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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,
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
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Methods
Study design
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
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)
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
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)
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)
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)
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)
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.
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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
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
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
079
061
129
144
p value
099
910 (60%)
996 (65%)
381 (25%)
347 (23%)
139 (9%)
142 (9%)
59 (4%)
43 (3%)
40 (3%)
15 (1%)
1026
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 (%)
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.
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Indacaterol (150 g)
Number of patients
Mean*
Tiotropium (18 g)
Treatment dierence
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
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
732/1496 (49%)
725/1503 (48%)
Week 26
673/1408 (48%)
707/1421 (50%)
041
051
Week 38
638/1328 (48%)
672/1357 (50%)
069
Week 52
626/1273 (49%)
646/1314 (49%)
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
1513
169 (015)
1511
155 (015)
Week 26
1427
165 (016)
1436
146 (016)
007
Week 38
1347
180 (016)
1368
168 (016)
027
Week 52
1288
201 (017)
1322
175 (016)
002
896/1513 (59%)
861/1511 (57%)
021
Week 26
817/1427 (57%)
811/1436 (57%)
064
Week 38
755/1347 (56%)
750/1368 (55%)
048
Week 52
745/1288 (58%)
728/1322 (55%)
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)
p value
Least squares
mean (SE)
1584
101 (011)
1561
039 (011)
<00001
1538
065 (007)
1494
029 (007)
<00001
1563
040 (005)
1538
013 (005)
1561
42 (139)
1526
34 (140)
<00001
80 (110; 59 to 102)
<00001
25 (091; 07 to 43)
00054
1564
67 (110)
1538
65 (111)
1541
6 (059)
1497
5 (059)
08 (048; 02 to 17)
010
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
153 (9%)
137 (8%)
Pneumonia
144 (8%)
Nasopharyngitis
Cough
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%)
16 (1%)
103 (6%)
18 (1%)
119 (7%)
Events
108 (6%)
56 (3%)
Dyspnoea
12 (1%)
99 (6%)
73 (4%)
12 (1%)
4 (<05%)
72 (4%)
64 (4%)
Myocardial ischaemia
6 (<05%)
4 (<05%)
Angina pectoris
5 (<05%)
5 (<05%)
Dyspnoea
66 (4%)
54 (3%)
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%)
4 (<05%)
Bronchitis
Inuenza
42 (2%)
47 (3%)
4 (<05%)
5 (<05%)
32 (2%)
28 (2%)
Myocardial infarction
4 (<05%)
8 (<05%)
Diarrhoea
27 (2%)
44 (3%)
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%)
2 (<05%)
4 (<05%)
Herpes zoster
1 (<05%)
4 (<05%)
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.
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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
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