abstract - research explorer web viewword count = 2680 [journal word-count ... radiographic imaging...
TRANSCRIPT
ORIGINAL ARTICLE
Indacaterol/Glycopyrronium Versus Salmeterol/Fluticasone for COPD Exacerbations
Jadwiga A. Wedzicha, M.D.1, Donald Banerji, M.D.2, Kenneth R. Chapman, M.D.3, Jørgen
Vestbo, M.D., DMSc.4, Nicolas Roche, M.D.5, R. Timothy Ayers, MSc.2, Chau Thach, PhD.2,
Robert Fogel, M.D.2, Francesco Patalano, M.D.6 and Claus F. Vogelmeier, M.D.7, for the
FLAME-COPD Investigators*
1National Heart and Lung Institute, Imperial College London, London, UK; 2Novartis
Pharmaceuticals Corporation, East Hanover, NJ, USA; 3Asthma and Airway Centre,
University Health Network and University of Toronto, Toronto, Ontario, Canada; 4Centre for
Respiratory Medicine and Allergy, The University of Manchester and University Hospital
South Manchester NHS Foundation Trust, Manchester, UK; 5Service de Pneumologie AP-
HP, University Paris Descartes (EA2511), Paris, France; 6Novartis Pharma AG, Basel,
Switzerland; 7Department of Medicine, Pulmonary and Critical Care Medicine, University
Medical Center Giessen and Marburg, Philipps-Universität Marburg, Marburg, Germany;
Member of the German Center for Lung Research (DZL)
*Investigators in the FLAME study are listed in the Supplementary Appendix, available at
NEJM.org.
Key words: COPD; dual bronchodilation; exacerbations; chronic bronchitis; emphysema;
FLAME
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References = 33 [journal limit = 40]
Figures and tables = 5 [3 figures and 2 tables] [journal limit = 5]
Supplementary figures and tables = 14 [8 figures and 8 tables]
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ABSTRACT
BackgroundMost guidelines recommend a long-acting β2-agonist/inhaled corticosteroid (LABA/ICS)
combination or a long-acting muscarinic antagonist (LAMA) as first-choice treatment for
patients with chronic obstructive pulmonary disease (COPD) with high exacerbation risk. The
role of a LABA/LAMA combination for these patients is unclear.
MethodsIn this 52-week, randomized, double-blind, double-dummy trial, we compared once-daily
LABA/LAMA indacaterol/glycopyrronium (IND/GLY) 110/50 μg with twice-daily LABA/ICS
salmeterol/fluticasone combination (SFC) 50/500 μg on exacerbations in COPD patients with
a history of ≥1 exacerbation in the preceding year.
ResultsPatients were randomized to IND/GLY (n=1680) or SFC (n=1682). Meeting non-inferiority
versus SFC (primary endpoint), IND/GLY further showed superiority in reducing the annual
rate of all exacerbations by 11% versus SFC (3.59 vs. 4.03; rate ratio [RR], 0.89; 95%
confidence interval [CI], 0.83 to 0.96; P=0.003) and prolonged time to first exacerbation, with
a 16% risk reduction (hazard ratio [HR], 0.84; 95% CI, 0.78 to 0.91; P<0.001). IND/GLY
reduced the annual rate of moderate or severe exacerbations (RR, 0.83; 95% CI, 0.75 to
0.91; P<0.001) and prolonged the time to first moderate or severe exacerbation (HR, 0.78;
95% CI, 0.70 to 0.86; P<0.001) and first severe exacerbation (HR, 0.81; 95% CI, 0.66 to
1.00; P=0.046) versus SFC. The effect on exacerbations was independent of baseline blood
eosinophil count. Incidence of adverse events and deaths was similar in both groups.
Incidence of pneumonia was 3.2% with IND/GLY and 4.8% with SFC.
ConclusionsIND/GLY is more effective than SFC in preventing exacerbations in COPD patients with a
history of exacerbations (Funded by Novartis; FLAME ClinicalTrials.gov number,
NCT01782326).
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INTRODUCTION
Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with
accelerated lung function decline,1-3 impaired quality of life,4 hospitalization,5 and increased
mortality.6 COPD exacerbations are costly to healthcare systems,7 thus prevention is a key
goal in COPD management.8
Inhaled long-acting bronchodilators, in addition to providing symptomatic control,
prevent COPD exacerbations.9-12 Inhaled corticosteroids (ICS) are also known to reduce
exacerbation frequency and have been studied in combination with inhaled long-acting β2-
agonists (LABAs).11,13,14 A LABA/ICS fixed combination (salmeterol/fluticasone propionate
[SFC]) and an inhaled long-acting muscarinic antagonist (LAMA; tiotropium) had similar
effects on exacerbations in exacerbation-prone patients.15 Consequently, treatment
guidelines have recommended that either a LABA/ICS or a LAMA can be used to prevent
exacerbations in at-risk patients.8
Long-term ICS use is associated with a small but significant risk of pneumonia16,17 and
other steroid-related adverse effects.18 An alternative strategy to the LABA/ICS combination
for exacerbation-prone patients is a dual bronchodilator regimen of LABA/LAMA.19
The hypothesis for the present study was that, in patients with COPD at risk of
exacerbations, a dual bronchodilator (indacaterol/glycopyrronium (IND/GLY) 110/50 μg,
once daily) would be at least as effective in preventing exacerbations as a LABA/ICS (SFC
50/500 μg, twice daily). As recent studies have indicated that exacerbation prevention with
ICS may relate to blood eosinophil level,20-22 the relationship of baseline blood eosinophils to
exacerbation reduction by both interventions was examined prospectively.
METHODS
STUDY DESIGN AND OVERSIGHTFLAME (NCT01782326) was a multicenter, randomized, double-blind, double-dummy,
parallel-group, non-inferiority study from July 2013 to September 2015 at 356 centers in 43
countries (Fig. S1). In the 4-week run-in (preceded by a 1-week screening period) all
patients received tiotropium 18 μg once daily. After run-in, patients discontinued tiotropium
and were randomized 1:1 to IND/GLY 110/50 μg once daily or SFC 50/500 μg twice daily for
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52 weeks, with a 30-day follow-up. Salbutamol 100 μg was provided as rescue medication.
Additional details in Supplementary Appendix.
The sponsor (Novartis) developed the protocol, with guidance from the first author and
advice from the other academic authors. The first draft was written by JAW and DB. All
authors reviewed and edited the manuscript and decided to submit the manuscript for
publication. All authors contributed to the interpretation of the data and had access to the full
data (non-disclosure agreements were in place). The trial was approved by the ethics
committee at each study center and all patients provided written informed consent. All
authors vouch for the accuracy and completeness of the data and the fidelity of the study to
the protocol (available at NEJM.org). Statistical analyses were performed by a statistician at
DataMap (funded by Novartis, who provided oversight and verified key results).
PATIENTSCOPD patients enrolled in the study were ≥40 years old, with a modified Medical
Research Council grade ≥2 for dyspnea, a post-bronchodilator forced expiratory volume in
one second (FEV1) ≥25 and <60% predicted and a post-bronchodilator FEV1/forced vital
capacity (FVC) <0.70. Patients were required to have a documented history of ≥1 COPD
exacerbation (that required treatment with systemic corticosteroids and/or antibiotics) in the
previous 12 months. Additional details in Supplementary Appendix.
OUTCOME MEASURESThe primary objective was to demonstrate that IND/GLY 110/50 µg was at least non-
inferior to SFC 50/500 µg regarding the rate of all COPD exacerbations (mild, moderate or
severe).
Our protocol lists 24 secondary objectives; we report data from 16 of these here
(additional details in Supplementary Appendix). An important secondary objective was to
demonstrate the superiority of IND/GLY versus SFC for the same endpoint, if non-inferiority
was met. Other secondary endpoints included time to first COPD exacerbation (all); rate and
time to first moderate or severe COPD exacerbation; and rate and time to first severe COPD
exacerbation. Trough FEV1 and FVC, FEV1 area under the curve from 0–12 hours (AUC0–12h;
in a subset of patients), health status (via the St George’s Respiratory Questionnaire
[SGRQ]) and rescue medication use were also assessed.
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Exacerbations, defined according to Anthonisen criteria23, were categorized as mild
(worsening of symptoms for more than two consecutive days, not treated with systemic
corticosteroids and/or antibiotics), moderate (treated with systemic corticosteroids and/or
antibiotics), or severe (requiring hospital admission [or an emergency room visit of >24
hours] in addition to treatment with systemic corticosteroids and/or antibiotics). Patients
recorded daily symptoms and rescue medication use in an electronic diary. When worsening
of symptoms met pre-defined exacerbation criteria, alerts were triggered and patients were
advised to contact the site.
Safety of IND/GLY and SFC were also assessed. An independent adjudication
committee assessed blinded safety data. Radiographic imaging was required to confirm
pneumonia. Additional details in Supplementary Appendix.
STATISTICAL ANALYSISApproximately 3332 randomized patients were required to rule out a 15% increase in
COPD exacerbation rate (all) with IND/GLY versus SFC, with greater than 95% power at the
level of 0.025 (one-sided), assuming 30% drop out and/or major protocol deviations.
The non-inferiority bound of 1.15 was based on a previous study,11 where the rate
ratio for SFC versus placebo on moderate or severe exacerbations was 0.75. If FLAME
could rule out a 1.15-fold increase with IND/GLY versus SFC on the same endpoint, the rate
ratio for IND/GLY versus placebo would be 0.8625, leading to a meaningful rate reduction of
>13.75% versus placebo.
The full analysis set (also known as a modified intention-to-treat set) included all
randomized patients who received at least one dose of double-blind drug and did not have
major violations of Good Clinical Practice identified prior to unblinding. The per-protocol set
included all patients in the full analysis set without major protocol deviations, defined prior to
unblinding. Main analysis of the primary endpoint was on the per-protocol set; the full
analysis set was supportive. Conclusions made on the primary endpoint were strengthened
by the concordance of results obtained in the per-protocol set and full analysis set. Analyses
of all other efficacy endpoints were performed on the full analysis set. All efficacy analyses,
unless stated otherwise, were based on on-treatment data.
The number of exacerbations during the treatment period was analyzed using a
negative binomial model, including terms for treatment, baseline smoking status, prior ICS
use, airflow limitation, and region as fixed effects, along with baseline total symptom score
and COPD exacerbation history as covariates. The overall Type I error from the two
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hypothesis tests (i.e. non-inferiority test followed by superiority test) was maintained at level
0.05 (two-sided) with the following statistical testing hierarchy:
1. Non-inferiority of IND/GLY versus SFC could be claimed if the upper limit of the
confidence interval (CI) of the exacerbation rate ratio (IND/GLY versus SFC) was
less than 1.15.
2. If non-inferiority was demonstrated, superiority of IND/GLY versus SFC in
reducing exacerbation rate could be claimed if the upper limit of the same CI was
less than 1.
No multiplicity adjustments were performed on any other endpoints.
Exacerbations were also analyzed according to 18 prespecified subgroups, including
baseline blood eosinophils, to assess the consistency of the treatment effect. Other
exacerbation endpoints were analyzed using the same negative binomial model. The time-
to-event endpoints were analyzed using a Cox regression model, which included the same
terms as the negative binomial model. Additional details in Supplementary Appendix.
RESULTS
PATIENTSFig. 1 and Fig. S3 display the reasons for discontinuation from screening, run in and
treatment. 3.6% of subjects discontinued run in due to an exacerbation. See Supplementary
Appendix for additional details. 3362 patients were randomized: 1680 to IND/GLY and 1682
to SFC. Four were excluded from all analyses for not taking any study medication. 3084
were included in the per-protocol set and 3354 in the full analysis set (Fig. 1). Treatment
discontinuation rates were 16.6% versus 19.0% on IND/GLY and SFC, respectively (Fig. 1).
Demographics and disease history for both treatment groups were well balanced (Table 1). 19.3% of patients had a history of ≥2 moderate or severe exacerbations in the past year
and 56.3% of patients were using ICS at screening. Treatment medication compliance was
>99%. Additional details in Supplementary Appendix.
PRIMARY ENDPOINTThe rate ratio (RR) for all exacerbations with IND/GLY versus SFC in the per-protocol
set was 0.89 (95% CI, 0.83 to 0.96; P=0.003; Fig. 2A and Fig. S5A). The upper bound of
the two-sided 95% CI was less than the non-inferiority margin of 1.15, demonstrating non-
inferiority and meeting the primary endpoint. Non-inferiority was also demonstrated in the full 6
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analysis set (RR, 0.88; 95% CI, 0.82 to 0.94; P<0.001; Fig. 2A). Similar results were
observed with additional sensitivity analyses performed using both on-treatment and off-
treatment data from those who discontinued treatment early (additional details in
Supplementary Appendix).
SECONDARY ENDPOINTSAnalyses of all other efficacy endpoints were performed on the full analysis set.
Superiority (a secondary endpoint adjusted for multiplicity) was demonstrated for IND/GLY
versus SFC for all exacerbations, as the upper bound of the same two-sided 95% CI was
less than 1 (Fig. 2A). IND/GLY prolonged the time to first exacerbation versus SFC, with a
16% reduction in risk (hazard ratio [HR], 0.84; 95% CI, 0.78 to 0.91; P<0.001; Fig. 2B).
IND/GLY also reduced the rate of moderate or severe exacerbations (healthcare utilization)
by 17% (RR, 0.83; 95% CI, 0.75 to 0.91; P<0.001; Fig. S5C) and prolonged the time to first
moderate or severe exacerbation, with a 22% reduction in risk (HR, 0.78; 95% CI, 0.70 to
0.86; P<0.001; Fig. 2C) versus SFC. Additionally, IND/GLY significantly prolonged the time
to first severe exacerbation versus SFC, with a 19% reduction in risk (HR, 0.81; 95% CI,
0.66 to 1.00; P=0.046; Fig. 2D). The rate ratio of severe exacerbations for IND/GLY versus
SFC was 0.87 (95% CI, 0.69 to 1.09; P=0.231).
The rate of moderate or severe exacerbations was analyzed by baseline blood
eosinophils at cut-offs of <2% and ≥2%. The exacerbation rate was significantly lower with
IND/GLY than SFC in both the <2% (RR, 0.80; 95% CI, 0.68 to 0.93; P=0.004) and ≥2%
subgroups (RR, 0.85; 95% CI, 0.75 to 0.96; P=0.010). The other three subgroup analyses
based on different cut-offs of baseline blood eosinophils, not presented here, provided
similar results. No meaningful interaction was seen between the rate of all or moderate or
severe exacerbations and prior therapy, or other baseline characteristics (Fig. 3; Figs. S5A and B). Additional details in Supplementary Appendix.
OTHER SECONDARY ENDPOINTSImprovement in trough FEV1 was significantly greater with IND/GLY versus SFC, with a
treatment difference of 62 mL at Week 52 (P<0.001; Fig. S7A and Table S5). FEV1 AUC0–12h
subset results are presented in the Supplementary Appendix.
Improvement in SGRQ-C total score was greater with IND/GLY versus SFC, with
treatment differences of –1.2 to –1.8 units between Weeks 12 and 52 (all P<0.01; Fig. S7C; 7
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Table S6). The percentage of patients achieving a clinically important improvement of ≥4
units in SGRQ-C total score was significantly higher with IND/GLY than with SFC at Week
52 (49.2% vs. 43.7%, respectively; odds ratio, 1.30; P<0.001). Rescue medication use
decreased with IND/GLY versus SFC (Figure S7D).
SAFETYThe incidence of adverse events, including serious adverse events, was similar
between the IND/GLY and SFC groups (Table 2). The number of deaths was 24 (1.4%) in
both groups with respiratory or cardiovascular deaths being the most common (Tables S7 and S8). The incidence of pneumonia was 3.2% with IND/GLY and 4.8% with SFC. The
median percentage change in the 24-hour urinary cortisol/creatinine ratio at Week 52 was
5.62% with IND/GLY and –10.39% with SFC in a subset of 535 patients (Fig. S8).
DISCUSSION
This is the first clinical trial powered to determine if a LABA/LAMA combination
(IND/GLY) is as effective as a LABA/LAMA combination (SFC) in patients at risk of COPD
exacerbations. Not only was the non-inferiority endpoint reached but, on subsequent
superiority testing, the LABA/LAMA was found to be consistently superior for all
exacerbation outcomes, lung function, and health status.
COPD clinical guidelines and strategy documents8,24 have recommended that in
patients at risk of exacerbations, first-line therapy should either be a LABA/ICS combination
or a LAMA. One previous study found no difference between a LABA/ICS and a LAMA
monotherapy in exacerbation rates.15 However, a recent combination bronchodilator study
using LABA/LAMA demonstrated greater exacerbation reduction efficacy than LAMA
monotherapy19. ICS withdrawal in patients on triple therapy did not increase exacerbation
rate significantly25, further supporting the hypothesis that ICS may not be essential for
exacerbation prevention in patients on LABA/LAMA.
The LABA/LAMA combination was superior and consistent on exacerbation
outcomes for all types of exacerbation, including exacerbations requiring healthcare
utilization. COPD exacerbations were carefully monitored with daily symptom recordings and
captured by electronic diaries4, allowing us to document all exacerbations, including those
requiring healthcare utilization. Studies have shown under-reporting of exacerbation events
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(mild exacerbations), yet these unreported events impact on patients’ health status.26-28
Therefore ‘all exacerbations’ was studied as the primary endpoint to reflect the importance of
preventing every exacerbation. Capturing all exacerbations is a major strength of this trial
and we have shown a very consistent benefit of dual bronchodilation across exacerbation
severities.
Post-hoc analyses from LABA/ICS trials in COPD have suggested that patients with
elevated blood eosinophil counts, such as ≥2% blood eosinophil levels, obtain larger benefits
from LABA/ICS medications on exacerbation reduction than patients with lower eosinophil
counts.20-22 This may suggest that a higher eosinophil count may be associated with a
greater response to ICS. Therefore, the FLAME trial prospectively examined the relationship
between blood eosinophils and exacerbation outcomes. The rate of moderate or severe
exacerbations and all exacerbations was significantly lower with IND/GLY than SFC in both
the <2% and ≥2% eosinophil subgroups, suggesting that the LABA/LAMA combination is
more effective at reducing exacerbations than SFC in both eosinophil subgroups.
The superiority of IND/GLY in terms of lung function was expected as two
bronchodilators improve lung function to a greater degree than a LABA/ICS combination.29-31
Further evidence of symptomatic benefit was seen with the reduction in use of rescue
medication and the improvement in health status (SGRQ-C score) in patients on IND/GLY
compared with SFC.
A potential limitation of the study is that some of the patients initially treated with
LABA/ICS before enrollment and then randomized into the IND/GLY treatment arm may
have suffered withdrawal effects from long-term LABA/ICS use, with an increase of
exacerbations. There was clearly no evidence that patients on ICS prior to the trial withdrew
preferentially during run in, and exacerbation rates during run in were low. Additionally,
analyses of exacerbation rates by prior therapy showed no meaningful interaction between
treatment and the type of prior therapy taken by the patient.
It may also be argued that our study design favored LABA/LAMA therapy over
LABA/ICS therapy because the regimens studied were once daily versus twice daily,
respectively. However, there is evidence that once-daily LABA/ICS combinations are no
more effective than those administered twice daily with regards to lung function.32 Our study
used electronic diaries to flag exacerbations and thus higher rates of all exacerbations were
detected compared with most exacerbation trials, though this is unlikely to bias treatment
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comparisons. The once-daily dose of IND/GLY is approved worldwide, with the exception of
the United States, where a lower, twice-daily dose of IND/GLY is approved. In studies of this
dosing regimen, IND/GLY demonstrated similar results on lung function as observed with
once-daily dosing.33,34 However, no study has compared the two dosing regimens directly.
Additionally, SFC 50/500 μg is approved worldwide, with the exception of the United States
and Japan, where the approved dose is lower (50/250 μg).
There were no safety concerns with either intervention, and the number of deaths,
serious adverse events, and adverse events including discontinuations were low and similar
in the two arms.
The consistent results on exacerbation outcomes have major implications for COPD
management, especially patients at risk of future exacerbations. Confirmation of these
findings using other combinations of long-acting bronchodilators would provide additional
evidence supporting the first-line use of LABA/LAMAs in this patient population. However,
we cannot rule out that some patients may benefit from addition of ICS.
In conclusion, in patients at risk of COPD exacerbations, IND/GLY is consistently
more effective than SFC in preventing exacerbations, with no detectable increase in adverse
events. Our data have major implications for the future management of COPD and should
now impact treatment algorithms.
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ACKNOWLEDGMENTS
Supported by Novartis.
We would like to thank the centers (listed in the Supplementary Appendix) and patients who
participated in the study.
We are grateful to Norbert Ahlers, Michael Larbig, Petter Olsson, and Angel FowlerTaylor
from Novartis for their assistance with the study.
The authors also thank eResearch Technology GmbH (Estenfeld, Germany) for their
assistance with the electronic diary for monitoring exacerbations and with centralized
spirometry, and the independent adjudication committee at Brigham and Women's Hospital
(Boston, MA, USA) for their assessment of the blinded safety data.
Editorial and technical support in the preparation of the manuscript was provided by
Elizabeth Andrew, a professional medical writer at CircleScience, an Ashfield company, part
of UDG Healthcare plc (Tytherington, UK). The medical writing support was funded by
Novartis (Basel, Switzerland).
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FIGURES AND TABLES
Figure 1. CONSORT Diagram of Patient Flow: Numbers of Patients Enrolled and Included in the Efficacy and Safety Analyses.
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* One subject was mistakenly recorded as discontinuing the screening epoch and entering the run-in epoch.† 179 (3.6%) subjects had an exacerbation that led to study discontinuation during the run-in epoch (number derived from exacerbation and
inclusion/exclusion CRFs; no “exacerbation” option on discontinuation CRF, majority classed as “screening failure”).‡ Screen failure due to inclusion/exclusion criteria§ Number included in safety analyses. One subject randomized to IND/GLY mistakenly received and took SFC before discontinuing treatment.¶ Patients can be excluded due to multiple reasons.
CONSORT = Consolidated Standards of Reporting Trials; CRF = case report form; FAS = full analysis set; GCP = Good Clinical Practice; GLY
= glycopyrronium; IND = indacaterol; PPS = per-protocol set; SFC = salmeterol/fluticasone propionate combination.
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Figure 2A. Primary Endpoint: Non-inferiority in Rate of All (Mild, Moderate or Severe)
COPD Exacerbations Over 52 Weeks.
CI = confidence interval; COPD = chronic obstructive pulmonary disease; GLY =
glycopyrronium; IND = indacaterol; SFC = salmeterol/fluticasone propionate combination.
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Figure 2B. Kaplan-Meier Plot of Time to First Mild, Moderate or Severe COPD Exacerbation During 52 Weeks of Treatment.
Analysis of the FAS.
b.i.d. = twice daily; CI = confidence interval; FAS = full analysis set; GLY = glycopyrronium;
HR = hazard ratio; IND = indacaterol; q.d. = once daily; SFC = salmeterol/fluticasone
propionate combination.
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Figure 2C. Kaplan-Meier Plot of Time to First Moderate or Severe COPD Exacerbation
During 52 Weeks of Treatment.
Analysis of the FAS.
b.i.d. = twice daily; CI = confidence interval; FAS = full analysis set; GLY = glycopyrronium;
HR = hazard ratio; IND = indacaterol; q.d. = once daily; SFC = salmeterol/fluticasone
propionate combination.
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Figure 2D. Kaplan-Meier Plot of Time to First Severe COPD Exacerbation During 52
Weeks of Treatment.
Analysis of the FAS.
b.i.d. = twice daily; CI = confidence interval; FAS = full analysis set; GLY = glycopyrronium;
HR = hazard ratio; IND = indacaterol; q.d. = once daily; SFC = salmeterol/fluticasone
propionate combination.
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Figure 3. Forest Plot of Estimated Mild, Moderate or Severe (All) COPD Exacerbation Rate
Ratio by Demographic and Disease Characteristics.
Analysis of the FAS.
CI = confidence interval; COPD = chronic obstructive pulmonary disease; FAS = full analysis
set; GLY = glycopyrronium; GOLD = Global Initiative for chronic Obstructive Lung Disease;
ICS = inhaled corticosteroid; IND = indacaterol; LABA = long-acting β2-agonist; LAMA =
long-acting muscarinic antagonist; SFC = salmeterol/fluticasone propionate combination.
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Table 1. Baseline Demographic and Clinical Characteristics.
IND/GLY110/50 μg q.d.
(N=1680)
SFC50/500 μg b.i.d.
(N=1682)Total
(N=3362)Age, years 64.6 (7.9) 64.5 (7.7) 64.6 (7.8)
Male, n (%) 1299 (77.3) 1258 (74.8) 2557 (76.1)
Duration of COPD, years 7.2 (5.3) 7.3 (5.5) 7.3 (5.4)
ICS use at baseline, n (%) 954 (56.8) 939 (55.8) 1893 (56.3)
LAMA use at baseline, n (%) 1008 (60.0) 1029 (61.2) 2037 (60.6)
LABA use at baseline, n (%) 1129 (67.2) 1128 (67.1) 2257 (67.1)
Current smoker, n (%) 664 (39.5) 669 (39.8) 1333 (39.6)
Severity of COPD (GOLD 2015), n (%)
Low risk and less symptoms (Group A) 2 (0.1) 0 2 (0.1)
Low risk and more symptoms (Group B) 400 (23.8) 422 (25.1) 822 (24.4)
High risk and less symptoms (Group C) 1 (0.1) 2 (0.1) 3 (0.1)
High risk and more symptoms (Group D) 1265 (75.3) 1249 (74.3) 2514 (74.8)
Severity of airflow limitation
(GOLD 2011–2014), n (%)
Mild (GOLD 1) 0 0 0
Moderate (GOLD 2) 560 (33.3) 563 (33.5) 1123 (33.4)
Severe (GOLD 3) 973 (57.9) 981 (58.3) 1954 (58.1)
Very severe (GOLD 4) 133 (7.9) 124 (7.4) 257 (7.6)
Pre-bronchodilator FEV1, L 1.0 (0.3) 1.0 (0.3) 1.0 (0.3)
Post-bronchodilator FEV1, L 1.2 (0.3) 1.2 (0.4) 1.2 (0.3)
Post-bronchodilator FEV1, % predicted 44.0 (9.5) 44.1 (9.4) 44.1 (9.5)
Post-bronchodilator FEV1 reversibility, % of
baseline value
22.2 (16.0) 22.5 (16.0) 22.4 (16.0)
Post-bronchodilator FEV1/FVC, % 41.7 (9.8) 41.5 (9.9) 41.6 (9.9)
Number of COPD exacerbations in
previous year, n (%)
1 1355 (80.7) 1355 (80.6) 2710 (80.6)
≥2 324 (19.3) 325 (19.3) 649 (19.3)
SGRQ-C total score 47.3 (15.8) 47.2 (15.9) 47.3 (15.8)
CAT score 16.9 (7.1) 16.6 (7.0) 16.7 (7.0)
mMRC Dyspnea Scale, n (%)
Grade 2 1202 (71.5) 1210 (71.9) 2412 (71.7)19
421422
Grade 3 439 (26.1) 432 (25.7) 871 (25.9)
Grade 4 36 (2.1) 38 (2.3) 74 (2.2)
Rescue medication use, puffs/day 3.95 (3.8) 4.12 (4.0) 4.0 (3.9)
Urine cortisol*, ng/mL 16.3 (20.7) 15.8 (24.0) 16.0 (22.4)
* 24-hour urine cortisol measured in a total of 535 patients (266 on IND/GLY and 269 on
SFC). Data are mean (SD) unless otherwise stated.
b.i.d. = twice daily; CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary
disease; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GLY =
glycopyrronium; GOLD = Global Initiative for chronic Obstructive Lung Disease; ICS =
inhaled corticosteroid; IND = indacaterol; LABA = long-acting β2-agonist; LAMA = long-acting
muscarinic antagonist; mMRC = modified Medical Research Council; q.d. = once daily; SD =
standard deviation; SFC = salmeterol/fluticasone propionate combination; SGRQ-C = St
George’s Respiratory Questionnaire C.
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423
424
425
426
427
428
429
430
431
432
433
Table 2. Adverse and Serious Adverse Events.
Preferred Term, n (%)
IND/GLY110/50 μg q.d.
(N=1678)
SFC 50/500 μg b.i.d.
(N=1680)
Patients with at least one AE 1459 (86.9) 1498 (89.2)
Adverse events ≥3% in any treatment group
Chronic obstructive pulmonary disease 1299 (77.4) 1374 (81.8)
Nasopharyngitis 197 (11.7) 195 (11.6)
Viral upper respiratory tract infection 132 (7.9) 138 (8.2)
Upper respiratory tract infection bacterial 125 (7.4) 168 (10.0)
Lower respiratory tract infection 82 (4.9) 98 (5.8)
Upper respiratory tract infection 81 (4.8) 83 (4.9)
Pneumonia 53 (3.2) 80 (4.8)
Cough 50 (3.0) 51 (3.0)
Dyspnea 49 (2.9) 51 (3.0)
Influenza 35 (2.1) 56 (3.3)
Oral candidiasis 20 (1.2) 71 (4.2)
SAE(s) 308 (18.4) 334 (19.9)
Death 24 (1.4) 24 (1.4)
Discontinuation due to AE(s) 126 (7.5) 143 (8.5)
Discontinuation due to SAE(s) 85 (5.1) 87 (5.2)
Discontinuation due to non-SAE(s) 49 (2.9) 70 (4.2)
Analysis of the Safety set.
AE = adverse event; b.i.d. = twice daily; GLY = glycopyrronium; IND = indacaterol; q.d. =
once daily; SAE = serious adverse event; SFC = salmeterol/fluticasone propionate
combination.
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437
438
439
440
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