Clinical trial NCT03137784
Conditions: Asthma
Keywords: asthma, NVA237, glycopyrronium bromide allergic asthma, allergy triggered asthma, reactive asthma, asthma attack, difficulty breathing
Sponsor: Novartis Pharmaceuticals
Start date: 2017-05-04; Completion date: 2017-12-29
Enrollment: 148 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this trial is to characterize the bronchodilator effects and safety of 25 ug and 50 ug o.d. NVA237 (glycopyrronium bromide) doses compared to placebo in asthma patients

Detailed description:
This study uses a randomized, double-blind, placebo controlled, 3-period cross-over clinical trial design. During a screening epoch patient eligibility will be assessed. The screening epoch will be followed by a 21-day Run-in epoch during which patients will continue their inhaled corticosteroids use but be withdrawn from LABA-treatment and switched to short-acting bronchodilator-rescue medication. After the Run-in period patients will be randomized to one of the 6 treatment sequences and enter the first 7-day study treatment period. Treatment period one is followed by a 10 to 14 days washout period after which patients begin the second 7-day treatment period which is then followed by a second 10 to 14 days washout period followed by the third 7-day treatment period. At the end of each treatment period spirometry will be performed to assess the primary endpoint in terms of trough FEV1. The study population will consist of approximately 144 patients with asthma who have been treated in a stable regimen of ICS/LABA for at least 4 weeks prior to screening.

Arms: arm 1: Treatment sequence: NVA 237 50 ug, 25 ug and placebo arm 2: Treatment sequence: NVA 237 50 ug, placebo and 25 ug arm 3: Treatment sequence: NVA237 25 ug, 50 ug and placebo arm 4: Treatment sequence: NVA 237 25 ug, placebo and 50 ug arm 5: Treatment sequence: Placebo, NVA237 50 ug and 25 ug arm 6: Treatment sequence: placebo, NVA237 25 ug and 50 ug
Interventions: intervention 1: NVA237 (glycopyrronium bromide) intervention 2: Placebo
Intervention descriptions: intervention 1: In each treatment arm, patient will receive NVA237 (glycopyrronium bromide) 25 ug and 50 ug dose intervention 2: In each treatment arm, patient will receive placebo

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine
[NVA237/Glycopyrronium bromide]
Clinical Trial Protocol [CQVM149B2204] / NCT03137784
A multicenter, randomized, double-blind, placebo-
controlled 3-period complete cross-over study to assess 
the bronchodilator effects and safety of glycopyrronium 
bromide (NVA237) (25 µg and 50 µg o.d.) in asthma patients
Document type:
Clinical Trial Protocol
EUDRACT number:
2015-005565-23
Version number:
00 (Original Protocol)
Clinical trial phase:
IIb
Release date:
01-Nov-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.1 (February 2016)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Protocol summary................................................................................................................9
1
Introduction .......................................................................................................................11
1.1
Background............................................................................................................11
1.2
Purpose ..................................................................................................................12
2
Study objectives and endpoints .........................................................................................12
2.1
Primary objective...................................................................................................12
2.2
Secondary objective(s)...........................................................................................12
12
3
Investigational plan ...........................................................................................................13
3.1
Study design...........................................................................................................13
3.2
Rationale for study design .....................................................................................14
3.3
Rationale for dose/regimen, route of administration and duration of treatment....14
3.4
Rationale for choice of comparator .......................................................................15
3.5
Purpose and timing of interim analyses/design adaptations..................................16
3.6
Risks and benefits..................................................................................................16
4
Population..........................................................................................................................17
4.1
Inclusion criteria ....................................................................................................18
4.2
Exclusion criteria...................................................................................................18
5
Treatment...........................................................................................................................21
5.1
Study treatment......................................................................................................21
5.1.1
Investigational and control drugs..........................................................21
5.1.2
Additional treatment..............................................................................21
5.2
Treatment arms ......................................................................................................22
5.3
Treatment assignment and randomization.............................................................22
5.4
Treatment blinding.................................................................................................23
5.5
Treating the patient................................................................................................23
5.5.1
Patient numbering .................................................................................23
5.5.2
Dispensing the study drug.....................................................................23
5.5.3
Handling of study and additional treatment..........................................24
5.5.4
Instructions for prescribing and taking study treatment........................25


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........25
5.5.6
Rescue medication ................................................................................25
5.5.7
Concomitant medication .......................................................................26
5.5.8
Prohibited medication ...........................................................................26
5.5.9
Emergency breaking of assigned treatment code..................................28
5.6
Study completion and discontinuation...................................................................29
5.6.1
Study completion and post-study treatment..........................................29
5.6.2
Discontinuation of study treatment .......................................................29
5.6.3
Withdrawal of informed consent...........................................................30
5.6.4
Lost to follow-up...................................................................................30
5.6.5
Early study termination by the sponsor.................................................31
6
Visit schedule and assessments .........................................................................................31
6.1
Information to be collected on screening failures..................................................35
6.2
Patient demographics/other baseline characteristics .............................................35
6.3
Treatment exposure and compliance .....................................................................35
6.4
Efficacy..................................................................................................................36
6.4.1
Spirometry.............................................................................................36
6.4.2
Assessments in electronic diary ............................................................37
6.4.3
Appropriateness of efficacy assessments..............................................38
6.5
Safety.....................................................................................................................38
6.5.1
Physical examination ............................................................................38
6.5.2
Vital signs..............................................................................................38
6.5.3
Height and weight .................................................................................38
6.5.4
Laboratory evaluations..........................................................................38
6.5.5
Electrocardiogram (ECG) .....................................................................39
6.5.6
Pregnancy and assessments of fertility .................................................40
6.5.7
Appropriateness of safety measurements..............................................40
40
40
7
Safety monitoring ..............................................................................................................40
7.1
Adverse events.......................................................................................................40
7.2
Serious adverse events...........................................................................................42
7.2.1
Definition of SAE .................................................................................42
7.2.2
SAE reporting........................................................................................43
7.3
Liver safety monitoring .........................................................................................44
7.4
Renal safety monitoring.........................................................................................45


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7.5
Reporting of study treatment errors including misuse/abuse ................................45
7.6
Pregnancy reporting...............................................................................................45
8
Data review and database management.............................................................................46
8.1
Site monitoring ......................................................................................................46
8.2
Data collection.......................................................................................................46
8.3
Database management and quality control............................................................47
8.4
Data Monitoring Committee..................................................................................47
8.5
Adjudication Committee........................................................................................47
9
Data analysis......................................................................................................................48
9.1
Analysis sets ..........................................................................................................48
9.2
Patient demographics and other baseline characteristics.......................................48
9.3
Treatments .............................................................................................................48
9.4
Analysis of the primary variable(s) .......................................................................49
9.4.1
Variable(s).............................................................................................49
9.4.2
Statistical model, hypothesis, and method of analysis..........................49
9.4.3
Handling of missing values/censoring/discontinuations.......................50
9.4.4
Sensitivity analyses ...............................................................................50
9.5
Analysis of secondary variables ............................................................................50
9.5.1
Efficacy variables..................................................................................50
9.5.2
Safety variables .....................................................................................50
9.6
Interim analyses .....................................................................................................51
9.7
Sample size calculation..........................................................................................51
10 Ethical considerations........................................................................................................52
10.1
Regulatory and ethical compliance........................................................................52
10.2
Informed consent procedures.................................................................................52
10.3
Responsibilities of the investigator and IRB/IEC..................................................53
10.4
Publication of study protocol and results...............................................................53
10.5
Quality Control and Quality Assurance.................................................................53
11 Protocol adherence ............................................................................................................53
11.1
Protocol amendments.............................................................................................54
12 References .........................................................................................................................55
13 Appendices ........................................................................................................................56
Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up Requirements ...56
Appendix 2 Instructions for using inhaler and capsules...........................................................58
Appendix 3 Spirometry Guidance ............................................................................................63
Appendix 4 Patient Asthma Control e-Diary ...........................................................................66


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Appendix 5 ICS Dose level ......................................................................................................67
List of tables
Table 5-1
Treatment arms......................................................................................22
Table 5-2
Prohibited asthma related medication ...................................................26
Table 5-3 
Other Prohibited medication .................................................................28
Table 6-1
Assessment schedule.............................................................................32
Table 6-2
Spirometry timings in relation to study drug administration ................36
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................45
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................56
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers ...56
Table 13-3
Low, medium and high Daily Doses of Inhaled 
Glucocorticosteroids for Adults and adolescents (12 years and 
older) (GINA 2015)...............................................................................67
List of figures
Figure 3-1
Study design..........................................................................................13


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List of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATS/ERS
American Thoracic Society / European Respiratory Society
AUC
Area under curve
AV
Atrioventricular
b.i.d.
twice a day
BMI
Body Mass Index
BPH
Benign Prostate Hyperplasia
BTPS
Body Temperature Pressure Saturated
BUN
Blood Urea Nitrogen
CFR
US Code of Federal Regulations
CRA
Clinical Research Associate
COPD
Chronic Obstructive Pulmonary Disease
CPO
Country Pharma Organization
DAR
Drug Administration Record
DALY
Disability–adjusted life years
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
Case Report/Record Form (electronic)
ECSC
European Community for Steel and Coal
EDC
Electronic Data Capture
EMA
European Medicines Agency
EOT
Early Treatment Discontinuation
EU
European Union
FAS
Full Analysis Set
FEV1
Forced expiratory volume in 1 second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GLI
Global Lung Function Initiative
γ-GT
Gamma Glutamyl Transferase
GINA
Global Initiative for Asthma
hCG
Human Chorionic Gonadotropin
IB
Investigator Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IN
Investigator Notification
IUD
Intrauterine device
IUS
Intrauterine system


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i.v.
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long Acting Beta-2 Agonist
LAMA
Long acting muscarinic antagonist
LFT
Liver function test 
MF
Mometasone furoate
MedDRA
Medical dictionary for regulatory activities 
NYHA
New York Heart Association
OC/RDC
Oracle Clinical/Remote Data Capture 
o.d.
once a day
PD
Pharmacodynamics
PEF
Peak Expiratory Flow
PPS
Per Protocol Set
p.o.
oral(ly)
QT
QT Interval (measure between Q wave and T wave in the heart's electrical cycle)
QTcF0
QT interval Fridericia's Correction Formula
RBC
Red Blood Cells
SABA
Short Acting beta-2 agonist
SAE
Serious Adverse Event
SAMA
Short acting muscarinic antagonist
SAP
Statistical Analysis Plan
SDDPI
Single Dose Dry Powder Inhaler
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum glutamic-pyruvic transaminase
SmPC
Summary of Product Characteristics
SNRI
Serotonin Noradrenaline Reuptake Inhibitors
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
US
United States
WBC
White Blood Cells
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort
A specific group of patients/subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the patient in a time unit (eg 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects
with established disease and in those with newly-diagnosed disease.
Patient/subject ID
A unique number assigned to each patient upon signing the informed 
consent 
Randomization number
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
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Protocol summary
Protocol number
CQVM149B2204
Title
A multicenter, randomized, double-blind, placebo-controlled 3-period 
complete cross-over study to assess the bronchodilator effects and safety 
of glycopyrronium bromide (NVA237) (25 µg and 50 µg o.d.) in asthma 
patients
Brief title
Bronchodilator effects and safety of glycopyrronium bromide (25 µg and 50 
µg o.d.) in asthma
Sponsor and
Clinical Phase
Novartis
Phase IIb
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this trial is to characterize the bronchodilator effects and 
safety of 25 µg and 50 µg o.d. glycopyrronium bromide doses compared to 
placebo in asthma
Primary Objective(s) 
Evaluate the bronchodilator effects of each dose of NVA237 (25 µg and 50 
µg o.d.) compared with placebo in terms of trough FEV1 after 1 week of 
treatment
Secondary Objectives
Evaluate the bronchodilator effects of each dose of NVA237 (25 μg and 50 
μg o.d.) compared with placebo in terms of:
●
Standardized FEV1 AUC after 1 week of treatment
●
Peak FEV1 after 1 week of treatment
●
FEV1, Forced Vital Capacity (FVC) and FEV1/FVC ratio after 1 week of
treatment
●
Safety and tolerability of each dose of NVA237 (25 μg and 50 μg o.d.) in
the respective period
To evaluate the effects of each dose of NVA237 (25 μg and 50 μg o.d.)
compared with placebo as determined by patient diary data and electronic
PEF meter in terms of:
●
Rescue medication usage over 1 week of treatment
●
Daily morning (pre-medication) and evening peak expiratory flow rate
(PEF) over 1 week of treatment
Study design
6 week randomized; double blind; placebo controlled; cross-over
Population
The study population will consist of approximately 144 male and female 
patients aged between 18 and 65 years with asthma
Key Inclusion criteria
●
Male and female adult patients aged ≥ 18 to ≤ 65 years
●
Patients with a diagnosis of asthma for a period of at least 1 year
receiving daily treatment of ICS/LABA in a stable regimen for ≥ 4 weeks.
●
Pre-bronchodilator FEV1 of ≥ 50% and ≤ 80% of the predicted normal
value and an increase in FEV1 of ≥ 12% and ≥ 200 mLs during reversibility
testing.


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Key Exclusion criteria
●
Patients who have had an asthma exacerbation that required either
treatment with systemic corticosteroids for at least 3 days, or an emergency
room visit, or hospital treatment within 6 weeks prior to screening Visit 1
and patients with a history of life-threatening asthma attacks (e.g. attacks
requiring ventilation)
●
Patients who have had a respiratory tract infection within 4 weeks prior
to screening.
●
Patients who have smoked or inhaled tobacco products within the past
6 month of screening.
●
Patients with a history of chronic lung diseases other than asthma,
including (but not limited to) chronic obstructive pulmonary disease,
bronchiectasis, sarcoidosis, interstitial lung disease, cystic fibrosis, and
tuberculosis (unless tuberculosis is confirmed as no longer active by
imaging).
●
Patients on Maintenance Immunotherapy (desensitization) for allergies
for at least 3 months prior to Run-in who are expected to change therapy
throughout the course of the study.
●
Patients who during the Run-in period are shown to be intolerable to
LABA withdrawal.
●
Patients who have discontinued LAMA therapy in the past (e.g. due to
intolerance or perceived lack of efficacy).
Study treatment
Glycopyrronium bromide (NVA237) (25 µg and 50 µg o.d.) and placebo
Efficacy assessments
Spirometry
PEF recorded in the electronic diary
Rescue medication usage recorded in the electronic diary
Key safety 
assessments
Vital signs
Hematology, Blood chemistry, Urinalysis
Electrocardiogram
Adverse Events
Pregnancy Test (female patients)
Data analysis
The primary endpoint is the trough FEV1 (mL) after 1 week of treatment 
defined as the mean of the two FEV1 values measured at 23 h 15 min and 
23 h 45 min post-dose.
The following hypotheses will be tested for each of NVA237 doses versus 
placebo separately:
H10: There is no difference between NVA237 50 µg and placebo treatment 
groups in term of the trough FEV1 after 1 week of treatment
H1a: There is a difference between NVA237 50 µg and placebo treatment 
groups in term of the trough FEV1 after 1 week of treatment
H20: There is no difference between NVA237 25 µg and placebo treatment 
groups in term of the trough FEV1 after 1 week of treatment
H2a: There is a difference between NVA237 25 µg and placebo treatment 
groups in term of the trough FEV1 after 1 week of treatment
The primary endpoint will be analyzed using a linear mixed-effect model. 
The model will include period, treatment, and sequence as fixed effect 
factors and baseline trough FEV1 as a covariate.
Key words
Asthma, NVA237, glycopyrronium bromide


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1
Introduction
1.1
Background 
Asthma is a chronic inflammatory disorder of the airways associated with hyper-
responsiveness of the airways that leads to recurrent episodes of wheezing, breathlessness, 
chest tightness, and coughing, particularly at night or in the early morning. These episodes are 
usually associated with widespread but variable airflow obstruction within the lungs that is 
often reversible, either spontaneously or with treatment. Airflow limitation occurs as a result 
of obstruction or narrowing of the airways when exposed to precipitating factors. Although 
exacerbations of asthma are episodic, inflammation is chronic (GINA 2015).
Despite existing therapies there is still significant unmet medical need in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years (DALYs) are lost annually due to 
asthma, representing 1% of the total global burden. It is estimated that asthma accounts for 
about one in every 250 deaths worldwide (Beasley R, 2004). 
Recently, tiotropium (Spiriva® Respimat®) has been approved in EU as an add-on 
maintenance bronchodilator treatment in adult patients (≥18 years) with asthma who are 
currently treated with the maintenance combination of inhaled corticosteroids (≥800µg 
budesonide/day or equivalent) and long-acting beta-2 agonists and who experienced one or 
more severe exacerbations in the previous year.
Following tiotropium regulatory approval in asthma, the GINA 2015 guideline recommends 
tiotropium as a new add-on option to the preferred controller choice for steps 4 and 5.
In line with these recommendations, Novartis is developing the fixed-dose combination 
QVM149 of indacaterol acetate (inhaled long-acting beta-2 agonist (LABA), with 24 hour 
duration of action), glycopyrronium bromide (inhaled long-acting muscarinic antagonist 
(LAMA), with 24 hours duration of action), and mometasone furoate (MF, ICS). QVM149 is 
intended for once daily maintenance treatment of asthma GINA step ≥4.
All three mono-components, indacaterol maleate, glycopyrronium bromide and MF have 
previously been developed as individual drugs for either COPD or asthma.
Glycopyrronium bromide (NVA237: 50 μg once daily in a lactose-based formulation) has 
been registered in the EU since 2012 as Seebri® Breezhaler® for the treatment of COPD. The 
dose is expressed as 44 μg as this is the dose (active moiety) that is delivered by the 
mouthpiece of the inhaler. Outside the EU, the dose of Seebri ® Breezhaler® is generally 
expressed as the dose of active moiety in the capsule, i.e. 50 μg and will be referred to as such 
in this protocol.
Glycopyrronium bromide 50 μg once daily has demonstrated a meaningful and statistically 
significant improvement in lung function in COPD patients which has been sustained over 24 
hours and has provided significant symptomatic benefits with a favorable safety and 
tolerability profile for up to 52 weeks in clinical trials. The fixed dose combination of 
indacaterol maleate and glycopyrronium bromide is also registered in the EU as Ultibro®, 


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Breezhaler® (QVA149) with the same and equivalent dose of glycopyrronium and indacaterol, 
respectively, as proposed for QVM149.
Previous studies with NVA237 were performed in COPD patient population and currently 
there is no data available on NVA237 efficacy and safety in patients with asthma. 
1.2
Purpose 
The purpose of this trial is to characterize the bronchodilator effects and safety of two doses 
(25 µg and 50 µg o.d.) of glycopyrronium bromide (NVA237) compared to placebo in asthma 
patients.
2
Study objectives and endpoints
2.1
Primary objective
To evaluate the bronchodilator effects of NVA237 delivered by the Concept1 single-dose dry-
powder inhaler in patients with asthma in terms of trough FEV1 (mean of 23 h 15 min and 23
h 45 min post-dose) following 1 week of treatment, by comparing NVA237 at a dose of 25 µg
and 50 μg o.d. with placebo.
2.2
Secondary objective(s)
To evaluate the bronchodilator effects of each dose of NVA237 (25 μg and 50 μg o.d.) 
compared with placebo in terms of:

Standardized FEV1 AUC (5 min - 1 h), (5 min - 4 h), and (5 min – 23 h 45 min) after 1
week of treatment in the respective period.

Peak FEV1 after 1 week of treatment in the respective period during 5 min to 4 h post-dose.

FEV1, Forced Vital Capacity (FVC) and FEV1/FVC ratio at all spirometry time-points
after 1 week of treatment in the respective period.

Safety and tolerability of each dose of NVA237 (25 µg and 50 μg o.d.) in the respective
period (laboratory tests, vital signs, ECG and adverse events).
To evaluate the bronchodilator effects of each dose of NVA237 (25 μg and 50 μg o.d.) 
compared with placebo as determined by patient diary data and electronic PEF meter in the 
respective period in terms of:

Rescue medication usage over 1 week of treatment

Daily morning (pre-medication) and evening peak expiratory flow rate (PEF) over 1 week
of treatment.


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3
Investigational plan
3.1
Study design
This study uses a randomized, double-blind, placebo controlled, 3-period cross-over clinical 
trial design. During a screening epoch patient eligibility will be assessed. The screening epoch 
will be followed by a 21-day Run-in epoch during which patients will continue ICS use but be 
withdrawn from LABA-treatment and switched to short-acting bronchodilator-rescue 
medication. 
After the Run-in period patients will be randomized to one of the 6 treatment sequences and 
enter the first 7-day study treatment period. 
Treatment period one is followed by a 10-day washout period after which patients begin the 
second 7-day treatment period which is then followed by a second 10-day washout period 
followed by the third 7-day treatment period. At the end of each treatment period spirometry 
will be performed to assess the primary endpoint. Procedures in treatment periods two and 
three mirror-image the procedures of treatment period one. 
Figure 3-1
Study design 
Each of the six treatment arms consists of three treatment periods:
Sequence 1: A-B-C Sequence 3: B-A-C Sequence 5: C-A-B 
Sequence 2: A-C-B Sequence 4: B-C-A Sequence 6: C-B-A
NVA 50 µg = A: NVA 25 µg = B: Placebo = C
Screening
Run In
Treatment 
Period 1
Wash out Period 
1
Treatment 
Period 2
Wash out 
Period 2
Treatment 
Period 3
Study 
Completion 
Visit
Treatment Sequences
A
B
C
Sequence 1
A
C
B
Sequence 2
B
A
C
Sequence 3
B
C
A
Sequence 4
C
A
B
Sequence 5
C
B
A
Sequence 6
-28 days 
to -21 
days
-21
to 0 
days
7 days
10 days
7 days
10 days
7 days 
1 day after 
last study
dose
ICS background / Rescue Medication


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3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.
This short-term treatment cross-over design is chosen to characterize lung function effects of 
two doses of once daily NVA237 (50 µg and 25 µg) compared to placebo in patients with 
asthma. To achieve optimal study adherence in the population of asthma patients there will be 
a 21-day Run-in period during which patients will be using short-acting rescue medication 
and ICS, but no LABA. This Run-in period will ensure that patients who cannot tolerate 
withdrawal from LABA during this period (e.g.: rescue medication use of more than five 
puffs on average per day) and therefore not expected to tolerate withdrawal for the entire 
duration of the trial will not be randomized.
The cross-over design (rather than a parallel group design) was chosen because within patient 
variability is expected to be less than between-subject variability for the assessed parameters. 
This allows for greater precision to be achieved whilst exposing a smaller number of patients 
to study treatment and assessments. In addition, the PD characteristics of NVA237, e.g. fast 
onset of bronchodilatory action and early plateauing of bronchodilatory action, approximately 
within the first 7 days of dosing, allow for a short study duration which also favors the use of 
a cross-over study design
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Glycopyrronium bromide (NVA237: 50 μg once daily in a lactose-based formulation) has 
been registered in the EU since 2012 as Seebri® Breezhaler® for the treatment of COPD.
The glycopyrronium doses that are being evaluated in this trial are based on the experience 
and dose ranging with glycopyrronium in COPD and the available data of LAMAs, in 
particular tiotropium, in asthma. The most relevant patient population in this context currently 
comprises patients with severe asthma. 
NVA237 50 μg once daily is supported by Phase II dose-ranging studies in COPD patients. 
Study NVA237A2205 evaluated NVA237 once daily in doses ranging from 12.5 μg o.d. to 
100 μg o.d. (active moiety in the capsule) in COPD patients and demonstrated dose-dependent 
increases in trough FEV1 at doses of and above 50 μg o.d. However, there was little difference 
in efficacy between 50 μg o.d. and 100 μg o.d. doses. Evidence from study NVA237A2208 
supported the results of NVA237A2205. In study NVA237A2208, the NVA237 50 µg o.d. 
dose provided clinically relevant improvements in FEV1 and was found to be safe and well 
tolerated in COPD patients. Phase III data from the NVA237 clinical program in COPD 
demonstrated efficacy of inhaled glycopyrronium bromide 50 μg o.d. which was superior to 
placebo and comparable to that observed with tiotropium 18 μg administered via the 
Handihaler®. Tiotropium administered via Handihaler® is considered well-comparable to 
Tiotropium Respimat® 5 µg which is approved for the asthma indication.
Based on recent literature (Kerstjens et al, 2012, Kerstjens et al, 2015, Peters SP et al 2010 ) 
supporting the efficacy of tiotropium in patients with severe asthma at the same doses used in 
COPD, it is expected that glycopyrronium bromide 50 μg once daily will provide similar 
bronchodilator effects in an asthma population that are comparable to those observed in 


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patients with COPD. Data with tiotropium Respimat® in patients with mild to moderate 
asthma may suggest that a lower dose (2.5 μg) of tiotropium can elicit bronchodilation in this 
milder patient population that is at least as good as a higher dose (5μg) (Chin et al,2016). 
In this study in asthma patients on low, mid and high dose ICS/LABA combination, 
glycopyrronium bromide at doses of 50 μg once daily and 25 μg once daily will be evaluated 
in comparison to placebo (on top of background ICS therapy). Since patients with asthma are 
typically younger and usually do not have co-morbid conditions than those observed with 
COPD, it is expected that NVA237 will also have an acceptable safety profile in asthmatic 
patients. 
In conclusion, 50 μg o.d. was selected as the high dose to be explored in the present study 
with the 25 μg o.d. dose also to be assessed to characterize the respective bronchodilator 
effects of these doses compared to placebo (on top of background ICS therapy) in moderate to 
severe asthma patients.
Budesonide is the selected background ICS therapy to ensure a standardization of patient 
treatment during the conduct of the study.
A one-week study duration is considered sufficient to investigate lung-function effects of 
NVA237 based on data from study NVA237A2205 in which there were clinically meaningful 
improvements in spirometric measurements after one-week of treatment. In study 
NVA237A2208 which investigated lung function over 28 days, FEV1 was improved on all 
assessment days compared to placebo (Day 1, Day 14, Day 28; no assessments on Day 7). As 
the totality of data in COPD patients suggests that no substantial further increase in lung 
function is observed after 7 days of treatment, a7 day treatment duration is also considered 
appropriate for the asthma indication.
The washout period between the two treatment periods is 10 days (but may be extended to a 
maximum of 14 days to allow for some flexibility for visit attendance). Based on 24 hour 
spirometry data, the half-life of the bronchodilatory effect of NVA237 is estimated to be ≤80 
hours. Therefore the bronchodilatory effect is expected to be washed-out following 17 days 
after last dose administration. Consequently, the proposed minimum 10 days of washout plus 
1 week of treatment in the next following treatment period are sufficient to avoid a carry-over 
pharmacodynamic effect between treatment periods.
3.4
Rationale for choice of comparator
To characterize the bronchodilator effects of 50 µg and 25 µg doses of NVA237 once daily, a 
comparison will be made between the different NVA237 doses vs. placebo, when added to 
background ICS therapy. A placebo arm will add rigor and reduce bias in assessing the study 
endpoints. It should be noted that at no point in the study will patients be receiving placebo 
only, it will always be administered in addition to background ICS, and patients will always 
be provided with rescue medication (short-acting beta-2 agonists, (SABA), such as 
salbutamol/albuterol) to control symptoms. Patients will be required to abstain from using 
SABA rescue medication within the 6 hours of spirometric assessments to maintain the 
scientific integrity related to the determination of the primary endpoint.


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3.5
Purpose and timing of interim analyses/design adaptations
Not applicable
3.6
Risks and benefits 
The risks to which patients participating in this study will be exposed may be divided into 
those associated with the conduct of the study itself, and those associated with the 
investigational treatment, NVA237.
Patients will be required to perform repetitive lung function measurements during the study, 
and these can lead to cough, shortness of breath, dizziness, or exhaustion. Since patients only 
carry out full forced maneuvers during clinic visits (not at home), these will be performed 
under medical supervision to ensure availability of immediate aid if required. Considering the 
1 week treatment duration, the number of assessments is small and these are part of the 
regular medical assessments of this patient population. Other procedural risks are related to 
blood sampling for safety laboratory. Puncturing of the veins can cause discomfort, pain, 
hematoma, or in rare cases lead to an infection.
NVA237 50 µg dose is registered in EU since 2012 as Seebri® Breezhaler® for the treatment 
of COPD.
The risks of side effects from NVA237 are similar to other anticholinergics such as tiotropium. 
The most common (≥1/100 to < 1/10) anticholinergic side effect for NVA237 is dry mouth. 
Other common adverse drug reactions reported with NVA237 in COPD patients include 
insomnia and gastroenteritis. Atrial fibrillation was an uncommon (≥1/1,000 to < 1/100), but 
potentially serious adverse drug reaction reported with NVA237 in patients with COPD (also 
please compare exclusion criteria in Section 4.2). Please refer to the current NVA237 
Investigator’s Brochure for more information. Adverse drug reactions reported in individual 
patients taking other anticholinergic agents include: constipation, increased heart rate, blurred 
vision, glaucoma, urinary difficulty, and urinary retention. Clinical studies in COPD patients 
so far conducted with NVA237 have not demonstrated any unexpected safety/tolerability 
issues beyond those expected for an anticholinergic medication. 
NVA237 50 µg in COPD is contraindicated in patients with a hypersensitivity to the active 
substance or to any of it excipients. Therefore, patients with a history of hypersensitivity to 
muscarinic antagonist agents, sympathomimetic amines, adrenoreceptor agonist agents, 
lactose or any of the other excipients of the study drug, or corticosteroids are excluded from 
participation in this study. 
Other “Special warnings and precautions” listed in the Seebri® Breezhaler® EU SmPC are 
also accounted for in the protocol. Patients with conditions that may be worsened by 
anticholinergic agents, including narrow-angle glaucoma, urinary retention, or severe renal 
impairment are excluded from the study along with patients with a history of cardiovascular 
diseases, history of paradoxical bronchospasm, galactose intolerance, Lapp lactase deficiency 
or glucose-galactose malabsorption.
The co-administration of NVA237 with other anticholinergic–containing medicinal products 
is not recommended in the EU SmPC and therefore not allowed in the study. In addition, there 


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are no clinically relevant interactions expected between glycopyrronium and other medicinal 
products. 
Sections 4.3, 4.4, and 4.5 of the current Seebri® Breezhaler® EU SmPC can be referred to for 
additional information.
There are, however, potentially unknown risks to NVA237, which may be serious and 
unforeseen.
Altering the current asthma medication regimen of enrolled asthma patients carries a potential 
risk of de-stabilizing the patient. Patients who cannot tolerate the change in medication 
regimen are expected to be identified during the Run-in period and if deemed intolerable of 
the change in medication will not be randomized. In randomized patients the continuous 
background treatment with ICS throughout the study, the short duration of the trial and the 
provision of short-acting bronchodilator rescue medication for the entire study duration is 
considered to provide sufficient risk mitigation for the patients. Regular contacts will occur in 
terms of clinic visits and telephone contacts to each patient. In addition, safety monitoring (e.g. 
rescue medication use via electronic diary), assessment of compliance with the study 
medication regimen and daily PEF measurements throughout the study will help to assess the 
status of the patient’s asthma symptom control. Therefore, investigators may have an early 
indication of worsening symptoms and will be able to monitor the patient closely throughout 
the study.
During the study, patients will continue using inhaled corticosteroids and may use their 
provided rescue medication (short-acting beta-2agonists, provided at the end of Visit 1) until a 
window of 6 hours before any spirometric assessment.
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
(inclusion/exclusion criteria, see Sections 4.1 and 4.2) and close clinical monitoring. In 
addition, investigators can withdraw a patient if they feel, based on their medical judgment, 
that this would be in the best interest of the patient. Patients are also instructed that they can 
withdraw from the trial at any time, and for any reason. 
The potential individual benefit for the patient lies in a thorough medical evaluation of the 
patient’s disease and close clinical monitoring for the duration of the study. This is a research 
study and although lung function may improve compared to ICS treatment alone it is not 
expected to provide a significant medical benefit in this short-term study
4
Population
The study population will consist of approximately 144 male and female patients aged 
between 18 and 65 years with asthma who have been treated in a stable regimen of 
ICS/LABA for at least 4 weeks prior to screening.
It is anticipated that at least 215 patients will need to be screened (assuming a screening 
failure rate of 33%) in order to randomize approximately 144 patients. It is intended that 
approximately 115 patients will complete the study. Dropouts will not be replaced. The study 
will be a multinational multi-center study.


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4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1.
Written informed consent must be obtained before any assessment is performed.
2.
Male and female adult patients aged ≥ 18 to ≤ 65 years
3.
Patients with a documented physician diagnosis of asthma for a period of at least 1 year
prior to screening, receiving daily treatment of ICS/LABA in a stable regimen for ≥ 4
weeks prior to screening.
4.
Pre-bronchodilator FEV1 of ≥ 50% and ≤ 80% of the predicted normal value for the
patient after withholding bronchodilators in accordance with Table 5-2 at Visit 101 and
confirmed after Run-in period at Visit 102.

Withholding period of bronchodilators prior to spirometry: SABA for ≥ 6 hours and
fixed-dose or free combinations of ICS*/LABA for ≥ 48 hours if with b.i.d. LABAs
and ≥ 7 days if with o.d. LABAs, SAMA for ≥ 8 hours, LAMA for ≥ 7 days,
theophylline for ≥ 7 days
* ICS must be continued.

A one-time re-testing is allowed only at Visit 101. Re-assessment of percentage
predicted FEV1 should be done in an ad-hoc visit to be scheduled on a date that would
provide sufficient time to receive confirmation from the spirometry data central
reviewer of the validity of the assessment before randomization.
5.
Patients who demonstrate an increase in FEV1 of ≥ 12% and ≥ 200 mLs within 30
minutes after inhalation of 400 µg salbutamol/360 µg albuterol during reversibility
testing at Visit 101 before entering the Run-in period. Spacer devices are not permitted
during reversibility testing.

A one-time re-testing is allowed. Re-assessment of reversibility should be done in an
ad-hoc visit to be scheduled on a date that would provide sufficient time to receive
confirmation from the spirometry data central reviewer of the validity of the
assessment before randomization.
4.2
Exclusion criteria
Patients/subjects fulfilling any of the following criteria are not eligible for inclusion in this 
study. No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients/subjects.
1.
Contraindicated for treatment with, or having a history of reactions/hypersensitivity to
any of the following inhaled drugs, drugs of a similar class, or any component thereof.

Muscarinic antagonist agents

Sympathomimetic amines/adrenoreceptor agonist agents

Lactose or any of the other excipients of the study drug (including patients with
history of galactose intolerance, Lapp lactase deficiency or glucose-galactose
malabsorption)


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
Corticosteroids
2.
History or current diagnosis of the following ECG abnormalities:

Clinically significant cardiac arrhythmias (for example sustained ventricular
tachycardia, and second or third degree AV block)

History of familial long QT syndrome or known family history of Torsades de Pointes

Paroxysmal (e.g., intermittent) atrial fibrillation.

Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for
at least 6 months and controlled with a rate control strategy (i.e., selective beta
blockers, calcium channel blocker, pacemaker placement, digoxin or ablation therapy)
for at least 6 months may be considered for inclusion. In such patients, atrial
fibrillation must be present at Visit 101 with a resting ventricular rate < 100/min.
3.
Resting QTcF ≥450 ms (male) or ≥460 ms (female) at Visit 101.
4.
History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in situ cervical cancer), treated or untreated, within the past 5 years,
regardless of whether there is evidence of local recurrence or metastases.
5.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive
hCG laboratory test.
6.
Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 30 days after stopping of study medication. Highly effective
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking
investigational drug. In case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the
study, the vasectomized male partner should be the sole partner for that subject

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure
rate <1%), for example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child-bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow-up hormone level assessment is she considered not of child-bearing potential.


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7.
Patients with uncontrolled Type 1 or Type 2 diabetes.
8.
Patients who, either in the judgment of the investigator or the responsible Novartis
personnel, have a clinically significant condition such as (but not limited to) unstable
ischemic heart disease, NYHA Class III/IV heart failure, clinically relevant arrhythmia
with exception of rate-controlled persistent atrial fibrillation, uncontrolled hypertension,
cerebrovascular disease, neurodegenerative diseases, or other neurological disease,
uncontrolled hypo- and hyperthyroidism and other autoimmune diseases, hypokalemia,
hyperadrenergic state, or ophthalmologic disorder or patients with a medical condition
that might compromise patient safety or compliance, interfere with evaluation, or
preclude completion of the study.
9.
Patients with a history of myocardial infarction within the previous 12 months.
10. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or
bladder-neck obstruction or moderate to severe renal impairment or urinary retention
(BPH patients who are stable on treatment can be considered).
11. Patients who have had an asthma exacerbation that required either treatment with
systemic corticosteroids for at least 3 days, or an emergency room visit, or hospital
treatment within 6 weeks prior to screening Visit 1 and patients with a history of life-
threatening asthma attacks (e.g. attacks requiring ventilation)
12. Patients who develop an asthma attack/exacerbation between screening and prior to
study drug treatment will not be eligible but may be permitted to be re-screened after a
minimum of 6 weeks after the resolution of the asthma exacerbation.
13. Patients who have had a respiratory tract infection within 4 weeks prior to screening.
14. Patients who develop a respiratory tract infection between screening and prior to study
drug treatment will not be eligible, but may be permitted to be re-screened 4 weeks after
the resolution of the respiratory tract infection.
15. Patients who have smoked or inhaled tobacco products (including electronic cigarettes)
within the 6 month period prior to screening, or who have a smoking history of greater
than 10 pack years (Note: 10 pack years = 1 pack /day x 10 yrs., or one-half pack/day x
20 yrs.).
16. Patients with any chronic conditions affecting the upper respiratory tract (eg. chronic
sinusitis) which in the opinion of the investigator may interfere with the study evaluation
or optimal participation in the study.
17. Patients with a history of chronic lung diseases other than asthma, including (but not
limited to) chronic obstructive pulmonary disease, bronchiectasis, sarcoidosis, interstitial
lung disease, cystic fibrosis, and tuberculosis (unless tuberculosis is confirmed as no
longer active by imaging).
18. Patients who have not achieved acceptable spirometry results at Run-in in accordance
with ATS/ERS criteria for acceptability and repeatability.
19. Patients receiving any medications in the classes listed in Table 5-3 unless the
medication has been stabilized for the specified period and the stated conditions have
been met.
20. Patients receiving any asthma related medications in the classes specified in Table 5-2
unless they undergo the required washout period prior to Visit 101 and follow the
adjustment to treatment program.


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21. Patients on Maintenance Immunotherapy (desensitization) for allergies for at least 3
months prior to Run-in who are expected to change therapy throughout the course of the
study.
22. Patients unable to use a dry powder inhaler device.
23. Patients with a known history of non-compliance to medication or who are unable or
unwilling to complete a patient diary or who are unable or unwilling to use the Electronic
Peak Flow meter.
24. Use of other investigational drugs within 30 days of Visit 101 or 5 half-lives whichever
is longer.
25. Patients who during the Run-in period are shown to be intolerable to LABA withdrawal
as assessed by investigator (based on patient diary data, PEF during the Run-in period;
clinical judgement) or by patient self-assessment
26. History of paradoxical bronchospasm in response to inhaled medicines.
27. Patients who have discontinued LAMA therapy in the past (e.g. due to intolerance or
perceived lack of efficacy).
28. Patients in whom the absolute variability in pre-bronchodilator FEV1 between Visits 101
and 102 is > 20%.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs

NVA237 50 µg capsules for inhalation, delivered via Concept1

NVA237 25 µg capsules for inhalation, delivered via Concept1

Placebo capsules for inhalation, delivered via Concept1
NVA237 and matching placebo will be provided as powder filled capsules with a Concept1 
inhalation device. 
Under no circumstances is an alternative inhalation device to be used for the administration of 
NVA237 or placebo capsules during the treatment period.
Both NVA237 and placebo will be supplied by Novartis Drug Supply Management in blister 
packs, providing sufficient quantity of medication to last each patient between visits.
5.1.2
Additional treatment
All patients will be required to have been on a stable ICS/LABA treatment regimen for at 
least 4 weeks prior to screening. Patients will be switched prior to the start of the Run-in 
period to the following ICS mono treatment regimen:

Patients on a low dose of ICS at screening will be switched to an equivalent low dose of
budesonide

Patients on a mid dose of ICS at screening will be switched to an equivalent mid dose of
budesonide


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
Patients on a high dose of ICS at screening will be switched to an equivalent high dose of
budesonide
Any long-acting bronchodilators will be withdrawn during the screening period and patients 
will receive SABA as rescue medication throughout the trial.
Patients will be instructed not to take any rescue medication within 6 hours prior to any 
spirometric assessment if possible. If a patient has to use rescue medication within 6 hours 
prior to any spirometric assessment, the visit has to be rescheduled.
5.2
Treatment arms
Patients will be assigned to one of the following six treatment arms in a ratio of 1:1:1:1:1:1, 
expecting 24 patients allocated to each of the treatment arms. Each treatment arm consists of 3 
treatment periods during which study drug will be administered in the sequence as laid forth 
in Table 5-1
Table 5-1
Treatment arms
Treatment arms
Treatment sequence description 
Period 1
Period 2
Period 3
1
A
B
C
2
A
C
B
3
B
A
C
4
B
C
A
5
C
A
B
6
C
B
A
NVA237 50 µg o.d. is denoted as treatment A
NVA237 25 µg o.d. is denoted as treatment B
Placebo is denoted as treatment C
In this cross-over trial all patients will receive the three study medications in one of the given 
arms.
All study treatments will be assigned according to the corresponding treatment sequence 
whilst the patient receives ICS background therapy. 
5.3
Treatment assignment and randomization 
At Visit 201 all eligible patients/subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will 
contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the 
patient to a treatment arm and will specify a unique medication number for the first package 
of study drug to be dispensed to the patient. The randomization number will not be 
communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 


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that automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under
the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group. 
5.4
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blinded to the identity of the treatment from the time of randomization until database lock, 
using the following methods: 

Randomization data are kept strictly confidential until the time of unblinding, and will not
be accessible by anyone else involved in the study.

The identity of the treatments will be concealed by the use of study drugs that are all
identical in packaging, labeling, schedule of administration and appearance.

Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at
the conclusion of the study.
Any patient whose treatment code has been broken inadvertently or for any emergency-related 
or non-emergency reason will be discontinued from the study
5.5
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site mus t 
select the CRF book with a matching Subject Number from the EDC system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
epoch Study Disposition CRF
5.5.2
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to the specific drug contained in that study drug 


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packaging. Investigator staff will identify the study drug package(s) to dispense to the patient 
by contacting the IRT and obtaining the medication number(s). Immediately before 
dispensing the package to the patient, investigator staff will detach the outer part of the label 
from the packaging and affix it to the source document (Drug Label Form) for that patient’s 
unique subject number.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.3.2
Handling of additional treatment 
The following non-investigational treatment will be monitored as follows:
The non-investigational treatment must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designees have access. Clinical supplies are to be dispensed only in 
accordance with the protocol.
The investigator must maintain an accurate record of the shipment and dispensing of the non-
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits or remotely and at the completion of the trial. 
Patients will be asked to return all unused non-investigational treatment and packaging at the 
end of the study or at the time of discontinuation of investigational treatment for the rescue 
medication. 
These medications are:


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
Salbutamol (100 µg) or albuterol (90 µg) used as rescue medication from Visit 1 to Visit
403

Budesonide for ICS dose standardization if needed from Visit 1 to Visit 403
Details will be described in the CRF completion guidelines.
5.5.4
Instructions for prescribing and taking study treatment 
Patients will be provided with medication as described in Section 5.1.
At Visit 1 all patients will be instructed how to use an inhaler to administer rescue 
salbutamol/albuterol and ICS (if applicable) correctly. Patients will also be trained how to use
the e-diary at Visit 1 and the peak flow meter at Visit 101. At Visit 102 all patients will be 
fully trained in the correct use of the Concept1 inhaler devices used to administer study 
medication. Patients who are unable to use either device correctly at Visit 102 will not be 
eligible to enter the treatment epoch. Additional training devices will be supplied for 
demonstration purposes. At clinic visits the investigator should check the patient’s use of the 
inhalational devices to ensure correct use of each device. If required, further device training 
should be provided. Patients will be instructed to contact the site if the device is not 
functioning properly.
It is important that patients be instructed to take their dose of study medication at 
approximately the same time every morning. 
Instructions for use of the Concept1 inhaler are provided in Appendix 2.
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be ins tructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Investigational or other treatment dose adjustments and/or interruptions are not permitted 
However if a dose interruption occurs the patient will not be discontinued from the study.
5.5.6
Rescue medication
At Visit 1, all patients will be provided with a short-acting beta-2 agonist (100 μg 
salbutamol/90 μg albuterol) and they will be instructed to use it throughout the study as rescue 
medication on an ‘as needed basis’. Patients will be advised that between visits they can take 
their rescue medication for symptoms of intercurrent bronchospasm. Nebulized salbutamol is 
not allowed as rescue medication throughout the entire trial. No other rescue treatment is 
permitted.
In order to standardize measurements, patients will be instructed to abstain from taking rescue 
medication (salbutamol) within 6 hours of the start of each visit where spirometry is being 
performed unless absolutely necessary. If rescue medication is taken within 6 h prior to 
spirometry assessments, then the visit should be rescheduled to the next day if possible. 


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Bronchodilator medications that the patients used prior to Visit 1 must be recorded in the 
asthma-related prior/concurrent medication page of the eCRF, with the stop date for these 
bronchodilators recorded as the date of Visit 1. The rescue salbutamol/albuterol provided at 
Visit 1 for use during the study should NOT be recorded on the asthma-related 
prior/concurrent medication page of the eCRF. From Visit 1, daily use of rescue medication 
will be recorded by the patient in their electronic diary.
The rescue salbutamol/albuterol will be provided to the patients by the study center and 
reimbursed locally by Novartis or supplied to the investigator sites locally by Novartis
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications/significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-2 and Table 5-3 is NOT allowed after screening 
(unless for the treatment of asthma exacerbations). The specified minimum washout periods 
prior to the Run-in epoch (Visit 101) or visit 1 are described. Each concomitant drug must be 
individually assessed against all exclusion criteria and the tables below to see if it is allowed. 
If in doubt the investigator should contact the Novartis medical monitor before randomizing a 
patient or allowing a new medication to be started.
Table 5-2
Prohibited asthma related medication
Medication2
Minimum cessation period prior to Visit 1 or Run in (Visit 101)
Long-acting anticholinergics 
(LAMA)
7 days prior to Run-in (Visit 101). All patients will be provided with 
SABA at Visit 1 for use throughout the study. 
Short acting anticholinergics 
(SAMA) 
8 hours prior to Run-in (Visit 101). 
Fixed combinations of β2-
agonists and inhaled 
corticosteroids
Must be discontinued ≥48 hours prior to Run-in (Visit 101) if with 
LABAs b.i.d. and for 7 days if with LABAs o.d.
Patients can continue with an ICS until Visit 101 when patients will 
be switched to their corresponding ICS dose for run-in. 
Inhaled corticosteroids
All patients must be treated for asthma with a corresponding dose 
of budesonide throughout the trial. Any other ICS must be 
discontinued prior to Run-In (Visit 101)
Fixed combinations of short-
acting β2-agonist and short-
acting anticholinergic
Must be discontinued 8 hours prior to Run-in (Visit 101).


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Medication2
Minimum cessation period prior to Visit 1 or Run in (Visit 101)
Leukotriene Antagonist and 
leukotriene synthesis inhibitors
7 days prior to Run-in (Visit 101)
Long-acting β2-agonists (LABAs) 
LABAs b.i.d. must be discontinued 48 hours prior to Run-in (Visit 
101). LABAs o.d. must be discontinued ≥7 days prior to reversibility 
testing. All patients will be provided with SABA at Visit 1 for use 
throughout the study. 
Salbutamol/albuterol (SABA) 
provided at Visit 1 and 
throughout study as required for 
rescue medication prn1
Must be withheld 6 hours prior to any visit with a spirometric 
assessment 
Short acting β2-agonists 
(SABAs) (other than 
Salbutamol/albuterol provided at 
Visit 1 for rescue medication)
Must be discontinued at Visit 1 and are not permitted during the 
study
Parenteral or oral corticosteroids 
(systemic corticosteroids are 
permitted for the treatment of 
asthma exacerbations)
4 weeks prior to Run-in (Visit 101)
Intra-muscular depot 
corticosteroids
3 months prior to Run-in (Visit 101)
IgE inhibitors (e.g., omalizumab
4 months prior to Run-in (Visit 101)
Monoclonal antibodies /other 
biologics for treatment of asthma
4 months prior to Run-in (Visit 101)
Xanthines (e.g Theophylline)
7 days prior to Run-in (Visit 101)
Systemic mast cell stabilizers 
e.g cromoglycate, nedocromil,
ketotifen
7 days prior to Run-in (Visit 101)
Mucolytic agents not containing 
bronchodilators
Prohibited unless has been stabilized for at least 4 weeks prior to 
Visit 1 and will be continued at a stable dose throughout the trial
Intranasal corticosteroids
Prohibited unless taken at a Stable dose for at least 30 days prior 
to Visit 101
In the case of prn, use is permitted providing an established 
pattern of
use has been documented.
Antihistamines
Prohibited unless has been stabilized for at least 4 weeks prior to 
Visit 1 and will be continued at a stable dose throughout the trial'
1 SABA (salbutamol/albuterol rescue medication) should be withheld for at least 6 hours prior to 
spirometry measurements at clinic visits. Clinic visits may be rescheduled to the next day if rescue 
medication were taken less than 6 hours prior to the spirometry assessments
2 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.


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Table 5-3 
Other Prohibited medication
Medication
Minimum cessation period prior to Run-in (Visit 
101) or as indicated
Non-potassium sparing diuretics (unless
administered as a fixed-dose combination with 
a potassium conserving drug)
7 days prior to Run-in (Visit 101)
Non-selective systemic β–blocking agents
7 days prior to Run-in (Visit 101)
Cardiac anti-arrhythmics Class Ia
7 days prior to Run-in (Visit 101)
Cardiac anti-arrhythmics Class III
7 days, amiodarone 3 months prior to Run-in (Visit 
101)
All antipsychotic agents (first, second and third 
generation, inclusive of atypical
antipsychotics). Combinations of antipsychotic 
agents with antidepressants are prohibited
14 days prior to Run-in (Visit 101)
Serotonin Noradrenaline Reuptake Inhibitors
(SNRIs)
14 days prior to Run-in (Visit 101)
Monoamine-oxidase inhibitors
14 days prior to Run-in (Visit 101)
Systemic anticholinergics
7 days prior to Run-in (Visit 101)
Strong inhibitors of cytochrome P4503A 
e.g.ketoconazole
7 days prior to Run-in (Visit 101)
Tricyclic antidepressants (Please note that
tetracyclics which are similar in class with
regards to drug interaction are also to be
excluded)
14 days prior to Run-in (Visit 101)
Other investigational drugs
30 days or 5 half-lives, whichever is longer prior to 
Run-In (Visit 101)
Noradrenaline reuptake inhibitors
7 days prior to Run-in (Visit 101)
Live attenuated vaccine
30 days prior to Run-in (Visit 101)
Topical corticosteroids for treatment of eczema
Prohibited unless used at recommended doses and 
dosage regimens
Inactivated influenza vaccination, 
pneumococcal vaccination or any other 
inactivated vaccine
Not administered within 48 hours prior to a study 
visit
Pure selective Serotonin Reuptake Inhibitors 
Prohibited unless has been stabilized for at least 4 
weeks prior to Visit 1 and will be continued at a 
stable dose throughout the trial
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 


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will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT code break at any time in case of emergency. The investigator will 
provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un -
blinding can be performed at any time. 
After an emergency break the patient will not continue in the study.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment 
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol (Visit 403)
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the patient or the investigator. 
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation.
Study treatment must be discontinued under the following circumstances: 

Patient wish

Pregnancy (see Section 6.5.6 and 7.6 )

Use of prohibited treatment as per recommendations in Table 5-2 and Table 5-3

Any situation in which study participation might result in a safety risk to the patient

Patient experiences at least one asthma exacerbation that required treatment with systemic
corticosteroids

Any laboratory abnormalities that, in the judgment of the investigator, taking into
consideration the subject’s overall status, prevents the subject from continuing
participation in the study

Unblinding of study treatment for any reason
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should to be collected at clinic visits or via telephone visits: 

new/concomitant treatments


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
Adverse Events/Serious Adverse Events
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If a patient/investigator interrupts the treatment during a specific treatment period for other 
reasons than safety the patient can return for the next treatment period if it is considered 
adequate by the investigator.
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9.
5.6.3
Withdrawal of informed consent
Patients/subjects may voluntarily withdraw consent to participate in the study for any reason 
at any time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1.
5.6.4
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.


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5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. Patients/subjects 
who prematurely discontinue the study for any reason should be scheduled for a visit as soon 
as possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, all dispensed investigational product should be reconciled and the adverse 
event and concomitant medications reconciled on the CRF.
When the following assessments are scheduled to be performed at the same timepoint, the 
order of priority will be as follows:ECG, spirometry, vital signs and samples for 
urine/hematology/blood chemistry. Spirometry assessments will be performed such that the 
spirometry measurements occur at the scheduled timepoint and other tests subsequently as 
close as possible to scheduled timepoints. When an ECG is needed to be taken after 
spirometry, a 10 minute rest from the end of spirometry to start of ECG assessments should be 
considered.


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Table 6-1
Assessment schedule
Epoch
Screen
Run-in
Treatment (Period 1)
Treatment (Period 2)
Treatment (Period 3)
PSD**
Visit
1
101
102*
201
202
203
301
302
303
401
402
403
Day 3
-28 to -
21
-21
to 0
1
1
2 
to 
5
6
7
8
9 
to 
17
18
19 
to 
22
23
24
25
26 
to 
34
35
36 
to 
39
40
41
42
Obtain informed 
consent
x
Inclusion/Exclusion 
Criteria
x
x
x
Current Medication 
review /Adjustment
x
Medical History 
x
Demography
x
Smoking History
x
Physical Exam
S
S
S
S
S
S
S
S
Height
x
Weight
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
ECG
x
x
x
x
x
Safety Laboratory 
assessments 
(Hematology, 
Chemistry)
x
x
x
x
x
Pregnancy test 
(serum)1
x
Pregnancy test 
(urine) 1
x
x
x
x
x
Urine analysis 
(dipstick)
S
S
S
S
S


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Epoch
Screen
Run-in
Treatment (Period 1)
Treatment (Period 2)
Treatment (Period 3)
PSD**
Visit
1
101
102*
201
202
203
301
302
303
401
402
403
Day 3
-28 to -
21
-21
to 0
1
1
2 
to 
5
6
7
8
9 
to 
17
18
19 
to 
22
23
24
25
26 
to 
34
35
36 
to 
39
40
41
42
Spirometry for 
eligibility
x
x
Spirometry 
(efficacy and 
safety
assessments)
x
x
x
x
x
x
x
x
x
x
Randomization
S
Device training2
S
S
S
S
S
Provide e-Diary 
x
Provide Peak Flow 
Meter
x
Provide rescue 
medication
x
x
x
x
x
x
x
x
Study Drug 
Administration at 
site
x
x
x
x
x
x
Study Drug 
Administration by 
patient at home
x
x
x
x
x
x
Collect unused 
medication
S
S
S
S
Overnight stay
x
x
x
Telephone patient 
1 day in advance 
of visit
S
S
S
Review and 
upload e-diary 
recordings
S
S
S
S
S
S
S


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Epoch
Screen
Run-in
Treatment (Period 1)
Treatment (Period 2)
Treatment (Period 3)
PSD**
Visit
1
101
102*
201
202
203
301
302
303
401
402
403
Day 3
-28 to -
21
-21
to 0
1
1
2 
to 
5
6
7
8
9 
to 
17
18
19 
to 
22
23
24
25
26 
to 
34
35
36 
to 
39
40
41
42
AE recordings
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SAE recordings
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant 
Medication 
recordings
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Study Disposition 
(Screening)
x
Study Disposition 
(Run-in)
x
Study Disposition 
(Treatment Phase)
x
x
x
* Visit 102 and Visit 201 will be performed on the same day. Patients are required to repeat the Spirometry for eligibility prior to moving into Visit 201 Treatment.
**,PSD = Premature patient discontinuation to be performed on the same day as discontinuation/withdrawal.
S: these assessments are source documentation only and will not be entered into the eCRF.
X: these assessments are to be reported in the clinical database.
1 For females of child-bearing potential only. Additional pregnancy testing might be performed if requested by local requirements.
2 Device training at Visit 1 and/or Visit 101 is for e-diary/peak flow meter and rescue medication /ICS (if required) inhaler. Device training at Visit 102/201 is for Concept1.
The diary is an electronic device to collect information on rescue medication use and to store PEF meter measurements.
3 Day numbering described in the table of assessments is based on the minimum washout period of 10 days at each treatment period.


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6.1
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next epoch 
will have the study completion page for the screening epoch, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 

Year of birth

Age (calculated)

Gender

Race and ethnicity

Height and Weight

BMI (calculated)

Baseline physical examination (not databased other than in the context of relevant medical
history)

Vital signs

ECG

Date of diagnosis of asthma

Relevant medical history/current medical condition present before signing the informed
consent

Smoking history and status

Prior concomitant medication (asthma and non-asthma related)

Pre and post-bronchodilator spirometry (screening spirometry and reversibility testing)
6.3
Treatment exposure and compliance 
The time of study treatment administration at each clinic dosing visit (Day 1 and Day 7 of 
each treatment period) will be collected on the eCRF as well as any dosing interruptions. For 
assessments where spirometry is performed, the time of dosing is to be taken from the 
spirometer. 
Study treatment compliance should be assessed by the investigator and/or center personnel at 
all clinic visits. Where necessary, the Investigator will discuss compliance/documentation 
issues with the patient. The Investigator or designee will collect, from the patient, the 
used/unused investigational medication and packaging (unused capsules/blister strips and 
SDDPIs) at Visits 202, 302 and 402 and/or at Premature Patient Discontinuation visit if 
applicable. Study treatment compliance will be assessed from the capsule count from 
previously dispensed blister strips for the Concept1. All study treatment dispensed and 
returned must be recorded in the drug accountability log


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6.4
Efficacy
The following efficacy assessments will be performed:

Spirometry

PEF recorded in the electronic diary

Rescue Medication usage recorded in the electronic diary
6.4.1
Spirometry
The following spirometric assessments will be performed:

Forced expiratory volume in one second (FEV1)

Forced Vital Capacity (FVC)
Patients will be admitted to the center in the morning of the last treatment day of each 
treatment period and stay overnight until the next day to perform the spirometric assessments 
indicated in Table 6-2.
Site staff will ensure that for each individual patient the last dose of study medication and 
lung function assessments are done at the same hour of the respective day ( +/- one hour) 
during each treatment period.
Table 6-2
Spirometry timings in relation to study drug administration
Visit (Day) 
Spirometry (timing in relation to study drug 
administration)
Visit 201 (Day 1)
At 45 and 15 min prior to dosing
At 30 min -1 h (post dosing)
Visit 202 (Day 7)
15 min prior to dosing
5 min (post dosing)
15 min (post dosing)
30 min (post dosing)
1 h (post dosing)
2 h (post dosing)
4 h (post dosing)
8 h (post dosing)
Visit 203 (Day 8)
23 h 15 min (post dosing)
23 h 45 min (post dosing)
Visit 301 (Day 18)
At 30 min -1 h (post dosing)
Visit 302 (Day 24)
15 min prior to dosing
5 min (post dosing)
15 min (post dosing)
30 min (post dosing)
1 h (post dosing)
2 h (post dosing)
4 h (post dosing)
8 h (post dosing)


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Visit (Day) 
Spirometry (timing in relation to study drug 
administration)
Visit 303 (Day 25)
23 h 15 min (post dosing)
23 h 45 min (post dosing)
Visit 401 (Day 35)
At 30 min -1 h (post dosing)
Visit 402 (Day 41)
15 min prior to dosing
5 min (post dosing)
15 min (post dosing)
30 min (post dosing)
1 h (post dosing)
2 h (post dosing)
4 h (post dosing)
8 h (post dosing)
Visit 403 (Day 42)
23 h 15 min (post dosing)
23 h 45 min (post dosing)
Assessments in Table 6-2 are to be performed as close as possible to designated timeframes; however a ± 5 min 
window is permitted.
Trough FEV1 is defined as the mean of the two FEV measurements at 23 hr 15 min and 23 hrs 
45 min after the last dose of each treatment period.
6.4.2
Assessments in electronic diary
At visit 1 all patients will be provided with an electronic diary to record rescue medication 
(salbutamol/albuterol) use and PEF. The patients will be instructed to routinely complete the 
e-Diary twice daily at the same time in the morning (before taking the study drug) and
evening, approximately 12 hours apart. The e-Diary is to be reviewed at each clinic visit until
study completion. Sites and patients will receive appropriate training and guidance on the use
of the e-Diary device. A list of e-Diary questions is provided in Appendix 4.
6.4.2.1
Peak Expiratory Flow (PEF)
An electronic Peak Flow Meter will be given to each patient at Visit 101 for the measurement 
of the morning and the evening PEF during the screening and treatment periods.
PEF will be measured at consistent times for a patient: in the morning prior to taking study 
medication and in the evening. Patients should be encouraged to perform the measurements 
before the use of any rescue medication. At each timepoint the patient should be instructed to 
perform 3 consecutive maneuvers within 10 minutes. These PEF values are captured in the e-
Diary. The best of 3 values will be used for analysis.
6.4.2.2
Rescue medication usage
The use of rescue salbutamol/albuterol should be recorded by patients in their e-Diary twice a 
day. In the morning the patients should record the number of puffs of rescue medication they 
have taken during the night and since the last diary entry, and in the evening patients should 
record the number of puffs of rescue medication they have taken during the day since the 
morning diary entry.


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6.4.3
Appropriateness of efficacy assessments 
The efficacy assessments selected (spirometry, PEF, and recording of rescue medication 
usage) are standard for this indication/patient population.
6.5
Safety 
The following safety assessments will be performed:

Medical History and physical examination

Vital signs

Hematology, blood chemistry and urinalysis

ECG

Adverse events including serious adverse events

Pregnancy test (female patients)
Additional pregnancy testing might be performed if requested by local requirements.
6.5.1
Physical examination
A complete physical examination will include the examination of general appearance, skin,
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes,
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. Assessments will be 
performed as indicated in Table 6-1.
Information for all physical examinations must be included in the source documentation at the
study site. Significant findings that are present prior to informed consent being signed must be
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s
eCRF. Significant findings made after informed consent (Visit 1) is given which meet the
definition of an Adverse Event must be recorded on the Adverse Event screen of the patient’s
eCRF.
6.5.2
Vital signs 
Systolic and diastolic blood pressure and radial pulse rate (over a 30 seconds interval), 
performed in the sitting position will be recorded at each scheduled visits as indicated in 
Table 6-1. Vital signs should be measured after ECG assessments.
6.5.3
Height and weight 
Height and weight will be measured as indicated in Table 6-1. Body weight will be measured 
in indoor clothing, but without shoes 
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
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All patients with laboratory tests containing clinically significant abnormalities should be 
followed regularly until the values return to within the normal ranges or until a valid reason 
other than drug-related adverse experiences is identified, even after the medication has 
discontinued
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils), and platelet 
count will be measured
6.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, AST (SGOT), ALT (SGPT), bilirubin, creatinine, γ-GT, 
glucose, potassium, magnesium, BUN and uric acid will be measured.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal range, 
total bilirubin should be differentiated into the direct and indirect reacting bilirubin
6.5.4.3
Urinalysis
Urine dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments. Dipstick measurements for specific gravity, pH, protein, glucose and blood will 
be performed.
If the urine dipstick is abnormal, the sample will be sent to central laboratory for additional
testing, including assessment of WBC and RBC sediments
6.5.5
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
When the ECG recording time coincides with vital signs, spirometry and blood draws the 
ECG must be performed first, followed by vital signs and blood draws but with enough time 
planned to ensure the spirometry is performed at the planned timepoint. 
A screening ECG will be obtained to confirm eligibility for trial inclusion. At Day 1 of every 
Treatment period or early discontinuation visit, an ECG will be measured.
Single 12 lead ECGs are collected. 
For each ECG performed original traces and identical duplicate traces should be printed. Each 
ECG will be sent electronically for central review directly from the ECG machine. Two 
‘identical’ duplicate print-outs will be generated and kept at the investigator site as source 
documentation and as back-up for submission to the central laboratory in case of problems 
with the electronic transmission. Each print out will be kept at the investigator site and will be 
dated and signed. The patient's number, the date, actual time of the tracing, and Study Code 
must appear on each page of the tracing.
Full details of all procedures relating to the ECG collection and reporting will be contained in 
an investigator manual to be provided by the central laboratory to each investigator site. In the 


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event that the central cardiologist reports that an ECG is abnormal, the investigator must 
assess whether the ECG abnormality is clinically significant or not.
Clinically significant ECG findings at baseline must be discussed with the sponsor before 
administration of study treatment.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF/eCRF page as appropriate.
6.5.6
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. A 
serum and urine pregnancy test will be performed (tests provided by the Central Laboratory) 
per Assessment schedule Table 6-1. A positive pregnancy test at any time during the study 
requires the patient to be discontinued from the study treatment. Refer to Section 7.6 for more 
details. 
Additional pregnancy testing can be performed if required by local authorities
6.5.7
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population 
7
Safety monitoring
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 


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clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must 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 findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment

Yes

No

its duration (start and end dates) or if the event is ongoing an outcome of not
recovered/not resolved must be reported

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE)
and which seriousness criteria have been met

action taken regarding investigational treatment
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only)

[investigational] treatment dosage increased/reduced

[investigational] treatment interrupted/withdrawn

concomitant medication or non-drug therapy given


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
non-drug therapy given

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events 
7.2.1
Definition of SAE 
An SAE is defined as any adverse event (appearance of or worsening of any pre-existing)
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s
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
is medically significant, e.g. defined as an event that jeopardizes the patient or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30 day
period after the last study visit should only be reported to Novartis if the investigator suspects 
a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment 
and complete the SAE Report Form in English, and submit the completed form within 24 
hours to Novartis. Detailed instructions regarding the submission process and requirements 
for signature are to be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 


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investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion
of the standard base liver CRF pages
Please refer to Appendix 1 for complete definitions of liver laboratory triggers and liver 
events. 
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 1 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 of Appendix 1.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease,
co-medications)

An investigation of the liver event which needs to be followed until resolution.


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These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring 
Not required
7.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
7.6
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 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.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 


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Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the
patients/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 


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database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
8.3
Database management and quality control 
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis.
Spirometry readings will be processed centrally and the results will be sent electronically to 
Novartis.
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor, who will also manage the database. The database will be sent electronically to 
Novartis personnel.
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
Not required.
8.5
Adjudication Committee 
Not required.


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9
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
9.1
Analysis sets 
The following analysis sets are defined for data analysis.

The Randomized Set (RAN) will consist of all patients who were assigned a
randomization number; regardless they actually received study medication. The RAN set
will be used for a summary of patient disposition, demographics and baseline
characteristics.

The Full Analysis Set (FAS) will consist of all patients in the RAN who received at least
one dose of study medication. Following the intent-to-treat principle, patients in the FAS
will be analyzed according to the treatment they were randomized to in the assigned
treatment sequence. The FAS will be used in the analysis of all efficacy variables.

The Per Protocol Set (PPS) will include all patients in the FAS who did not have any
protocol deviations that could affect the primary analysis. Rules for complete exclusion of
subjects from the PPS, respectively exclusion of subjects' data from single periods will be
defined in the Statistical Analysis Plan (SAP) prior to database lock and the un-blinding of
the study. Patients in the PPS will be analyzed according to the treatment they actually
received. The PPS will be used for supportive analysis and sensitivity analysis to assess
robustness of the primary efficacy analysis.

The Safety Set will consist of all patients who received at least one dose of study
medication. Patients in the Safety Set will be analyzed according to treatment received.
The Safety Set will be used in the analysis of all safety variables
9.2
Patient demographics and other baseline characteristics 
Demographic and baseline characteristics measured before randomization including age, 
gender, race, ethnicity, height, weight, body mass index (BMI), relevant medical history, 
screening spirometric parameters (FEV1, FVC, FEV1/FVC), FEV1 reversibility, predicted and 
percentage of predicted FEV1, duration of asthma, history of asthma exacerbations, smoking 
history, prior concurrent medications (non-asthma and asthma-related), vital signs (systolic 
and diastolic blood pressure, pulse rate) and QTc using Fridericia’s correction will be 
summarized using the Randomized set.
Continuous variables will be summarized using descriptive statistics (n, mean, 25th percentile, 
median, 75th percentile, standard deviation, minimum and maximum) and categorical variables 
will be summarized in terms of the number and percentage of patients in each category.
9.3
Treatments 
Study drug administration and concomitant medication data will be listed and summarized 
using the Safety set. 


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The duration of exposure, the number of patients randomized who completed the treatment 
period, and who discontinued from study medication will be summarized.
Medications started and stopped prior to study drug of the first treatment period, taken 
concomitantly, and will be summarized by total in separate tables in the Safety Set.
Concomitant therapies will be recorded, listed and summarized separately for asthma related
medications/non-drug therapies and other medications. Concomitant medications will be 
tabulated by pre-specified categories, route of administration, and preferred term.
Patients taking prohibited concomitant medications will be noted in the summary of protocol
deviations.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
The primary endpoint is the trough FEV1 (mL) after 1 week of treatment. The trough FEV1 is 
defined as the mean of the two FEV1 values measured at 23 h 15 min and 23 h 45 min post-
dose of the last study treatment in a given period. The mean baseline measurement is defined 
as the average of the FEV1 values taken in the clinic at 45 and 15 min prior to dosing at Visit 
201 (Day 1).
9.4.2
Statistical model, hypothesis, and method of analysis
The following hypotheses will be tested for each of NVA237 doses versus placebo separately:
H10: There is no difference between NVA237 50 µg and placebo treatment groups in term of 
the trough FEV1 after 1 week of treatment
H1a: There is a difference between NVA237 50 µg and placebo treatment groups in term of 
the trough FEV1 after 1 week of treatment
H20: There is no difference between NVA237 25 µg and placebo treatment groups in term of 
the trough FEV1 after 1 week of treatment
H2a: There is a difference between NVA237 25 µg and placebo treatment groups in term of 
the trough FEV1 after 1 week of treatment
The primary endpoint will be analyzed using a linear mixed-effect model. The model will 
include period, treatment, and sequence as fixed effect factors and baseline trough FEV1 as a 
covariate. The within-patient correlation will be modeled using the unstructured covariance 
matrix. Restricted maximum likelihood method will be used. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. In case of the 
analysis failing to converge, compound symmetric covariance structure will be used.
The treatment differences of each NVA237 dose versus placebo along with the corresponding 
2-sided 95% confidence intervals will be presented.
Each of the primary analyses is performed at the nominal 2-sided 5% level without 
multiplicity adjustment.


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9.4.3
Handling of missing values/censoring/discontinuations
If any of the 23 h 15 min and 23 h 45 min values contributing to the trough FEV1 are collected 
within 6 h of rescue medication, or actual measurement times are outside the 22 - 25 hour 
post-dose time window then the individual FEV1 value will be set to missing.
If one of the two values is missing (or set to missing) then the remaining non-missing value 
will be taken as trough FEV1. If both values are missing, or if the patient withdrew from the 
study, regardless of the reason for discontinuation, then trough FEV1 will be regarded as 
missing in which case the missing value(s) of the patient at the particular visit(s) would not 
directly contribute to the primary analysis.
The model used for the primary variable is based on missing at random mechanism for the 
missing values and assesses the treatment effects of trough FEV1 without explicit imputation.
9.4.4
Sensitivity analyses 
As a sensitivity analysis a model adding a factor for carry-over could be run to investigate 
whether relevant carry-over effects were observed
As a sensitivity analysis, the same model used in the primary analysis will be also performed 
on the PPS to assess the robustness of the results from the primary analyses. 
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The secondary endpoints obtained from spirometry data are 

Standardized AUC in FEV1 across different time intervals (5 min – 1 h, 5 min – 4
h, 5 min – 23 h 45 min)

Peak FEV1 during 5 min – 4 h.

FVC and FEV1/FVC at day 7
Further secondary endpoints obtained from the e-diary data are:

PEF pre-dose morning and evening

Number of rescue puffs during the previous night and during the day
The same model used in the primary analysis will be used for the above secondary endpoints 
from spirometry data and from the e-Diary data except to include the appropriate baseline 
covariate
9.5.2
Safety variables 
All safety parameters will be summarized on the safety set.
Adverse events
All study emergent adverse events will be summarized and listed. Adverse events starting on 
or after the time of the first inhalation of study drug will be classified as a treatment emergent 


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adverse event. Any adverse events that started during a washout period will be assigned to a 
treatment just prior to that washout period. Any adverse events that started during the study 
before the time of the first inhalation of study drug of the first period will be classified as a 
prior adverse event. 
The following treatment emergent adverse event summaries will be produced, overall by 
system organ class and preferred term, overall by system organ class, preferred term and 
maximum severity, suspected drug-related adverse events by system organ class and preferred 
term, serious adverse events by system organ class and preferred term, and adverse events 
leading to permanent discontinuation of study-drug by system organ class and preferred term.
The number and percentage of patients with the most frequent AEs will be summarized by 
treatment.
Electrocardiogram (ECG) and vital signs
Data from the electrocardiogram will be listed by treatment.
Vital signs (blood pressure and radial pulse rate) will be listed.
QTc will be calculated from the QT interval and RR (in seconds) using Fridericia’s formula:
QTc = QT / 3√RR, where 3√denotes the cube root.
Laboratory data
All laboratory data will be listed with abnormal values being flagged.
9.6
Interim analyses
No interim analyses are planned for this study. 
9.7
Sample size calculation
The assumptions to support the sample size calculations were based on 7 historical cross-over 
studies: NVA237A2205, NVA237A2208, QVA149A2210, QMF149A2202, GSK study 
HZA113310 (clinicaltrials.gov nr. NCT00980200) and the dose ranging studies with 
Tiotropium (Beeh et al., 2014) and Umeclidinium (Lee et al., 2015).
The two doses of interest were investigated in studies NVA237A2205 and NVA237A2208. 
The mean treatment estimates observed in these studies suggest that a treatment difference to 
Placebo of at least 100 mL in trough FEV1 could be expected after treatment with 
glycopyrronium bromide 50 g o.d. and a treatment difference to Placebo of around 70 mL 
and up to 90 mL could be expected after treatment with glycopyrronium bromide 25 g o.d. 
This is considered conservative estimates as both studies were conducted in COPD patients 
and asthma patients may be expected to show larger treatment effects.
The within subject standard deviations observed in the above mentioned 7 studies varied 
substantially between 102 mL and 237 mL. Only those historical studies with a similar patient 
population were considered (i.e. excluding the Umeclidinium study which enrolled mild 
asthmatics). This resulted in a standard deviation of 209 mL being used for powering the 
current study. 


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Randomizing 144 subjects and assuming a drop-out rate of up to 20% (i.e. 115 subjects 
completing the study) the power for the comparison of glycopyrronium bromide 50 g o.d. 
with Placebo on a 2-sided 5% level would be 95%. For the comparison of glycopyrronium 
bromide 25 g o.d. with Placebo the power would be 71% assuming a true underlying 
treatment difference of 70mL and 90% for an underlying difference of 90 mL. The sample 
size was calculated via simulation in a program written in R3.2.2.
No adjustment for multiple comparisons is made.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient must be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she must indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (e.g. all of the procedures described in the protocol). 
The process of obtaining informed consent must be documented in the patient source 
documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child-bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.


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10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to 
patients/subjects. Prior to study start, the investigator is required to sign a protocol signature 
page confirming his/her agreement to conduct the study in accordance with these documents 
and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 


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and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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12
References
References are available upon request
Annex IV, ICH-E2D Guideline. Available from www.ich.org
[Beasley R (2004)] The Global Burden of Asthma Report, Global Initiative for Asthma 
(GINA). Available from www.ginasthma.org 
[Beeh KM et al (2014)]Tiotropium Respimat® in asthma: a double-blind randomized, dose-
ranging study in adult patients with moderate asthma. Respiratory Research; 15:61
[Chin SJ et al (2016)]Tiotropium Respimat Is Effective for the Treatment of Asthma at a Dose 
Lower Than That for Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc. 
13(2):173-9.
[European Medicines Agency (2013)] Note for guidance on clinical investigation of medicinal 
products for treatment of asthma. CHMP/EWP/2922/01-rev.1.
[Global Initiative for Asthma (GINA) (2015)] Global Strategy for Asthma Management and 
Prevention. Available from http://ginasthma.org
[Kerstjens HAM et al (2012)] Tiotropium in asthma poorly controlled with standard 
combination therapy. N Engl J Med; 367:1198-207.
[Kerstjens HAM et al (2015)]Tiotropium or salmeterol as add-on therapy to inhaled
corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, 
placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med.
2015 May;3(5):367-76.
[Lee LA et al (2015)]A randomized, three-period cross-over study of umeclidinium as 
monotherapy in adult patients with asthma. Respiratory Med;109:63-73.
[Peters SP et al (2010)]Tiotropium bromide as step-up therapy for adults with uncontrolled 
asthma. N Engl J Med; 363(18): 1715-26.
[Quanjer PH et al (1993)] Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and Coal. Official 
Statement of the European Respiratory Society. Eur Respir J; 6 suppl. 16: 5-40.


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13
Appendices
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 13-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5

Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and
TBL > 2 × ULN [mainly conjugated fraction] without notable
increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue,
abdominal pain, nausea, or vomiting, or rash with eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
TBL: total bilirubin; ULN: upper limit of normal
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN and INR >
1.5

Discontinue the study treatment
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-up
monitoring

If elevation persists for more than 2
weeks, discontinue the study drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 × ULN
accompanied by
symptomsb

Discontinue the study treatment
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
> 3 to ≤ 5 × ULN
(patient is
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the
absence of known
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
TBL (isolated)
> 2 × ULN (in the
absence of known
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the study
drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice

Discontinue the study treatment
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption or
discontinuation

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.


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Appendix 2 Instructions for using inhaler and capsules.
Do not swallow capsules.
Follow the instructions below for using your inhaler. You will take the study drug contained 
within the capsules by inhalation using the inhaler. If you have any questions, please ask the 
doctor or nurse at the study center.
Your inhaler and capsules
The study drug package consists of both the inhaler and one or more blister-packaged 
capsules.

Capsules are supplied in blisters.

Inhaler consists of a cap, mouthpiece and a base.
Your inhaler is designed to deliver the medicine contained within the capsules.
Do not use the study medication capsules with any other capsule inhaler, and do not use the 
inhaler to take any other capsule medicine.


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How to use your inhaler
Pull off cap.
Open inhaler:
Hold the base of the inhaler firmly and tilt back the 
mouthpiece. This opens the inhaler.
Prepare capsule:
Immediately before use, with dry hands, separate one of the 
blisters from the blister card by tearing along the perforations 
and lift the corner of the foil.
Remove a capsule:
Peel away the foil and remove the capsule from the blister.
Insert capsule:
Place the capsule into the capsule chamber.
Never place a capsule directly into the mouthpiece.


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Close the inhaler:
You should hear a “click” as the mouthpiece closes onto the 
inhaler base.
Pierce the capsule:

Hold the inhaler upright with the mouthpiece pointing up.

Pierce the capsule by firmly pressing together both side
buttons at the same time. Do this only once.

You should hear a “click” as the capsule is being pierced.
Release the side buttons fully.
Breathe out:
Before placing the mouthpiece in your mouth, breathe out 
fully.
Do not blow into the mouthpiece.
Inhale the medicine
To breathe the medicine deeply into your airways:

Hold the inhaler as shown in the picture. The side buttons
should be facing left and right. Do not press the side
buttons.

Place the mouthpiece in your mouth and close your lips
firmly around it.

Breathe in rapidly but steadily and as deeply as you can.


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Note:
As you breathe in through the inhaler, the capsule spins 
around in the chamber and you should hear a whirring noise. 
You will experience a sweet flavor as the medicine goes into 
your lungs.
Additional information
Occasionally, very small pieces of the capsule can get past the 
screen and enter your mouth. If this happens, you may be able 
to feel these pieces on your tongue. It is not harmful if these 
pieces are swallowed. The chances of the capsule breakage 
will be increased if the capsule is accidentally pierced more 
than once (step 7). Therefore it is recommended that you 
follow the storage directions, remove the capsule from the 
blister immediately before use and pierce each capsule only 
once.
If you do not hear a whirring noise:
The capsule may be stuck in the capsule chamber. If this 
happens:

Open the inhaler and carefully loosen the capsule by
tapping the base of the inhaler. Do not press the side
buttons.

Inhale the medicine again by repeating steps 9 to 11.
Hold breath:
After you have inhaled the medicine:

Hold your breath for at least 5-10 seconds or as long as
you comfortably can while taking the inhaler out of your
mouth.

Then breathe out.

Open the inhaler to see if any powder is left in the
capsule.
If there is powder left in the capsule:

Close the inhaler.

Repeat steps 9, 10, 11 and 12.
Most people are able to empty the capsule with one or two
inhalations.
Additional information
Some people may occasionally cough briefly soon after
inhaling the medicine. If you do, don’t worry. As long as the
capsule is empty, you have received your medicine.


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After you have finished taking your medicine:

You may be directed by your physician to rinse mouth
with water and spit it out; do not swallow the water.

Open the mouthpiece again, and remove the empty
capsule by tipping it out of the capsule chamber. Put the
empty capsule in your household waste.

Close the inhaler and replace the cap.
Do not store the capsules in the inhaler.
REMEMBER:

Do not swallow capsules.

Only use the inhaler contained in this pack.

Capsules must always be stored in the blister, and only removed immediately before use.

Never place a capsule directly into the mouthpiece of the inhaler.

Do not press the side buttons more than once.

Never blow into the mouthpiece of the inhaler.

Always release the push buttons before inhalation.

Never wash the inhaler with water. Keep it dry. See “How to clean your inhaler”.

Never take the inhaler apart.

Always use the new inhaler that comes with your new medication pack.

Do not store the capsules in the inhaler.

Always keep the inhaler and capsules in a dry place, and avoid very hot or cold
temperatures.
How to clean your inhaler

Clean your inhaler once a week.

Wipe the mouthpiece inside and outside to remove any powder with a clean, dry lint-free
cloth.

Do not wash your inhaler with water. Keep it dry.

Do not take the inhaler apart.


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Appendix 3 Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print FVC tracings. All spirometry values 
should be reported at BTPS by the method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site. 
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry

Smoking within at least 1 hour of testing

Exposure to environmental smoke, dust or areas with strong odors
Every effort should be made to assure consistent testing conditions throughout the study. A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope.
When possible, spirometry should be conducted by the same technician using the same 
spirometer. To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer. It is important that 
the height is measured accurately at the study site. Spirometry, an effort-dependent test, 
requires careful instruction and cooperation of the subject. The technician should ensure a 
good seal around the mouthpiece, and confirm that the subject’s posture is correct. The 
subject should be instructed to perform a maximal inspiration, followed by maximum forced 
expiration until no more air can be exhaled or for at least 6 seconds. Expiration must be rapid 
with exertion of maximal effort. The results of spirometry should meet the ATS/ERS criteria 
for acceptability and repeatability. Acceptability criteria should be applied before repeatability 
is determined.
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued. 


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Acceptability
An acceptable maneuver has the following characteristics: 

No hesitation or false start;

A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures

No early termination of exhalation (minimum exhalation time of 6 seconds is
recommended, or no volume change for at least 1 second) or the subject cannot continue
to exhale further
Repeatability
The 2 largest FVC and FEV1 values from 3 acceptable maneuvers should not vary by more 
than 0.150 L.
Recording of data
The highest FEV1 and FVC from any of the acceptable curves are recorded. (The highest 
FEV1 and FVC may not necessarily result from the same acceptable curve).
Predicted normal
This study will utilize the spirometric predication equation standards as described by the ERS 
Global Lung Function Initiative (GLI)2 or Japanese Respiratory Society3. Further details will 
be provided in a specification document for the central spirometry assessments.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing
Administer 400 µg of salbutamol/360 µg albuterol following the completion of the baseline 
assessment. A second spirometry assessment is then performed within 30 minutes after 
administration of the salbutamol/albuterol. 
Reversibility is calculated as: 
100 x       FEV1 (post β2-agonists) – FEV1 (baseline)
FEV1 (baseline)
Subjects will be considered reversible if an increase of at least 12% (and 200 mL) is 
demonstrated after administration of the bronchodilator. 


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References
1 Miller MR et al, Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.
2 Quanjer PH, et al. ERS Global Lung Function Initiative, Multi ethnic reference values for 
spirometry for the 3-95 year age range: the global lung function 2012 equations. Report of the 
Global Lung Function Initiative (GLI). ERS Task Force to establish improved Lung Function 
Reference Values. Eur Respir J 2012; 40: 1324-1343.
3 Kubota, Kobayashi, Quanjer PH, et al. Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values. Clinical Pulmonary Functions Committee of the Japanese Respiratory Society.
Respiratory Investigations 2014, 242-250. 


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Appendix 4 Patient Asthma Control e-Diary
(For illustrative purposes only)
The following information will be captured:
In the MORNING
In the EVENING
Peak expiratory flow rate
Number of puffs of rescue medication 
during the past 12 hours 
Peak expiratory flow rate
Number of puffs of rescue medication 
during the past 12 hours


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Appendix 5 ICS Dose level 
Table 13-3
Low, medium and high Daily Doses of Inhaled Glucocorticosteroids 
for Adults and adolescents (12 years and older) (GINA 2015)
Drug
Total Daily Dose (µg/day)
Low
Medium
High
Beclomethasone dipropionate –
CFC*
200-500
> 500 -– 1000
> 1000
Beclomethasone dipropionate –
HFA
100-200
> 200 -– 400
> 400
Budesonide- DPI
200-400
> 400 – 800
> 800
Ciclesonide – HFA
80-160
> 160 – 320
> 320
Fluticasone propionate – DPI
100-250
> 250 – 500
> 500
Fluticasone propionate – HFA
100-250
> 250 – 500
> 500
Mometasone furoate
110-220
> 220-440
≥440
Triamcinolone acetonide
400-1000
> 1000 -– 2000
> 2000
DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant.
* Beclomethasone dipropionate CHF is included for comparison with older literature.

SAP_000.pdf: 
Clinical Development 
NVA237/Glycopyrronium bromide 
CQVM149B2204 / NCT03137784 
A multicenter, randomized, double-blind, placebo-
controlled 3-period complete cross-over study to assess 
the bronchodilator effects and safety of glycopyrronium 
bromide (NVA237) (25 µg and 50 µg o.d.) in asthma patients 
Statistical Analysis Plan (SAP) 
Author: 
Document type: 
Trial Statistician, 
 
Trial Statistician (CRO), 
 
SAP Documentation 
Document status: 
Amendment 1 
Release date: 
7-Feb-2018
Number of pages: 
29 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP Amendment 1 
CQVM149B2204 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Section and 
title impacted 
(Current) 
02-Mar-
2017
Prior to 
DB 
lock 
Creation of draft version 
N/A- 
First 
version 
28-Apr-
2017
Prior to 
DB 
lock 
Draft- Second 
version 
Section 2.1.1; 
2.1.1.;, 2.1.1.2; 
2.3.1;  2.3.2; 
2.4.1.1;  2.4.2; 
2.5.2;  2.5.4; 
2.7.1.2;  2.7.2; 
2.8.2;  and 5.2 
04-May-
2017
Prior to 
DB 
lock 
Final version 
1.0 
7-Feb-
2018
Prior to 
DB 
lock 
Addressed the reviewers 
comments on first draft version 
Creation of final version 1.0 
 
Added supportive analysis to 
explore the effect of patients 
taking IMP for more than 10 days 
Completed section 4, including 
removing FEV1/FVC inferential 
analysis, clarifying standard vital 
signs analysis which are already 
planned in TFLs.  
Added protocol deviations 
leading to exclusion from 
analysis sets 
Amendment 1 Sections 2.1.1, 
 2.5, 2.7, 
2.8, 4, 5.4, 5.5, 
5.6  
…. 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
1.2.1 
Primary objective .................................................................................... 7 
1.2.2 
Secondary objective(s) ............................................................................ 8 
 
 8 
2 
Statistical methods ............................................................................................................... 8 
2.1 
Data analysis general information ........................................................................... 8 
2.1.1 
General definitions .................................................................................. 8 
2.2 
Analysis sets .......................................................................................................... 10 
 
 11 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 11 
2.3.1 
Patient disposition ................................................................................. 11 
2.3.2 
Patient demographics and baseline characteristics ............................... 12 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 13 
2.4.1 
Study treatment / compliance ................................................................ 13 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective .......................................................................... 13 
2.5.1 
Primary endpoint ................................................................................... 13 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.5.4 
Supportive analyses ............................................................................... 15 
2.6 
Analysis of the key secondary objective ............................................................... 15 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 16 
2.7.1 
Spirometry data other than the primary endpoint ................................. 16 
2.7.2 
Rescue medication ................................................................................ 17 
2.7.3 
Peak Expiratory Flow Rate (PEF) ......................................................... 17 
2.8 
Safety analyses ....................................................................................................... 18 
2.8.1 
Adverse events (AEs) ............................................................................ 18 
2.8.2 
Deaths .................................................................................................... 19 
2.8.3 
Laboratory data ..................................................................................... 19 
2.8.4 
Other safety data ................................................................................... 20 
2.9 
Pharmacokinetic endpoints .................................................................................... 21 


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2.10 
PD and PK/PD analyses......................................................................................... 21 
2.11 
Patient-reported outcomes ..................................................................................... 21 
2.12 
Biomarkers ............................................................................................................. 21 
 
 21 
2.14 
Interim analysis ...................................................................................................... 21 
3 
Sample size calculation ..................................................................................................... 21 
4 
Change to protocol specified analyses .............................................................................. 22 
5 
Appendix ........................................................................................................................... 22 
5.1 
Imputation rules ..................................................................................................... 22 
5.1.1 
Study drug ............................................................................................. 22 
5.1.2 
AE date imputation ............................................................................... 22 
5.1.3 
Concomitant medication date imputation ............................................. 23 
5.2 
AEs and Concomitant medications coding/grading .............................................. 23 
5.3 
Data pooling and assessment windows .................................................................. 23 
5.4 
Laboratory parameters derivations ........................................................................ 23 
5.5 
Vital signs and ECG – definition of clinically notable values ............................... 25 
5.6 
Statistical models ................................................................................................... 26 
5.6.1 
Primary analysis .................................................................................... 26 
5.6.2 
Sensitivity analysis ................................................................................ 26 
5.6.3 
Key secondary analysis ......................................................................... 27 
5.7 
Rule of exclusion criteria of analysis sets.............................................................. 27 
6 
Reference ........................................................................................................................... 29 


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List of abbreviations 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
FAS 
Full Analysis Set 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
h 
Hour 
ICS 
Inhaled Corticosteroid 
LABA 
Long Acting Beta-2 Agonist 
LFT 
Liver Function Test 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
min 
minutes 
µg 
Microgram 
o.d.
Once Daily 
PEF
Peak Expiratory Flow 
PK
Pharmacokinetics 
PPS
Per-Protocol Set 
PT
Preferred Term 
QTc
Corrected QT interval 
RAN
Randomized Set 
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan 
SAS
Statistical Analysis System 
SBP
Systolic Blood Pressure 
SGOT
Serum Glutamic Oxaloacetic Transaminase 
SGPT
Serum Glutamic Pyruvic Transaminase 
SOC
System Organ Class 
TFLs
Table, Figure, Listing 
ULN
Upper Limit of Normal 


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1 
Introduction 
This document contains details of the statistical methods that will be used in the phase IIb 
clinical trial CQVM149B2204. This study is designed to evaluate the bronchodilator effects 
and safety of two doses (25 µg and 50 µg o.d.) of glycopyrronium bromide (NVA237) compared 
to placebo in asthma patients. 
Data will be analyzed according to Section 9 of the study protocol. 
Important information is given in the following sections and details are provided, as applicable, 
in section 5: Appendix. 
1.1 
Study design 
This study uses a randomized, double-blind, placebo controlled, 3-period cross-over clinical 
trial design to assess the bronchodilator effects and safety of two doses (25 µg and 50 µg o.d.) 
of glycopyrronium bromide (NVA237) compared to placebo in asthma patients (Figure 1). 
Approximately 144 male and female patients will be randomized into one of the following six 
treatment sequence in a ratio of 1:1:1:1:1:1, expecting 24 patients allocated to each of the 
treatment sequences. It is intended that approximately 115 patients will complete the study. 
Each treatment sequence consists of 3 treatment periods during which study drug will be 
administered in the sequence as laid forth in Table 1. Detailed information regarding sample 
size calculation is provided in section 3. 
This study will enroll patients at multiple centers multi-nationally. Patients will not be stratified 
to any prognostic or non-prognostic factors.  
No interim analysis for efficacy is planned in this study. An independent Data Monitoring 
Committee (DMC) will not be formed to review any blinded / semi-blinded data. 


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Figure 1 
Study design 
A= NVA237 50 µg: B= NVA237 25 µg: C= Placebo 
During a screening epoch, patient eligibility will be assessed. The screening epoch will be 
followed by a 21-day Run-in epoch during which patients will continue ICS use but be 
withdrawn from LABA-treatment and switched to short-acting bronchodilator-rescue 
medication. After the Run-in period, patients will be randomized to one of the 6 treatment 
sequences and enter the first 7-day study treatment period.  
Treatment period one is followed by a 10-day washout period after which patients begin the 
second 7-day treatment period which is then followed by a second 10-day washout period 
followed by the third 7-day treatment period. At the end of each treatment period spirometry 
will be performed to assess the primary endpoint. Procedures in treatment periods two and three 
mirror-image the procedures of treatment period one. 
1.2 
Study objectives and endpoints 
1.2.1 
Primary objective 
The primary objective of this study is to evaluate the bronchodilator effects of NVA237 
delivered by the Concept1 single-dose dry-powder inhaler in patients with asthma in terms of 
trough FEV1 (mean of 23 h 15 min and 23 h 45 min post-dose) following 1 week of treatment, 
by comparing NVA237 at a dose of 25 µg and 50 μg o.d. with placebo. 
Screening
Run In
Treatment 
Period 1
Wash out Period 
1
Treatment 
Period 2
Wash out 
Period 2
Treatment 
Period 3
Study 
Completion 
Visit
Treatment Sequences
A
B
C
Sequence 1
A
C
B
Sequence 2
B
A
C
Sequence 3
B
C
A
Sequence 4
C
A
B
Sequence 5
C
B
A
Sequence 6
-28 days 
to -21 
days
-21
to 0 
days
7 days
10 days
7 days
10 days
7 days 
1 day after 
last study
dose
ICS background / Rescue Medication


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1.2.2 
Secondary objective(s) 
Secondary objectives will evaluate the bronchodilator effects of each dose of NVA237 (25 μg 
and 50 μg o.d.) compared with placebo in terms of: 
•
Standardized FEV1 AUC (5 min - 1 h), (5 min - 4 h), and (5 min – 23 h 45 min) after 1
week of treatment in the respective period.
•
Peak FEV1 after 1 week of treatment in the respective period during 5 min to 4 h post-
dose.
•
FEV1, Forced Vital Capacity (FVC) and FEV1/FVC ratio at all spirometry time-points
after 1 week of treatment in the respective period.
•
Safety and tolerability of each dose of NVA237 (25 µg and 50 μg o.d.) in the respective
period (laboratory tests, vital signs, ECG and adverse events).
To evaluate the bronchodilator effects of each dose of NVA237 (25 μg and 50 μg o.d.) compared 
with placebo as determined by patient diary data and electronic PEF meter in the respective 
period in terms of: 
•
Rescue medication usage over 1 week of treatment
•
Daily morning (pre-medication) and evening peak expiratory flow rate (PEF) over 1
week of treatment.
2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be performed by 
. The most recent version of SAS available 
in the statistical programming environment of 
 will be used for the analysis.  
2.1.1 
General definitions 
Study treatment is the treatment administered in each treatment period (i.e. treatment period 1, 
treatment period 2, and treatment period 3). 
ECG, vital signs and laboratory values which have complete date and time values are assigned 
to pre or post-dose assessment based on the actual date/time. However, values with missing 
date/time are assigned to their respective scheduled visit date and time given the visit number 
and time point are non-missing. If a measurement scheduled as pre-dose is actually performed 
post-dose, or vice versa, the data will not be used for assessments but will be included in the 
summaries of the notable values and extreme values.  


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For efficacy measurements, any measurements scheduled as pre- dose but actually taken post- 
dose will be set to missing, also any measurements scheduled as post- dose but actually taken 
pre- dose will be set to missing.   
Safety measurements (vital signs) and efficacy data measurements (Spirometry, rescue 
medication and PEF) will be assigned to the treatment starting in the particular treatment period. 
Safety data (only AEs) will be assigned to treatment if it starts on or after the time of first 
administration of study drug in a treatment period but not later than the time of first 
administration of study drug in subsequent treatment period. 
Study day will be defined as the number of days since the date of first dose of study medication. 
The date of first dose of study medication will be defined as Day 1 and the day before the first 
dose of study medication was defined as Day -1.  
Therefore, for a particular date, study day will be calculated as follows: 
•
for dates on or after the first date of study medication,
Study day = Assessment date – Date of first dose of study medication + 1;
•
for dates prior to the first date of study medication,
Study day = Assessment date – Date of first dose of study medication.
Period day will be defined as the number of days since the date of dose given in start of that 
particular period. The date of dose given in start of that particular period will be defined as 
period Day 1 and the day before the dose of study medication was defined as period Day -1 for 
that period.  
Therefore, for a particular date, period day will be calculated as follows: 
•
for dates on or after the date of dose given in start of particular period,
Period day = Assessment date – Date of dose given in start of that particular period + 1;
Period day will be used for calculation of summary statistics. 
2.1.1.1 
Baseline definition 
In general, baseline data is defined as the last assessment taken prior to the first dose of study 
drug on Day 1. 
Checks will be performed to ensure the assessments were indeed taken prior to the first dose of 
study drug on Day 1. If this assessment is missing or not confirmed to be pre-dose, then baseline 
data will be set to missing without imputation. 


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Parameter 
Baseline assessment 
Detail 
Trough FEV1 
45 min and 15 min prior to 
dosing  at Visit 201 (Day 1) 
Average of the FEV1 values 
taken in the clinic at 45 and 
15 min prior to dosing at 
Visit 201 (Day 1) 
FVC 
45 min and 15 min prior to 
dosing  at Visit 201 (Day 1) 
Average of the FVC values 
taken in the clinic at 45 and 
15 min prior to dosing at 
Visit 201 (Day 1) 
Standardized AUC in 
FEV1
 across different time 
intervals (5 min – 1 h, 5 
min – 4 h, 5 min – 23 h 45 
min) 
45 min and 15 min prior to 
dosing  at Visit 201 (Day 1) 
Average of the FEV1 values 
taken in the clinic at 45 and 
15 min prior to dosing at 
Visit 201 (Day 1) 
Peak FEV1 
45 min and 15 min prior to 
dosing  at Visit 201 (Day 1) 
Average of the FEV1 values 
taken in the clinic at 45 and 
15 min prior to dosing at 
Visit 201 (Day 1) 
eDiary data  
(PEF and rescue medication 
use) 
Assessment at run-in visit 101 
prior to dosing at Visit 201 
(Day 1) 
The average from all non-
missing records of PEF or 
rescue medication use 
Vital signs  
(pulse rate and systolic and 
diastolic blood pressures) 
Assessment at screening 
visit 1 
Height and weight 
Assessment at screening 
visit 1 
Detail descriptions for calculating baseline values are provided in the latter sections. 
2.1.1.2 
Post-baseline measurement 
Post-baseline measurements are defined as those assessments after the first dose of study drug. 
When change from baseline is of interest the following formula will be used for each visit and 
time-point where baseline and post-baseline values are both available: 
Change from baseline = post baseline value – baseline value. 
Detail descriptions for calculating post-baseline values are provided in the latter sections. 
2.2 
Analysis sets 
The following analysis sets are defined: 
•
The Randomized Set (RAN) will consist of all patients who were assigned a randomization
number; regardless they actually received study medication. The RAN set will be used for
a summary of patient disposition, demographics and baseline characteristics.


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•
The Full Analysis Set (FAS) will consist of all patients in the RAN who received at least
one dose of study medication. Following the intent-to-treat principle, patients in the FAS
will be analyzed according to the treatment they were randomized to in the assigned
treatment sequence. The FAS will be used in the analysis of all efficacy variables.
•
The Per Protocol Set (PPS) will include all patients in the FAS who did not have any major
protocol deviations that could affect the primary analysis. The list of major protocol
deviations is available in Appendix 5.7. Patients in the PPS will be analyzed according to
the treatment they actually received. The PPS will be used for supportive and sensitivity
analysis to assess robustness of the primary efficacy analysis.
•
The Safety Set will consist of all patients who received at least one dose of study medication.
Patients in the Safety Set will be analyzed according to treatment received. The Safety Set
will be used in the analysis of all safety variables.
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number of patients will be summarized by treatment sequence for the RAN set.  Patients 
disposition for the screening epoch (Screened patients) and run-in epoch (Patients who entered 
run-in) will be summarized including the reasons for discontinuation. The overall number of 
patients who entered, completed, and discontinued in treatment period will be summarized 
including the reasons for discontinuation by treatment. The overall number of patients who 
entered, completed, and discontinued in treatment epoch will be summarized including the 
reasons for discontinuation by treatment sequence. 


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The overall number of patients with protocol deviations and protocol deviations that lead to 
exclusion from analysis sets will be tabulated by deviation category (e.g., selection criteria not 
met, prohibited concomitant medication, key procedures not performed as per protocol) and 
treatment sequence. 
The number of patients with protocol deviations leading to exclusion from each treatment 
period will be tabulated by deviation category (e.g., selection criteria not met, prohibited 
concomitant medication, key procedures not performed as per protocol) and treatment. Number 
of patients with protocol deviations leading to exclusion from the PPS will be tabulated by 
deviation category, verbatim term and treatment sequence.  
The number of patients included in each analysis set will be tabulated, as well as the reasons 
for exclusions from analysis sets by treatment. 
2.3.2 
Patient demographics and baseline characteristics 
Demographic and baseline characteristics measured before randomization including age, 
gender, race, ethnicity, height, weight, body mass index (BMI), relevant medical history, 
screening spirometry parameters (FEV1, FVC, FEV1/FVC), FEV1 reversibility, predicted and 
percentage of predicted FEV1, duration of asthma, history of asthma exacerbations, smoking 
history, prior concurrent medications (non-asthma and asthma-related), vital signs (systolic and 
diastolic blood pressure, pulse rate) and QTc using Fridericia’s correction will be summarized 
by treatment sequence using RAN set. Prior asthma treatment, will be summarized by ICS dose 
level category (ICS/LABA low, medium and high, No ICS/LABA). 
Continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, standard deviation, median, first and third quartiles, minimum, and maximum) and 
categorical variables will be summarized in terms of the number and percentage of patients in 
each category including a category for missing data if any. 
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 
History/conditions will be summarized for the RAN set by primary system organ class and 
preferred term and treatment sequence. Verbatim recorded history/conditions will be listed 
together with the coded terms, date of diagnosis/surgery and whether the problem was ongoing 
at start of the study. 
In addition, medical histories/current medical conditions will be summarized by their status at 
baseline (current medical conditions, past medical conditions) and primary system organ class. 
Current medical conditions are defined as those which were reported as "Ongoing" at screening. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
2.4.1.1 
Duration of exposure 
Duration of exposure for the randomized patients will be calculated as the number of days 
between the first dose date and the last dose date exposed to particular study treatment for a 
given period (expressed as: Duration of exposure = Date of last known dose of study treatment 
– Date of first dose of study treatment + 1).
The duration of exposure (in days) and the number of patients exposed will be summarized by
treatment for the safety set as a continuous variable with the standard descriptive statistics.
The number of patients who completed the 3-period crossover study and discontinued 
prematurely will be shown including the reasons for discontinuation of study treatment. 
2.4.2 
Prior, concomitant and post therapies 
Each medication, either an asthma or non-asthma medication, will have the start and end dates 
recorded on the eCRF. Separate tables will be provided for medications which were started and 
stopped prior to the first dose of study drug and medications which were taken after the first 
dose of  the study drug (regardless of whether continued or started after the first dose of study 
drug). 
Asthma medications will be summarized by the route of administration, the recorded 
prespecified drug subcategories (including types of combination) and the coded preferred terms. 
The summary will be repeated by showing ingredients instead of preferred terms. Non-asthma 
medications will be summarized by route of administration and preferred term.  
Surgical and medical procedures (non-drug therapies) will be coded using MedDRA and 
presentations will be done by MedDRA primary system organ class and preferred term, 
separately for prior procedures and those after start of study drug. 
Short acting beta2 agonist (SABA) rescue medication usage (mean number of puffs) during the 
screening/run-in epoch will be summarized. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is the trough FEV1 (mL) after 1 week of treatment. 
The trough FEV1 is defined as the mean of the two FEV1 values measured at 23 h 15 min and 
23 h 45 min post- dose of the last study treatment in a given period. For trough FEV1, the mean 


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baseline measurement is defined as the average of the FEV1 values taken in the clinic at 45 and 
15 min prior to dosing at Visit 201 (Day 1). 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The comparison of NVA237 50 µg and 25 μg o.d. versus placebo will be evaluated by testing 
the following null hypotheses (H10, H20) versus the alternative hypotheses (H1a, H2a): 
H10: There is no difference between NVA237 50 µg and placebo treatment groups in term of 
the trough FEV1 after 1 week of treatment 
H1a: There is a difference between NVA237 50 µg and placebo treatment groups in term of the 
trough FEV1 after 1 week of treatment 
H20: There is no difference between NVA237 25 µg and placebo treatment groups in term of 
the trough FEV1 after 1 week of treatment 
H2a: There is a difference between NVA237 25 µg and placebo treatment groups in term of the 
trough FEV1 after 1 week of treatment 
The primary endpoint will be analyzed using a linear mixed-effect model on FAS. The model 
will include period, treatment, and sequence as fixed effect factors and baseline trough FEV1 as 
a covariate and patient within sequence as random factor. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom (Kenward and Roger, 1997). The 
within-patient correlation will be modeled using the unstructured covariance matrix. If the 
model does not converge, then the compound symmetric covariance structure will be used in 
the model. Restricted maximum likelihood method will be used for estimation of variance 
components in mixed model. 
The estimated treatment difference of (NVA237 50 µg – Placebo) and (NVA237 25 µg – 
Placebo) will be displayed along with the standard error, 2-sided 95% confidence interval (CI), 
and p-value  
2.5.3 
Handling of missing values/censoring/discontinuations 
If any of the 23 h 15 min and 23 h 45 min values contributing to the trough FEV1 are collected 
within 7 days of systemic corticosteroid use, 6 h of rescue medication, or actual measurement 
times are outside the 22 - 25 hour post-dose time window then the individual FEV1 value will 
be set to missing. 
If one of the two values is missing (or set to missing) then the remaining non-missing value will 
be taken as trough FEV1. If both values are missing, or if the patient withdrew from the study 
(regardless of the reason for discontinuation) then trough FEV1 will be regarded as missing in 
which case the missing value(s) of the patient at the particular visit(s) would not directly 
contribute to the primary analysis. 
The model used for the primary variable is based on missing at random mechanism for the 
missing values and assesses the treatment effects of trough FEV1 without explicit imputation. 


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2.5.4 
Supportive analyses 
As a sensitivity analysis, a model adding a factor for carry-over will be run to investigate 
whether relevant carry-over effects were observed. 
The estimated treatment difference of (NVA237 50 µg – Placebo) and (NVA237 25 µg – 
Placebo) will be displayed along with the standard error, 2-sided 95% confidence interval (CI), 
and p-value.  
Also as a supportive analysis, the same model used in the primary analysis will also 
be performed on the PPS to assess the robustness of the results from the primary analysis.  
As a supportive analysis, the same model used in the primary analysis will also be performed 
on the PPS excluding in addition patients with protocol devation TRT08 (Patient treated with 
IMP more than 10 days), to assess the robustness of the results from the primary analysis. 
2.6 
Analysis of the key secondary objective 
There is no key secondary efficacy endpoint in this study. 


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2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Spirometry data other than the primary endpoint 
2.7.1.1 
Standardized AUC in FEV1 across different time intervals (5 min – 1 h, 
5 min – 4 h, 5 min – 23 h 45 min) 
AUC: The trapezoidal rule will be used to calculate Standardized AUC in FEV1 for 0-1h, 0-
4h, and 0-24 h. 
AUC 0-1h will be calculated from 5 min to 1h post dose values. 
AUC 0-4h will be calculated from 5 min to 4h post dose values. 
AUC 0-24h will be calculated from 5 min to 23h 45min post dose values. 
For those patients who have more than one FEV1  assessment, their standardized AUC will be 
approximated by Σmk=2(tk - tk-1)*0.5*(yk + yk-1) / (tm - t1) where m is the number of assessments, k is 
an index from 1 to m, tk denotes the kth out of the m time-points t1 < …< tm, and yk denotes the 
FEV1 value measured at time-point tk. Note that if intermediate assessments are missing then 
the calculation corresponds to a linear interpolation of the missing assessments. 
The same model used in the primary analysis will be used for the Standardized AUC in FEV1 
across different time intervals (5 min – 1 h, 5 min – 4 h, 5 min – 23 h 45 min) with FEV1 value 
taken at 45 and 15 min prior to dosing at Visit 201 (Day 1) as baseline covariate. 
2.7.1.2 
Peak FEV1 during 5 min – 4 h 
Peak FEV1 value during 4 h post dose is defined as the maximum value achieved during 4 hours 
after the morning post dose, i.e. the values between 5 min and 4 h post dose. If any 
measurements are missing from 5 min onwards then the peak value will not be calculated. 
The same model used in the primary analysis will be used for the Peak FEV1 endpoint with 
FEV1 value taken at 45 and 15 min prior to dosing at Visit 201 (Day 1) as baseline covariate. 
2.7.1.3 
FVC at day 7 
The missing values will be handled similarly as mentioned for trough FEV1 (See Section 2.5.3). 
The same model used in the primary analysis will be used for the FVC endpoint at day 7 with 
FVC value taken at 45 and 15 min prior to dosing at Visit 201 (Day 1) as baseline covariate. 
2.7.1.4 
FEV1 / FVC 
For FEV1 / FVC, baseline value is defined as baseline FEV1  (See Section 2.1.1.1) divided by 
baseline FVC value taken at 45 and 15 min prior to dosing at Visit 201 (Day 1). 
The FEV1 / FVC  will be summarizd descriptively by time point. 


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2.7.2 
Rescue medication 
The number of puffs of the rescue medication use in the last 12-hour is recorded twice daily 
(morning/evening) by the patient in his/her e-Diary. For rescue medication use, the baseline 
values are defined in section 2.1.1.1. When calculating the baseline value there is no limitation 
to the 21 days immediately prior to Day 1 (Visit 201). Missing diary data will not be imputed. 
If for the value over the whole day (24 hours) the number of puffs is missing for part of the day 
(either day-time or night-time) then a half day will be used in the denominator to calculate the 
average value. Any values > 30 for the number of puffs of rescue medication in a 12 hour period 
will be set to missing. These high numbers are not realistic and could impact the analyses. If a 
patient has less than 7 days with non-missing data, then the baseline value will be set to missing. 
Post-baseline measurements start with the evening recordings at Day 1 (Visit 201) and end with 
the morning recordings one day after the last morning dose of treatment period 3. Summary 
data (i.e., mean values and percentage of days with) will be calculated for one week interval for 
all period. Summary values will only be calculated if a patient has at least 50% of their diary 
days with evaluable data for that variable in the period of interest. Similar calculations as for 
baseline diary data will be done.  
The mean daily number of puffs of rescue medication use over one week of treatment for 
particular treatment period will be summarized by treatment.  
The same model used in the primary analysis will be used for the analysis except that baseline 
trough FEV1 will be replaced with baseline rescue medication as the covariate.  
Rescue medication use during the run-in period (for randomized patients) and the wash-out 
periods will be listed. 
2.7.3 
Peak Expiratory Flow Rate (PEF) 
An electronic Peak Flow Meter will be given to each patient at visit 101 for the measurement 
of the morning and the evening PEF during the screening, run-in and treatment periods. 
PEF will be measured at consistent times for a patient: in the morning prior to taking study 
medication and in the evening. Patients should be encouraged to perform the measurements 
before the use of any rescue medication. At each timepoint the patient should be instructed to 
perform 3 consecutive maneuvers within 10 minutes. These PEF values are captured in the e-
Diary. The best of 3 values will be used for analysis. 
PEF (liters/min) will be averaged separately for morning and evening values with means over 
one week of treatment for each period and the baseline run-in phase. 
Baseline values are defined similarly as rescue medication and given in section 2.1.1.1 


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For post-baseline measurements, similar procedure will be followed, as mentioned for rescue 
medication use. 
The same model used in the primary analysis will be used for the analysis except that baseline 
trough FEV1 will be replaced with baseline morning/evening PEF as the covariate.  
2.8 
Safety analyses 
All safety evaluation will be based on the safety set. 
2.8.1 
Adverse events (AEs) 
. 
All adverse events including asthma exacerbations, coded with MedDRA using the most actual 
version at the time of database lock, will be listed. In general, summaries will include treatment-
emergent adverse events (TEAEs) only. 
TEAEs are those adverse events starting on or after the time of first administration of study 
drug in a treatment period but not later than the time of first administration of study drug in 
subsequent treatment period. AEs are considered as treatment emergent up to 14 days after last 
dose of study drug of the last period. 
Any adverse events that started during a washout period will be assigned to a treatment just 
prior to that washout period.  
Any AEs that started during the study before the time of the first inhalation of study drug will 
be classified as a prior AE.  
The number and percentage of patients who reported treatment-emergent adverse events will 
be summarized by primary system organ class (SOC), preferred term (PT), and treatment for 
•
all adverse events
•
all adverse events by maximum severity
•
adverse events suspected to be related to study drug
•
serious adverse events
•
adverse events leading to permanent study drug discontinuation
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the NVA237 50 μg treatment. If a patient reported more than one adverse event 
with the same preferred term, the adverse event will be counted only once. If a patient reported 
more than one adverse event within the same primary system organ class, the patient will be 
counted only once at the system organ class level. 
In addition, the most frequent adverse events will be presented by preferred term in descending 
order of frequency in the NVA237 50 μg treatment. 


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2.8.1.1 
Adverse events of special interest / grouping of AEs 
2.8.1.2 
AE reporting for CT.gov and EudraCT 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 2% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
•
a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end date
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.2 
Deaths 
A summary of deaths will be presented by primary system organ class, preferred term, and 
treatment regardless of study drug relationship.  
All the deaths in the clinical database will be listed with the investigator-reported principal 
cause, presented side by side, but only those between the first treatment up to 30 days after last 
dose of study drug of the last period will be included in summary tables. 
2.8.3 
Laboratory data 
All laboratory samples will be processed through the central laboratory. Laboratory data consist 
of hematology, clinical chemistry and urinalysis measurements. All data will be listed with 
abnormal values flagged.  
All data will be summarized by period. As laboratory samples are scheduled pre-dose at Day 1 
of the respective period, measurements cannot be assigned to any treatment. 
A listing of all patients with notable laboratory and a listings of patients with clinically notable 
LFT values will be provided. 


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2.8.4 
Other safety data 
2.8.4.1 
ECG 
ECG measurements include ventricular rate, QT interval, RR interval, PR interval, QRS 
duration, and Fridericia’s QTc (calculated as QTcF = QT / 3√ RR (in seconds), where 3√ 
denotes the cube root). Furthermore, an overall interpretation of the central cardiologist will be 
provided as well as a specification of abnormal findings. All data will be listed. 
All data will be summarized by period. As ECG is scheduled pre-dose at Day 1 of the respective 
period, measurements cannot be assigned to any treatment.A listing of all patients with notable 
QTc values will be provided. 
2.8.4.2 
Vital signs 
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), pulse 
rate, height and body weight (at selected visits only). 
Baseline vital signs (systolic and diastolic blood pressure (SBP and DBP), pulse rate) and 
baseline height and weight are defined in section 2.1.1.1.  
Vital signs data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
The following analyses will be performed by treatment: 
•
absolute values and change from baseline summarized by parameter, and visit
•
the number and percentage of patients by parameter, and visit with
- pulse rate < 40 bpm, 40 – 90 bpm, and > 90 bpm
- SBP < 90 mm Hg, 90 – 140 mm Hg, and > 140 mm Hg
- DBP < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg
•
the number and percentage of patients with newly occurring or worsening notable vital signs
values (see Section 5.5 for definition of notable values) summarized by parameter (except
height and weight), scheduled post-baseline visit and additionally at any time on treatment
considering all post-baseline data from scheduled, unscheduled and premature
discontinuation visits
The by-visit summaries will include the post-baseline SBP, DBP, and pulse rate values (even if 
from post-baseline unscheduled and premature discontinuation visits, if not measured more than 
7 days after last dose). 
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value that is not clinically notable for that parameter. For a patient to 


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meet the criterion of a worsening clinically notable value, the patient needs to have a baseline 
value that is clinically notable and also have a worse post-baseline value. For patients with 
missing baseline value, any post-baseline notable value will be considered as newly occurring. 
A listing of all patients with notable vital sign values and changes will be provided. 
2.9 
Pharmacokinetic endpoints 
Not Applicable 
2.10 
PD and PK/PD analyses 
Not Applicable 
2.11 
Patient-reported outcomes 
Not Applicable 
2.12 
Biomarkers 
Not Applicable 
2.14 
Interim analysis 
No interim analysis will be performed in this study. 
3 
Sample size calculation 
The assumptions to support the sample size calculations were based on 7 historical cross-over 
studies: NVA237A2205, NVA237A2208, QVA149A2210, QMF149A2202, GSK study 
HZA113310 (clinicaltrials.gov nr. NCT00980200) and the dose ranging studies with 
Tiotropium (Beeh et al., 2014) and Umeclidinium (Lee et al., 2015). 
The two doses of interest were investigated in studies NVA237A2205 and NVA237A2208. The 
mean treatment estimates observed in these studies suggest that a treatment difference to 
Placebo of at least 100 mL in trough FEV1 could be expected after treatment with 
glycopyrronium bromide 50 µg o.d. and a treatment difference to Placebo of around 70 mL and 
up to 90 mL could be expected after treatment with glycopyrronium bromide 25 µg o.d. This is 
considered conservative estimates as both studies were conducted in COPD patients and asthma 
patients may be expected to show larger treatment effects. 
The within subject standard deviations observed in the above mentioned 7 studies varied 
substantially  between 102 mL and 237 mL. Only those historical studies with a similar patient 
population were considered (i.e. excluding the Umeclidinium study which enrolled mild 


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asthmatics).  This resulted in a standard deviation of 209 mL being used for powering the 
current study.  
Randomizing 144 subjects and assuming a drop-out rate of up to 20% (i.e. 115 subjects 
completing the study) the power for the comparison of glycopyrronium bromide 50 µg o.d. with 
Placebo on a 2-sided 5% level would be 95%. For the comparison of glycopyrronium bromide 
25 µg o.d. with Placebo the power would be 71% assuming a true underlying treatment 
difference of 70mL and 90% for an underlying difference of 90 mL. The sample size was 
calculated via simulation in a program written in R3.2.2. 
No adjustment for multiple comparisons is made. 
4 
Change to protocol specified analyses 
FEV1/FVC ratio will be summarized descriptively only. The same model as for the primary 
endpoint will not be applied. 
Vital signs: Protocol states vital signs will be listed. In addition the following analysis will be 
performed 
•
absolute values and change from baseline summarized by parameter, and visit
•
the number and percentage of patients by parameter, and visit with
- pulse rate < 40 bpm, 40 – 90 bpm, and > 90 bpm
- SBP < 90 mm Hg, 90 – 140 mm Hg, and > 140 mm Hg
- DBP < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg
•
the number and percentage of patients with newly occurring or worsening notable vital
signs values (see Section 5.5 for definition of notable values) summarized by parameter
(except height and weight), scheduled post-baseline visit and additionally at any time
on treatment considering all post-baseline data from scheduled, unscheduled and
premature discontinuation visits
Laboratory and ECG data: Protocol states ECG and laboratory data will be listed. In addition 
descriptive summaries by period will be presented. 
5 
Appendix 
This appendix gives details about statistical methods in addition to the report text. All analyses 
will be performed by using SAS Version 9.4. 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing/partial start date or end date of study treatment will not be imputed. 
5.1.2 
AE date imputation 


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Rules for imputing AE end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details. 
5.1.3 
Concomitant medication date imputation 
Rules for imputing the CM end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details. 
5.1.3.1 
Prior therapies date imputation 
Missing/partial start date or end date of prior therapies will not be imputed. 
5.1.3.2 
Post therapies date imputation 
Rules for imputing the post therapies end date or start date will be provided in Programming 
Dataset Specification (PDS) document in details. 
5.2 
AEs and Concomitant medications coding/grading 
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. For coding purpose of the concomitant medications, the 
available WHO-DD (World Health Organization- Drug Dictionary) version at the time of 
database lock, will be used. 
5.3 
Data pooling and assessment windows 
Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed. For patients who do not complete the study treatment, the treatment 
discontinuation visit will be an unscheduled visit. 
Clinical laboratory measurements, vital signs and ECG data from unplanned or unscheduled 
visits will only be included in the summaries of the notable values and extreme values. All 
efficacy data (including spirometry data) from these visits will not be used for missing data 
imputation unless specified otherwise. 
Laboratory, vital signs, and ECG values that have complete data and time values will be slotted 
into pre- or post-dose assessment based on the actual date/time. For values with missing 
date/time, scheduled visit date and time will be used. This rule will be applied to data from 
scheduled visits only. If a measurement scheduled as pre-dose is actually performed post-dose, 
or vice versa, the data will not be used for by time point assessments. 
5.4 
Laboratory parameters derivations 
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.  


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Laboratory parameter (unit) 
Lower bound of 
clinically notable range 
Upper bound of 
clinically notable range 
Hematology 
Hematocrit (v/v) 
     Male 
     Female 
0.37 
0.32 
Hemoglobin (g/L) 
    Male 
    Female 
115 
95 
Platelets (x10E9/L) 
75 
700 
WBC (x109/L) 
2.8 
16.0 
Chemistry 
Albumin (g/L)  
25 
- 
Alkaline Phosphatase (U/L) 
- 
3xULN 
ALT/SGPT (U/L) 
- 
3xULN 
AST/SGOT (U/L) 
- 
3xULN 
Bilirubin Total (mcmol/L) 
- 
34.2 
BUN (mmol/L) 
- 
9.99 
Creatinine (mcmol/L) 
- 
176.8 
Glucose (mmol/L) 
2.78 
9.99 
Gamma GT (U/L) 
- 
3 x ULN 
Potassium (mmol/L) 
3 
6 
v = volume, ULN = upper limit of normal 
Notable liver function test values 
Criterion 
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin > 1 x ULN 
Total bilirubin > 1.5 x ULN 
Total bilirubin > 2 x ULN 
Total bilirubin > 3 x ULN 
ALP > 1.5 x ULN 
ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 


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ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law) 
ALT or AST > 3 x ULN and (nausea or vomiting or fatigue or general malaise or abdominal pain or (rash and 
eosinophilia))* 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
* Based on the signs/symptoms information as recorded on the liver events eCRF, not the adverse events eCRF.
5.5 
Vital signs and ECG – definition of clinically notable values 
The following table shows the clinical notable criteria for vital signs. 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of 
clinically notable range 
Notable value considering newly occurring or worsening cases 
Systolic blood pressure (mmHg) 
< 75 
> 200
Diastolic blood pressure (mmHg) 
< 40 
> 115
Pulse rate (bpm) 
< 40 
> 130
Notable change from baseline 
Systolic blood pressure (mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20  
≥ 180 and increase 
from baseline by ≥ 20 
Diastolic blood pressure (mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase 
from baseline by ≥ 15 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase 
from baseline by ≥ 15 


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The following table shows the clinical notable criteria for QTcF. 
Clinical notable criteria for QTcF (Fridericia's formula) 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTc (msec) 
> 450 (male)
QTc (msec) 
> 460 (female)
QTc (msec) 
> 500 (both)
5.6 
Statistical models 
5.6.1 
Primary analysis 
The following Liner Mixed Model will be used for trough FEV1, other spirometry endpoints, 
PEF and rescue medication use: 
The primary endpoint and other secondary endpoints will be analyzed using a linear mixed-
effect model. The model will include period, treatment, and sequence as fixed effect factors and 
patients within sequence as random factor and baseline trough FEV1 as a covariate. Restricted 
maximum likelihood method will be used. The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom. The within-patient correlation will be modeled using 
the unstructured covariance matrix. In case of the analysis failing to converge, compound 
symmetric covariance structure will be used.  
The following Liner Mixed Model will be used for trough FEV1, other spirometry endpoints, 
PEF and rescue medication use: 
Dependent variable = intercept + period + treatment + sequence + baseline value + 
random(patient (sequence)) + error.
Results will be presented with LSM and SE for treatment effects and LSM, SE, associated two-
sided 95% confidence interval, and two-sided p-value for treatment differences of each 
NVA237 dose versus placebo. 
The SAS procedure Proc MIXED will be used. 
5.6.2 
Sensitivity analysis 
The following Liner Mixed Model will be used for sensitivity analysis: 
The primary endpoint will be analyzed using a linear mixed-effect model. The model will 
include period, treatment, sequence and carry-over factor as fixed effect factors and patients 
within sequence as random factor and baseline trough FEV1 as a covariate. Restricted maximum 


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likelihood method will be used. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. The within-patient correlation will be modeled using the 
unstructured covariance matrix. In case of the analysis failing to converge, compound 
symmetric covariance structure will be used.  
The following Liner Mixed Model will be used for trough FEV1, other spirometry endpoints, 
PEF and rescue medication use: 
Dependent variable = intercept + period + treatment + sequence + carry-over factor + baseline 
value + random(patient (sequence)) + error.
Results will be presented with LSM and SE for treatment effects and LSM, SE, associated two-
sided 95% confidence interval, and two-sided p-value for treatment differences of each 
NVA237 dose versus placebo. 
The SAS procedure Proc MIXED will be used. 
5.6.3 
Key secondary analysis 
Not Applicable 
5.7 
Rule of exclusion criteria of analysis sets 
Rule of exclusion criteria from analysis sets due to protocol deviations will be included prior to 
database lock. 
Protocol deviations leading to exclusion from analysis sets. 
INCL01 
Informed consent not obtained or incorrect version signed or 
obtained after first assessment performed 
Exclude from PPS, RAN, 
FAS and SAF 
INCL02 
Age less than 18 years or greater than 65 years or missing 
Exclude from PPS 
INCL03 
No current diagnosis of persistent Asthma at least 12 months 
prior to V1 
Exclude from PPS 
INCL04 
Patient not  treated with  any dose of daily ICS/LABA 
combination or not in stable dose 4 weeks prior to Visit 1 
Exclude from PPS 
INCL05 
Pre- Bronchodilator FEV1 at V101 or V102 less than 50% or 
greater than 80% of predicted normal value 
Exclude from PPS 
INCL06 
Reversibility value not met (FEV1 less than 12% or greater 
than 200 ml) at visit 101 
Exclude from PPS 
EXCL01 
Patient has a contraindication to study drug  or 
hypersensitivity to any study drug or to similar drugs within the 
class or any component specified in the protocol 
Exclude from PPS 
EXCL09 
Clinical significant condition compromising patient safety or 
compliance, interfere with evaluation or preclude completion 
of the study 
Exclude from PPS 
EXCL12 
Patient had an Asthma attack/exacerbation requiring systemic 
corticosteroids or hospitalization or ER visits within 6 weeks 
prior to Visit 1  
Exclude from PPS 


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EXCL14 
Patient with a Respiratory Tract Infection 4 weeks prior to Visit 
1 
Exclude from PPS 
EXCL15 
Patient has a smoking history of > 10 pack years or missing 
Exclude from PPS 
EXCL16 
Patient smoked or inhaled tobacco within the 6 month period 
prior to Visit 1 
Exclude from PPS 
EXCL17 
Patient has a chronic condition affecting the upper respiratory 
tract that interfere with study evaluation or participation in the 
trial 
Exclude from PPS 
EXCL18 
Patient has a history of chronic lung diseases other than 
asthma 
Exclude from PPS 
EXCL19 
Patient taking prohibited asthma related medication after the 
minimum cesation period or taken medication not according to 
instructions specified in Table 5-2 of protocol prior to visit 101 
run in period 
Exclude from PPS 
EXCL20A 
Patient taking Prohibited  medication after the minimum 
cesation period or taken medication not according to 
instructions specified in Table 5-3 of protocol prior to visit 101 
run in period with impact in efficacy analysis (medical lead 
decision) 
Exclude from PPS 
EXCL21 
Patient is on maintenance immunotherapy for allergies for at 
least 3 months prior to Visit 101 who are expected to change 
therapy 
Exclude from PPS 
EXCL22 
Patient unable to use dry powder inhaler device  
Exclude from PPS 
EXCL24 
Patient using other Investigational drugs within 30 days of 
Visit 101 or 5 half lives whichever is longer. 
Exclude from PPS 
EXCL25 
Patient shown intolerable to LABA withdrawal during the Run-
In period 
Exclude from PPS 
EXCL26 
Patient with a history of Paradoxical bronchospasm 
Exclude from PPS 
EXCL27 
Patient who have discontinued LAMA therapy due to 
intolerance or lack of efficacy 
Exclude from PPS 
EXCL28 
Patient where variability in FEV1 value between visit 101 and 
102 is > 20% 
Exclude from PPS 
COMD03A Patient taking prohibited asthma related medication or taken 
medication not according to instructions after the Visit 101 (list 
specified in Table 5-2 of protocol) with potential impact on key 
efficacy  evaluations of period 1 
Exclude from PPS in 
period 1  
COMD03B Patient taking prohibited asthma related medication or taken 
medication not according to instructions after the Visit 101 (list 
specified in Table 5-2 of protocol) with potential impact on key 
efficacy evaluations of period 2 
Exclude from PPS in 
period 2 
COMD03C Patient taking prohibited asthma related medication or taken 
medication not according to instructions after the Visit 101 (list 
specified in Table 5-2 of protocol) with potential impact on key 
efficacy  evaluations of period 3 
Exclude from PPS in 
period 3  
COMD04A Patient taking prohibited medication or taken medication not 
according to instructions  after the Visit 101 (list specified in 
Table 5-3 of protocol) with potential impact on key efficacy 
evaluations of period 1 
Exclude from PPS in 
period 1  
COMD04B Patient taking prohibited medication or taken medication not 
according to instructions  after the Visit 101 (list specified in 
Exclude from PPS in 
period 2 


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Table 5-3 of protocol) with potential impact on key 
efficacyevaluations of period 2 
COMD04C Patient taking prohibited medication or taken medication not 
according to instructions  after the Visit 101 (list specified in 
Table 5-3 of protocol) with potential impact on key efficacy 
evaluations of period 3 
Exclude from PPS in 
period 3  
WITH02 
Unblinding of study treatment and patient still in the study 
Exclude from PPS 
TRT02 
Patient received expired treatment. 
Exclude from PPS 
TRT03 
Patient took more than one daily dose of study drug during 
treatment period  
Exclude from PPS 
TRT04A 
Patient took study drug during washout period of period 1 
Exclude from PPS in 
period 2 
TRT04B 
Patient took study drug during washout period of period 2 
Exclude from PPS in 
period 3  
TRT05 
Patient compliance with daily ICS dose is less than 80% 
Exclude from PPS 
OTH01 
Patient who received study medication before or without 
randomization 
Exclude from PPS, RAN 
and FAS 
OTH02 
Patient was Randomized but no study drug was taken 
Exclude from SAF, FAS 
and PPS 
OTH03 
Severe ICH-GCP non compliance of study site in the study 
(eg: fraud) 
Exclude from PPS, RAN, 
FAS and SAF 
6 
Reference 
Byron Jones, Michael G. Kenward (2014) Design and Analysis of Cross-Over Trials, Third 
Edition, Chapman and Hall/CRC Press