough FEV1 at week 26

Q1 2014

QVA, TIO, PL

Frequency of SAEs during study period

Q3 2014

RADIATE (52)b 1224 Key inclusion criteria

Estimated completion date

Moderate to severe (LANTERN and RADIATE) or moderate to very severe (FLAME) stable COPD FEV1 post-BD C30 and \80 % (RADIATE and LANTERN) or C25 and \60 % (FLAME) predicted At least one COPD exacerbation requiring treatment with ABs and/or systemic CS within previous 12 months (FLAME) ABs antibiotics, BD bronchodilator, COPD chronic obstructive pulmonary disease, CS corticosteroids, FC fluticasone, QVA QVA149 (indacaterol/glycopyrronium fixed-dose combination), PL placebo, pts patients, S salmeterol, SAE serious adverse event, TIO tiotropium bromide a

Noninferiority study

b

Safety study; SAEs reported from week 0 through 56 (i.e. up to 4 weeks after the last dose) are being analyzed

status that approached or achieved the threshold for clinical significance (Sect. 3.3), and statistically significant improvements in patient symptoms (Sect. 3.6) and rescue medication use (Sect. 3.6). Exercise tolerance was significantly improved with QVA149 versus placebo and the between-group difference reached the threshold for clinical significance in the one study that examined this endpoint (BRIGHT) (Sect. 3.5). QVA149 also reduced the moderate to severe COPD exacerbation rate significantly compared with placebo in the SHINE study, even though this trial was not specifically designed to examine this endpoint (Sect. 3.4). Regarding the active comparators in IGNITE trials, QVA149 provided bronchodilation that was noninferior to its monocomponents administered concurrently (BEACON), but significantly better than indacaterol, glycopyrronium or tiotropium administered alone (SHINE, SPARK, BLAZE and BRIGHT) [Sect. 3.1.2]. The improvement in lung function with QVA149 over that with LABA or LAMA monotherapy was rapid in onset and sustained over treatment periods of up to 64 weeks (Sect. 3.1.2). In terms of clinical significance, improvements in trough FEV1 with QVA149 over other active treatments either approached or equalled the MCID of 100 mL that is generally used for comparisons between active treatments and placebo [41]. In terms of interpreting these data, therefore, a notable development is the recently put forward proposal to introduce the ‘minimum worthwhile incremental advantage’—a concept based around the MCID to describe, for example, the benefit of one active treatment (regimen) relative to another [50]. In general, the improvements in lung function with QVA149 versus indacaterol or glycopyrronium alone were not accompanied by statistically significant improvements in dyspnoea (Sect. 3.2) and health status (Sect. 3.3) in low (exacerbation) risk patients with moderate to severe COPD (SHINE), although they were accompanied by a statistically

significant improvement in health status in high (exacerbation) risk patients with severe or very severe COPD (SPARK) (Sect. 3.3). In contrast, the improvements in lung function with QVA149 versus tiotropium were accompanied by statistically significant improvements in dyspnoea in low-risk patients (Sect. 3.2) and in health status in low- and high-risk patients (Sect. 3.3). It is unclear whether these improvements in dyspnoea and health status are clinically meaningful, as the MCID has not been established for comparisons between active treatments (see earlier discussion in this section). That noted, significantly more QVA149 recipients than tiotropium recipients in SHINE and BLAZE experienced a clinically meaningful improvement in dyspnoea (Sect. 3.2); significantly more QVA149 recipients than glycopyrronium recipients in SPARK and tiotropium recipients in SHINE and SPARK experienced a clinically meaningful improvement in health status (Sect. 3.3). Mean daily total symptom score and rescue medication use were also significantly improved with QVA149 versus glycopyrronium or tiotropium alone in SHINE and SPARK, as was the percentage of days able to perform usual daily activities (only assessed in SHINE) (Sect. 3.6). Moreover, QVA149 reduced the moderate to severe COPD exacerbation rate significantly compared with glycopyrronium (albeit not compared with tiotropium) in the SPARK study, which was specifically designed to examine this endpoint (Sect. 3.4). Among the IGNITE trials, therefore, the SHINE study in low-risk patients with moderate to severe disease is notable, since the results suggests that dual bronchodilation with QVA149 (a GOLD alternative choice therapy) may offer more symptomatic relief than monobronchodilator therapy with tiotropium (a GOLD recommended first choice therapy and currently the most widely prescribed LAMA). Similarly, the SPARK study in high-risk patients with severe or very severe disease is notable, since the results suggest that dual bronchodilation with QVA149 (a GOLD alternative choice therapy) is more effective than


mono-bronchodilator therapy with glycopyrronium (a GOLD recommended first choice therapy) in terms of preventing exacerbations and, additionally, may offer more symptomatic relief than LAMA monotherapy. Given current ICS (over)prescribing patterns, the ILLUMINATE study in low-risk patients with moderate to severe disease is another trial of interest, since the results suggest that QVA149 (a LABA/LAMA fixed-dose combination) may offer more symptomatic relief than salmeterol/fluticasone (a LABA/ICS fixed-dose combination) in this patient population. Specifically, QVA149 provided statistically significant improvements in bronchodilation compared with salmeterol/fluticasone that were rapid in onset and maintained over a treatment period of 6 months (Sect. 3.1.2.2). This improvement in lung function was associated with statistically significant improvements in dyspnoea (Sect. 3.2) and rescue medication use (Sect. 3.6). QVA149 was generally well tolerated during treatment periods of 6–12 months in patients with moderate to severe COPD and 64 weeks in patients with severe or very severe COPD (Sect. 4.1). The most common treatment-emergent AE and SAE was COPD worsening (Sect. 4.1); overall, the AE profile of QVA149 was similar to that of placebo (Sect. 4.2) and the active comparators in the IGNITE trials, namely indacaterol and glycopyrronium administered concomitantly or separately, as well as tiotropium and salmeterol/fluticasone (Sect. 4.3). These data therefore support the tenet that (long-acting) bronchodilators can be combined without increasing adverse events. Previous concerns that LABAs and LAMAs may increase cardiovascular risk in stable COPD have been refuted in the case of LABAs [97] and, notably, that of tiotropium delivered via the RespimatÒ inhaler, as opposed to the HandihalerÒ device [98]. Against this background, the cardiovascular safety profile of QVA149 was similar to that of placebo (Sect. 4.2) and its monocomponents (Sect. 4.3), based on data derived from IGNITE trials in patients with moderate to very severe disease. Moreover, there was no observable increase in MACEs with QVA149 versus glycopyrronium or tiotropium in the SPARK study in patients with severe or very severe disease (Sect. 4.3). However, while no significant cardiovascular safety concerns with this LABA/LAMA fixed-dose combination have been observed to date [6], the EU summary of product characteristics recommends that QVA149 be used with caution in patients with cardiovascular disorders [5]. Key design details of the three ongoing IGNITE trials, including treatment groups/dosages and primary endpoints, are summarized in Table 10. Of particular interest is the 1-year FLAME study in high-risk patients with moderate to very severe disease, which is primarily designed to demonstrate that QVA149 (a GOLD alternative choice therapy) is noninferior to salmeterol/fluticasone (a GOLD recommended

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first choice therapy) in terms of preventing COPD exacerbations [47] (Table 10). QVA149 is also being compared with salmeterol/fluticasone in the 6-month LANTERN study [39], which primarily aims to demonstrate that the bronchodilatory effect of the former is noninferior to that of the latter in low-risk patients with moderate to severe disease (Table 10). The primary objective of the remaining study, RADIATE [40], is to assess the long-term safety of treatment with QVA149; this trial includes tiotropium as an active comparator (Table 10). Available pharmacoeconomic data pertaining to the maintenance treatment of COPD have been reviewed recently [99]. Of note, a 1-year study conducted in Canada concluded that neither LABA/LAMA combination therapy (salmeterol plus tiotropium) nor triple therapy (salmeterol/ fluticasone plus tiotropium) was economically attractive compared with LAMA monotherapy (tiotropium) because of high cost increases not leading to substantially better health effects (in the case of combination treatment) or leading to a very high cost-effectiveness ratio (in the case of triple therapy) [100]. Well-designed studies, ideally based in the EU, that compare the cost-effectiveness of QVA149 versus LAMA or LABA monotherapy in patients with more moderate disease and LABA/ICS fixed-dose combination therapy in patients with more severe disease, are warranted. In conclusion, bronchodilators, administered alone or in combination, remain central to the symptomatic management of COPD. When dual bronchodilation is indicated, QVA149 offers the convenience of two effective bronchodilators in a single inhaler device coupled with a simple, once-daily dosing regimen that may foster improved patient adherence to treatment. As such, QVA149 is a valuable option in the treatment of COPD. Data selection sources: Relevant medical literature (including published and unpublished data) on QVA149 (indacaterol/glycopyrronium) was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 22 February 2014], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: QVA149, indacaterol and glycopyrronium, indacaterol and NVA237, COPD, chronic obstructive pulmonary disease, chronic obstructive lung disease. Study selection: Studies in patients with chronic obstructive pulmonary disease who received QVA149 (indacaterol/glycopyrronium). When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the authors on the basis of scientific and editorial merit.

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48. 49.

50.

51. 52. 53.

54.

55.

56.

57.

58.

59. 60.

61.

62. 63.

64.

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vilanterol: a review of its use in chronic obstructive pulmonary disease.

glycopyrronium.

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Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

vilanterol combination in the treatment of chronic obstructive pulmonary disease: a review.

[Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease].

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Once-daily glycopyrronium bromide (Seebri Breezhaler(®)) for the treatment of chronic obstructive pulmonary disease (COPD).

Small Airway Disease in Patients with Chronic Obstructive Pulmonary Disease.

Indacaterol and tiotropium combination therapy in patients with chronic obstructive pulmonary disease.

formoterol fumarate: a review of its effects in chronic obstructive pulmonary disease.

Circulating leptin concentrations in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Extracorporeal carbon dioxide removal in patients with chronic obstructive pulmonary disease: a systematic review.

Postural control in chronic obstructive pulmonary disease: a systematic review.

A review of halotherapy for chronic obstructive pulmonary disease.

Burn injury associated with home oxygen use in patients with chronic obstructive pulmonary disease.

Body composition in patients with chronic obstructive pulmonary disease.

Paraoxonase 1 activity in patients with chronic obstructive pulmonary disease.

Physical Activity Monitoring in Patients with Chronic Obstructive Pulmonary Disease.

Asynchronous breathing movements in patients with chronic obstructive pulmonary disease.

Lung cancer screening in patients with chronic obstructive pulmonary disease.

Cancer risk in patients with chronic obstructive pulmonary disease.