Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium.

Abstract

Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, double-blind study compared the bronchodilator efficacy of indacaterol with that of placebo and tiotropium in patients with moderate-to-severe COPD.
In an incomplete-block, multi-dose, three-period, crossover design, patients received three of the following four treatments: indacaterol 150 μg, indacaterol 300 μg, tiotropium 18 μg and placebo, each once-daily for 14 days. Each treatment period was separated by a 14-day washout. Study drug was supplied daily by blinded, third party study personnel to maintain blinding of patients and investigators. The primary efficacy variable was trough forced expiratory volume in one second (FEV1) at 24 h post-dose after 14 days. The study was powered to demonstrate non-inferiority of indacaterol to tiotropium for this variable.
A total of 169 patients were randomized (mean age 65 years); 153 (90.5%) completed. Trough FEV1 after 14 days with indacaterol 150 μg and 300 μg was statistically and clinically superior to placebo, with differences (95% CI) of 170 (120-220) and 150 (100-200) mL respectively (both p < 0.001). For this endpoint, both doses of indacaterol not only met the criterion for non-inferiority compared with tiotropium, but also achieved numerically higher values, with differences versus tiotropium of 40 and 30 mL for indacaterol 150 and 300 μg, respectively. At 5 min post-dose on Day 1, the mean FEV1 for both indacaterol doses was significantly higher than placebo (by 120 and 130 mL for indacaterol 150 and 300 μg, respectively; p < 0.001) and tiotropium (by 80 mL for both doses; p < 0.001). Adverse events were reported by similar proportions of patients: 31.4%, 29.5%, 28.3% and 28.5% for indacaterol 150 μg and 300 μg, tiotropium and placebo treatments, respectively.
Once-daily indacaterol provided clinically and statistically significant 24-h bronchodilation. Indacaterol was at least as effective as tiotropium, with a faster onset of action (within 5 min) on the first day of dosing. Indacaterol should prove useful in patients with moderate-to-severe COPD, for whom treatment with one or more classes of long-acting bronchodilator is recommended.
ClinicalTrials.gov: NCT00615459, EudraCT number: 2007-004071-19.

Full text

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RESEARCHOpen Access
Indacaterol provides 24-hour bronchodilation in
COPD: a placebo-controlled blinded comparison
with tiotropium
Claus Vogelmeier1, David Ramos-Barbon2, Damon Jack3, Simon Piggott3, Roger Owen3, Mark Higgins3,
Benjamin Kramer4*, INTIME study investigators (INdacaterol & TIotropium: Measuring Efficacy)
Abstract
Background: Indacaterol is a novel, inhaled, once-daily, ultra-long-acting b2-agonist for the treatment of chronic
obstructive pulmonary disease (COPD). This randomized, double-blind study compared the bronchodilator efficacy
of indacaterol with that of placebo and tiotropium in patients with moderate-to-severe COPD.
Methods: In an incomplete-block, multi-dose, three-period, crossover design, patients received three of the
following four treatments: indacaterol 150 μg, indacaterol 300 μg, tiotropium 18 μg and placebo, each once-daily
for 14 days. Each treatment period was separated by a 14-day washout. Study drug was supplied daily by blinded,
third party study personnel to maintain blinding of patients and investigators. The primary efficacy variable was
trough forced expiratory volume in one second (FEV1) at 24 h post-dose after 14 days. The study was powered to
demonstrate non-inferiority of indacaterol to tiotropium for this variable.
Results: A total of 169 patients were randomized (mean age 65 years); 153 (90.5%) completed. Trough FEV1after
14 days with indacaterol 150 μg and 300 μg was statistically and clinically superior to placebo, with differences
(95% CI) of 170 (120-220) and 150 (100-200) mL respectively (both p < 0.001). For this endpoint, both doses of
indacaterol not only met the criterion for non-inferiority compared with tiotropium, but also achieved numerically
higher values, with differences versus tiotropium of 40 and 30 mL for indacaterol 150 and 300 μg, respectively. At
5 min post-dose on Day 1, the mean FEV1for both indacaterol doses was significantly higher than placebo (by 120
and 130 mL for indacaterol 150 and 300 μg, respectively; p < 0.001) and tiotropium (by 80 mL for both doses;
p < 0.001). Adverse events were reported by similar proportions of patients: 31.4%, 29.5%, 28.3% and 28.5% for
indacaterol 150 μg and 300 μg, tiotropium and placebo treatments, respectively.
Conclusions: Once-daily indacaterol provided clinically and statistically significant 24-h bronchodilation. Indacaterol
was at least as effective as tiotropium, with a faster onset of action (within 5 min) on the first day of dosing.
Indacaterol should prove useful in patients with moderate-to-severe COPD, for whom treatment with one or more
classes of long-acting bronchodilator is recommended.
Trial registration: ClinicalTrials.gov: NCT00615459, EudraCT number: 2007-004071-19
Background
According to the Global Initiative for Chronic
Obstructive Lung Disease (GOLD), inhaled bronchodi-
lators, including b2-agonists and anticholinergics, are
central to the symptomatic management of chronic
obstructive pulmonary disease (COPD) [1]. Currently
available inhaled long-acting b2-agonists (LABAs), such
as salmeterol and formoterol, provide bronchodilation
for approximately 12 h at recommended doses, and
hence are administered twice daily [2,3]. Tiotropium,
the only currently available long-acting anticholinergic,
has a duration of action of 24 h with once-daily dos-
ing, and is effective in the long-term maintenance
bronchodilator treatment of COPD [4-6]. Once-daily
* Correspondence: benjamin.kramer@novartis.com
4Novartis Pharmaceuticals Inc., One Health Plaza, East Hanover, NJ 07936-
1080, USA
Full list of author information is available at the end of the article
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© 2010 Vogelmeier et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

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dosing of tiotropium has been shown to improve a
range of clinical outcomes and exacerbations in
patients with COPD compared with twice-daily LABAs
and the anticholinergic ipratropium four times daily
[5,7-9]. However, COPD remains a chronic disabling
condition and additional therapeutic options are
needed to achieve optimal disease management.
Furthermore, patients’ compliance with treatment
could be improved if regimens are simplified by redu-
cing the dosing frequency - especially given that the
high incidence of comorbidities means that many
patients with COPD require polypharmacy [10].
Indacaterol is a novel, inhaled, once-daily ultra LABA
for the treatment of COPD [11]. Indacaterol has shown
good overall safety and tolerability in clinical studies of
up to 1-year duration with 24-h bronchodilator efficacy
on once-daily dosing [12-17].
Two previous clinical trials have compared indacaterol
with tiotropium, but due to the unavailability of a
matching placebo, tiotropium was administered open-
label [13,15]. The first study was a 7-day placebo-
controlled dose ranging study, with an 8-day open-label
tiotropium extension [13]. The second study was a 26-
week pivotal study, in which, compared with open-label
tiotropium, indacaterol 150 and 300 μg significantly
increased the 24-h post-dose (trough) forced expiratory
volume in 1 s (FEV1) after 12 weeks (primary endpoint)
by 50 and 40 mL, respectively (both p ≤ 0.01 vs tiotro-
pium), with one or both indacaterol doses also signifi-
cantly improving dyspnea, use of rescue medication and
health status compared with tiotropium at most time-
points [15]. The present study was designed to comple-
ment these two earlier studies, by comparing the 24-h
spirometry profile of indacaterol 150 and 300 μg once-
daily with that of placebo and blinded tiotropium.
Methods
This was a multinational, randomized, double-blind, dou-
ble-dummy, placebo-controlled, multi-dose, Phase III,
crossover study in patients with moderate-to-severe
COPD. The study was conducted in accordance with the
Declaration of Helsinki (1989) and local applicable laws
and regulations. Institutional Review Board or Indepen-
dent Ethics Committee approval was obtained for each
participating study center. All participants provided
informed written consent prior to taking part in the study.
Study population
Male and female patients aged ≥40 years with moderate-
to-severe COPD (GOLD 2006), a smoking history of at
least 10 pack-years (current or previous smokers), post-
bronchodilator FEV1≥30% but <80% of the predicted
normal value, and post-bronchodilator FEV1/forced vital
capacity (FVC) <70% were included in the study.
Patients were excluded from the study if they had
been hospitalized for a COPD exacerbation in the
6 weeks prior to screening or during the run-in period;
had a history of asthma; or had concomitant pulmonary
disease or a significant unstable cardiovascular or meta-
bolic comorbidity.
Study design and treatments
The study comprised a pre-screening visit, a 14-day
screening period, followed by three 14-day treatment
periods, each of which was separated by a 14-day wash-
out. At the pre-screening visit, patients’ ongoing COPD
medications were reviewed and, if necessary, adjusted to
exclude prohibited COPD therapies. On completion of
the screening period, eligible patients were randomized
using a validated automated system to receive three of
the four treatments (with a different treatment in each
treatment period), each once-daily. An incomplete-block
design was selected (with three treatment periods rather
than four) to reduce the overall burden on patients, and
to increase the likelihood of patients completing the
study (given the complexity in delivering the third-party
blinded study medication - see below). Due to the use
of different inhalers to deliver the study drugs, patients
were randomized not only to a treatment sequence, but
also to a sequence of inhalers. Indacaterol 150 or
300 μg was delivered via single-dose dry powder inhaler
(SDDPI); tiotropium 18 μg was delivered via the manu-
facturer’s proprietary single-dose dry powder inhalation
device (HandiHaler®). Study drugs were inhaled between
06:00 h and 10:00 h on each day throughout the treat-
ment periods.
Indacaterol and its matching placebo were made iden-
tical in appearance and were dispensed in such a man-
ner so as to make them indistinguishable to patients
and all blinded study personnel. As an exact physical
match to tiotropium was not available, full blinding was
achieved by third-party blinding procedures. These pro-
cedures were as follows: study drug was prepared and
provided to the patient each morning, either at home or
in the clinic, by persons who were independent of the
other clinical trial processes (referred to as ‘independent
study blinding coordinators’ or ‘ISBCs’) to preserve the
integrity of the blind. Two ISBCs were required for each
daily study drug administration to each individual
patient. The first (unblinded) ISBC (who had no contact
whatsoever with the patient) prepared the study drugs
and devices, maintained patient, investigator and the
second ISBC blinding and ensured that the patients
strictly adhered to their allocated drug sequence. The
second (blinded) ISBC provided the patient with the
prepared study drug and devices and monitored admin-
istration of the drug by patients and also ensured that
the blinding was maintained throughout. Both ISBCs
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completed the Third Party Blinding Log for every drug
administration, in order to evidence that the blinding
procedure was strictly followed.
Concomitant medication
Allowable concurrent COPD therapies included the use of
inhaled corticosteroids (ICS), provided the regimen had
been stabilized for at least 1 month prior to the screening
visit. Patients taking fixed-dose combinations of ICS and
LABAs were switched to equivalent ICS monotherapy at a
dose and dosage regimen maintained for the duration of
the study. The following medications could not be used
after the screening visit (except as study medication):
long- or short-acting anticholinergic agents, long- or
short-acting b2-agonists, xanthine derivatives, and parent-
eral or oral corticosteroids. Salbutamol was the only rescue
medication permitted throughout the study, although not
within 6 h prior to the start of each visit.
Assessments and outcomes
All clinic visits started in the morning. In addition to
the assessments during the screening visits, serial spiro-
metry was performed on Day 1 and Day 14 of each
treatment period, at 50 and 15 min pre-dose and at 5,
15 and 30 min and 1, 2, 4, 8, 10, 12 and 14 h post-dose.
Spirometry was also assessed on Day 2 and Day 15 of
each treatment period at 23 h 10 min and 23 h 45 min
post-dose (based on the time of study drug administra-
tion on the previous day) to enable trough values of
FEV1to be determined. All spirometry evaluations were
performed according to American Thoracic Society/
European Respiratory Society standards [18].
Adverse events (AEs) and serious AEs were recorded,
along with their severity, duration and relationship to
study drug. Other safety assessments included: urinaly-
sis; regular monitoring of hematology, blood chemistry
(including serum potassium and blood glucose) and vital
signs; and assessment of corrected QT interval (QTc).
The primary objective of the study was to determine
whether indacaterol was superior to placebo as assessed
by trough FEV1after 14 days of treatment, with trough
FEV1defined as the mean of FEV1measurements at 23
h 10 min and 23 h 45 min post-dose. The key secondary
objective was a non-inferiority comparison between
indacaterol and tiotropium for this endpoint (and if
achieved, to then test for superiority). Other efficacy
variables included trough FEV1after the first dose, and
FEV1measurements at individual timepoints after the
first dose and on Day 14 in each treatment period.
Sample size calculation and statistical analysis
he study was powered for the key secondary objective,
the non-inferiority comparison of indacaterol versus tio-
tropium for trough FEV1after 14 days, where a non-
inferiority margin of 55 mL based on a Cochrane review
[19] was adopted. An advantage of 30 mL for indacaterol
over tiotropium was assumed and a standard deviation of
220 mL for the difference between repeated measures on
the same patient (based on information from previous
studies). Taking account of the incomplete block nature
of the design, 126 evaluable patients would provide a
power of 90% for a one-sided test at the 1.25% signifi-
cance level (half the usual alpha level to adjust for multi-
plicity). Allowing for a dropout rate of 15%, a total of 148
patients were planned to be randomized into this study.
This number of patients would give 99% power for the
primary endpoint, assuming a minimum clinically impor-
tant difference (MCID) of 120 mL.
All efficacy variables, including the primary efficacy
variable, were analyzed for the modified intent-to-treat
(mITT) population comprising all randomized patients
who received at least one dose of study drug. The non-
inferiority comparison between indacaterol and tiotro-
pium for trough FEV1after 14 days was analyzed for the
per-protocol population, which included all patients in
the mITT population who had no major protocol devia-
tions. The safety population included all patients who
received at least one dose of study drug. Patients were
analyzed according to treatment received.
An analysis of covariance model was used to analyze
the primary endpoint and included terms for treatment,
period, patient and period baseline value (pre-dose FEV1
on Day 1 of each treatment period), with results pre-
sented as least squares means, i.e., means adjusted for the
covariates in the model. To allow for multiplicity, a Bon-
ferroni adjustment was applied to maintain the overall
Type I error rate at 5%. A similar model was used to ana-
lyze the secondary endpoints (with the non-inferiority
and superiority comparisons between indacaterol and tio-
tropium also controlled for multiplicity).
Results
Patient disposition, demographics and baseline
characteristics
A total of 211 patients were screened, 169 were rando-
mized, and 153 (90.5%) completed. The most common
reason for premature discontinuation was adverse events
(n = 5), followed by administrative problems (4), abnor-
mal test procedure results (3), withdrawal of consent
(2), and unsatisfactory therapeutic effect (1). One patient
was lost to follow up. Demographic and baseline charac-
teristics of patients are summarized in Table 1.
Efficacy
For the primary endpoint (24-h post-dose [trough]
FEV1after 14 days of treatment), treatment with both
doses of indacaterol resulted in statistically superior
improvements compared with placebo, with least
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squares mean (LSM) treatment-placebo differences of
170 and 150 mL for the 150 and 300 μg doses that
exceeded the 120 mL prespecified MCID (Table 2 and
Figure 1). For this endpoint, both doses of indacaterol
not only met the criterion for non-inferiority compared
with tiotropium, but also achieved numerically higher
values, with differences versus tiotropium of 40 and
30 mL for indacaterol 150 and 300 μg, respectively, in
the per-protocol population. The p-value for the
statistical comparison of superiority between indaca-
terol 150 μg and tiotropium was 0.043, with a LSM
treatment difference of 50 mL (mITT population),
although this comparison did not meet the formal
requirement for superiority (which was for the 97.5%
confidence interval to be entirely above zero).
For trough FEV1after the first dose, both doses of inda-
caterol were again statistically superior to placebo, with
the 300 μg dose exceeding the 120 mL MCID (LSM
treatment-placebo difference 130 mL, p < 0.001; Table 2).
The mean trough FEV1values after treatment with both
indacaterol 150 and 300 μg were numerically higher than
with tiotropium, by 10 and 30 mL, respectively.
At all time points on both the first day and after 14
days of treatment, all active treatments resulted in statis-
tically significantly greater FEV1results compared with
placebo (Figure 2). The LSM FEV1for indacaterol was
numerically larger than for tiotropium at all timepoints
for the 300 μg dose, and at a majority of timepoints for
the 150 μg dose.
Both indacaterol doses had a fast onset of action on
Day 1, providing clinically relevant treatment-placebo
differences in LSM FEV1at 5 min post-dose of 120 and
130 mL for indacaterol 150 and 300 μg, respectively
(p < 0.001 for both), compared with 50 mL for tiotro-
pium (p < 0.004). At this timepoint, treatment with both
indacaterol doses resulted in statistically superior FEV1
to tiotropium (LSM differences of 80 mL for both inda-
caterol doses, p < 0.001).
Safety
The overall incidence of AEs was similar across all treat-
ments, and were predominantly mild or moderate in
Table 1 Demographics and baseline characteristics
(safety population)
Characteristics
Age (years), mean (SD)
Sex, n (%)
Male
Female
Race, n (%)
Caucasian
Others
BMI (kg/m2), mean (SD)
Duration of COPD (years), mean (SD)
Smoking history, n (%)
Ex-smoker
Current smoker
Number of pack-years, mean (SD)
Post-bronchodilator FEV1(% predicted), mean (SD)
Post-bronchodilator FEV1/FVC (%), mean (SD)
FEV1reversibility (% increase), mean (SD)
Patients (N = 167)
64.5 (7.92)
128 (76.6)
39 (23.4)
165 (98.8)
2 (1.2)
26.8 (4.71)
9.1 (7.91)
95 (56.9)
72 (43.1)
43.1 (19.62)
56.7 (13.58)
50.1 (10.04)
14.3 (12.26)
SD = standard deviation; BMI = body mass index; FEV1= forced expiratory
volume in 1s; FVC = forced vital capacity; pack-years = total years of smoking
multiplied by cigarette packs smoked per day.
Table 2 Treatment contrasts of trough FEV1(L) after 1 and 14 days of treatment (mITT population)
Treatment contrast
LS mean ± SE
Day 14
Indacaterol 150 μg - Placebo 0.17 ± 0.023
Indacaterol 300 μg - Placebo0.15 ± 0.023
Tiotropium - Placebo0.12 ± 0.023
Indacaterol 150 μg - Tiotropium0.05 ± 0.023
Indacaterol 300 μg - Tiotropium 0.03 ± 0.023
LS mean ± SE
Day 1
Indacaterol 150 μg - Placebo0.10 ± 0.021
Indacaterol 300 μg - Placebo 0.13 ± 0.021
Tiotropium - Placebo 0.10 ± 0.021
Indacaterol 150 μg - Tiotropium0.01 ± 0.021
Indacaterol 300 μg - Tiotropium0.03 ± 0.021
Treatment difference
97.5% CI^p-value
(0.12,0.22)
(0.10,0.20)
(0.07,0.17)
(-0.01,0.10)
(-0.03,0.08)
95% CI
< 0.001*
< 0.001*
< 0.001*
0.043
0.249
p-value
(0.06,0.15)
(0.09,0.17)
(0.06,0.14)
(-0.04,0.05)
(-0.01,0.08)
<0.001*
<0.001*
<0.001*
0.772
0.101
LS = least squares, SE = standard error of the mean, CI = confidence interval.
^ 95% confidence interval for the comparison tiotropium minus placebo.
*Statistically significant comparison (two-sided p-value < 0.05).
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severity (Table 3). The most frequent AEs were cough
(indacaterol 150 μg, 6.8%; indacaterol 300 μg, 4.9%; tio-
tropium, 2.5%; placebo, 2.4%), COPD worsening (5.1,
3.3, 8.3, 8.9%) and nasopharyngitis (3.4, 7.4, 4.2, 4.9%).
None of the AEs leading to study drug discontinuation
were suspected to be study-drug-related.
SAEs were reported in one patient while taking inda-
caterol 300 μg (COPD exacerbation), two patients while
taking indacaterol 150 μg (both COPD exacerbations),
four patients while taking tiotropium (three reported as
COPD exacerbation and one reported as cerebrovascular
accident), and one patient while taking placebo (COPD
exacerbation). None of these were suspected to be
related to study medication by the investigators. There
were no deaths during the study, although one patient
died during the 30-day follow-up period due to an acute
myocardial infarction and infection; this was not sus-
pected to be study-drug-related (the patient received
indacaterol 300 μg in the first treatment period, indaca-
terol 150 μg in the second, and tiotropium in the third).
There were no clinically notable serum potassium
values (defined as a post-baseline value <3.0 mmol/L)
during treatment with either of the indacaterol doses.
One patient experienced a clinically notable potassium
value during treatment with tiotropium. The incidence
of clinically notable blood glucose levels (defined as a
post-baseline value of >9.99 mmol/L) during treatment
with indacaterol 150 μg was 8.5% (10/118), 7.4% (9/122)
during treatment with indacaterol 300 μg, 2.5% (3/120)
during treatment with tiotropium and 7.3% (9/123) dur-
ing placebo treatment.
No patient had an abnormally high pulse rate (>130
bpm, or ≥120 bpm and increase from baseline ≥15
bpm). The proportion of patients with newly occurring
or worsening QTc interval (Fridericia’s) >450 ms
(males) or >470 ms (females) was lower during treat-
ment with indacaterol 150 μg (2.5%) compared with
indacaterol 300 μg (4.9%), tiotropium (5.0%) and placebo
(4.1%). No patient had a maximum post-baseline
increase in Fridericia’s QTc of >60 ms or an absolute
value >500 ms.
Discussion
This randomized, double-blind study compared the 24-h
spirometry profile of indacaterol 150 and 300 μg once-
daily with that of tiotropium 18 μg once-daily and pla-
cebo in patients with moderate-to-severe COPD. The
primary efficacy analysis showed that once-daily indaca-
terol 150 μg and 300 μg provided clinically relevant
improvements in 24-h post-dose (trough) FEV1after 14
days of treatment. The improvement versus placebo in
bronchodilation with both indacaterol doses was not
only higher than the 100 mL criterion described by
Donohue [20] as a difference that COPD patients can
perceive but also exceeded the prespecified clinically
relevant difference of 120 mL, and moreover was above
the range (100-140 mL) that has been proposed as a
range of values for a minimal clinically important differ-
ence [21]. These results are consistent with those
observed in long-term studies [16,17,22], which also
confirm that there is no loss in efficacy with once-daily
dosing of indacaterol for up to a year.
In the current study, indacaterol provided a 30-50 mL
higher bronchodilator effect than tiotropium in terms of
trough FEV1after 14 days of treatment. Although there
is no consensus for a clinically relevant threshold for
differences between active treatments, in other studies
tiotropium was associated with improvements in trough
FEV1over both salmeterol (52 mL, p < 0.01) and formo-
terol (42 mL, p < 0.05) [5,23]; the further improvements
over tiotropium of a similar magnitude achieved with
indacaterol may be considered at least noteworthy.
Further, the efficacy results of this study support the
results of the previous 26-week pivotal study conducted
by Donohue et al [15], in which tiotropium was admi-
nistered on an open-label basis. The magnitude of treat-
ment difference between indacaterol and tiotropium
after 2 weeks in the present study (50 and 30 mL for
indacaterol 150 and 300 μg, respectively) was similar to
that observed after 12 weeks of treatment in the pivotal
study (50 and 40 mL, respectively) [15]. Therefore, the
results from the current blinded study validate the
results of the earlier pivotal study. In the present study,
indacaterol demonstrated a fast onset of action after the
first dose with FEV1improvements that were statistically
superior to both placebo and tiotropium at the first
post-dose timepoint (5 min), with differences from
placebo at or above the prespecified 120 mL minimum
Figure 1 24-h post-dose (trough) FEV1(L) after 14 days of
treatment (mITT population). Data are LSM ± SE. ***p < 0.001 vs
placebo;†p = 0.043 vs tiotropium. FEV1, forced expiratory volume in 1 s
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clinically important difference. This result is also consis-
tent with the findings of the pivotal study, in which at
5 min following the first dose both indacaterol doses
resulted in statistically superior FEV1to tiotropium (p <
0.001) [15].
Given that an exact physical match to tiotropium was
not available, a very difficult third-party blinded
approach - probably the first of its kind - was employed
in this study. This required two study personnel, inde-
pendent of any other study procedures, to visit each
Figure 2 24-h profile of least squares means of FEV1on Day 1 (A) and 14 (B) (mITT population). A) Data are LSM ± SE. p < 0.001 for
indacaterol (150 and 300 μg) vs placebo at each timepoint, p < 0.001 for indacaterol, 150 μg vs tiotropium at 5 and 15 min,†p < 0.05 for
indacaterol 300 μg vs tiotropium, p < 0.05 for tiotropium vs placebo at each timepoint. B) Data are LSM ± SE. p < 0.001 for indacaterol (150 and
300 μg) and tiotropium vs placebo at each timepoint,†p < 0.05 for indacaterol 150 μg vs tiotropium at -50 to 30 min, 12 h and 23 h 10 min,
p < 0.05 for indacaterol 300 μg vs tiotropium at 5 min.
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patient daily during the treatment periods, with one of
these personnel blinded to the identity of the study
medication then handing the prepared inhalers to the
patient. It is of note that despite this, a low premature
discontinuation rate was observed in this study. A cross-
over design (rather than a parallel-group design) was
chosen because the within-patient variability in FEV1
was expected to be less than between-patient variability
with each patient acting as their own control. An
incomplete-block, rather than a complete-block, cross-
over design was adopted (with three periods) to reduce
the overall burden on patients. For the incomplete-block
design the within-patient variability is higher than that
of a complete block design, and this therefore required
a higher number of patients to be recruited. The 14-day
time point was selected as primary endpoint in the pre-
sent study, because previous studies have shown that
indacaterol reaches pharmacodynamic steady-state prior
to this time [12,17], as does tiotropium [24], with the
bronchodilator efficacy observed after 2 weeks similar to
that observed after 12 weeks for both drugs [15]. The
duration of two weeks for washout was also sufficient to
minimize the possibility of carry-over effects of both
indacaterol and tiotropium, and the length of this wash-
out period increased the practicability of the study by
permitting each treatment period to start on the same
day of the week. Further, the difference in trough FEV1
between tiotropium and placebo observed in this study
was similar to that reported previously [4].
Overall, all treatments in this study (including
placebo) had good safety and tolerability profiles. The
overall incidence of AEs was comparable across all treat-
ment groups. Most AEs were mild or moderate in sever-
ity, and the majority were related to COPD and
respiratory symptoms - as expected in this patient popu-
lation. Although the most common AE in patients trea-
ted with indacaterol was cough, these events were mild
or moderate in severity and were not associated with
discontinuation from the study. Class-related side effects
of inhaled b2-agonists (e.g., hyperglycemia, hypokalemia
or prolonged QTc interval) were observed at a similar
incidence with both indacaterol doses as with placebo.
Conclusions
Indacaterol at doses of both 150 and 300 μg given once
daily, resulted in clinically relevant 24-h bronchodilation
with a fast onset of action in patients with moderate-to-
severe COPD, and demonstrated a good overall safety
and tolerability profile. The bronchodilator efficacy of
indacaterol appears to be at least comparable with that
of tiotropium, with a faster onset of action. Indacaterol
may prove useful in patients with moderate-to-severe
COPD, for whom treatment with one or more classes of
long-acting bronchodilator is recommended.
Table 3 Adverse events overall and by primary system organ class (safety population)
Indacaterol 150 μg
N = 118
n (%)
37 (31.4)
Indacaterol 300 μg
N = 122
n (%)
36 (29.5)
Tiotropium
N = 120
n (%)
34 (28.3)
Placebo
N = 123
n (%)
35 (28.5) Patients with any AE(s)
MedDRA primary system organ class
Respiratory, thoracic & mediastinal disorders
Infections & infestations
Musculoskeletal & connective tissue disorders
Nervous system disorders
Gastrointestinal disorders
Injury, poisoning & procedural complications
Metabolism & nutrition disorders
Blood & lymphatic system disorders
Cardiac disorders
General disorders & administration site conditions
Investigations
Psychiatric disorders
Ear & labyrinth disorders
Neoplasms benign, malignant & unspecified (including cysts and polyps)
Renal & urinary disorders
Skin & subcutaneous tissue disorders
Vascular disorders
17 (14.4)
7 (5.9)
6 (5.1)
4 (3.4)
2 (1.7)
2 (1.7)
2 (1.7)
1 (0.8)
1 (0.8)
1 (0.8)
1 (0.8)
1 (0.8)
0
0
0
0
0
14 (11.5)
14 (11.5)
6 (4.9)
3 (2.5)
3 (2.5)
0
2 (1.6)
1 (0.8)
1 (0.8)
2 (1.6)
0
0
0
0
2 (1.6)
2 (1.6)
2 (1.6)
15 (12.5)
10 (8.3)
2 (1.7)
5 (4.2)
8 (6.7)
1 (0.8)
0
1 (0.8)
0 (0.0)
3 (2.5)
1 (0.8)
1 (0.8)
0
1 (0.8)
1 (0.8)
1 (0.8)
1 (0.8)
15 (12.2)
10 (8.1)
9 (7.3)
3 (2.4)
3 (2.4)
1 (0.8)
0
0
2 (1.6)
3 (2.4)
0
0
1 (0.8)
0
0
0
4 (3.3)
Primary system organ classes are sorted in descending order of frequency in the indacaterol 150 μg treatment.
Vogelmeier et al. Respiratory Research 2010, 11:135
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Page 8

Acknowledgements
The authors thank the patients who took part and the staff at the
participating clinical centres. The authors would like to thank Sam T Mathew,
professional medical writer (Novartis) and David Young (Novartis) for
assistance in the preparation of this manuscript.
Author details
1Universitätsklinikum Gießen und Marburg, Standort Marburg,
Baldingerstraße, D-35043, Marburg, Germany.2Respiratory Department and
Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo
Hospitalario Universitario A Coruña, 15006, A Coruña, Spain.3Novartis
Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12
5AB, UK.4Novartis Pharmaceuticals Inc., One Health Plaza, East Hanover, NJ
07936-1080, USA.
Authors’ contributions
DJ, SP, RO, MH and BK (as employees of the study sponsor, Novartis)
contributed to the design, analysis and interpretation of the study, and
oversaw its conduct. CV and DRB were involved in the collection of data. All
authors contributed equally to the development of the manuscript, and
approved the final version for submission.
Competing interests
This study was funded by Novartis Pharma AG, Basel, Switzerland. Damon
Jack, Simon Piggott, Roger Owen, Mark Higgins, Benjamin Kramer are
employees of Novartis. Claus Vogelmeier gave presentations at symposia
sponsored by (in alphabetical order) Altana, Astra Zeneca, Aventis, Bayer,
Boehringer, Chiesi, GlaxoSmithKline, Merck Darmstadt, Novartis, Pfizer,
Talecris, and received fees for consulting from (in alphabetical order) Altana,
Astra Zeneca, Bayer, Boehringer, GlaxoSmithKline, Janssen-Cilag, Talecris.
David Ramos-Barbon was a speaker at conferences sponsored by
AstraZeneca, Merck Sharp&Dohme, GlaxoSmithKline, Pfizer and Esteve and
received advisory board fees from GlaxoSmithKline.
Received: 11 June 2010 Accepted: 5 October 2010
Published: 5 October 2010
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doi:10.1186/1465-9921-11-135
Cite this article as: Vogelmeier et al.: Indacaterol provides 24-hour
bronchodilation in COPD: a placebo-controlled blinded comparison
with tiotropium. Respiratory Research 2010 11:135.
Vogelmeier et al. Respiratory Research 2010, 11:135
http://respiratory-research.com/content/11/1/135
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