Indacaterol and glycopyrronium versus indacaterol on body plethysmography measurements in COPD—a randomised controlled study
Salomon et al. Respiratory Research
Indacaterol and glycopyrronium versus indacaterol on body plethysmography measurements in COPD-a randomised controlled study
Joerg Salomon 3
Daiana Stolz 1
Guido Domenighetti 0
Jean-Georges Frey 7
Alexander J. Turk 6
Andrea Azzola 5
Thomas Sigrist 4
Jean-William Fitting 9
Ulrich Schmidt 8
Thomas Geiser 2
Corinne Wild 11
Konstantinos Kostikas 12
Andreas Clemens 12
Martin Brutsche 10
0 Regional Hospital La Carità , Locarno , Switzerland
1 University Hospital Basel , Basel , Switzerland
2 University Hospital of Bern , Bern , Switzerland
3 Lung Centre Salem-Spital , Bern , Switzerland
4 Hospital, Klinik Barmelweid , Barmelweid , Switzerland
5 Regional Hospital Civico , Lugano , Switzerland
6 Hospital , Zürcher Rehazentrum Wald, Wald , Switzerland
7 Hospital du Valais , Sion , Switzerland
8 Kliniken Valens, Rehabilitation Centre , Walenstadtberg, St. Gallen , Switzerland
9 Lausanne University Hospital , Lausanne , Switzerland
10 Cantonal Hospital , St. Gallen , Switzerland
11 Novartis Pharma Schweiz AG , Rotkreuz , Switzerland
12 Novartis Pharma AG , Basel , Switzerland
Background: Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. Methods: This multicentre, randomised, double-blind, single-dose, cross-over, placebo-controlled study evaluated efficacy and safety of the free combination of indacaterol maleate (IND) and glycopyrronium bromide (GLY) versus IND alone on spirometric and body plethysmography parameters, including inspiratory capacity (IC), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), total lung capacity (TLC) and airway resistance (Raw) in moderate-to-severe COPD patients. Results: Seventy-eight patients with FEV1 % pred. (mean ± SD) 56 ± 13% were randomised. The combination of IND + GLY versus IND presented a numerically higher peak-IC (Δ = 0.076 L, 95% confidence interval [CI]: −0.010 - 0.161 L; p = 0.083), with a statistically significant difference in mean IC over 4 h (Δ = 0.054 L, 95%CI 0.022 - 0.086 L; p = 0.001). FEV1, FVC and Raw, but not TLC, were consistently significantly improved by IND + GLY compared to IND alone. Safety profiles of both treatments were comparable. Conclusion: The free combination of IND + GLY improved lung function parameters as evaluated by spirometry and body plethysmography, with a similar safety profile compared to IND alone. Trial registration: NCT01699685
COPD; Indacaterol; Glycopyrronium; Spirometry; Body plethysmography
Static lung hyperinflation is one of the significant
challenges in patients with COPD. It is characterised by a
decrease in the elastic recoil of the lungs with a
premature closure of small airways leading to air trapping. The
impact on lung function parameters is expressed by an
increase in functional residual capacity (FRC) and a
progressive decrease in inspiratory reserve volume and
12Novartis Pharma AG, Basel, Switzerland
Full list of author information is available at the end of the article
inspiratory capacity (IC). During exercise, dynamic
compression of the airways intensifies and this results
in increased dynamic hyperinflation, leading to further
exercise limitation . The major clinically relevant
mechanism of action of long-acting bronchodilators in
COPD is related to the reduction of hyperinflation [1–5],
which can be assessed by improvements in IC .
Whereas short-acting bronchodilators are used for
immediate relief from symptoms, one or more long-acting
bronchodilators (long-acting β2-agonists [LABAs], e.g.,
indacaterol maleate [IND], and long-acting muscarinic
antagonists [LAMAs], e.g., glycopyrronium bromide
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[GLY]) are recommended for long-term maintenance
therapy in patients with moderate-to-severe COPD .
Since LABAs and LAMAs have different mechanisms
of action, they may exert additive bronchodilation
effects when used together. This suggests that IND and
GLY could be used in combination to optimise and
maximise bronchodilation in patients with COPD
whose needs are not adequately met by LABA or
LAMA monotherapy [8–10]. However, there are limited
data on the effects of a combination of two long-acting
bronchodilators on body plethysmography lung function
parameters in patients with COPD .
In this study we evaluated the efficacy and safety of
the free combination of IND + GLY versus IND alone on
lung function parameters evaluated by body
plethysmography, including inspiratory capacity (IC), forced
expiratory volume in 1 s (FEV1), forced vital capacity (FVC),
total lung capacity (TLC) and airway resistance (Raw), in
patients with moderate-to-severe COPD.
The study was conducted in 11 centres in Switzerland
between November 2012 and June 2014, and included a
total of 78 eligible patients who were randomised to one
of two treatment sequences. The study protocol was
reviewed and approved by institutional review boards
and ethics committees.
Eligible patients were adults aged ≥40 years with a
diagnosis of moderate or severe COPD according to
GOLD criteria  who had signed an informed consent
form, and fulfilling the following: smoking history of at
least 10 pack-years [both current and ex-smokers];
post-bronchodilator FEV1 <80% and ≥30% of the
predicted value, and post-bronchodilator FEV1/FVC <70%.
The main exclusion criteria were COPD exacerbations
requiring systemic glucocorticoid treatment or
antibiotics and/or hospitalisation or a history of respiratory
tract infection within 6 weeks prior to screening,
concomitant pulmonary disease other than COPD, history
of asthma or lung cancer, a known history of alpha-1
antitrypsin deficiency, or a history of hypersensitivity to
any of the study medications or to medications from
similar drug classes.
Study design and treatment
This was a multicentre, randomised, double-blind,
singledose, cross-over, placebo-controlled study to assess the
effect of a single-dose combination of inhaled IND
(150 μg) + GLY (50 μg) versus inhaled IND (150 μg) +
placebo (corresponding GLY placebo) on static
hyperinflation (Fig. 1). Patients had lung function assessments
(spirometry) at each study visit and body
plethysmography at Visits 2 and 3. Safety assessments included
physical examinations, vital signs, and monitoring of
adverse events (AEs) and serious adverse events (SAEs).
All patients prematurely withdrawing from the study
underwent study completion evaluations.
The primary objective was to demonstrate superiority of
a single dose of the combined inhalation of IND + GLY
versus IND alone on peak-IC, defined as the maximum
value within 4 h of inhalation. The key secondary objective
was to compare the efficacy of IND + GLY versus IND in
terms of FEV1 over 4 h (30, 60, 120, 180 and 240 min)
post dosing. Other secondary objectives were to compare
the efficacy of IND + GLY versus IND on IC, FVC, and
airway resistance (Raw) over 4 h (30, 60, 120, 180 and
240 min) after dosing.
Sample size calculation
With regard to peak-IC, a sample size of 69 patients
was expected to provide 80% power to detect a
difference of 0.12 L in IC at peak between the groups,
assuming a standard deviation of differences of 0.35 L
(test level α = 0.025 one-sided or α = 0.05 two-sided).
Assuming a dropout rate of approximately 10%, a total
of ~78 patients had to be randomised to ensure that at
least 70 patients completed the study. Regarding FEV1,
a sample size of 70 patients provided 99% power to
detect a difference of 0.18 L in FEV1 mean values between
The intention to treat (ITT, full analysis set [FAS])
population consisted of all randomised patients who received at
least one dose of study medication and had at least one
post-baseline assessment of the primary efficacy variable.
The per-protocol (PP) population consisted of all patients
in the ITT population without major protocol violations or
who discontinued the study due to treatment-related
reasons. A supportive analysis on the PP population was
performed for the primary endpoint peak-IC and the key
secondary endpoint FEV1. The safety population (full
analysis set; FAS) was defined as all randomised
patients who received at least one dose of study
medication with at least one post-baseline safety assessment.
Study endpoints were analysed by an analysis of
covariance (ANCOVA) model with treatment sequence
(AB or BA) and treatment as fixed effects, the lung
function parameter as a covariate and patient as a random
effect. Treatment effect was estimated as the contrast of
the treatment effect in the statistical model and
presented as point estimates and corresponding 95%
twosided confidence intervals (CIs). The null hypothesis for
the primary analysis was that combination of IND + GLY
is not superior to IND alone regarding the lung function
parameters. The alternative hypothesis was that
treatment with a combination of IND + GLY is superior to
IND alone. The null hypothesis was rejected in favour of
the alternative hypothesis if the 95% CI of the least
squares means treatment contrast of the difference
“combination therapy — single therapy” was greater
than 0 in its entirety. This corresponds to a planned
alpha error of 5% two-sided or 2.5% one-sided. An
interim analysis was performed after 20 patients had
completed Visit 3. No adjustments were needed.
The mean ± SD age of the patients was 64.8 ± 8.4 years
(Table 1), 59.2% were male, all Caucasian, and 24
(31.2%) current smokers. Mean time since COPD
diagnosis was 5.2 ± 5.2 years. The mean FEV1% predicted
was 56 ± 13 and 38.7% of patients had a GOLD stage of
III or above. The mean total lung capacity (TLC) was
120.68 ± 18.75% pred. and the mean Raw was 210.99 ±
117.11% pred. The patient disposition and
randomisation is given in Fig. 2.
The combination of IND + GLY versus IND presented
a numerically higher peak-IC (2.95 L versus 2.88 L), with
an adjusted treatment difference (Δ) of 0.076 L (95%
−0.010 – 0.161 L; p = 0.083) (Fig. 3a). IND + GLY
presented also a statistically significant difference in mean
IC over 4 h versus IND (2.76 L versus 2.70 L; Δ =
0.054 L, 95% CI 0.022 – 0.086 L; p = 0.001) (Fig. 3b).
FEV1, FVC and Raw, but not TLC, were significantly
improved by IND + GLY compared to IND alone. A
statistically significant adjusted treatment difference in FEV1
was noted at all time points in favour of IND + GLY
treatment (p <0.001 for all comparisons), reaching a peak
difference of Δ = 0.099 L (95%CI 0.060 – 0.139 L) at
120 min post-dose (Fig. 4a). Similarly, IND + GLY
resulted in higher FVC mean values at all time points after
a single-dose inhalation (p <0.01 for all comparisons),
reaching a peak difference of Δ = 0.163 L (95%CI 0.092 –
0.234 L) at 240 min post-dose (Fig. 4b). Raw
measurements were consistently lowered by IND + GLY
treatment at all time points after the single-dose inhalation
Age at informed consent, years
Number of pack-years, years
Years since COPD diagnosis
Age at COPD diagnosis, years
FEV1 % predicted
Total Lung Capacity (TLC), L
TLC % of predicted normal value
Airway Resistance (Raw)
Raw % of predicted normal value
Number of patients with
current medical condition
Number of patients
according COPD GOLD-stage
Mean (SD), N = 76
ITT intention to treat, N/n number of patients, BMI body mass index, SD
standard deviation, COPD chronic obstructive pulmonary disease, FEV1 forced
expiratory volume in 1 s, FVC forced vital capacity, IC inspiratory capacity,
CAD coronary artery disease, GOLD stage defined as: stage I = FEV1/FVC <70%
and FEV1 ≥80% predicted; stage II = FEV1/FVC <70% and 50% ≤FEV1 <80%
predicted; stage III = FEV1/FVC <70% and 30% ≤FEV1 <50% predicted; stage
IV = FEV1/FVC <70% and FEV1 <30% predicted
*N = 75
(p <0.001 for all comparisons), reaching a peak difference
of Δ = -0.667 cmH2O/L/sec (95%CI -0.928 – -0.406
cmH2O/L/sec) at 240 min post-dose (Fig. 4c), in favour
of dual bronchodilation (p ≤0.001). There were no
differences in TLC between the study treatments.
Eight (10.4%) patients experienced treatment-emergent
adverse events (TEAEs) (Table 2). No patient died in the
course of the study or experienced any
treatment-emergent SAE. According to the investigators’ assessment, a
relation to study medication was not suspected for any
of the TEAEs. The intensity of TEAEs was mostly mild
0 did not complete treatment
0 did not complete follow-up
4 other protocol deviations
FAS, full analysis set; PP, Per protocol set
Fig. 2 Disposition of patients
99 patients registered (= Total set)
78 patients undergoing randomization
0 did not complete treatment
0 did not complete follow-up
3 other protocol deviations
In this prospective, randomised study we showed that
the combination of two long-acting bronchodilators
provided a greater improvement in lung hyperinflation and
lung function parameters compared to a single
long-acting agent. Specifically, IND + GLY provided a numerical
improvement in peak-IC combined with a statistically
significant difference in mean IC over 4 h compared to
IND monotherapy. Additionally, the treatment with
IND + GLY resulted in consistent statistically significant
improvements in FEV1, FVC and Raw compared to
IND alone. The two treatments presented a similar
As a unique feature of the trial, the use of body
plethysmography allowed us to observe the significant
difference in Raw in favour for IND + GLY in this study. Raw
is not frequently reported in studies evaluating the effect
of bronchodilators in COPD. However, this parameter
is suggested to be sensitive and to reflect airflow
obstruction, particularly of the peripheral airways, more
accurately than the FEV1/FVC ratio. In assessing the
acute functional effect of bronchodilators, specific Raw
change-based criteria may be preferable to FEV1- or
FVC-based criteria, being more closely related to
bronchodilator-induced improvements in lung
mechanics and dyspnoea at rest . Raw measurements were
strongly improved by IND + GLY treatment compared
to IND monotherapy at all time points after single-dose
A possible explanation of the non-statistically significant
result in SYNERGY on peak-IC might be attributed to the
high variability of this measurement. This is supported by
the fact that in contrast to the peak-IC measurement, the
adjusted mean IC in the SYNERGY study (which included
several values) presented a statistically significant
difference between the two treatments. Additionally, the results
of the present study are consistent with those of other
published studies that have investigated the efficacy and
safety of LABA/LAMA combination therapy in patients
with COPD [7, 11, 14–18]. In order to allow for higher
power and better generalisability of the results, we
additionally evaluated with a similar analysis as in SYNERGY
the peak-IC and FEV1 in a pooled analysis of patient-level
data (n = 1,548) from 3 studies that evaluated the
combination of IND + GLY versus IND, i.e. SYNERGY (present
study), SHINE  and GLOW6  (see details in the
Additional file 1 Online Supplement). Mean adjusted
peak-IC in this pooled analysis was statistically
significantly higher for patients treated with IND + GLY versus
IND alone (Δ = 0.075 L; 95% CI 0.040 – 0.109 L; p ≤0.001)
(Additional file 2 Figure S1). Additionally, FEV1 was
statistically significantly higher for IND + GLY versus IND
at 30, 120 and 240 min after a single dose inhalation,
with a maximal difference at 120 min (Δ = 0.094 L; 95%
(6 patients) or moderate (2 patients). Prior to the first
dose of study medication, one patient experienced atrial
fibrillation of moderate intensity. In conclusion, the
treatments were well tolerated with a good safety
Least Squares Means values were displayed; ^Adjusted treatment difference (95% CI);
Peak-IC is defined as the highest IC measurement
observed at one of the post-dose measurements (30min, 60min, 120min, 180min and 240min);
*P-value based on ANCOVA model with
treatment, sequence and period as fixed effects, the pre-dose IC as a covariate and patient
as a random effect; #Two periods were used, some observations were not included due to
CI, confidence interval; IC, inspiratory capacity; IND, indacaterol; GLY, glycopyrronium
Fig. 3 Improvements in a Peak Inspiratory Capacity (peak-IC) [L]
(N = 74) and (b) Mean inspiratory Capacity [L] (N = 77) by IND +
GLY versus IND alone
Least Squares Means values were displayed; ^Adjusted treatment difference (95% CI); *P-value based on ANCOVA model with treatment,
sequence and period as fixed effects, the pre-dose FEV1 as a covariate and patient as a random effect; **P-value based on ANCOVA model with
treatment, sequence and period as fixed effects, the pre-dose FVC as a covariate and patient as a random effect; ***P-value based on ANCOVA
model with treatment, sequence and period as fixed effects, the pre-dose Raw as a covariate and patient as a random effect
CI, confidence interval; IND, indacaterol; GLY, glycopyrronium
(Raw) [cmH2O/L/s] (N = 77)
The physiological and clinical significance of these
These results further support the reduction of static
results can be attributed to prolonged maximal
bronhyperinflation, as expressed by IC, by a combination of
chodilation that minimises air trapping and leads to
two bronchodilators compared to a single agent.
Respiratory, thoracic & mediastinal disorders
Infections & infestations
Musculoskeletal and connective tissue disorders
TEAEs treatment-emergent adverse events, IND indacaterol, IND + GLY indacaterol and glycopyrronium, N or n number of patients, AE adverse event
hyperinflation. Improved IC is associated with improved
exercise endurance and dyspnoea [2, 3] and potentially
improved long-term outcomes. Casanova et al. showed
that lung hyperinflation, as expressed by the IC/TLC ratio,
is an independent predictor of mortality .
Furthermore, Tantucci et al. identified IC as a powerful functional
predictor of all-cause and respiratory mortality and of
exacerbation-related hospital admissions in patients
with COPD .
The improvement in bronchodilation and measures of
hyperinflation observed in the present study is supported
by data from the BRIGHT study (IND/GLY fixed-dose
combination versus placebo and tiotropium), which
showed significantly improved dynamic IC, trough
FEV1, residual volume (RV) and FRC in patients with
moderate-to-severe COPD receiving IND/GLY that
were accompanied by increased exercise endurance
. Mahler et al. showed that IND + tiotropium provided
greater bronchodilation and lung deflation compared with
tiotropium monotherapy . To what extent these
effects have a clinically significant impact on outcomes
other than lung function and exercise endurance requires
further evaluation. However, there is significant evidence
that exacerbations, the relevant trigger for progression,
are more effectively prevented by IND + GLY than by a
single long-acting bronchodilator .
We acknowledge that there were limitations in the
study. These include the cross-over study design, the
short study duration, and the potentially limited patient
population due to the clinical trial settings. Additionally,
we need to acknowledge that in patients with severe
airflow limitation, the plethysmographic Raw may be of
limited validity. Finally, post hoc it became obvious that
possibly the initially taken assumptions for the power
calculations were overestimated, resulting in a relatively
small sample size to reach statistical significance. This is
supported by the results of the pooled analysis showing
the statistical significance for peak-IC.
In our study all treatments were equally well tolerated
and showed a good safety profile, which is also
documented in multiple clinical trials and the use in clinical
practice [7, 8, 10, 11, 14, 16, 17, 21].
In summary, the results of the present study show that
treatment with IND + GLY had a stronger beneficial
effect on lung hyperinflation and airflow obstruction
parameters in patients with COPD than treatment
with IND alone. The treatment was well tolerated and
had a good safety profile. These data support the use
of dual bronchodilator therapy to not only improve
airway calibre (FEV1) but also decrease hyperinflation
and its associated negative consequences in patients
Additional file 1: Online supplement. (DOCX 182 kb)
Additional file 2: Figure S1. Peak Inspiratory Capacity [L] – pooled
analysis of SYNERGY, SHINE and GLOW6 (N = 1538)#. (PDF 376 kb)
Additional file 3: Figure S2. Forced expiratory volume in 1 s (FEV1) [L] –
pooled analysis of SYNERGY, SHINE and GLOW6 (N = 1503). (PDF 371 kb)
AEs: Adverse events; ANCOVA: Analysis of covariance; CI: Confidence interval;
COPD: Chronic obstructive pulmonary disease; FAS: Full analysis set;
FEV1: Forced expiratory volume in 1 s; FRC: Functional residual capacity;
FVC: Forced vital capacity; GLY: Glycopyrronium bromide; IC: Including
inspiratory capacity; IND: Indacaterol maleate; IND: Indacaterol maleate;
ITT: Intention to treat; LABAs: Long-acting β2-agonists; LAMAs: Long-acting
muscarinic antagonists; PP: Per-protocol; SAEs: Serious adverse events;
TEAEs: Treatment-emergent adverse events; TLC: Total lung capacity
The study was sponsored by Novartis Pharma Schweiz AG. The authors
thank the physician investigators who contributed to patient enrolment,
together with the nursing and technical staff at each participating centre.
For statistical support in the pooled analysis, the authors thank Giovanni
Bader from Novartis Pharma AG, Switzerland. The clinical trial was conducted
in collaboration with THERAMetrics (previously Pierrel Research), who
monitored the conduct of the study, performed randomisation and were
responsible for the collection of the data. The authors were assisted in the
preparation of the manuscript by THERAMetrics (previously Pierrel Research)
and Rohit Bhandari (professional medical writer; Novartis) for assistance in
the preparation of this manuscript. Writing support was funded by Novartis
Pharma AG, Switzerland.
Study was funded by Novartis Pharma AG, Switzerland.
Writing support was funded by Novartis Pharma AG, Switzerland.
Availability of data and materials
Trial was registered at clinicaltrials.gov (NCT01699685). The datasets used
and/or analysed during the current study available from the corresponding
author on reasonable request. All data generated or analysed during
this study are included in this published article and its supplementary
All authors have provided substantial contribution for the study conception
and design, acquisition of data, or analysis and interpretation of data.
All authors were involved in drafting/revising this manuscript for
important intellectual content and have given final approval of the
version to be published.
Corinne Wild (CW) is a full-time employee of Novartis Pharma Schweiz AG.
Andreas Clemens (AC) and Konstantinos Kostikas (KK) are full-time employees
and shareholders of Novartis Pharma AG. Thomas Geiser (TG) has received
advisory board and speaker fees from Novartis. Joerg Salomon (JS),
JeanWilliam Fitting (J-WF), Thomas Sigrist (TS), Jean-Georges Frey (J-GF), Guido
Domenighetti (GD) and Daiana Stolz (DS), Alexander J. Turk (AT), Andrea
Azzola (AA), Ulrich Schmidt (US) and Martin Brutsche (MB) have no conflict
of interests related to this manuscript.
Consent for publication
Ethics approval and consent to participate
The study protocol and all amendments were reviewed by the Independent
Ethics Committee or Institutional Review Board for each center. Lead Ethic
Committee: Ethikkommission des Kantons St. Gallen (Reference Number:
EKSG 12/093/L/1B). Sub-ethic committees: Kantonale Ethikkommission Bern
(Reference Number: 161/12), Comitato etico cantonale (Ticino) (Reference
Number: Rif. CE 2618), Commission cantonale valaisanne d’éthique médicale
(Reference Number: CCVEM 037/12), Commission cantonale d’éthique
de la recherche sur l’être humain (Reference Number: 334/12), Kantonale
Ethikkommission (Aargau) (Reference Number: 2012/062), Kantonale
Ethikkommission Basel (Reference Number: 246/12), and Kantonale
Ethikkommission Zürich (Reference Number: KEK-ZH-Nr. 2012-0396).
This trial is registered at ClinicalTrials.gov (NCT01699685). The study was
conducted in accordance with the ethical principles of the Declaration
of Helsinki. Written informed consent was obtained from all patients.
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