Indacaterol 110µg/ Glycopyrronium 50µg (Ultibro®) Versus Tiotropium (Spiriva®) Alone to Reduce Exertional Dyspnea in Patients With Moderate to Severe COPD
Phase: PHASE4
Conditions: COPD
Sponsor: Laval University

Version May 30th 2016 
 
Page 1 / 13 
Investigator-Initiated Trial (IIT) 
Product: Indacaterol 110 µg/Glycopyrronium 50 µg (Ultibro®) and Tiotropium 18 µg 
(Spiriva®) 
Indication: Moderate to severe COPD 
Country: Canada 
Sponsor: Novartis 
Principal Investigator (PI): François Maltais, IUCPQ, Québec City 
 
Has the Principal Investigator conducted IITs supported by Novartis? 
YES   NO X 
 
Title of study: Indacaterol 110 µg/Glycopyrronium 50 µg (Ultibro®) versus 
Tiotropium 18 µg (Spiriva®) alone to reduce exertional dyspnea in patients with 
moderate to severe COPD. The RED Trial 
 
Study Rationale 
Long-acting bronchodilators such as tiotropium, salmeterol, formoterol, aclidinium, 
indacaterol and glycopyrronium are effective in improving cycling exercise tolerance in 
COPD1-7. In well-designed, randomized, placebo controlled trials, these bronchodilators 
have been convincingly shown to reduce operating lung volume at rest and during 
exercise and to improve the endurance time to submaximal cycling exercise in COPD. 
For a given exercise stimulus, long-acting β2-agonists (LABA) and long acting 
muscarinic antagonist (LAMA) also reduce the perception of dyspnea1-4. 
 
The foundation of COPD therapy is to combine inhaled therapy to optimize benefits as it 
was done several years ago by associating short-acting β2-agonists and muscarinic 
antagonist8. The recent availability of once-daily LABA/LAMA fixed combination 
products makes this therapeutic strategy even more appealing and appears as a promising 
treatment option in COPD. One relevant question regarding these new LABA/LAMA 
combinations is whether they provide superior benefits compared to a single agent. Once-
daily LABA/LAMA fixed combinations consistently improves lung function compared to 
monotherapy9-12. The key question is whether they provide superior efficacy to 
monotherapy on patient’s oriented clinical outcomes, beyond lung function improvement. 
In regards, once-daily LABA/LAMA fixed combinations can reduce exacerbation rate11 
and perception of dyspnea13, further to what can be obtained with the monocomponents. 
Once-daily LABA/LAMA fixed combinations also improve exercise tolerance compared 
to placebo but whether they provide additional benefit over monotherapy is uncertain14-16. 
 
Dyspnea is the most troublesome symptom in COPD and it is felt that the main 
mechanism through which bronchodilators improve exercise tolerance is by reducing 
dyspnea1,17. As such, dyspnea measurement appears a valid surrogate of exercise 
tolerance. One advantage of dyspnea measurement over the measurement of exercise 
endurance is that it does not require a maximal effort. In this regard, it may be a less 
noisy outcome than exercise duration. Dyspnea can be quantified during the 6-min 
walking test but pre and post-intervention comparisons are made difficult since the 
walking speed and thus the exercise stimulus is not controlled during the test. Another 
strategy to evaluate the effects of interventions on exertional dyspnea is to compare 

Version May 30th 2016 
 
Page 2 / 13 
dyspnea at isotime while controlling the walking or cycling speed during the endurance 
shuttle walking test18 or the constant rate cycling test1,3(endurance test). One limitation of 
this approach is that pre and post intervention dyspnea measurement is not always 
obtained at the same time point since the duration of the test is variable. To overcome this 
problem, linear interpolation can be used to estimate dyspnea. However, this approach is 
not as robust as when a “real” dyspnea score is directly obtained from the patients. 
 
To circumvent these difficulties, we have recently developed a strong and simple exercise 
methodology whose primary objective is to assess exertional dyspnea in patients with 
COPD: the 3-min constant speed shuttle test19,20. During this test, which is a modification 
of the endurance shuttle walking test, patients are asked to walk around two cones set-up 
in a flat corridor and separated by 10 meters. An audio signal is used to impose the 
walking speed and the test ends at a fixed duration of 3 minutes or until symptoms 
become intolerable. At pre-specified time point during the test, and at the end of the test 
(3 min), patients are asked to score their perception of dyspnea on a 10-point modified 
Borg scale. The feasibility and reproducibility of this test in providing a standardized 
physical stimulus and a measurable level of dyspnea in patients with moderate to severe 
COPD has been reported19. In one study, we also confirmed the responsiveness of this 
test to bronchodilation, reporting statistically and clinically significant reduction in 
modified Borg scale dyspnea score with ipratropium bromide compared to placebo20. 
 
Based on these considerations, the proposed trial will compare the effectiveness of dual 
(Indacaterol 110 µg/Glycopyrronium 50 µg [Ultibro®]) versus single (Tiotropium 18 µg 
[Spiriva®]) bronchodilation to reduce exertional during the 3-min constant speed shuttle 
test in patients with moderate to severe COPD. 
 
Objectives 
Primary objective 
To compare the reduction in modified Borg scale dyspnea score during the 3-min 
constant speed shuttle test after 3 weeks of indacaterol 110 µg/Glycopyrronium 50 µg 
(Ultibro®) versus Tiotropium 18 µg (Spiriva®) alone in patients with moderate to severe 
COPD. 
 
Hypothesis 
Indacaterol 110 µg/Glycopyrronium 50 µg (Ultibro®) will provide superior reduction in 
dyspnea during the 3-min constant speed shuttle test than Tiotropium 18 µg (Spiriva®) 
alone in patients with moderate to severe COPD. 
 
Secondary objectives 
To evaluate the impact of indacaterol 110 µg/Glycopyrronium 50 µg (Ultibro®) and 
Tiotropium 18 µg (Spiriva®) alone on pulmonary function and quality of life after 3 
weeks of treatment in patients with moderate to severe COPD. 
 
To evaluate the impact of indacaterol 110 µg/Glycopyrronium 50 µg (Ultibro®) and 
Tiotropium 18 µg (Spiriva®) alone on exertional dyspnea after the first dose of therapy in 
patients with moderate to severe COPD. 
 

Version May 30th 2016 
 
Page 3 / 13 
To do a prospective determination of the initial walking speed during the 3-min CSST. 
Study Design 
This will be a, randomized, double-blinded, cross-over trial. 
 
Figure 1: Design Flow-chart 
 
 
 
Methodology 
The study will require 7 visits; the run-in and familiarization phase (visits #1-3), the 
treatment A phase (visits #4-5), and the treatment B phase (visits #6-7). 
 
The first visit will be used to review the inclusion criteria and to obtain consent. Patients 
will be asked to perform a pulmonary function test including spirometry, lung volumes 
and diffusion capacity measurements. Patient on tiotropium, glycopyrronium, aclidinium, 
umeclidinium or any LAMA drugs will be switched to open label ipratropium (see 
allowed medication). At Visit#2 a progressive maximal exercise test will be obtained by 
performing the incremental shuttle walking test, the COPD assessment test (CAT) and 
the MRC scale will be also be completed. Patients will then be familiarized with the 3-
min constant speed shuttle test. During Visit #3, patients will perform up to three 3-min 
constant speed shuttle test which will serve to determine dyspnea at baseline. We will 
aim for a dyspnea Borg Score > 3, the rationale being that it is important to obtain a 
significant dyspnea signal considering that the objective of the study is to evaluate the 
efficacy of bronchodilation to improve dyspnea. Patients in whom it will not be possible 
to achieve this level of dyspnea at the end of the 3-min constant speed shuttle test will be 
excluded for further study participation. 
 
Patients will then enter the cross-over study design during which they will receive one of 
the two study treatments: indacaterol 110 µg/Glycopyrronium 50 µg (Ultibro®) once a 
day or Tiotropium 18 µg (Spiriva®) once a day. The treatment period will be three 
weeks. There will be a two-week washout period between the two treatment phases. Total 
study duration will thus be 11 weeks. 
 
Visit #4 and Visit #6 will be the baseline visits for each treatment period (except for 
dyspnea after the 3-min constant speed shuttle test which will be determined at Visit #3). 
Patients will perform spirometry, lung volume measurements before and 1h 20 min after 
receiving the study medication. One 3-min constant speed shuttle test will be performed 
2h25 min after dosing, starting with the one performed and completed at the highest 

Version May 30th 2016 
 
Page 4 / 13 
speed at Visit #3. This time schedule was chosen based on previous studies in this 
field1,21. Dyspnea will be assessed with the baseline dyspnea index (BDI)22 and health 
status will be evaluated by the COPD Assessment Test (CAT)23. 
 
The same procedures will be repeated at the end of each three-week study treatment 
(Visits #5 and #7) the only difference being that chronic dyspnea will be assessed with 
the transitional dyspnea index (TDI). 
 
Allowed medication  
There will be a three-week run-in period during which patients will receive open label 
ipratropium (Atrovent® MDI 20 µg/ puff, 4 puffs QID) and prn salbutamol (Ventolin® 
MDI 100 µg/puff, 2 puffs every 3-4 hours prn). Ipratropium will be allowed only during 
the run-in and washout periods. Ipratropium will be stopped twelve hours before study 
visits (Visit # 2, #4, and #6). 
 
Salbutamol on prn basis will be allowed throughout the study except that it will be 
stopped 6 hours prior to Visit #2, #4, #5, #6 and #7. Long-acting 2-agonist will be 
prohibited after Visit #1 and throughout study duration. Inhaled corticosteroids will be 
allowed at the same dosage as before the study. PDE4 inhibitors and leukotriene 
antagonists will also be allowed. 
 
Population 
Patients with moderate to severe COPD will be recruited for this study. 
 
Key inclusion criteria 
1) Age > 50 years 
2) Smoking history > 10 packs/year 
3) FEV1 30 - 79% of predicted and FEV1/FVC < 70% (GOLD 2-3) 
4) FRC > 120 % predicted 
5) Borg dyspnea score > 3 during the 3-min constant speed shuttle test at Visit #3 
 
Key exclusion criteria 
1) Respiratory exacerbation within the 2 months preceding the study 
2) Current diagnostic of asthma 
3) Significant O2 desaturation (SpO2 < 85%) at rest or during exercise 
4) Presence of another pathology that could influence exercise tolerance 
5) Use of home oxygen 
 
Number of centers & patients 
Planned number of centers 
Three centres will be necessary to complete the study. 
 
Total number of patients 
Based on a target dyspnea score of 5-6 during the placebo exercise and a standard 
deviation of 219,20 and looking for a change in dyspnea Borg score ≥ 0.75 with Indacaterol 
110 µg/Glycopyrronium 50 µg (Ultibro) versus Tiotropium 18 µg (Spiriva), we 
calculated that 40 completed patients would be necessary to provide an  of 0.05 and a  

Version May 30th 2016 
 
Page 5 / 13 
of 0.85. Expecting that 20% of screened patients will fail to reach a modified Borg 
dyspnea score > 3 during the 3-min constant speed shuttle test at baseline20 and an 
attrition rate of 15% during the trial, we will recruit 60 patients into the study. 
 
Investigational and Reference Therapy 
# of 
Patients  
Treatment  
Arm  
Type of 
Study 
Drug 
 
Compound 
Dose 
Freq. 
Admin. 
Route 
40 
cross 
over 
design 
Arm 1 
Spiriva 
handihaler 
Tiotropium 
18 µg 
Daily 
21 days 
Inhalation 
Arm 2 
Ultibro 
Indacaterol/ 
Glycopyrronium 
110 µg/50 
µg 
Daily 
21 days 
Inhalation 
 
 
Evaluation schedule: Timelines and Study duration 
 
Table 1. Study visits 
 
Run-in and 
familiarization 
Treatment A 
Treatment B 
Visit number 
1 
2 
3 
4 
5 
6 
7 
Time of visit 
Week 1 
Week 2 
Week 3 
Week 4 
Week 6 
Week 9 
Week 11 
Inclusion/Exclusion 
criteria 
 
X 
 
 
 
 
 
 
Information & consent 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
X 
Baseline dyspnea 
index (self-
administered 
and computerized 
version) - BDI 
 
 
 
 
X 
 
 
X 
 
Transitional dyspnea 
index - TDI 
 
 
 
 
 
X 
 
 
X 
CAT questionnaire 
 
X 
 
X 
X 
X 
X 
MRC score 
 
X 
 
 
 
 
 
Spirometry 
X 
X 
 
X 
X 
X 
X 
Lung volumes 
X 
 
 
X 
X 
X 
X 
DLCO 
X 
 
 
 
 
 
 
Explanation of the 
ISWT 
X 
 
 
 
 
 
 
ISWT 
 
X 
 
 
 
 
 
Familiarization with 
3-min CSST 
 
X 
 
 
 
 
 
3-min CSST 
 
 
X 
X 
X 
X 
X 
Dispense study 
medication 
 
 
 
 
X 
 
 
 
X 
 
Adverse events 
 
 
 
 
X 
 
X 

Version May 30th 2016 
 
Page 6 / 13 
Randomization 
Randomization stratified by site will occur at Visit #4 and will be centralized using a 
computerized system and pre-packaged study medication. The number display by the 
computer will be correlated to a numbered envelope which will contain a specified order 
of drug. The corresponding number and the treatment period will only be known by the 
assigned pharmacist responsible of the trial. This code will be broken only if there is a 
need for an emergency treatment and it will need to be authorized by the trial principal 
investigator. 
 
Blinding 
Patient and study staff will be blinded to the treatment administration during the 2 study 
periods. Treatments will consist, for one treatment period of active Ultibro® once a day 
and placebo Spiriva® handihaler, and for the other period of placebo Ultibro® once a day 
and active Spiriva® handihaler. Active medication and placebo will be of identical 
appearance and the order of study medication will be randomized. Pre-package envelopes 
containing equal quantities of inhaler combination will be numbered and kept in a secure 
place (pharmacy of the hospital or the research site). At the end of the study data 
collection the blind code will be opened after having completed the primary data analysis. 
 
Compliance 
Patients will be provided with 21 days (3 weeks) of numbered study inhalers each marked 
from Day 1 to Day 21. Compliance will be assessed by counting the returned empty 
inhalers. Administration of ≥ 80% of the study medication will be determined as 
compliant. 
 
Evaluation criteria 
Primary endpoint will be the difference in modified Borg dyspnea score after the 3-min 
constant speed shuttle test after 3 weeks of treatment between indacaterol 
110 µg/Glycopyrronium 50 µg (Ultibro®) versus Tiotropium 18 µg (Spiriva®) alone. 
Secondary endpoints will be the difference in modified Borg dyspnea score after the 3-
min constant speed shuttle test after 3 weeks of treatment between indacaterol 
110 µg/Glycopyrronium 50 µg (Ultibro®) versus baseline value (Visit #3) and between 
Tiotropium 18 µg (Spiriva®) alone versus baseline value (Visit #3). The dyspnea 
response after the first dose of therapy will also be assessed. The between-treatment 
differences in the improvement of pulmonary function (FEV1 and inspiratory capacity), 
TDI and CAT scores from baseline (Visit #4) to end of treatment period (Visit #5 and #7) 
will also be evaluated. Exploratory analyses will be performed on the cardio-pulmonary 
responses during exercise (ventilation, breathing pattern, heart rate, inspiratory capacity) 
under the different treatment conditions. 
 
Assessment and procedures 
 
Pulmonary function testing 
Spirometry, lung volumes and diffusion capacity will be measured according to routine 
techniques. 
 
 
 

Version May 30th 2016 
 
Page 7 / 13 
Progressive maximal exercise test (Incremental shuttle walk test) 
As originally described by Singh and colleagues24, the incremental shuttle walk test will 
be performed in an enclosed corridor on a flat 10-m-long course. The course will be 
identified by two cones, each positioned 0.5 m from either end to allow patients to walk 
in circle and thereby avoid the need for abrupt changes in direction. Patients will walk at 
a predetermined rhythm, as dictated by an audio signal played from an audio recording. 
Walking speed will initially be set at 0.50 m/sec and will be increased by 0.17 m/sec 
every minute until the patient reaches maximal capacity. Since the effects of 
encouragement on walking performance have been demonstrated25, no encouragement 
will be given to patients throughout the test. The final measure will be distance walked, 
expressed in meters.  
 
3-min constant speed shuttle test 
This test consists in one bout of three minutes of walking at the initial walking speed of 
4.0 km/h. Thirty minutes after this first bout of walking, a second test will be performed 
at either a faster or slower walking speed (see Manual of procedures for standardization 
of pulmonary and exercise testing). The second walking speed will be determined by the 
ability to carry through the test at 4.0 km/h. If a patient cannot complete the first test, then 
the second speed will be stepped down. If a patient is able to carry though the first test, 
then the second walking speed will be raised. Patients will be asked to perform two tests 
at two different speeds in order to determine, amongst the different speeds, the highest 
speed that can be sustained for the entire 3 minutes while reaching a dyspnea score > 3 on 
the modified Borg scale. In doing so, our objective is to induce a level of dyspnea that is 
sufficiently high to be amenable to therapy. These speeds are selected based on our 
previous work19 showing that these were sufficiently demanding to induce measurable 
levels of dyspnea and that most moderate to severe patients with COPD are able to 
complete the test for the desired duration19,20. Patients will be directed to follow the audio 
signals for the entire 3 minutes of the test or until they became symptom limited. They 
will be instructed to walk, jog or run around the two cones of the shuttle course, in a set-
up identical to that of the ISWT, in the hospital or medical clinic hallway pacing their 
walk/jog/run in a continuous way as not to wait at the cones for the following audio 
signal. A device (McRoberts’ MoveTest) will used during all the walk tests to confirm if 
the selected walk speed is respected. 
 
Cardiac and ventilatory measures 
During each exercise test, cardiac and ventilatory parameters will be measured using a 
commercially available portable exercise circuit (Oxycon Mobile). Dyspnea will be 
assessed using a 10-point modified Borg scale that will be assessed by the operator that 
will enter the course to ask the patient while they are in movement or positioned at one 
extremity of the course. During the maximal incremental shuttle walking test, inspiratory 
capacities and dyspnea will be measured at rest, at two-minute intervals and at the end of 
test. During the 3-min constant speed shuttle test, dyspnea will be assessed at rest, at 
minute 1, 2, 2.5 and 3. During this test, inspiratory capacities will be measured at rest and 
at the end of the test, immediately following the assessment of dyspnea.  
 
 
 

Version May 30th 2016 
 
Page 8 / 13 
Pharmacovigilance requirements 
 
Safety data collection and reporting must be compliant with the local regulations of 
the country/countries where the study is being run 
This section summarizes the procedures for the collection, management and reporting of 
individual cases of serious adverse events and should include the collection of any new 
information that might influence the evaluation of the benefit-risk balance of the product 
while the study is being conducted. Any Serious adverse event (SAE) exempt from this 
reporting process must be clearly identified in the study protocol with a scientific/medical 
justification e.g. SAEs due to disease progression, SAEs due to surgical procedure, pain 
in cancer patients, etc. Any SAE study protocol exemptions must be agreed with the 
respective country health authority as part of the protocol approval process. For studies 
where reporting is not required, this should be stated. Details on which data collected by 
the sponsor must be shared with Novartis, how this data is transferred to Novartis and the 
timelines for this transfer must be captured in the Third Party Study/Investigator Initiated 
Trial agreement. Additionally sharing of randomization data should be done as per Third 
Party Study/Investigator Initiated Trial agreement. 
 
SAE Reconciliation 
For integrated studies SAE reconciliation should be performed as defined in the Trial 
specific agreement including periodicity of reconciliation to avoid any missed SAEs from 
clinical and safety databases. Any deviation to the below text should be discussed with 
Novartis Drug Safety and Epidemiology. 
 
Definition of an AE 
Any untoward medical occurrence in a subject administered a pharmaceutical product 
that does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the investigational 
medicinal product. 
 
Investigational Medicinal Product (IMP) includes the drug under evaluation and the 
comparator drug(s) if specified as part of the research objective, given at any time during 
the study. Medical conditions/diseases present before starting the drug of interest are only 
considered adverse events if they worsen after starting the drug of interest. 
 
The occurrence of adverse events will be sought by non-directive questioning of the 
patient at each visit during the study. Adverse events also may be detected when they are 
volunteered by the patient during or between visits or through physical examination, 
laboratory test, or other assessments. All adverse events will be recorded in the study 
database including the following information: 
 
1. The severity grade (mild, moderate, severe)  
2. Its relationship to the drug(s) of interest (suspected/not suspected) 
3. Its duration (start and end dates or if continuing at final exam) 
 
 

Version May 30th 2016 
 
Page 9 / 13 
4. Whether it constitutes a serious adverse event (SAE) A SAE is any untoward medical 
occurrence that at any dose: 
- Results in death, 
- Is life-threatening, 
- Requires inpatient hospitalization or prolongation of existing hospitalization, 
- Results in persistent or significant disability/incapacity, 
- Is a congenital anomaly/birth defect, 
- Is otherwise a significant medical event. 
 
This includes any SAEs likely to arise from the trial indication or progression of 
underlying/concomitant illness(es) (e.g. progression of cancer in oncology trials), unless 
specified in the protocol as study specific exemptions. 
 
Any SAE, irrespective of causality, occurring after the subject has provided informed 
consent and until four weeks after the subject has stopped study participation must be 
reported unless otherwise stated in the protocol. SAEs occurring after four weeks from 
ending study participation should only be reported if considered by the Investigator 
attributable to the exposure to the investigational drug(s) during the trial period. This 
includes the period in which the study protocol interferes with the standard medical 
treatment given to a subject, even if study treatment has not yet started (e.g. withdrawal 
of previous treatment during washout period, change in treatment to a fixed dose of 
concomitant medication). 
 
Timelines 
All serious adverse events (SAEs) from interventional clinical trials must be reported by 
the sites to Sponsor within 24 hours of occurrence of the SAE. The timelines for 
investigator initiated trials reporting to Novartis will be done as per Third Party 
Study/Investigator Initiated Trial Agreement. 
 
Follow-up reports 
SAEs will be followed until resolution or until it is judged to be permanent, and an 
assessment will be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the drug of interest, the interventions required to 
treat it, and the outcome. 
 
The Sponsor shall support Novartis in the following-up of all SAEs so that complete 
information is available to maintain patient safety and also as part of any commitments 
by Novartis to any Health authority OR specific Health authority follow-up requests for 
the product under investigation. 
 
Pregnancies 
Any occurrences of a pregnancy in a patient (or a patients partner) during study 
participation will be collected. All pregnancies will be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 

Version May 30th 2016 
 
Page 10 / 13 
Unsual lack of efficacy (LOE) 
For drugs marketed in Canada, domestic reports of unusual failure in efficacy must be 
reported to Health Canada, by the sponsor of the trial. Lack of efficacy is defined as lack 
of anticipated clinical benefit or response with or without worsening. A copy should also 
be sent within 15 days of awareness to the local Novartis Drug Safety and Epidemiology 
Department at drug.safety@novartis.com.  The original copy of the e-mail 
correspondence should be kept at the study site.  
 
Analysis: Prospective determination of the initial walking speed during the 3-min 
CSST 
The approach that we have adopted in this protocol and in previous studies involving the 
3-min CSST to determine the initial walking speed to be used in patients is a pragmatic 
one; based on our experience, 4.0 km/hr is a walking speed that can be tolerated for 3 
minutes in a majority of patients with moderate to severe COPD. However, in a 
proportion of patients, it is not the optimal walking speed, being either too fast or too 
slow in some patients. In this regard, it would be extremely useful to be able to predict, in 
a given patient, the optimal walking speed to be used during the CSST. Based on 
retrospective analysis of the studies we have conducted with the 3-min CSST26,27, we are 
currently developing a promising predictive equation to determine the optimal walking 
speed. The equation is based on simple clinical characteristics such as age, sex, BMI, 
FEV1 and mMRC dyspnea score. We will use to data collected as a part of the current 
study to prospectively validate this equation. 
 
 
Start date: Fall 2015  
End date: Fall 2016 
Study Report date: January 2017 
Publication date: Submission June 2017 
 
Note: The Study Report should include data on demographics, all efficacy endpoints, 
secondary endpoints, exploratory endpoints and safety events. Final Study Report to be 
sent to the Novartis Medical Responsible no later than 12 months after the last visit of the 
last patient.  
 
 

Version May 30th 2016 
 
Page 11 / 13 
Key-references: 
1. O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects 
of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23:832-
840. Template Version 20 April 2014 
 
2. O'Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to 
exercise in chronic obstructive pulmonary disease. Eur Respir J 2004;24:86-94. 
 
3. Maltais F, Hamilton A, Marciniuck D, Hernandez P, Sciurba F, Richter K, Kesten S, O'Donnell DE. 
Improvements in symptom-limited exercise performance over eight hours with once-daily tiotropium in 
patients with COPD. Chest 2005;128:1168-1178. 
 
4. Neder JA, Fuld JP, Overend T, Thirlwell J, Carter R, Stevenson R, Ward SA. Effects of formoterol on 
exercise tolerance in severely disabled patients with copd. Respir Med 2007;101:2056-2064. 
 
5. Maltais F, Celli B, Casaburi R, Porszasz J, Jarreta D, Seoane B, Caracta C. Aclidinium bromide 
improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. 
Respir Med 2011;105:580-587. 
 
6. O'Donnell DE, Casaburi R, Vincken W, Puente-Maestu L, Swales J, Lawrence D, Kramer B. Effect of 
indacaterol on exercise endurance and lung hyperinflation in copd. Respir Med 2011;105:1030-1036. 
 
7. Beeh KM, Singh D, Di Scala L, Drollmann A. Once-daily NVA237 improves exercise tolerance from 
the first dose in patients with COPD: The GLOW3 trial. Int J Chron Obstruct Pulmon Dis 2012;7:503-513. 
 
8. Combivent Inhalation Aerosol Study G. In chronic obstructive pulmonary disease, a combination of 
ipratropium and albuterol is more effective than either agent alone. Chest 1994;105:1411-1419. 
 
9. Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, Banerji D. Dual 
bronchodilation with qva149 versus single bronchodilator therapy: The SHINE study. Eur Respir J 
2013;42:1484-1494. 
 
10. Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of 
once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013;107:1538-1546. 
 
11. Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandstrom T, Taylor AF, D'Andrea P, Arrasate 
C, Chen H, Banerji D. Analysis of chronic obstructive pulmonary disease exacerbations with the dual 
bronchodilator QVA149 compared with glycopyrronium and tiotropium (spark): A randomised, double-
blind, parallel-group study. Lancet Respir Med 2013;1:199-209. 
 
12. Celli B, Crater G, Kilbride S, Mehta R, Tabberer M, Kalberg CJ, Church A. Once-daily 
umeclidinium/vilanterol 125/25 mcg in COPD: A randomized, controlled study. Chest 2014;145:981-991. 
 
13. Mahler DA, Decramer M, D'Urzo A, Worth H, White T, Alagappan VK, Chen H, Gallagher N, Kulich 
K, Banerji D. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: BLAZE 
study. Eur Respir J 2014;43:1599-1609. 
 
14. Maltais F, Mahler DA, Pepin V, Nadreau E, Crater GD, Morris AN, Emmett AH, Ferro TJ. Effect of 
fluticasone propionate/salmeterol plus tiotropium versus tiotropium on walking endurance in COPD. Eur 
Respir J 2013;42:539-541. Template Version 20 April 2014 
 
15. Beeh KM, Korn S, Beier J, Jadayel D, Henley M, D'Andrea P, Banerji D. Effect of qva149 on lung 
volumes and exercise tolerance in COPD patients: The BRIGHT study. Respir Med 2014;108:584-592. 
 

Version May 30th 2016 
 
Page 12 / 13 
16. Maltais F, Singh S, Donald AC, Crater G, Church A, Goh AH, Riley JH. Effects of a combination of 
umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: 
Two randomized, double-blind clinical trials. Ther Adv Respir Dis 2014;8:169-181. 
17. O'Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance 
after anticholinergic therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 
1999;160:542-549. 
 
18. Brouillard C, Pepin V, Milot J, Lacasse Y, Maltais F. Endurance shuttle walking test: Responsiveness 
to salmeterol in COPD. Eur Respir J 2008;31:579-584. 
 
19. Perrault H, Baril J, Henophy S, Rycroft A, Bourbeau J, Maltais F. Paced-walk and step tests to assess 
exertional dyspnea in COPD. COPD 2009;6:330-339. 
 
20. Sava F, Perrault H, Brouillard C, Darauay C, Hamilton A, Bourbeau J, Maltais F. Detecting 
improvements in dyspnea in COPD using a three-minute constant rate shuttle walking protocol. COPD 
2012;9:395-400. 
 
21. O'Donnell DE, Sciurba F, Celli B, Mahler DA, Webb KA, Kalberg CJ, Knobil K. Effect of fluticasone 
propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Chest 2006;130:647-656. 
 
22. Mahler DA, Waterman LA, Ward J, McCusker C, ZuWallack R, Baird JC. Validity and responsiveness 
of the self-administered computerized versions of the baseline and transition dyspnea indexes. Chest 
2007;132:1283-1290. 
 
23. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation 
of the COPD assessment test. Eur Respir J 2009;34:648-654. 
 
24. Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of 
disability in patients with chronic airways obstruction. Thorax 1992;47:1019-1024. 
 
25. Guyatt GH, Pugsley S, Sullivan MJ, Thompson PJ, Berman L, Jones NL, Fallen EL, Taylor DW. Effect 
of encouragement on walking test performance. Thorax 1984;39:818-822. 
 
26. Perrault H, Baril J, Henophy S, et al. Paced-walk and step tests to assess exertional dyspnea in copd. 
COPD 2009;6:330-339. 
 
27. Sava F, Perrault H, Brouillard C, et al. Detecting improvements in dyspnea in copd using a three-
minute constant rate shuttle walking protocol. COPD 2012;9:395-400. 
 
François Maltais 
May 30, 2016 
 
To be completed for all Third Party Studies (TPS)/ Investigator-Initiated Trials (IITs) by 
the investigator Novartis supports medically and scientifically sound independent 
research initiated by external investigators and aimed at the advancement of scientific 
knowledge in therapeutic areas of interest for Novartis. Novartis evaluates unsolicited 
proposals from independent researchers or their institutions for support. By signing below 
you represent that the research proposal you are submitting was independently conceived 
by you and not solicited by any Novartis employee. 
 
 
 
 
 

Version May 30th 2016 
 
Page 13 / 13 
___________________________________         _______________________ 
Investigator’s Signature  
Date