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Once-daily indacaterol versus tiotropium for patients with


severe chronic obstructive pulmonary disease (INVIGORATE):
a randomised, blinded, parallel-group study
Marc L Decramer, Kenneth R Chapman, Ronald Dahl, Peter Frith, Gilles Devouassoux, Carlos Fritscher, Ray Cameron, Muhammad Shoaib,
David Lawrence, David Young, Danny McBryan, on behalf of the INVIGORATE investigators

Summary
Background We compared the ecacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive
pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months.
Methods In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged
40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computergenerated sequence to randomly allocate patients (1:1; stratied by baseline inhaled corticosteroid use, with the
balance of treatments maintained at country level) to receive either indacaterol (150 g) or tiotropium (18 g) oncedaily for 52 weeks. Our primary and key secondary objectives were to investigate whether indacaterol was noninferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate
of exacerbations at week 52 (secondary endpoint). Analysis populations for the primary and key secondary
endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug.
This study is registered with ClinicalTrials.gov, number NCT00845728.
Findings Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol
and 1721 to tiotropium. At week 12, the estimated least squares mean trough FEV1 dierence between the groups was
0011 L (least squares mean with indacaterol [n=1450] 1134 L [SE 0008] vs tiotropium [n=1467] 1145 L [0008]; onesided 975% CI lower limit 0026 L; p<00001). The lower limit of the 975% CI was above the prespecied noninferiority margin of 0055 L, suggesting that indacaterol was non-inferior to tiotropium. Indacaterol did not show
non-inferiority in terms of annualised exacerbation rates: 079 (indacaterol, n=1529) versus 061 (tiotropium, n=1543);
ratio 129 (one-sided 975% CI upper limit 144). In the safety set, we recorded no between-group dierence in the
number of patients who had adverse events (indacaterol 1119 [65%] of 1721 patients vs tiotropium 1065 [62%] of 1718
patients) or serious adverse events (indacaterol, 263 [15%] of 1721 patients vs tiotropium, 255 [15%] of 1718 patients).
Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747
[43%] of 1721 patients and tiotropium, 665 [39%] of 1718 patients) and serious adverse events (COPD: indacaterol, 147
[9%] of 1721 patients and tiotropium, 121 [7%] of 1718 patients).
Interpretation Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable
safety proles. Tiotropium aorded greater protection from exacerbations, although the absolute number of events
was small and the dierence between treatments is of uncertain clinical importance. The present data oer evidence
consistent with current guidelines.
Funding Novartis Pharma AG.

Introduction
Long-acting inhaled bronchodilators used for treatment
of stable chronic obstructive pulmonary disease (COPD)
include two classes of pharmacological agents: longacting 2-agonists (LABA; eg, indacaterol) and longacting muscarinic antagonists (LAMA; eg, tiotropium).
Both tiotropium1 and indacaterol2 have shown clinically
meaningful bronchodilation, symptomatic benets, and
improved health outcomes in patients with COPD, and
both have acceptable safety proles.
Higher rates of COPD exacerbations have previously
been associated with impaired health-related quality of
life3,4 and a more rapid decrease in lung function.5,6 The
mechanical eects of an exacerbation are complex,

involving worsening airow limitation, increases in


dynamic hyperination, and increased end-expiratory
lung volume and residual volume.7 Bronchodilators
improve airow limitation and reduce breathlessness,
which might in part explain their eectiveness in
preventing exacerbations.8
Findings from three studies comparing once-daily
indacaterol (150 g or 300 g) with once-daily tiotropium
(18 g), all done in patients with moderate-to-severe
airow limitation (ie, 30% and <80% predicted forced
expiratory volume in 1 s [FEV1]), have shown a faster
onset of bronchodilation at rst dose together with noninferiority or superiority of indacaterol versus tiotropium
with regards to trough FEV1.911 Dyspnoea, as measured

www.thelancet.com/respiratory Published online August 21, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70158-9

Published Online
August 21, 2013
http://dx.doi.org/10.1016/
S2213-2600(13)70158-9
See Online/Comment
http://dx.doi.org/10.1016/
S2213-2600(13)70177-2
Respiratory Division,
University Hospital Leuven,
Leuven, Belgium
(Prof M L Decramer MD);
University Health Network,
Toronto Western Hospital,
Toronto, Ontario, Canada
(Prof K R Chapman MD);
Department of Respiratory
Diseases, rhus University
Hospital, rhus C, Denmark
(Prof R Dahl MD); Department
of Respiratory Medicine,
Flinders University, Adelaide,
Australia (Prof P Frith MD);
Service de Pneumologie,
Hpital de la Croix-Rousse,
Hospices civils de Lyon,
UCBLyon1, France
(Prof G Devouassoux MD);
Pontifcia Universidade
Catlica do Rio Grande do Sul,
Brazil (Prof C Fritscher MD);
Novartis Horsham Research
Centre, West Sussex, UK
(R Cameron BSc,
D Young BPharm, M Shoaib MD);
and Novartis Pharma AG, Basel,
Switzerland (D McBryan MD);
Novartis Pharmaceuticals
Corporation, East Hanover, NJ,
USA (D Lawrence PhD)
Correspondence to:
Prof Marc L Decramer,
Diensthoofd Pneumologie, UZ
Leuven, Campus Gasthuisberg,
Herestraat 49, B-3000 Leuven,
Belgium
marc.decramer@uzleuven.be

Articles

with the Transition Dyspnoea Index (TDI) total scores at


week 12, was improved for once-daily indacaterol (300 g)
versus open-label tiotropium10 in one of these trials, and
for indacaterol (150 g) versus blinded tiotropium in
another.9 Once-daily indacaterol (150 g) improved health
status (as shown by improving St Georges Respiratory
Questionnaire [SGRQ ] total scores) at week 12 versus
tiotropium in both trials.9,10
For patients who are at increased risk of exacerbations
(eg, patients with greater airow limitation or those with
a history of exacerbations), prevention of exacerbations is
a key treatment goal of COPD disease management.12 We
therefore assessed the eect of indacaterol on exacerbations in a long-term, blinded study in patients with
severe COPD and a history of exacerbations, versus
tiotropium, a bronchodilator with long-term ecacy on
exacerbations.13,14

Methods
Study design

See Online for appendix

INVIGORATE (indacaterol: providing opportunity to reengage patients with life) was a 52 week, international,
multicentre (408 centres in 41 countries, appendix),
randomised, blinded, double-dummy, parallel group
study comparing the eects of once-daily indacaterol
maleate (150 g) and tiotropium bromide (18 g) on lung
function, exacerbations and related outcomes in about
3500 patients with COPD and severe airow limitation.15
We enrolled both men and women (aged 40 years) who
had a smoking history of 10 or more pack-years, a postbronchodilator FEV1 between 30% and less than 50%
predicted value, a post-bronchodilator FEV1 to forced vital
capacity (FVC) ratio of less than 07, and a documented
history of one or more moderate or severe exacerbations in
the previous 12 months. We excluded patients with a bodymass index of less than 15 kg/m or more than 40 kg/m, a
respiratory tract infection or COPD exacerbation needing
systemic corticosteroids within 6 weeks of the screening
visit (visit two), or a history of asthma.
There were three protocol amendments during the
study. One amendment appointed an independent,
masked, mortality adjudication committee and a
second gave details on the management of patients
aected by drug supply issues. A third amendment
altered the primary endpoint from a superiority to a
non-inferiority analysis. The latter was changed
because data emerged suggesting that indacaterol
might not be superior to tiotropium in terms of lung
function in this severe COPD population. The decision
was not based on data from the present trial because
the database had not been locked. The decision was
taken in February, 2012, when all patients had been
randomly allocated. In view of the fact that the study
was designed to assess the eect of these treatments
on exacerbations, with alpha protected by employing a
hierarchical testing procedure across the primary
endpoint (trough FEV1 at week 12) and key secondary

endpoint (COPD exacerbations over 52 weeks), we


decided that the scientic rigour of the study would be
best retained by this amendment. The revision had no
eect on the assessments in the study protocol, or the
data collected (appendix).
The study was approved by institutional review boards
or ethics committees and was done in accordance with
the Declaration of Helsinki and Good Clinical Practice.
The data from all patients used in the per-protocol
population for spirometry were from sites where ethics
committees and Health Authorities approval were
gained for the primary objective protocol amendment.
All patients gave written informed consent.

Randomisation and masking


We randomly allocated patients in a one-to-one ratio to
receive once-daily indacaterol maleate (150 g; Novartis
Pharma AG, Basel, Switzerland) or tiotropium bromide
(18 g; Boehringer Ingelheim GmbH, Ingelheim,
Germany) for a 52 week treatment period with assessments done at day 2 and weeks 2, 12, 26, 38, and 52. The
randomisation sequence was computer-generated by an
interactive voice response system (IVRS; Oracle America
Inc, Redwood City, CA, USA) and subsequently reviewed
and approved by a member of the Novartis Biostatistics
Quality Assurance group. Randomisation was stratied
by inhaled corticosteroid use, with balance of treatments
maintained at country level. Balance was maintained at
the strata level by using randomly permuted blocks.
Participants, investigators, and those assessing the outcomes were masked to treatment intervention. We used a
double-dummy design because the identity of the study
drugs (indacaterol and tiotropium) could not be disguised
due to their dierent inhaler devices. Patients were
dispensed the two devices and their corresponding
capsules (either active or placebo). Drug packs were
dispensed by a third party who was not involved in any
other aspect of the study.

Procedures
Indacaterol and placebo to indacaterol were given via the
Breezhaler device (Novartis Pharma AG, Basel,
Switzerland) and tiotropium and placebo to tiotropium
were given via the HandiHaler device (Boehringer
Ingelheim GmbH, Ingelheim, Germany). Use of inhaled
corticosteroid was allowed if a patients treatment
regimen had been stable for at least a month before
study entry; patients were instructed to continue this
regimen for the duration of the study. Treatments with
xed dose combinations of a LABA plus inhaled
corticosteroid were discontinued before the start of the
study, as were those with SAMA plus a SABA and those
with LABA plus a LAMA. Treatment with a xed-dose
combination of a LABA plus inhaled corticosteroid was
replaced by the equivalent monotherapy inhaled
corticosteroid for the duration of the trial. All patients
were provided with a SABA, salbutamol or albuterol,

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Indacaterol
(n=1721)

5398 patients screened

Age in years (Median [range])


1954 excluded
3444 randomised

Men

640 (4091)

1721 to tiotropium
1718 exposed*

640 (4087)

All patients
(n=3439)
640 (4091)

1344 (78%)

1313 (76%)

2657 (77%)

White

1330 (77%)

1324 (77%)

2654 (77%)

Asian

266 (15%)

268 (16%)

534 (16%)

Race

Black
1723 to indacaterol
1721 exposed*

Tiotropium
(n=1718)

5 (<05%)

5 (<05%)

10 (<05%)

Native American

31 (2%)

33 (2%)

64 (2%)

Other

89 (5%)

88 (5%)

177 (5%)

Weight in kg
386 discontinued treatment
105 withdrew consent
101 had edverse events
51 perceived lack of eect
36 protocol deviation
34 administrative problems
24 death
22 lost to follow-up
7 abnormal test procedure
results
4 inability to use device
2 abnormal laboratory
values

342 discontinued treatment


108 withdrew consent
96 had edverse events
39 perceived lack of eect
24 protocol deviation
26 administrative problems
26 death
13 lost to follow-up
2 abnormal test procedure
results
6 inability to use device
2 abnormal laboratory
values

Mean (SD)

722 (1682)

717 (1680)

719 (1681)

Median (range)

710 (3381450)

700 (3301320)

701 (3301450)

Body-mass index
30 kg/m

1388 (81%)

1398 (81%)

2786 (81%)

>30 kg/m

331 (19%)

317 (19%)

648 (19%)

Missing

2 (<05%)

3 (<05%)

5 (<05%)

Mean (SD)

70 (569)

66 (542)

68 (556)

Median (range)

54 (00360)

52 (00389)

53 (00389)

Duration of COPD in years

Number COPD exacerbations in previous year


1337 completed 52 weeks of
treatment

1379 completed 52 weeks of


treatment

Figure 1: Trial prole


*Some patients were incorrectly randomised due to site errors and did not
receive treatment.

which they were instructed to use throughout the study


as rescue treatment.

Assessments
Spirometry (FEV1 and FVC) was done in accordance with
ATS/ERS standards16 on the morning of clinic visits.
Patients were given electronic diaries (an accepted
method used for exacerbation detection17,18) to complete
twice a day (once in the morning and once in the
evening), recording symptoms and the number of pus
of rescue drug taken during the previous 12 h. The
morning assessments had to be completed before taking
study treatment.
COPD exacerbations were dened as worsening for at
least two consecutive days of two or more of the major
symptoms (dyspnoea, sputum volume, or sputum
purulence) or worsening of any one major symptom
together with any one minor symptom (sore throat, colds
[nasal discharge or nasal congestion], fever without other
cause, increased cough, or increased wheeze).
COPD exacerbations were considered of moderate
severity if treatment with systemic corticosteroids or
antibiotics was needed, and severe if admission to
hospital (including a visit to the emergency room for
more than 24 h) was needed in addition to treatment
with systemic corticosteroids or antibiotics.
Dyspnoea was assessed using baseline and transition
dyspnoea indices,19 and health status was assessed using
the St Georges Respiratory Questionnaire.20

6 (<05%)

7 (<05%)

13 (<05%)

1365 (79%)

1342 (78%)

2707 (79%)

244 (14%)

251 (15%)

495 (14%)

59 (3%)

69 (4%)

128 (4%)

47 (3%)

49 (3%)

96 (3%)

Median (range)

100 (10010)

100 (10010)

100 (10010)

Baseline spirometry (post-bronchodilator)


FEV1 (mean litres [SD])
FEV1 (mean % predicted [SD])
<30%

1133 (0278)
402 (601)

1138 (0280)
407 (606)

1136 (0279)
405 (604)

19 (1%)

20 (1%)

39 (1%)

30 to <50%

1680 (98%)

1679 (98%)

3359 (98%)

50 to <80%

17 (1%)

14 (1%)

31 (1%)

80%

Missing

5 (<05%)

5 (<05%)

10 (<05%)

460 (967)

465 (977)

463 (972)

FEV1 to FVC ratio (mean [SD])

Inhaled corticosteroids use


Yes

1235 (72%)

1234 (72%)

2469 (72%)

No

486 (28%)

484 (28%)

970 (28%)

1125 (65%)

1133 (66%)

2258 (66%)

596 (35%)

585 (34%)

1181 (34%)

Smoking history
Ex-smoker
Smoker
Number of pack-years
Mean (SD)

428 (2327)

432 (2388)

430 (2357)

Median (range)

400 (1002580)

400 (1002300)

400 (1002580)

Baseline SGRQ total score


Mean (SD)
BDI total score
Mean (SD)
Baseline daily rescue treatment use
Mean number of pus (SD)

1664
479 (174)
1684
59 (21)
1668
387 (356)

1669
487 (178)
1677
60 (21)
1638
390 (367)

3333
483 (176)
3361
60 (21)
3306
389 (362)

Data are n (%) unless otherwise stated. COPD= chronic obstructive pulmonary disease. SGRQ=St Georges Respiratory
Questionnaire. BDI=Baseline Dyspnoea Index. FEV1=forced expiratory volume in 1 s. FVC=forced vital capacity.
TDI=transition dyspnoea index.

Table 1: Baseline characteristics (safety set)

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We recorded adverse events and serious adverse events


(including admissions to hospital and deaths), along
with physical examination measurements, vital signs,
laboratory assessments, blood test results, and
electrocardiogram readings. An independent data
monitoring committee was established to review all
safety data and an independent masked mortality
adjudication committee was established, after a protocol
amendment, to standardise the assessment of cause of
death of any patients during study participation and for
30 days after study drug discontinuation.

Statistical analysis
Analysis for the primary and key secondary endpoints
were done in per-protocol populations. These populations
included all randomised patients who received at least
one dose of study drug and did not have any major
protocol deviations (as pre-dened in the analysis plan)
that could aect the analysis of spirometry or exacerbations data. All other analyses of ecacy endpoints
were done on the full analysis set, which consisted of all
randomised patients who received at least one dose of
study drug. Once patients discontinued from the study,
either being lost to follow-up or by undertaking a study
discontinuation visit, data for FEV1 and exacerbations
were no longer collected.
We analysed the primary endpoint of trough FEV1 at
week 12 using a mixed model for the per-protocol
population for spirometry with treatment. Baseline FEV1,
FEV1 reversibility components to salbutamol and
ipratropium, inhaled corticosteroid use, smoking history,
and country were used as xed eects, with centre nested
within country as a random eect. Non-inferiority was to
be shown if the one-sided 975% CI for the comparison
of indacaterol minus tiotropium was greater than
0055 L.
We analysed the key secondary endpoint of
exacerbation rates over 52 weeks using a negative
binomial model for the per-protocol population for
exacerbations with duration of time on study as the

oset variable. The model included the same covariates


for the primary analysis (excluding centre), but with the
addition of the number of COPD exacerbations in the
previous year and number of days of poor control at
baseline (dened as any day in the patient diary on
which a score of 2 [ie, moderate or severe symptoms]
was recorded for at least two of ve symptoms). Noninferiority of indacaterol to tiotropium would be shown
if the upper limit of the 975% CI was lower than 112
(ie, the upper limit was less than a 12% increase in
exacerbation rate vs tiotropium). A hierarchical testing
procedure was prespecied in the protocol to control the
type I error rate across the primary and key secondary
endpoints (see the appendix for the statistical analysis
plan for other endpoints).
Study sample size was based on the key secondary
objective of showing non-inferiority of indacaterol to
tiotropium in terms of rate of COPD exacerbations over the
52 week treatment period. On the basis of available studies
at the time we designed the study, the expected exacerbation
rate was 11 per year in both groups. The overdispersion
factor was estimated to be 16. The non-inferiority margin
selected was 12%, based on half the reduction in
exacerbations (2025%) seen in previous studies of active
treatments versus placebo. Using these assumptions, the
nal sample size needed was 1750 patients per group for
80% power, including an allowance for drop-out. This
sample size also gave more than 99% power for the primary
objective of non-inferiority in terms of trough FEV1 after
12 weeks treatment. For this comparison the non-inferiority
margin was dened as 55 mL, based on the treatment
dierence between tiotropium and placebo.21 A standard
deviation of 225 mL was assumed based on the results of
previous indacaterol trials. Full details of the assumptions
made are given in the appendix. We used SAS (version 9.3)
for all statistical analyses, with all programs written and
validated before the database was locked.
This study is registered with ClinicalTrials.gov, number
NCT00845728.

Role of the funding source

Least squares mean of trough FEV1 (L)

116

114

1 mL; p=086

17 mL; p=0042
19 mL; p=0018

12 mL; p=0018

20 mL; p=0022

112

110

108

106

n= n=
1679 1677

n= n=
1645 1638

n= n=
1465 1472

n= n=
1381 1405

n= n=
1324 1362

Day 2

Week 2

Week 26
Time

Week 38

Week 52

Figure 2: Trough FEV1 by other visits (full analysis set)


Datapoints are least squares mean and error bars are SE. FEV1=forced expiratory volume in 1s.

Indacaterol (150 g)
Tiotropium (18 g)

RC, MS, DL, DY, and DMcB are employees of the trial
sponsor and contributed to the design, preparation, and
conduct of the study. They also made substantial
contributions to the analysis and interpretation of the
study. MD was the principal investigator of the study who
critically reviewed the full study report and had the nal
responsibility for the decision to submit for publication.
All authors had full access to the results of pre-specied
statistical analyses, were encouraged to suggest
appropriate post-hoc analyses, and made substantial
contributions to the content of each draft.

Results
Between March 16, 2009, and July 5, 2012, we enrolled
and randomly allocated 3444 patients: 1723 to indacaterol
and 1721 to tiotropium (gure 1). Baseline characteristics

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Indacaterol
(n=1529)

Tiotropium Treatment
(n=1543)
dierence

1520

1533

Treatment comparison non-inferiority to tiotropium


Number included in the analysis

Rate (negative binomial model)

079

061

Rate ratio (indacaterol/tiotropium)

129

Upper limit of 975% CI

144

p value

099

Number of exacerbations per patient (without imputation;


n [%])
None

910 (60%)

996 (65%)

381 (25%)

347 (23%)

139 (9%)

142 (9%)

59 (4%)

43 (3%)

40 (3%)

15 (1%)

Total number of exacerbations

1026

Total number of treatment years

137250

830

139764

Non-inferiority of indacaterol (150 g) to tiotropium (18 g) is shown if the upper limit of the 975% CI is lower than
112 (ie, the upper limit is less than a 12% increase in exacerbation rate compared with tiotropium)

Table 2: Number and rate of exacerbations per patient during 52 weeks (non-inferiority comparison)

Indacaterol (150 g)
Tiotropium (18 g)

100
90
80
Patients with exacerbations (%)

were much the same between the treatment groups


(table 1). Most patients were white men.
We recorded improvements from baseline in trough
FEV1 in patients in both groups at week 12 (0114 L with
indacaterol and 0126 L with tiotropium) and week 52
(0073 L with indacaterol and 0092 L with tiotropium).
At week 12, the estimated least squares mean trough
FEV1 dierence between the groups was 0011 L (least
squares mean with indacaterol [n=1450] 1134 L
[SE 0008] vs tiotropium [n=1467] 1145 L [0008]; onesided 975% CI lower limit 0026 L; p<00001). The
lower limit of the 975% CI was above the prespecied
non-inferiority margin of 0055 L, meeting the noninferiority criteria at week 12.
In the subsequent superiority comparison, we
detected no between-group dierence at week 12 in
trough FEV1 in the full analysis set (least squares mean
indacaterol [n=1651] 1130 L [SE 0008] vs tiotropium
[n=1646] 1141 L [0008]; 95% CI 0026 to 0003;
p=012). Statistically signicantbut not clinically
relevantbetween-group dierences in favour of
tiotropium were seen in least squares mean trough
FEV1 at day 2 and weeks 26, 38, and 52 (gure 2). We
recorded no between-group dierence in trough FEV1
decrease from day 15 to week 52 (4460 mL per month
with indacaterol [n=1657] and 3191 mL per month
with tiotropium [n=1650]; p=0054).
For the key secondary endpoint (rate of exacerbations
for indacaterol vs tiotropium in the per-protocol set), the
upper level of the 975% CI was above the predened
non-inferiority margin, so non-inferiority was not
claimed (absolute dierence in rate: 018; table 2).
We did a second, pre-specied superiority analysis for the
full analysis population as a whole. The annualised rate of
exacerbations was higher with indacaterol (n=1693) than it
was with tiotropium (n=1689; 090 vs 073; rate ratio 124;
95% CI 112 to 137; p<00001), showing superiority of
tiotropium. In the sub-analyses of the rates of exacerbations
requiring treatment with corticosteroids, antibiotics, or
both (moderate), or admission to hospital or ER visits for
more than 24 h (severe), rates were higher in the indacaterol
group than they were in the tiotropium group (appendix).
The one exception was in the rates of exacerbations leading
to admission to hospital in patients receiving inhaled
corticosteroid, when exacerbation rates were not
signicantly dierent between groups (appendix). These
results should be interpreted with caution given potential
issues of multiple comparisons and lack of power for
subgroup analyses.
Most patients in both groups did not have an
exacerbation during the study (table 2). Time to rst
moderate or severe exacerbation was longer with
tiotropium (hazard ratio 120 [95% CI 1073 to 1332];
p=00012; gure 3).
In subgroup analyses of the times to rst exacerbation
needing systemic corticosteroids or antibiotics (moderate),
times were shorter in the tiotropium group than they were

70
60
50
40
30
20
10
0
0

Number at risk
Indacaterol 1711
Tiotropium 1708

4
5
6
7
8
Time to rst exacerbation (months)

1309
1355

1078
1154

901
985

10

11

12
621
696

Figure 3: Time to rst moderate or severe COPD exacerbation up to Month 12 (full analysis set)
COPD=chronic obstructive pulmonary disease.

in the indacaterol group (appendix). The times to rst


COPD exacerbation needing admission to hospital
(severe) were not dierent between treatment groups,
irrespective of inhaled corticosteroid use (appendix).
These results should be interpreted with caution given
potential issues of multiple comparisons and lack of
power for subgroup analyses.
We recorded no between-group dierence in the
number of patients who had clinically relevant
improvements in health status or dyspnoea (ie,
changes from baseline in SGRQ scores 4 [health
status] or TDI total scores 1 [dyspnoea]; table 3).

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Indacaterol (150 g)
Number of patients

Mean*

Tiotropium (18 g)

Treatment dierence

Number of Patients Mean*

LS mean (SE); 95% CI

Odds ratio (95% CI)

p value

Health status
SGRQ total score: change from baseline
Week 12

1505

46 (130)

1514

45 (127)

Week 26

1416

45 (144)

1432

52 (138)

Week 38

1336

43 (146)

1368

49 (145)

Week 52

1281

45 (155)

1325

49 (148)

051

SGRQ total score


Week 12

1496

433 (051)

1503

436 (050)

03 (042); 11 to 06

Week 26

1408

435 (058)

1421

429 (058)

05 (047); 04 to 14

027

Week 38

1328

434 (062)

1357

429 (061)

05 (050); 0415

028

Week 52

1273

423 (066)

1314

422 (065)

02 (052); 08 to 12

073

SGRQ total score: % patients with improvement 4 units


Week 12

732/1496 (49%)

725/1503 (48%)

106 (092 to 124)

Week 26

673/1408 (48%)

707/1421 (50%)

095 (081 to 111)

041
051

Week 38

638/1328 (48%)

672/1357 (50%)

097 (083 to 113)

069

Week 52

626/1273 (49%)

646/1314 (49%)

103 (088 to 121)

072

Dyspnoea
TDI total score: change from baseline
Week 12

1522

189 (326)

1521

171 (333)

Week 26

1435

203 (343)

1446

182 (342)

Week 38

1354

197 (343)

1377

181 (342)

Week 52

1296

222 (353)

1332

192 (356)

016

TDI total score


Week 12

1513

169 (015)

1511

155 (015)

015 (010); 006 to 035

Week 26

1427

165 (016)

1436

146 (016)

020 (011); 001 to 040

007

Week 38

1347

180 (016)

1368

168 (016)

012 (011); 009 to 033

027

Week 52

1288

201 (017)

1322

175 (016)

026 (012); 004 to 005

002

TDI total score: % patients with improvement 1


Week 12

896/1513 (59%)

861/1511 (57%)

110 (095 to 127)

021

Week 26

817/1427 (57%)

811/1436 (57%)

104 (089 to 120)

064

Week 38

755/1347 (56%)

750/1368 (55%)

106 (091 to 123)

048

Week 52

745/1288 (58%)

728/1322 (55%)

112 (096 to 131)

015

SGRQ=St Georges Respiratory Questionnaire. TDI=Transition Dyspnoea Index. *Data are mean SD for change from baseline and least squares mean for total score. Only
patients with a value at both baseline and post-baseline were included.

Table 3: Health status and dyspnoea during 52 weeks of treatment (full analysis set)

Indacaterol (150 g)

Tiotropium (18 g)

Treatment dierence

Least squares
mean (SE)

Least squares mean


(SE; 95% CI)

p value

Least squares
mean (SE)

Rescue treatment over 52 weekchange from baseline in:*


Daily number of pus

1584

101 (011)

1561

039 (011)

062 (009; 079 to 045)

<00001

Daytime number of pus

1538

065 (007)

1494

029 (007)

036 (005; 046 to 026)

<00001

Night-time number of pus

1563

040 (005)

1538

013 (005)

027 (004; 035 to 019)

1561

42 (139)

1526

34 (140)

Percentage of days with no rescue use

<00001

80 (110; 59 to 102)

<00001

25 (091; 07 to 43)

00054

Night or day symptoms and daily living activities (over 52 weeks)*


Percentage of nights with no night-time awakenings

1564

67 (110)

1538

65 (111)

Percentage of days with no daytime symptoms

1541

6 (059)

1497

5 (059)

08 (048; 02 to 17)

010

Percentage of days able to perform usual daily activities

1541

31 (114)

1497

30 (116)

12 (095; 07 to 30)

022

LS mean=least squares mean. *Only patients with a value at both baseline and post-baseline were included.

Table 4: Rescue treatment use and symptoms over 52 weeks of treatment (full analysis set)

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Indacaterol 150 g
(N=1721)

Tiotropium 18 g
(N=1718)

1119 (65%)

1065 (62%)

Worsening of COPD

747 (43%)

665 (39%)

Worsening of COPD

Upper respiratory tract


infection (bacterial)

153 (9%)

137 (8%)

Pneumonia

Lower respiratory tract


infection

144 (8%)

Nasopharyngitis
Cough

Patients with any adverse


events

Indacaterol 150 ug
(N=1721)

Tiotropium 18 g
(N=1718)

263 (15%)

255 (15%)

147 (9%)

121 (7%)

29 (2%)

24 (1%)

28 (2%)

18 (1%)

111 (7%)

Lower respiratory tract


infection

16 (1%)

103 (6%)

Upper respiratory tract


infection (bacterial)

18 (1%)

119 (7%)

Events

Patients with any serious


adverse event
Events

108 (6%)

56 (3%)

Dyspnoea

12 (1%)

Viral upper respiratory


tract infection

99 (6%)

73 (4%)

Viral upper respiratory


tract infection

12 (1%)

4 (<05%)

Upper respiratory tract


infection

72 (4%)

64 (4%)

Myocardial ischaemia

6 (<05%)

4 (<05%)

Angina pectoris

5 (<05%)

5 (<05%)

Dyspnoea

66 (4%)

54 (3%)

Acute respiratory failure

4 (<05%)

2 (<05%)

Hypertension

64 (4%)

49 (3%)

Back pain

4 (<05%)

Headache

55 (3%)

49 (3%)

Inuenza

4 (<05%)

2 (<05%)

Pneumonia

47 (3%)

42 (2%)

Lobar pneumonia

4 (<05%)

4 (<05%)
2 (<05%)

11 (1%)

Back pain

43 (2%)

40 (2%)

42 (2%)

36 (2%)

Lower respiratory tract


infection (bacterial)

4 (<05%)

Bronchitis
Inuenza

42 (2%)

47 (3%)

Lung neoplasm malignant

4 (<05%)

5 (<05%)

Urinary tract infection

32 (2%)

28 (2%)

Myocardial infarction

4 (<05%)

8 (<05%)

Diarrhoea

27 (2%)

44 (3%)

Non-cardiac chest pain

4 (<05%)

1 (<05%)

Fever

22 (1%)

27 (2%)

Pneumothorax

4 (<05%)

2 (<05%)

Respiratory failure

4 (<05%)

6 (<05%)

Atrial brillation

3 (<05%)

4 (<05%)

Data are n (%). Events listed are those which were treatment-emergent and
occurred in 15% or more of patients in either treatment group. Events sorted in
descending order of frequency in the indacaterol 150 g treatment group.
COPD=chronic obstructive pulmonary disease.

Cardiac failure

3 (<05%)

5 (<05%)

Transient ischaemic attack

2 (<05%)

4 (<05%)

Table 5: Adverse events (safety set)

Herpes zoster

1 (<05%)

4 (<05%)

Indacaterol and tiotropium both showed clinically


relevant improvements from baseline in mean SGRQ
and TDI total scores at all visits (table 3). At most
visits, least squares mean SGRQ total scores or least
squares mean TDI total scores were similar for both
treatments, except for TDI scores at week 52 when we
recorded a between-group dierence favouring
indacaterol.
During the 52 week trial, patients given indacaterol
needed rescue treatment less often than did those given
tiotropium (table 4). Indacaterol was superior to
tiotropium in terms of change from baseline in
percentage of nights with no night-time awakenings
(table 4). We recorded no between-group dierence in
the percentage of days with no daytime symptoms or
the days able to do usual daily activities (table 4)
The total duration of exposure to study drug was much
the same between groups for the indacaterol and
tiotropium groups (mean 3178 days [SD 1012] with
indacaterol vs 3215 days [987] with tiotropium). Mean
compliance (percentage of doses taken over whole
treatment period) was about 97% for both groups.
The incidence of adverse events was similar between
the indacaterol and tiotropium groups (table 5). In both

Data are n (%). Events listed are those which were treatment-emergent and
occurred in 02% or more of patients in either treatment group. Preferred terms
are sorted in descending order of frequency in the indacaterol 150 g treatment
group. COPD=chronic obstructive pulmonary disease.

Table 6: Serious adverse events, including COPD exacerbations


(safety set)

groups, the most common adverse events were


respiratory disorders, in particular worsening of COPD
and upper and lower respiratory tract infections
(including viral or bacterial infections; table 5). The
incidence of serious adverse events was also similar
between treatment groups; the most frequent serious
adverse events were respiratory disorders (table 6).
The same number of patients in each group died
during the study (24 [1%] of 1721 patients in the
indacaterol group and 24 [1%] of 1718 in the tiotropium
group; a further four deaths occurred in each group
within 30 days of the last dose). The proportion of
patients who permanently discontinued study treatment
because of serious adverse events was also balanced
between the groups (80 [5%] of 1721 patients with
indacaterol vs 79 [5%] of 1718 patients with tiotropium)
or non-serious adverse events (45 [3%] of 1721 patients vs
42 [2%] of 1718 patients). We saw no statistically

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Articles

signicant dierences, as assessed by the mortality


adjudication committee, in the time to death between
the indacaterol and tiotropium groups (hazard ratio
094, 95% CI 0576 to 1811; p=0943).

Discussion
In this 1-year blinded comparison, once-daily treatment
with indacaterol or tiotropium in patients with severe
COPD and a history of exacerbations gave equally
eective and clinically relevant improvements in lung
function, health status, and breathlessness. Patients
receiving indacaterol had a 29% higher rate of
exacerbations versus patients receiving tiotropium, and
a statistically signicant 20% increase in the risk of the
time to rst COPD exacerbation. Compared with
patients given tiotropium, those given indacaterol
needed rescue treatment less often and had fewer nighttime awakenings. Improvements from baseline in
health status and dyspnoea were similar between
groups. The safety and tolerability proles for both
treatments were acceptable and consistent with available
reviews of the most serious adverse events due to lower
respiratory causes.1,2
By contrast with the present study, earlier comparative
clinical studies between indacaterol (150 g or 300 g) and
tiotropium (18 g) were done in a broader population
group ranging in severity from moderate to severe
COPDone study compared indacaterol (150 g and
300 g) with placebo and open-label tiotropium over
26 weeks (INHANCE) and one compared indacaterol
(150 g) with blinded tiotropium over 12 weeks
(INTENSITY).9,10 In both studies, treatment with
indacaterol 150 g and tiotropium gave similar
improvements in trough FEV1.9,10 In INTENSITY,9 when
lung function data (trough FEV1 at week 12) were analysed
by COPD severity, tiotropium (18 g) showed superior
improvements in trough FEV1 versus indacaterol (150 g)
in patients with severe COPD (by contrast with the present
study, in which we recorded no statistically signicant
dierence between groups), but indacaterol 150 g was
superior to tiotropium 18 g in patients with moderate
airow limitation, suggesting that treatment eect could
vary with disease severity.
The annualised exacerbation rate in this study was 079
for indacaterol and 061 for tiotropium (per-protocol
population for exacerbations). These exacerbation rates
are lower than those previously reported in TRISTAN
(baseline pre-bronchodilator FEV1 2570% predicted;
exacerbation rates salmeterol plus uticasone 097,
salmeterol 104, uticasone 105, placebo 130)22 and
INSPIRE (baseline post-bronchodilator FEV1 <50%
predicted; exacerbation rates salmeterol plus uticasone
50/500 g 128 vs tiotropium 18 g 132);23 INSPIRE was
done in patients with severe airow limitation similar to
the present study. Moreover, compared with the present
study in a population with severe and very severe airow
limitation (ie, <50%), moderate or severe exacerbation
8

rates were higher for QVA149 (a xed dose combination of


indacaterol and glycopyrronium), tiotropium and
glycopyrronium (annualised rates 084, 093, 095,
respectively).24 However, in patients with a wider range of
airow limitation (ie, 70%) such as those in POET-COPD
(baseline post-bronchodilator FEV1 70% predicted;
exacerbation rates: tiotropium [18 g] 064, salmeterol
[50 g] 072)14 and UPLIFT (post-bronchodilator 70%
predicted; 073 with tiotropium vs 085 with placebo), the
rates were similar.13 Thus, although there seem to be
dierences in exacerbation rates across studies,
comparative conclusions are dicult to make because
there are no clear reasons for this dierence.
60% of patients treated with indacaterol and 65% of
patients treated with tiotropium did not have an
exacerbation throughout the study, despite patients
having had at least one exacerbation in the year preceding
the study, suggesting that both treatments reduced the
rate of exacerbations (although the absence of a placebo
group in this study precludes such a conclusion). The
apparently low exacerbation rates in this study could be
due to several factors in addition to the potential benet
of the two treatments, including improved clinical care
during the trial and diering exacerbation criteria before
(self-assessed) and during the trial (stricter denitions).
However, the reduction in exacerbation rates seen in
clinical studies over the past decade, together with the
low exacerbation rates seen in the present study, suggest
that although exacerbations are an important target for
treatment, for many patients (especially those at low risk
of exacerbations), the management of symptoms might
be an important treatment goal.
Exacerbations are generally associated with a decrease
in lung function5,6 and worse health outcomes.3,4 It is
therefore surprising that, despite the dierence in
exacerbation rates, our data show equivalent ecacy in
terms of SGRQ and TDI, with both treatments giving
clinically relevant improvements from baseline in both
health status and dyspnoea at all visits, and with similar
rates of decrease in FEV1. An explanation for this nding
could be the low rate of exacerbations (and the high
proportion of patients who did not have an exacerbation
during the study), with the result that at a group level
there was an improvement in these parameters. In the
INTENSITY study, TDI total score at week 12 was better
in the indacaterol 150 g group than it was in the masked
tiotropium group.9 Furthermore, indacaterol (150 g)
improved SGRQ total scores at week 12, and rescue
treatment use over the duration of INTENSITY and
INHANCE versus tiotropium.9,10 Findings from these
earlier comparative studies, done in broader populations
of patients with moderate to severe COPD, contrast with
ndings from the present study, in which we recorded no
dierences between the two treatments in terms of
dyspnoea and health status improvements from baseline
in patients with severe COPD and an exacerbation
history, suggesting that disease severity might be one

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Articles

Panel: Research in context


Systematic review
We searched PubMed for peer-reviewed articles published in
English using keyword search terms indacaterol,
tiotropium, exacerbations, COPD, inammation, and
inammatory. We applied no date restrictions. The
relevance of the references to chronic obstructive pulmonary
disease (COPD) exacerbations, inammatory activities, and
direct clinical comparisons of these bronchodilators were
judged on the basis of the article title. When relevant, the
reference lists of papers were also searched for further
relevant papers including older widely cited publications.
Interpretation
We know of no other study to compare indacaterol and
tiotropium in patients with severe COPD and a history of
exacerbations. Monotherapy with LABAs is recommended in
patients in GOLD groups A (alternative choice) and B (rst
choice), as maintenance therapy to control symptoms of
COPD.12 Both drugs were equally eective at providing
clinically-relevant improvements in lung function and health
outcomes. However, tiotropium gave better protection from
exacerbations. Thus, the present data oer ndings
consistent with current guideline treatment
recommendations in not supporting the use of LABA
monotherapy in patients with more severe COPD and a
history of frequent exacerbations.

reason for these dierences between studies.


Some investigators have suggested that duration of
action might be important with regards to clinical
outcomes of bronchodilator treatment because oncedaily bronchodilators might smooth bronchial tone over
24 h whereas short-acting bronchodilators would cause
peaks and troughs.8,25 Indeed, ndings from a previous
study14 showed that once-daily tiotropium was associated
with a reduction in the rate of moderate-to-severe
exacerbations compared with twice-daily salmeterol.14
Furthermore, in the 26 week INHANCE study,10 the rate
ratio versus placebo for moderate-to-severe exacerbations
was 067 for indacaterol (150 g) and 070 for open-label
tiotropium (18 g).10 In this context, because indacaterol
and tiotropium have similar durations of action, factors
other than duration of bronchodilation must account for
the additional eect on exacerbations seen with
tiotropium in the present study. One reason could be
related to diering pharmacological eects, especially
with regards to anti-inammatory eects. Acetylcholine,
for example, can act on muscarinic receptors in the
airways promoting airway inammation and
remodelling via multiple mechanisms.26 Both LABAs
and LAMAs have possible anti-inammatory eects in
vitro27,28 and might also alter aspects of mucous
production or mucociliary clearance.29,30 These potential
non-bronchodilatory eects leading to reduced
exacerbation rates need further investigation.

Another discordant result is that patients used less


rescue treatment with indacaterol than with tiotropium,
although the two groups had very similar symptoms, and
individuals in the indacaterol group had higher rates of
exacerbation. One possible explanation is that even on a
background of increased exacerbations, indacaterol could
be providing better symptomatic control than tiotropium.
In hindsight, we could have included mild exacerbations
as an outcome measure in the study, and this inclusion
could have allowed an analysis of the correlation between
mild exacerbations and rescue drug use.
Some of the discordant ndings in this study are
dicult to explain and need to be studied further.
However, the present data oer ndings consistent with
current guideline treatment recommendations in not
supporting the use of LABA monotherapy in patients with
severe COPD and a history of frequent exacerbations
(panel). Monotherapy with LABAs is recommended in
patients in Global Initiative for Chronic Obstructive Lung
Disease groups A (alternative choice) and B (rst choice),
as maintenance treatment to control symptoms of COPD.
Contributors
All authors had access to the study data, were involved in interpretation
or presentation of the data for this report, reviewed and revised the
initial draft and subsequent versions of the paper, had nal
responsibility for the decision to submit for publication, and approved
the version submitted.
Conicts of interests
MLD has received speaker fees from AstraZeneca, GlaxoSmithKline,
Boehringer-Pzer, and Novartis, consulting fees from AstraZeneca,
Boehringer-Pzer, Domp, GlaxoSmithKline, Novartis, Nycomed, and
Vectura, and grant support of AstraZeneca, Boehringer-Pzer,
GlaxoSmithKline, and Chiesi. GD received payment for national board
membership from Novartis and MSD, and lecture fees from Novartis,
GlaxoSmithKline, Takeda, ALK, and ABscience. CF received payment for
national board membership from GlaxoSmithKline and Takeda, and
lecture fees from Novartis, GlaxoSmithKline, Ache, AstraZeneca, and
Merck. RD has received compensation for consulting with BoehringerIngelheim, Novartis, Vectura, MEDA, and Norpharma, and has received
speaker fees from AstraZeneca, Boehringer-Ingelheim,
GlaxoSmithKline, ALK-Abello, Novartis, Almirall, and MEDA. PF has
received speaker honoraria from AstraZeneca, GlaxoSmithKline,
Boehringer-Pzer, Novartis, and Nycomed-Takeda, consulting fees for
advisory board membership from AstraZeneca, Boehringer-Pzer,
GlaxoSmithKline, Novartis, Chiesi, and Nycomed-Takeda, and grant
support from Boehringer-Pzer, GlaxoSmithKline, and Novartis. KRC
has received speaker fees from GlaxoSmithKline, Grifols, Merck,
Novartis, and Takeda, consulting fees from CSL Behring, Genentech,
GlaxoSmithKline, Grifols, Novartis, Roche, and Takeda, and grant
support of Amgen, AstraZeneca, CSL Behring, Forest, GlaxoSmithKline,
Kamada, Novartis, Roche, and Takeda. RC, MS, DL, DY, and DMcB are
employees of Novartis.
Acknowledgments
This study was sponsored by Novartis Pharma AG. We would like to thank
patients and sta at the participating centres in the study. We also thank
members of the data monitoring committee and the mortality adjudication
committee for their contribution to the conduct and reporting of this trial.
We also thank Melanie Stephens and Maggie Davis (professional medical
writers; CircleScience, UK) for assistance in the preparation of this paper.
Writing support was funded by the study sponsor.
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