Conditions: Asthma
Keywords: QVM149 Asthma Japanese Allergic asthma Allergy triggered asthma Reactive asthma Asthma attack Difficulty breathing
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 96
Healthy volunteers: no

Brief summary:
The purpose of this study is to provide long term safety data of QVM149 in Japanese patients with asthma for the registration of QVM149 in Japan.

Detailed description:

Arms:
arm 1: All eligible patients take QVM149 150/50/160 μg once daily over 52 weeks.

Interventions: intervention 1: QVM149
Intervention descriptions: intervention 1: QVM149 (indacaterol acetate/glycopyrronium bromide/mometasone furoate)

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
QVM149B (Indacaterol acetate/Glycopyrronium 
bromide/Mometasone furoate)
Clinical Trial Protocol CQVM149B1304 / NCT03100825
A multicenter, open-label, single arm, 52-week treatment 
study to assess the safety of QVM149 in Japanese patients 
with asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
01 (Clean)
Clinical trial phase:
III
Release date:
6-Apr-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 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
Amendment 01 .........................................................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................18
2
Study objectives and endpoints .........................................................................................18
2.1
Objectives and related endpoints...........................................................................18
3
Investigational plan ...........................................................................................................19
3.1
Study design...........................................................................................................19
3.2
Rationale for study design .....................................................................................20
3.3
Rationale for dose/regimen, route of administration and duration of treatment....20
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................21
3.6
Risks and benefits..................................................................................................21
4
Population..........................................................................................................................22
4.1
Inclusion criteria ....................................................................................................22
4.2
Exclusion criteria...................................................................................................23
5
Treatment...........................................................................................................................26
5.1
Study treatment......................................................................................................26
5.1.1
Investigational and control drugs..........................................................26
5.1.2
Additional treatment..............................................................................27
5.2
Treatment arms......................................................................................................27
5.3
Treatment assignment and randomization.............................................................27
5.4
Treatment blinding.................................................................................................27
5.5
Treating the patient................................................................................................27
5.5.1
Patient numbering .................................................................................27
5.5.2
Dispensing the study drug.....................................................................27
5.5.3
Handling of study and additional treatment..........................................28
5.5.4
Instructions for prescribing and taking study treatment........................28
5.5.5
Permitted dose adjustments and interruptions of study treatment ........29


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5.5.6
Rescue medication ................................................................................29
5.5.7
Concomitant medication .......................................................................30
5.5.8
Prohibited medication ...........................................................................30
5.5.9
Emergency breaking of assigned treatment code..................................33
5.6
Study completion and discontinuation...................................................................33
5.6.1
Study completion and post-study treatment..........................................33
5.6.2
Discontinuation of study treatment .......................................................33
5.6.3
Withdrawal of informed consent...........................................................36
5.6.4
Loss to follow-up ..................................................................................36
5.6.5
Early study termination by the sponsor.................................................36
6
Visit schedule and assessments .........................................................................................37
6.1
Information to be collected on screening failures..................................................40
6.2
Patient demographics/other baseline characteristics .............................................40
6.3
Treatment exposure and compliance .....................................................................41
6.4
Efficacy..................................................................................................................41
6.4.1
Spirometry.............................................................................................41
6.4.2
Electronic Diary ....................................................................................42
6.4.3
Asthma Control Questionnaire 7 (ACQ-7) ...........................................42
6.4.4
Worsening of asthma.............................................................................43
.44
6.4.6
Appropriateness of efficacy assessments..............................................45
6.5
Safety.....................................................................................................................45
6.5.1
Physical examination ............................................................................46
6.5.2
Vital signs..............................................................................................46
6.5.3
Height and weight .................................................................................46
6.5.4
Laboratory evaluations..........................................................................46
6.5.5
Electrocardiogram (ECG) .....................................................................47
6.5.6
Serious Asthma outcomes.....................................................................48
6.5.7
Pregnancy and assessments of fertility .................................................48
6.5.8
Appropriateness of safety measurements..............................................49
6.6
Other assessments..................................................................................................49
7
Safety monitoring..............................................................................................................49
7.1
Adverse events.......................................................................................................49
7.2
Serious adverse events...........................................................................................51
7.2.1
Definition of SAE .................................................................................51
7.2.2
SAE reporting........................................................................................51


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7.3
Pneumonia Reporting ............................................................................................52
7.4
Liver safety monitoring .........................................................................................52
7.5
Reporting of study treatment errors including misuse/abuse ................................53
7.6
Pregnancy reporting...............................................................................................54
8
Data review and database management.............................................................................54
8.1
Site monitoring ......................................................................................................54
8.2
Data collection.......................................................................................................55
8.3
Database management and quality control............................................................55
8.4
Data Monitoring Committee..................................................................................56
8.5
Adjudication Committee........................................................................................56
9
Data analysis......................................................................................................................56
9.1
Analysis sets ..........................................................................................................57
9.2
Patient demographics and other baseline characteristics.......................................57
9.3
Treatments .............................................................................................................57
9.4
Analysis of the primary variable(s) .......................................................................58
9.4.1
Primary Variable(s)...............................................................................58
9.4.2
Statistical model, hypothesis, and method of analysis..........................58
9.4.3
Handling of missing values/censoring/discontinuations.......................58
9.4.4
Sensitivity analyses ...............................................................................58
9.5
Analysis of secondary variables ............................................................................58
9.5.1
Efficacy variables..................................................................................58
9.5.2
Safety variables .....................................................................................59
9.5.3
Resource utilization...............................................................................61
9.5.4
Pharmacokinetics ..................................................................................61
9.5.5
DNA......................................................................................................61
9.5.6
Biomarkers............................................................................................61
9.5.7
PK/PD ...................................................................................................61
61
9.7
Interim analyses.....................................................................................................62
9.8
Sample size calculation..........................................................................................62
10 Ethical considerations........................................................................................................62
10.1
Regulatory and ethical compliance........................................................................62
10.2
Informed consent procedures.................................................................................62
10.3
Responsibilities of the investigator and IRB/IEC..................................................63
10.4
Publication of study protocol and results...............................................................63
10.5
Quality Control and Quality Assurance.................................................................63


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11 Protocol adherence ............................................................................................................64
11.1
Protocol amendments.............................................................................................64
12 References .........................................................................................................................65
13 Appendices ........................................................................................................................66
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................66
13.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................67
13.3
Appendix 3: Spirometry Guidance ........................................................................69
13.4
Appendix 4: Patient Asthma Control e-Diary .......................................................72
13.5
Appendix 5: Instruction for Use of Concept1........................................................73
List of tables
Table 1-1
Comparison of nominal MF doses in Asmanex Twisthaler, 
QMF149 and QVM149 drug products delivered by Concept1 
(Breezhaler)...........................................................................................17
Table 2-1
Objectives and related endpoints ..........................................................18
Table 5-1
Prohibited Asthma-related medications1...............................................30
Table 5-2
Prohibited Medications1........................................................................31
Table 5-3
Medications allowed under certain conditions1 ....................................31
Table 5-4
Table of assessment for the patients who discontinue 
investigational drug prematurely...........................................................35
Table 6-1
Assessment schedule.............................................................................38
Table 6-2
Timing of clinic visit procedures ..........................................................40
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................67
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers...67
List of figures
Figure 3-1
Study design..........................................................................................20


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List of abbreviations
ACQ
Asthma Control Questionnaire
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CCV
Cardiovascular and cerebrovascular
CFR
US Code of Federal Regulations
COPD
Chronic Obstructive Pulmonary Disease
CPO
Country Pharma Organization
CRO
Contract Research Organization
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
ePEF
electronic Peak Flow Meter
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in 1 second
FPM
Fine Particle Mass
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
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
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intra Uterine System
JGL
Asthma Prevention and Management Guideline
LABA
Long-Acting β2 Agonist
LAMA
Long-Acting Muscarinic Antagonist
LFT
Liver Function Test
MDDPI
Multi Dose Dry Powder Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
MF
Mometasone Furoate
OC/RDC
Oracle Clinical/Remote Data Capture
OCS
Oral Corticosteroids
o.d.
once a day


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PC
Personal Computer
PEF
Peak Expiratory Flow
pMDI
pressurized Metered Dose Inhaler
RBC
Red Blood Cell
SABA
Short-Acting β2 Agonist
SAE
Serious Adverse Event
SAMA
Short-Acting Muscarinic Antagonist
SCS
Systemic Corticosteroids
SDDPI
Single Dose Dry Powder Inhaler
SUSAR
Suspected Unexpected Serious Adverse Reactions
ULN
Upper Limit of Normal range
WBC
White Blood Cell
WHO
World Health Organization


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Glossary of terms
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
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
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.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination.
Investigational treatment generally does not include protocol-specified 
concomitant background therapies when these are standard treatments 
in that indication.
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Premature study
withdrawal (PSW)
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
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/investigational 
treatment discontinuation
Point/time when patient permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature patient withdrawal
Subject number
A number assigned to each patient who enrolls into the study
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


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Withdrawal of consent
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 
material


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Amendment 01
Amendment rationale
Modification of inclusion criteria for duration of baseline ICS/LABA requirements from 6 
months to 3 months. This is based on investigator feedback from real world asthma 
populations and intended to address evolving treatment patterns, whereby patient medications 
are more rapidly up-titrated in response to symptoms. This will help identify previously 
ineligible patients who may potentially benefit from treatment with LAMA as add-on therapy 
to existing ICS/LABA treatment.
Changes to the protocol
The described changes pertaining to the aforementioned amendment rationale are 
implemented throughout the protocol.
In addition, the following clarifications/additions are included in this protocol amendment:

Change the required pre-treatment period of ICS/LABA to 3 months prior to Visit 1 in
inclusion criteria 4 (Section 4.1)

Add the guidance of washout period in inclusion criteria 6 (Section 4.1)

Update the repeat spirometry test including reversibility in inclusion criterion 6, inclusion
criterion 7, and exclusion criterion 21 (Section 4.1 and Section 4.2)

Change the condition of spacer use for reversibility testing in inclusion 7 and excluding  
spacer use for rescue medication in exclusion criterion 30 (Section 4.1 and Section 4.2)

Add a clarification of Myocardial Infarction in exclusion criteria 16 and 19 (Section 4.2)

Correct the condition under antihistamines (except mizolastin) is permitted (Section 5.5.8)

Enhance importance of alert to have appropriate actions taken (Section 6.4.4).

Correct urinalysis item(Section 6.5.4.3)

Clarify SAE reporting (Section 7.2.2)

Remove ATC code for summarizing concomitant medication(Section 9.3)

Update the definition of repeatability in the spirometry guidance (Appendix 3)
An opportunity was also taken to make smaller changes such as some minor editorial changes 
that include correction of typographical errors and some clarifications and rewording to 
ensure consistency between protocol sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein do NOT affect the trial specific model ICF.


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Protocol summary
Protocol number
CQVM149B1304
Full Title
A multicenter, open-label, single arm, 52-week treatment study to assess 
the safety of QVM149 in Japanese patients with asthma
Brief title
A long-term safety study of QVM149 in Japanese patients with asthma
Sponsor and Clinical 
Phase
Novartis Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to provide long term safety data of QVM149 in 
Japanese patients with asthma for the registration of QVM149 in Japan.
Primary Objective(s)
To assess the safety/tolerability of 52 weeks of treatment with QVM149 
(high dose) in Japanese patients with inadequately controlled asthma, by 
the incidence and severity of treatment emergent adverse events
Secondary Objectives

To assess the safety of QVM149 over 52 weeks of treatment, in terms 
of ECG, Vital signs, laboratory parameters, and plasma cortisol

To assess the efficacy of QVM149 in terms of lung-function in 
Japanese patients with inadequately controlled asthma after 26 and 52 
weeks of treatment

To assess the efficacy of QVM149 in terms of asthma control after 26 
and 52 weeks of treatment

To assess the efficacy of QVM149 in terms of rescue medication use 
during 52 weeks treatment
Study design
52 weeks multi-center, open-label, single arm study
Population
The study population will consist of approximately 100 Japanese males and 
females aged ≥18 years with asthma.
Key Inclusion criteria

Written informed consent must be obtained before any assessment is 
performed.

Male and female adult patient ≥18 years old.

Patients with a diagnosis of persistent asthma (GINA 2016) for a period 
of at least 1 year prior to Visit 1.

Patients who have used medium or high dose of ICS/LABA 
combinations for asthma for at least 3 months and at stable dose and 
regimen for at least 4 weeks prior to Visit 1.

An ACQ-7 score ≥1.5 at Visits 2.

Pre-bronchodilator FEV1 of ≥40% and ≤85% of the predicted normal 
value for the patient after withholding bronchodilators at Visit 2.

Repeating is allowed once only. Repeating 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 Visit 99.

Patients must demonstrate reversibility defined as an increase in FEV1
of ≥12% and 200 mL within 15 to 30 minutes after administration of 
400 µg of salbutamol at Visit 2. Spacer devices are permitted during 
reversibility testing only. The Investigator or delegate may decide 
whether or not to use a spacer for the reversibility testing.


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
If reversibility is not proven at Visit 2, patients may be permitted to 
enter the study with historical evidence of reversibility that was 
performed within 5 years prior to Visit 1.

Alternatively, patients may be permitted to enter the study with a 
historical positive bronchoprovocation test (defined as a provoked 
fall in FEV1 of 20% by bronchoconstriction agent e.g., 
methacholine, histamine) or equivalent test (e.g., astography) that 
was performed within 5 years prior to Visit 1.

If reversibility is not proven at Visit 2 and historical data is not 
available, reversibility should be repeated once in an ad-hoc visit 
scheduled as close as possible from the first attempt (but not on 
the same day).
Key Exclusion criteria

Patients who have had an asthma attack/exacerbation requiring 
systemic steroids or hospitalization or emergency room visit within 6-
weeks of Visit 1.

Patients who have ever required intubation for a severe asthma 
attack/exacerbation.

Patients who have a clinical condition which is likely to be worsened by 
ICS administration (e.g. glaucoma, cataract and fragility fractures) who 
are according to investigator's medical judgment at risk participating in 
the study.

Patients with narrow-angle glaucoma, symptomatic benign prostatic 
hyperplasia (BPH) or bladder-neck obstruction or severe renal 
impairment or urinary retention. BPH patients who are stable on 
treatment can be considered.

Patients who have had a respiratory tract infection or asthma 
worsening as determined by investigator within 4 weeks prior to Visit 1 
or between Visit 1 and Visit 99. Patients may be re-screened 4 weeks 
after recovery from their respiratory tract infection or asthma 
worsening.

Patients with a history of chronic lung diseases other than asthma, 
including (but not limited to) COPD, sarcoidosis, interstitial lung 
disease, cystic fibrosis, clinically significant bronchiectasis and active 
tuberculosis.

Patients with severe narcolepsy and/or insomnia

Pregnant or nursing (lactating) women

Women of child-bearing potential unless they are using highly effective 
methods of contraception during dosing and for 30 days after stopping 
of investigational medication
Study treatment
High dose QVM149 150/50/160 µg (indacaterol acetate/glycopyrronium 
bromide/MF) once daily delivered as powder in capsules via Concept1
Efficacy assessments

Spirometry

Peak Expiratory Flow

ACQ-7

Rescue Medication Use
Key safety 
assessments

Adverse events and serious adverse events

ECG

Vital signs

Laboratory findings


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
Evening plasma cortisol
Other assessments
Not applicable
Data analysis
The primary variable is the number and percentage of patients who 
reported treatment emergent adverse events during the 52 weeks study 
period.
Adverse events will be summarized with descriptive statistics for the Safety 
Set.
Key words
QVM149, asthma, Japanese


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1
Introduction
1.1
Background
Asthma is a chronic inflammatory disorder of the airways associated with airways hyper 
responsiveness 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 lung 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. Exacerbations 
of asthma are episodic whereas inflammation is chronic (GINA 2016).
Despite existing therapies there is still significant unmet medical needs in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years are lost annually due to asthma,
representing 1% of the total global burden. Annual worldwide deaths have been estimated at 
250 000 (Masoli et al 2004). In Japan, asthma death has been significantly decreased with the 
recent advance in asthma treatments and the widespread use of Asthma Prevention and 
Management Guideline (JGL). But then again, a nationwide survey conducted in Japanese 
adult asthma patients revealed that the proportion of patients with asthma control status of 
well-controlled, insufficiently-controlled and poorly-controlled were 9.1%, 73.6% and 17.3% 
respectively (Adachi et al 2015), indicating that there is still unmet needs for the new and 
better treatment option to improve asthma control.
GINA and JGL recommend similar diagnostic methods, treatment goals and treatment 
strategies and share the same treatment goal of long-term clinical asthma symptom control.
The current mainstay of asthma treatment is LABA/ICS-based, and the LAMA is expected to 
be an add-on option for patients whose asthma symptoms are poorly controlled. A clinical 
study of a LAMA (tiotropium) added to ICS or LABA/ICS in poorly controlled moderate to 
severe persistent asthma patients showed significant respiratory function improvements 
(forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF)) without a 
particular safety issue (Befekdadu et al 2014). Tiotropium was approved for asthma indication 
in Japan in 2014.
Following tiotropium regulatory approval in asthma, GINA 2016 guideline recommends 
tiotropium as a new add-on option on top of the preferred controller choice for steps 4 and 5 
in patients aged with a history of exacerbations. The preferred controller choice in asthma step 
4 is med/high ICS/LABA and in step 5 add-on treatment e.g. anti-IgE.
QVM149 is a fixed-dose combination of indacaterol acetate (inhaled LABA with 24 hour 
duration of action), glycopyrronium bromide (inhaled LAMA with 24 hours duration of 
action), and mometasone furoate (MF, ICS) in development 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. Novartis is developing QVM149 (LABA/LAMA/ICS) fixed dose 
combination (FDC) as a lactose-blended inhalation powder to be delivered via Concept1 


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(Breezhaler®), a single dose dry powder inhaler (SDDPI) for maintenance treatment for severe 
asthma (GINA 2016 Step ≥4).
In parallel, Novartis is developing QMF149, which is a fixed dose combination of 
mometasone furoate (MF) and indacaterol, in the Concept1 device.
Data from QVM149 monocomponents:
QVM149 is being developed in parallel with QMF149 (indacaterol acetate/MF) and existing 
efficacy and safety data for the three mono-components of the QVM149 FDC as well as for 
the two combinations indacaterol/mometasone (QMF149) and glycoppyronium/indacaterol 
(Ultibro®) support investigation in Phase III.
Indacaterol maleate, delivered via Concept1, a single dose dry powder inhaler (SDDPI) 
(Onbrez® Breezhaler®), is approved in over 110 countries worldwide for the once daily 
maintenance bronchodilator treatment of airflow obstruction in patients with COPD. 
Treatment guidelines state that LABAs are most effective when combined with an ICS 
(GINA 2016). The Phase III clinical development of indacaterol maleate that included studies 
in patients with asthma (who were receiving background ICS therapy), demonstrated that 
indacaterol maleate was effective and well-tolerated. A study in adolescent and adult patients 
with moderate to severe persistent asthma showed that doses of up to 600 µg o.d. over a 
26-week treatment period (when administered with concomitant ICS therapy) was well-
tolerated and resulted in effective bronchodilation which was superior to that provided by 
salmeterol (CQAB149B2338).
Studies comparing the indacaterol maleate salt with the acetate salt found that the alternative 
salts were associated with a lower incidence of post-inhalation cough (CQAB149B2102) with 
no impact on efficacy, safety or systemic exposure (CQAB149D2301). Indacaterol acetate 
dilates the bronchi quickly and continuously over 24 hours when administered once daily at 
150 µg in moderate to severe asthma patients (CQMF149E2203).
Glycopyrronium bromide (50 µg once daily in a lactose-based formulation) is registered in the 
EU since 2012 as Seebri®
Breezhaler®
(Concept1) for the treatment of COPD. 
Glycopyrronium bromide 50 µg has demonstrated clinically meaningful and statistically 
significant improvements in lung function in COPD patients which is sustained over 24 hours 
and provides significant symptomatic benefits with a favorable safety and tolerability profile.  
The fixed dose combination of indacaterol maleate and glycopyrronium bromide is also 
registered as Ultibro®, Breezhaler® in the EU and Japan (QVA149 110/50 µg with proven 
equivalent fine particle mass (FPM) of indacaterol maleate as obtained in indacaterol maleate 
150 µg) with the same doses as proposed for QVM149 (150/50/80 µg). Glycopyrronium 
bromide has been studied in adults and demonstrated optimal bronchodilation from the first 
dose and efficacy was maintained on once-daily dosing for treatment periods of up to a year, 
with good safety and tolerability.
MF is marketed in inhalation, nasal, cream, ointment and lotion formulations. The inhalation 
powder formulation which may be administered once or twice daily is marketed as a multi 
dose dry powder inhaler (MDDPI) called Asmanex® Twisthaler® for the treatment of asthma. 
Asmanex® Twisthaler® is currently approved in the United States for the treatment of asthma 


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in adults and children ≥4 years of age and is approved in over 55 countries world-wide for the 
treatment of asthma in adults and adolescents ≥12 years of age.
MF doses in QVM149
The MF doses in QMF149 program with Concept1 device are comparable to MF 200 µg, 
400 µg and MF 800 µg (400 µg twice a day) in Twisthaler® device as demonstrated in study 
(CQMF149E2101, Vaidya et al 2012) and after in-vitro fine particle mass adjustment. 
In a 4-week study in patients with persistent asthma (Study CQMF149E2201), MF doses of 
80 µg and 320 µg delivered once daily via Concept1 showed comparable efficacy and 
systemic exposure to MF doses of 200 µg and 800 µg (2 x 400 µg) delivered once daily via 
Twisthaler® confirming the selected doses for MF Concept1 are appropriate for further 
QMF149 Concept1 development.
The nominal doses of MF are 80 µg and 160 µg in the QVM149 FDC to ensure that the FPM 
(in-vitro aerosol performance) in the lactose blend formulation for the triple FDC is similar to 
the nominal MF doses of 160 µg and 320 µg for QMF149 Concept1 program, respectively. In 
this current study the medium and high doses of MF taken forward in QVM149 are 80 µg and 
160 µg which are comparable to the MF doses of 160 µg and 320 µg in the QMF149 products 
in QMF149B2301.
No adjustments to the doses of indacaterol acetate or glycopyrronium bromide in the FDC 
combinations were required.
Table 1-1
Comparison of nominal MF doses in Asmanex Twisthaler, QMF149 
and QVM149 drug products delivered by Concept1 (Breezhaler)
MF dose 
level
MF in Asmanex delivered 
by Twisthaler
MF in QMF149 delivered 
by Concept1
MF in QVM149 delivered 
by Concept1
Mid
400 µg
160 µg
80 µg
High
800 µg
320 µg
160 µg
The role of long-acting anticholinergics on top of medium and high dose ICS and LABA 
(FDC) as controller medication (QVM149) is supported based on the asthma clinical trial data 
with tiotropium on top of ICS and LABA/ICS in patients with severe persistent asthma 
(Kerstjens et al 2012).
Given that literature suggests that many asthma patients have poorly controlled disease 
despite currently available controller medications and there is increasing evidence of lung 
function benefit and improved control with triple combination therapy, further investigation of 
QVM149 triple therapy is supported.
On-going CQVM149B2302 is the pivotal study for regulatory submission, in which the 
superiority of QVM149 to QMF149 is evaluated and Japanese subjects are involved. Efficacy 
and safety data of 1 year treatment in Japanese patients will be obtained from this study.
The regulatory requirement for the long term safety data is to collect data for at least 100 
Japanese patients exposed to the study drug for one year. To comply with the requirement, 


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this study (CQVM149B1304) is intended to support the assessment of the long term safety 
and efficacy of QVM149 in Japanese population.
Additional information to QVM149 can be found in the QVM149 Investigator's brochure.
1.2
Purpose
The purpose of this study is to provide long term safety data of QVM149 in Japanese patients
with asthma for the registration of QVM149 in Japan.
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To assess the safety/tolerability of 52 weeks 
of treatment with QVM149 (150/50/160 µg, 
once daily) in Japanese patients with
inadequately controlled asthma
Endpoint(s) for primary objective(s) 

The incidence and severity of treatment 
emergent adverse events (AEs) over 52 
weeks of treatment
Secondary Objective(s)

To assess the safety of QVM149 over 
52 weeks of treatment
Endpoint(s) for secondary objective(s)

ECG, vital sign (blood pressure, pulse rate), 
laboratory parameters (hematology, clinical 
chemistry and urinalysis), plasma cortisol
over 52 weeks of treatment

To assess the efficacy of QVM149 in terms of 
lung-function in Japanese patients with 
inadequately controlled asthma

Change from baseline of pre-dose FEV1
measured after 26 and 52 weeks treatment

Change from baseline of morning and 
evening PEF during 52 weeks

To assess the efficacy of QVM149 in terms of 
asthma control

Change from baseline of ACQ-7 after 26 and 
52 weeks treatment

Responder rate of patients achieving the 
minimal important difference (MID) of ACQ-7
≥0.5 after 26 and 52 weeks treatment

To assess the efficacy of QVM149 in terms of 
rescue medication use

Change from baseline rescue medication 
use during 52 weeks treatment


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3
Investigational plan
3.1
Study design
This study uses a 52-week treatment, multicenter, open-label, single-arm design in Japanese 
patients with asthma (Figure 3-1). One interim analysis is planned after the last patient 
completed the assessments at Week 26 (Visit 107).
Screening epoch
All patients must have used medium or high dose ICS/LABA for at least 3 months and been 
on stable dose and regimen for at least 4 weeks prior to Visit 1. A screening epoch of 
maximum of 4 weeks (from Visit 1 to 99) will be used to assess eligibility and to taper 
patients off prohibited medications (Section 5.5.8). At Visit 1, all patients will be given 
salbutamol to use as rescue medication throughout the screening and treatment epochs and 
will be given an electronic diary to record asthma symptoms and rescue medication use. In 
addition, patients will be given an electronic Peak Flow meter to record PEF. The last 2 weeks 
of screening epoch (from Visit 2 to 99) will be used to assess eligibility of the patients to enter 
the treatment epoch and to collect baseline values for some variables.
Screening epoch must have a minimum of 2 weeks prior to start taking study medication at 
Visit 101 (Day 1).
Treatment epoch
Visits 99 and 101 take place sequentially on the same date. The assessments at Visit 99 should 
be performed prior to administration of the first dose of investigational drug; eligible patients 
will be assigned to QVM149 150/50/160 µg o.d. (high ICS dose), and enter 52-week 
treatment epoch. Patients will be required to inhale QVM149 150/50/160 µg via Concept1 
once daily in the evening throughout treatment epoch. The first dose of investigational drug
will be administered at the clinic in the evening (between 4:00 and 8:00 pm) at Visit 101. 
Subsequent clinic visits will be scheduled so that patients will be reassessed as close as 
possible to the same time relative to the evening doses. Patients will be instructed not to take 
their evening dose of investigational drug on the days of the clinic visits, as these doses will 
be administered at the clinic under the supervision of study personnel. Clinic visits to assess 
safety and efficacy are scheduled at weeks 4, 12, 26, 36 and 52.
Follow-up epoch
A safety follow-up (telephone contact, Visit 201) will be conducted at 30 days after the last 
treatment date (Visit 111 or early discontinuation). Investigator will prescribe appropriate 
asthma controller medication to the patients and investigational drug will not be given after 
the last treatment date.


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Figure 3-1
Study design
*Duration of screening epoch may vary from 2 to 4 weeks. Screening epoch must have a minimum of 
2 weeks prior to start taking study medication at Day 1. Visit 1 and Visit 2 may occur on the same day 
depends on concomitant medication and appropriate washout prior to spirometry testing. Please refer 
to Table 5-1, Table 5-2, and Table 5-3 for details.
3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.
As stated in Section 1.2, this study is planned to fulfil the Japanese regulatory requirement for 
a registration of QVM149 (indacaterol acetate/glycopyrronium bromide/mometasone furoate) 
in Japan. 
 
 
 
 
 
 
 
An open-label design without comparator arm is considered adequate to evaluate Japanese 
long term safety for asthma and accepted by Japanese Health Authority previously (Ohta et al 
2010, Tohda et al 2013).
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
On-going Phase III study CQVM149B2302 is evaluating two doses of QVM149 
150/50/80 µg (medium ICS dose) o.d. inhalation and 150/50/160 µg once daily inhalation in 
asthma. The difference between the two doses of QVM149 is the dose of mometasone 
component (ICS). For the purpose of collecting additional long term safety data in Japanese 
patients, high dose of QVM149 150/50/160 µg o.d. is chosen on the basis that exposure of 
asthma patients to high (ICS) dose can generate supportive safety information for the 
lower/medium (ICS) dose in the fixed triple combination.


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Treatment duration of 52 weeks is chosen to comply with Japanese regulatory requirement 
(Section 3.2).
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
 
Details of statistical considerations are described in Section 9.6.
3.6
Risks and benefits
QVM149 is an orally inhaled fixed-dose combination of indacaterol acetate (a LABA), 
glycopyrronium bromide (a LAMA), and mometasone furoate (an ICS). All three 
mono-components
of QVM149, indacaterol maleate, glycopyrronium bromide and 
mometasone furoate have previously been developed and approved as individual drugs for 
COPD or asthma, respectively. QVM149 as a lactose-blended inhalation powder is delivered 
via Concept1 (Breezhaler®), a single dose dry powder inhaler (SDDPI). The favorable benefit-
risk ratio of a fixed-dose combination of indacaterol acetate and mometasone furoate 
(QMF149, in the Phase III development worldwide) in asthma and glycopyrronium bromide 
in COPD as well as the so far acquired knowledge about LAMA (tiotropium) on top of 
LABA/ICS in asthma (Kerstjens et al 2012) is a rationale to conduct this study.
Dual bronchodilation with ICS controller would be expected to achieve good symptom 
control, minimize airflow obstruction, minimize risk of exacerbations, and hospitalizations in 
asthma patients inadequately controlled on medium- or high-dose LABA/ICS. Use of multiple, 
often different devices represents a significant burden for asthma patients. Availability of 
three effective once-daily controller medications in a single device may offer advantages in 
terms of efficacy by improved adherence and convenience. Based on available data of 
components, it is expected that QVM149 will have a favorable benefit to risk profile in 
patients with asthma.
In line with current medical treatment guidelines, all patients participating in the study will 
receive active “controller” treatment for their asthma throughout the screening epoch and 52-
week treatment epoch. In addition, the patients will be provided with rescue medication for 
use as needed throughout study. At no time, will any patient be without treatment for asthma.
QVM149 is under development and therefore it is possible that unexpected safety issues may 
be identified. The risk will be minimized by compliance with the eligibility criteria and close 
clinical monitoring of patients. In addition, safety monitoring (e.g. symptom collection and 
rescue medication use via electronic diary) and daily PEF measurements at regular intervals 
throughout the study will help assess 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. The risks of side effects from the study 
medication are those known for the individual compounds indacaterol acetate, 


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glycopyrronium bromide and mometasone furoate. Up to now no additional risks have been 
identified which might occur when the three components are administered concurrently or 
from the same inhaler. Detailed risk-benefit information can be obtained from the QVM149 
Investigator's Brochure (IB).
There are concerns that LABA treatment used alone in asthma might cause severe asthma 
exacerbations. To address this safety concern all patients are treated with a FDC of 
LABA/LAMA/ICS in this study so LABA alone will not be allowed.
Potential risk of inappropriate use of inhaler devices will be mitigated by detailed instructions 
and trainings provided by the Investigators to patients.
Guidance to manage potential worsening of asthma symptoms will be provided to 
investigators consistent with guideline recommendations (GINA 2016 and JGL). Patients will 
receive well written instructions as to how to contact the investigator in the event of 
worsening of their asthma symptoms. The investigator should discontinue study treatment for 
a given patient and/or withdraw the patient from the study if, on balance, he/she believes that 
continuation would be detrimental to the patient's well-being. Patients are also instructed that 
they can withdraw from the study at any time, and for any reason.
In summary, based on available data of components, it is anticipated that QVM149 
150/50/160 µg once daily will have an acceptable benefit to risk profile in patients with 
asthma.
4
Population
The study population will consist of approximately 100 Japanese males and females aged ≥18
years with asthma, who are currently treated with or qualify for treatment with 
LABA/LAMA/ICS triple therapy. Since a 25% screening failure rate and a 10% dropout rate 
are expected, approximately 134 patients will be screened in order to collect a total of 
approximately 90 completed patients. Dropouts will not be replaced. This study is a single 
national trial to be conducted in Japan.
4.1
Inclusion criteria
Patients/subjects 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 patient ≥18 years old.
3. Patients with a diagnosis of persistent asthma (GINA2016) for a period of at least 1 year 
prior to Visit 1.
4. Patients who have used medium or high dose of ICS/LABA combinations for asthma for 
at least 3 months and at stable dose and regimen for at least 4 weeks prior to Visit 1.
5. An ACQ-7 score ≥1.5 at Visit 2.
6. Pre-bronchodilator FEV1 of ≥40% and ≤85% of the predicted normal value for the 
patient after withholding bronchodilators at Visit 2.

Withholding period of bronchodilators prior to spirometry:

SABA for ≥6 hrs,


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
LABA (or FDC of ICS/LABA) for ≥24 hrs,

Tiotropium for ≥7 days, 

SAMA for ≥8 hrs,

Short acting xanthines for ≥12 hrs,

Long acting xanthines for ≥24 hrs.

Washout period of each drug should be kept as close as possible as above and should
not be longer. If longer washout period is needed due to scheduling issues, please
contact Novartis Medical monitor.

Repeating is allowed once only. Repeating 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 Visit 99.
7. Patients must demonstrate reversibility defined as an increase in FEV1 of ≥12% and 
200 mL within 15 to 30 minutes after administration of 400 µg of salbutamol at Visit 2.
Spacer devices are permitted during reversibility testing only. The Investigator or delegate 
may decide whether or not to use a spacer for the reversibility testing.

If reversibility is not proven at Visit 2, patients may be permitted to enter the study 
with historical evidence of reversibility that was performed within 5 years prior to 
Visit 1.

Alternatively, patients may be permitted to enter the study with a historical positive 
bronchoprovocation test (defined as a provoked fall in FEV1 of 20% by
bronchoconstriction agent e.g., methacholine, histamine) or equivalent test (e.g.,
astography) that was performed within 5 years prior to Visit 1.

Where patient is assessed as eligible based on historical evidence, a copy of the 
original printed report must be available as source documentation.

If reversibility is not proven at Visit 2 and historical data is not available, reversibility 
should be repeated once in an ad-hoc visit scheduled as close as possible from the first 
attempt (but not on the same day).

If reversibility is not demonstrated at Visit 2 (or after repeated assessment at ad-hoc 
visit) and historical evidence of reversibility/bronchoprovocation/astography is not 
available, patients must be screen failed.
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. Use of other investigational drugs within 30 days or 5 half-lives of enrollment, or until the 
expected pharmacodynamic effect has returned to baseline, whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes including untoward reactions to sympathomimetic amines or inhaled 
medication or any component thereof (including lactose).


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3. Patients who have a clinical condition which is likely to be worsened by ICS 
administration (e.g. glaucoma, cataract and fragility fractures) who are according to 
investigator's medical judgment at risk participating in the study.
4.
Patients with evidence upon visual inspection (laboratory culture is not required) of 
clinically significant (in the opinion of investigator) oropharyngeal candidiasis at Visit 99
or earlier, with or without treatment. Patients may be re-screened once their candidiasis 
has been treated and has resolved.
5. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH
patients who are stable on treatment can be considered) or bladder-neck obstruction or 
severe renal impairment or urinary retention.
6.
Patients who have smoked or inhaled tobacco products within the 6 month period prior to 
Visit 1, or who have a smoking history of greater than 10 pack years (Note:1 pack is 
equivalent to 20 cigarettes. 10 pack years = 1 pack/day x 10 yrs., or ½ pack/day x 20 yrs).
This includes nicotine inhalers such as e-cigarettes at time of Visit 1.
7.
Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients 
experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or 
emergency room visit between Visit 1 and Visit 99 they may be re-screened 6 weeks after 
recovery from the exacerbation.
8.
Patients who have ever required intubation for a severe asthma attack/exacerbation.
9. Patients who have had a respiratory tract infection or asthma worsening as determined by 
investigator within 4 weeks prior to Visit 1 or between Visit 1 and Visit 99. Patients may 
be re-screened 4 weeks after recovery from their respiratory tract infection or asthma 
worsening.
10. Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic 
sinusitis) which in the opinion of the investigator may interfere with the study evaluation 
or optimal participation in the study.
11. Patients with a history of chronic lung diseases other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, 
cystic fibrosis, clinically significant bronchiectasis and active tuberculosis.
12. 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.
13. Patients with Type I diabetes or uncontrolled Type II diabetes.
14. 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, New York Heart Association (NYHA) Class III/IV left ventricular 
failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric 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.


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15. Patients with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. 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 2 with 
a resting ventricular rate < 100/min.  At Visit 2 the atrial fibrillation must be confirmed by 
central reading.
16. Patients with a history of myocardial infarction (this should be confirmed clinically by 
the investigator) within the previous 12 months.
17. Concomitant use of agents known to prolong the QT interval unless it can be 
permanently discontinued for the duration of study.
18. Patients with a history of long QT syndrome or whose QTc measured at Visit 2
(Fridericia method) is prolonged (> 450 msec for males and > 460 msec for females) and 
confirmed by a central assessor (these patients should not be rescreened).
19. Patients who have a clinically significant ECG abnormality at Visit 2. ECG evidence of 
myocardial infarction at Visit 2 (via central reader) should be clinically assessed by the 
investigator with supportive documentation.
20. Patients who have a clinically significant laboratory abnormality at Visit 2.
21. Patients who have not achieved an acceptable spirometry result at Visit 2 in accordance 
with ATS/ERS criteria for acceptability and repeatability. A one-time repeat spirometry is
allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on 
the same day) if the spirometry did not qualify due to ATS/ERS criteria. If the patient fails 
the repeat assessment, the patients may be rescreened, provided the patient returns to the 
required treatment as per inclusion criteria 4.
22. Patients taking any asthma-related prohibited medications in the classes specified in
Table 5-1 unless they undergo the required washout period.
23. Patients in need of any prohibited medications listed in Table 5-2.
24. Patients taking medications listed in Table 5-3 should be excluded unless the medication 
has been stabilized for the specified period and the stated conditions have been met.
25. Patients on Maintenance Immunotherapy (desensitization) for allergies or less than 3 
months prior to Visit 1 or patients on Maintenance Immunotherapy for more than 3 
months prior to Visit 1 but expected to change throughout the course of the study.
26. Patients with severe narcolepsy and/or insomnia.
27. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
28. History of alcohol or other substance abuse.
29. Patients who are directly associated with any members of the study team or their family 
members.
30. Patients unable to use the Concept1 dry powder inhaler or a metered dose inhaler. Spacer 
devices are not permitted for rescue medication.
31. Patients with a known history of non-compliance to medication or who were unable or 
unwilling to complete a patient diary or who are unable or unwilling to use Electronic 
Peak Flow with e-Diary device.


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32. 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.
33. 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 investigational 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 6 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*.
*
Not approved in Japan.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
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), total hysterectomy or tubal ligation at least 6 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.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The investigational drug is as follows: 

QVM149 (indacaterol acetate/glycopyrronium bromide/mometasone furoate) 
150/50/160 µg o.d. delivered as powder in hard capsules via Concept1 (Appendix 5)
There is no control drug for this trial.


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5.1.2
Additional treatment
Starting at Visit 1, patients will receive short-acting β2 agonist (salbutamol) inhaler to use as 
rescue medication on an “as needed” basis.
More details regarding rescue medication are in Section 5.5.6.
5.2
Treatment arms
All eligible patients will be assigned to the investigational drug (Section 5.1.1) at Visit 101.
5.3
Treatment assignment and randomization
This study is a single-arm, non-randomized trial. For the purpose of the investigational drug 
accountability and tracking, Interactive Response Technology (IRT) will be used.
At Visit 101, 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 unique number to the 
patient, which will be used to link the patient to a unique medication number for the first 
package of study drug to be dispensed to the patient.
5.4
Treatment blinding
Not applicable.
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 must 
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 eCRF.
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 a specific visit. 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 


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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
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
The investigator should promote compliance by instructing the patient to take the study 
treatment (Section 5.1) exactly as prescribed and by stating that compliance is necessary for 
the patient's safety and the validity of the study. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
At Visit 1 all patients will be instructed how to use a pMDI to administer rescue salbutamol 
correctly. At Visit 99 all patients will be fully trained in the correct use of the Concept1 to 
administer QVM149. Patients who are unable to use Concept1 correctly at Visit 99 will not be 
eligible to enter the treatment epoch. For this training purpose, training kits (placebo capsules 
of QVM149 and Concept1 inhalers) will be supplied to the investigator site. At each clinic 
visit the investigator should check the patient's use of the inhalational devices to ensure that 
they are using each device correctly. Additional device training should be provided if required.
Starting at Visit 101, all eligible patients will be instructed to take QVM149 150/50/160 µg 
via Concept1 once daily in the evening at approximately the same time of day. Patients will 
be instructed to rinse their mouth (e.g., 2 times with approximately 30 mL water) after 


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inhalation of QVM149. Water used for mouth rinsing should be spat out and should NOT be 
swallowed.
The study treatment can be taken without regard to sleep, meals, and other activities. On days 
of scheduled clinic visits, patients should take QVM149 at the clinic (approximately between 
4:00 to 8:00 pm) under the supervision of investigator or his/her delegate.
The duration of treatment epoch is 52 weeks, with the last dose of study treatment occurring 
in the evening of Day 365 (Visit 111).
All kits of investigational drug assigned by the IRT will be recorded in the IRT. All used and 
unused study medication/packaging must be returned by the patient at each study visit and/or 
at the time of discontinuation.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
If any faults are identified with either the device and/or the blisters, these should be returned 
to Novartis Drug Supply Management with the completed Device Return Form. The forms 
will be supplied to each investigator site by the Field Monitor.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Dose adjustments and/or interruptions of QVM149 are not permitted unless the investigator 
considers an interruption is necessary for the treatment of an adverse event. Any interruption 
of QVM149 should be for the shortest time period possible and must be recorded on the 
Dosage Administration Record CRF.
5.5.6
Rescue medication
At Visit 1, all patients will be provided with a short-acting β2 agonist (100 µg salbutamol via 
pMDI) which they will be instructed to use throughout the screening and treatment epoch as 
rescue medication on an 'as needed' basis. Patients will be advised that between visits they can 
take their rescue medication for symptoms. The rescue salbutamol will be provided to the 
patients by the investigator site and reimbursed locally by Novartis or supplied to the 
investigator sites locally by Novartis. Nebulized salbutamol is not allowed as rescue 
medication and use of a spacer for rescue medication is not allowed at any time throughout 
the study.
In order to standardize measurements, patients will be instructed to abstain from taking rescue 
salbutamol within 6 hours of the start of each spirometry visit unless absolutely necessary. If 
rescue medication is taken within 6 hours prior to spirometry assessments, then the visit 
should be rescheduled to the next day if possible.
Bronchodilator medications that the patients used prior to Visit 1 must be recorded in the 
asthma-related prior/concurrent medication page of the CRF, with the stop date for these 
bronchodilators recorded as the date of Visit 1. The rescue salbutamol provided at Visit 1 for 
use during the study should NOT be recorded on the asthma-related prior/concurrent 
medication page of the eSource. From Visit 1, daily use of rescue medication (number of 
puffs taken in the previous 12 hours) will be recorded each morning and evening throughout 
the 52 week treatment epoch by the patient using their electronic diary.


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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' and 'Surgical and Medical Procedures' CRF.
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 
entering the treatment epoch or allowing a new medication to be started.
5.5.8
Prohibited medication
The class of medications listed in Table 5-1 and Table 5-2 are not permitted to be taken 
during the study. The medications in Table 5-3 are only permitted under the circumstances 
given. 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 
before allowing a new medication to be started.
If indicated for the treatment of an asthma exacerbation, any treatment deemed necessary by 
treating physician for the safety of the patient is allowed from the start of the asthma 
exacerbation event (defined as per protocol Section 6.4.5) until the asthma exacerbation event 
is resolved. Patients may NOT self-medicate (other than administration of rescue medication) 
or adjust therapy without permission/guidance from treating physician.
Table 5-1
Prohibited Asthma-related medications1
Medication
Minimum cessation prior to Screening (Visit 1) 
and Baseline (Visit 99)
Long-acting anticholinergics (LAMA)
Must not be used from 7days prior to Visit 2 
onwards.
Short-acting anticholinergics (SAMA)
Must not be used from 8 hours prior to spirometry 
at Visit 2 onwards.
Fixed dose combinations of β2-agonists and 
inhaled corticosteroids
Must be discontinued 24 hours prior to Visit 99. 
Must be withheld 24 hours prior to spirometry at 
Visit 2.
Long-acting β2-agonists (LABA)
Must be discontinued 24 hours prior to Visit 99. 
Must be withheld 24 hours prior to spirometry at 
Visit 2.
Inhaled corticosteroid
Must be discontinued one day prior to Visit 99 
(after the evening dose).
Short acting β2-agonists (SABAs) (other than 
Salbutamol provided at Visit 1 for rescue 
medication)
Must be discontinued at Visit 1
Salbutamol/albuterol (SABA) provided at Visit 1 
Must be withheld 6 hours prior to spirometry2
Parenteral corticosteroids (systemic 
corticosteroids are permitted for the treatment of 
asthma exacerbations)
Must be discontinued 4 weeks prior to Visit 1
Intra-muscular depot corticosteroids
Must be discontinued 3 months prior to Visit 1


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1 These tables are not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. These medications are also prohibited if administered 
for other indications.
2 Clinic visits may be rescheduled if rescue medication were taken less than 6 hours prior to the 
spirometry assessments.
Table 5-2
Prohibited Medications1
Medication
Minimum cessation prior to Visit 2
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
(Biologics and/or monoclonal antibody need to 
have a 6 month wash out period)
Non-selective systemic beta-blocking agents
7 days
Non-potassium sparing diuretics (unless 
administered as a fixed-dose combination with a 
potassium conserving drug)
7 days
Cardiac anti-arrhythmics Class Ia
7 days
Cardiac anti-arrhythmics Class III
7 days, amiodarone 3 months
Other drugs with potential to significantly prolong 
the QT interval
14 days or 5 half-lives, whichever is longer
Mizolastin
5 days
Tricyclic antidepressants (Please note that 
tetracyclics, which are similar in class with 
regards to drug interaction are also to be 
excluded)
14 days
All antipsychotic agents (first, second and third 
generation, inclusive of atypical antipsychotics). 
Combinations of antipsychotic agents with 
antidepressants are prohibited
14 days
Strong inhibitors of cytochrome P450 3A (e.g. 
ketoconazole) (may depend on compound) 
7 days
Serotonin Noradrenaline Reuptake Inhibitors
14 days
Monoamine-oxidase inhibitors
14 days
Noradrenaline reuptake inhibitors
7 days
Systemic anticholinergics
7 days
Live attenuated vaccine
30 days
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. The washout of these prohibited medications is not to 
be encouraged.
Table 5-3
Medications allowed under certain conditions1
Medication
Condition under which medication is permitted
Topical Corticosteroids for treatment of
eczema
Recommended doses and dosage regimens
Maintenance Immunotherapy for allergies
Stable dose for at least 3 months prior to 
screening (Visit 1) and unchanged throughout the 
study.


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Medication
Condition under which medication is permitted
Pure Selective Serotonin Reuptake Inhibitors 
(they must have no documented effect on any 
other neurotransmitters or other biological 
pathways. e.g. muscarinic pathway)
Stable regimen for at least 30 days prior to 
screening (Visit 1).
Intra-nasal corticosteroids
Stable dose for at least 4 weeks prior to screening
(Visit 1)
In the case of as needed, provided an established 
pattern of use has been documented.
Antihistamines (except mizolastin) (e.g. 
loratadine, cetirizine)
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1).
In the case of as needed, provided an established 
pattern of use has been documented.
Mucolytic agents not containing bronchodilators
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study.
Systemic mast cell stabilizers
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study.
Inactivated influenza vaccination, pneumococcal 
vaccination or any other inactivated vaccine
Not administered within 48 hours prior to a study 
visit
Rescue Short-acting β2 agonists
Not used within 6 hours prior to spirometry
Leukotriene Antagonist and leukotriene 
synthesis inhibitors
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study.
Long-acting theophylline
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study. Not administered within 24 hours prior 
to spirometry.
Short-acting theophylline
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study. Not administered within 12 hours prior 
to spirometry.
Monoclonal antibodies for the treatment of 
asthma (e.g., omalizumab, mepolizumab)2
Stable dose for at least 3 months prior to 
screening (Visit 1)
Oral corticosteroids3
Stable dose for at least 30 days prior to screening 
(Visit 1) and throughout the study at prednisone 
equivalent dose of 5 mg daily to 10 mg every other 
day
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.
2 Omalizumab or mepolizumab may be discontinued at the investigator's discretion. Once 
discontinued, resuming omalizumab or mepolizumab is not permitted during the study. Omalizumab 
dosing should be guided by Japanese labelling.
3 Oral corticosteroids may be continued at a low stable dose after a course of steroid taper for
exacerbations at the discretion of the investigator (in doses not to exceed equivalent of prednisone 
5 mg daily). If steroids are continued beyond 7 to 10 day taper, the stable low dose (≤prednisone 
5 mg daily) should be maintained for at least 3 months prior to stopping. Otherwise patient must be 
discontinued from study treatment.


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5.5.9
Emergency breaking of assigned treatment code
Not applicable for this open-label 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 (Visit 111, Week 52) planned in the protocol.
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up.
For all patients a safety follow-up visit (Visit 201) should be conducted (e.g. by telephone) 30 
days after last visit (Visit 111, Week 52). The information to be collected at this follow up 
visit includes serious adverse events, asthma exacerbations, and survival status.
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.
Patients may voluntarily discontinue study treatment for any reason at any time. In the case 
the patients would want to discontinue the treatment, it is particularly important to ask the 
reason and if they would be willing to remain in the trial to share their safety and vital status 
information (e.g., via telephone contact) until the scheduled final visit in order to ensure the 
scientific integrity of the trial.
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

Adverse events for which continued inhalation of the investigational drug would be 
detrimental

Abnormal test procedure results indicating risk for the patient on continued inhalation of 
the investigational drug 

Pregnancy (see Section 6.5.7 and Section 7.6)

If a patient develops a medical condition that requires use of prohibited treatment as per 
Section 5.5.8 or if patient exhibits a behavior of non-compliance regarding prohibited 
medications

Patients who experience 5 or more asthma exacerbations during the treatment epoch that 
required treatment with systemic corticosteroids

Patients with > 50% decrease in FEV1 from baseline (Visit 101) during treatment epoch

Any situation in which study participation might result in a safety risk to the patient
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of investigational drug, for a study treatment discontinuation visit. If the 


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patient fails to return for the study treatment discontinuation visit for unknown reasons, every 
effort (e.g., telephone, e-mail, letter) should be made to contact him/her as specified in 
Section 5.6.4. Treatment discontinuation visit assessments detailed in the “unscheduled 
treatment discontinuation visit” (UNS) in Table 5-4 and Table 6-1 should be completed and 
recorded in the eCRF. The investigator must determine the primary reason for the patient's
premature discontinuation of study treatment and record this information on the Dosage 
Administration eCRF.
The investigator and study staff must discuss with the patient the continued participation in 
the study by maintaining regular telephone contact with him/her or with a person pre-
designated by the patient. This telephone contact should preferably be done according to the 
study visit schedule. After study treatment discontinuation, the following data should to be 
collected via telephone visits:

Asthma exacerbation

Serious Adverse Events
The investigator must also contact the IRT to register the patient's discontinuation from study 
treatment.


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Table 5-4
Table of assessment for the patients who discontinue investigational 
drug prematurely
Assessment
Early study 
treatment 
discontinuation 
visit
Unscheduled 
safety follow-up 
visit
At time of 
scheduled 
clinic 
visit1
Early Study 
discontinuation 
(Premature study 
withdrawal)2
Follow-up 
Visit 201
Visit type
Clinic visit
Telephone
Telephone
Telephone
Telephone
Week
Discontinuation 
date
Discontinuation 
date + 4 weeks
56
Day
Discontinuation 
date
Discontinuation 
date + 30 days
395
IRT treatment discontinuation 
call
X
Vital signs
X
Physical exam
S
Oropharyngeal examination
S
Pregnancy test (serum)
X
Collect study medication
X
Record asthma/non-asthma 
related concomitant medication
X
X
Record interruption/changes in 
drug administration to assess 
compliance
X
Download/review e-Diary
S
Review rescue medication use
S
Review AEs
X
X
Review SAEs
X
X
X*
X*
X*
Review asthma exacerbations
X
X
X
X
X
Review surgery and procedures
X
X
Safety lab assessments 
(hematology, clinical chemistry, 
urinalysis)
X
Spirometry3
X
ECG3
X
ACQ-73, 4
X
Evening plasma cortisol3
X
Survival status
X
X
X
X
Record Healthcare visit for 
asthma worsening
X
X
Record end of treatment epoch 
disposition page
(Study Phase Completion)
X
X
S These assessments are source documentation only and will not be entered into the eCRF
X assessment to be reported in the clinical database
* If a subject experienced a serious adverse event (SAE), complete a corresponding AE CRF.
1 Refer to Table 6-1.
2 Refer to Section 5.6.3 and Section 5.6.5
3 Details of timed assessments are provided in Table 6-2.
4 ACQ assessed at clinic should be completed before any other assessment.


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5.6.3
Withdrawal of informed consent
Patients 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 the 
Table 5-4.
5.6.4
Loss 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 must 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.
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.


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6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients 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.
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.


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Table 6-1
Assessment schedule
Epoch
Screening
Treatment
Follow-up1
Visit number
1
2
99
101
102
103
104
105
106
107
108
109
110
111
EOT
Early 
treatment 
discontinuation
PSW
Early Study 
Discontinuation
201
Clinic (C)/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
C
T
C
C
T
T
Week
-4 to -2 -2
0
0
4
8
12
16
20
26
32
36
44
52
56
Obtain informed consent
X
Relevant Medical 
History/Demographics
X
History of Asthma exacerbation
X
Smoking History
X
Current asthma medication review
X
Inclusion/Exclusion criteria
X
X
X
Central pregnancy test (Serum)
X
X
X
Local pregnancy test (urine)
X
X
Urinalysis (dipstick)
S
S
S
S
Hematology/biochemistry
X
X
X
X
X
Evening plasma cortisol
X
X
X
X
Inhalation device training
S
Drug dispensing
X
X
X
X
X
Administer study drug at the visit
X
X
X
X
Reversibility test
X
Spirometry (centralized)
X
X
X
X
X
X
Issue and training on patient e-Diary
S
S
e-Diary, ePEF device training
S
S
S
Concomitant medication review
(for asthma & for non-asthma)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Epoch
Screening
Treatment
Follow-up1
Visit number
1
2
99
101
102
103
104
105
106
107
108
109
110
111
EOT
Early 
treatment 
discontinuation
PSW
Early Study 
Discontinuation
201
Clinic (C)/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
C
T
C
C
T
T
Week
-4 to -2 -2
0
0
4
8
12
16
20
26
32
36
44
52
56
Review and upload patient e-Diary
S
S
S
S
S
S
S
ACQ-7
X
X
X
X
X
X
Physical examination
S
S
S
S
S
S
S
S
Oropharyngeal examination
S
S
S
S
S
S
S
S
Vital sign: BP and pulse
X
X
X
X
X
X
X
X
Record height and weight
X
ECG
X
X
X
X
X
SAE recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review surgery and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record healthcare visits for asthma 
worsening
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
X
Study Disposition (Screening)
X
X
Study Disposition (Study Phase 
Completion)
X
X
X
Record End of Treatment page
X
X
X
Study Disposition (Follow-up)
X
Early Study Discontinuation Visit should be used for Premature study withdrawal (PSW, please refer to Section 5.6.2) 
X = assessment to be recorded on clinical data base
S = these assessments are source documentation only and will not be entered into the eCRF
1 Information about patients’ survival will be obtained by a telephone call during the study treatment period and 30 days after the patient’s last dose of study drug for 
completed patients. For patients who withdraw early, please refer to discontinuation of study treatment and premature patient withdrawal section.


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Table 6-2
Timing of clinic visit procedures
Time 
Point1
ACQ-7
ECG
Vital Signs2 Hematology
Chemistry /Plasma 
cortisol/ Urinalysis3
Spirometry4
Visit 99/
Visit 101
Day 1
-50 min
X
-45 min
X
-30 min
X
X
X
-15 min
X
30 min
X
Visit 104
Week 12
-50 min
X
-45 min
X
-30 min
X
-15 min
X
Visit 107
Week 26
-50 min
X
-45 min
X
-30 min
X
X
X
-15 min
X
Visit 111
Week 52
Day 365
-50 min
X
-45 min
X
-30 min
X
X
X
-15 min
X
1: Time relates to the dose given from the device at visit. When multiple measurements are scheduled 
at a single time-point, they should wherever possible be done in the following order: ECG, vital signs 
and then samples for hematology/clinical chemistry/plasma cortisol and urinalysis.
2: Systolic and diastolic blood pressure and heart rate (radial pulse)
3: Urine analysis at central laboratory is to be done only if the urine dipstick is abnormal, and only 
done pre-dose.
4: A minimum 10 min rest period from the end of spirometry maneuvers and the beginning of ECG 
assessments must be observed at all times.
6.1
Information to be collected on screening failures
All patients 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

Sex

Race and ethnicity


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
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

ACQ-7

Prior concomitant medication (Both asthma related and non-asthma related)

Pre and post-bronchodilator spirometry (screening spirometry and reversibility testing).

Baseline PEF
6.3
Treatment exposure and compliance
The time of study treatment administration at each in-office dosing visit 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. While at home, the time of study 
treatment administration will be recorded by the patient in the e-Diary once a week. The data 
from the e-Diary will be reviewed at each visit.
Study treatment compliance should be assessed by the investigator and/or center personnel at 
all visits. In order to ensure compliance and safety follow-up, the patients will be requested to
record once per week in the e-Diary whether he/she missed any dosage in the evening from 
Visit 101 to 111. 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 102, 104, 107, 109, 111 (or at Early Treatment Discontinuation/end of 
treatment (EOT) Visit or Study Withdrawal visit if applicable). Study treatment compliance 
will be assessed from the capsule count from previously dispensed blister strips for the 
Concept1.
6.4
Efficacy
6.4.1
Spirometry
The following spirometric assessments will be made:

Forced expiratory volume in one second (FEV1)

Forced Vital Capacity (FVC)
Spirometric assessments will be measured at Visits 2, 101, 104, 107, 111 and EOT if 
applicable as indicated in Table 6-1.


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Pre-dose FEV1 is defined as the mean of the two FEV1 values measured at -45 min and -15 
min prior to evening dose taken at the site.
All clinic visits must occur in the evening. Please refer to Table 6-2 for full details of the 
scheduling of spirometry measurements. Equipment for spirometry assessments will be 
provided to all study sites by a Central Spirometry vendor, and all measurements will be 
reviewed by trained spirometry technicians at the central vendor.
Please refer to the latest version of Spirometry Guidance in Appendix 3 for full details on 
performing spirometry.
6.4.2
Electronic Diary
All patients will be provided with a patient electronic diary (referred to as e-Diary or 
e-Diary/ePEF) to record daily clinical symptoms, peak flow or rescue medication (salbutamol) 
use. The patients will be instructed to routinely complete the patient diary twice daily at the 
same time morning or evening (before taking the study drug) and 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 (see 
Appendix 4 for questions).
6.4.2.1
Number of inhalations of Rescue Medication
The total number of inhalation used of rescue medication (number of puffs taken in the 
previous 12 hours) will be recorded morning and evening by the patient, in the e-Diary.
The patient will input the number of puffs of rescue medication they have used during the 12 
hours previous. The patients mean evening and morning recue medication usage will be 
automatically be calculated by the e-Diary.  This SABA data collected by the patient during 
the last 7 days of screening will be used to set alerts to the patient to contact the investigator 
in case of worsening asthma (see Section 6.4.4 Asthma worsening criteria).
6.4.2.2
Peak expiratory flow (PEF)
An electronic Peak Flow Meter (ePEF) will be given to each patient at Visit 1 for the 
measurement of morning and evening PEF from Visit 1 until the end of the treatment epoch.
PEF will be measured at consistent times for a patient, in the morning and evening each day 
during the study from Visit 1 to 111. The measurements will be performed using an ePEF 
provided to the patients at Visit 1. PEF will be measured twice a day; in the evening just prior 
to taking study medication and again 12 hours later and as soon as possible after waking in the 
morning. Patients should be encouraged to perform morning and evening PEF measurements 
BEFORE the use of any rescue medication. At each time point, the patient should be 
instructed to perform 3 consecutive maneuvers within 10 minutes. These PEF values are 
captured in the e-Diary/ePEF. The best of 3 values will be used.
6.4.3
Asthma Control Questionnaire 7 (ACQ-7)
In this study, the ACQ-7 will be used to assess improvements in asthma symptom control. 
The ACQ-7 (Juniper et al 1999, Juniper et al 2005, Juniper et al 2006) is a seven-item disease-
specific instrument developed and validated to assess asthma control in patients in clinical 


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trials as well as in individuals in clinical practice. The ACQ-7 questionnaire will be provided 
to the site. The ACQ-7 questionnaire consists of five items to assess symptoms and activity 
limitations, one question to assess rescue medication use, and one question to assess airway 
caliber (FEV1% predicted). All seven items are scored on a 7-point Likert scale, with 0 
indicating total control and 6 indicating poor control. The questions are equally weighted and 
the total score is the mean of the seven items. The proportion of patients who achieve an 
improvement of at least 0.5 in ACQ-7 (i.e. decrease of ACQ-7 score of at least 0.5 from 
baseline) at post-baseline visits will also be analyzed.
The first 6 questions of the ACQ-7 should be completed by the patient based on one recall 
over the prior week. The last question should be completed by the investigator at the site 
using data from the Master Scope spirometer. The ACQ-7 should be completed at the 
investigators site at Visits 2, 101, 104, 107, 111 and EOT if applicable.
6.4.4
Worsening of asthma
Investigators and patients will be instructed how to deal with worsening of asthma symptoms. 
The data captured in the patient diary will also be used to alert the patient and/or investigator 
to possible signs of worsening asthma. The investigator must provide the patient with written 
instructions to contact the investigator if at any time during the trial from the screening
onwards one or more of the following criteria of worsening asthma develops:
Asthma Worsening Criteria
1. > 20% decrease in FEV1 from the baseline value (Criteria only be applicable to the 
investigator review at the time of study visit or possibly an alert setting if device is 
structured to capture)
2. > 50% increase in SABA use and > 8 puffs on 2 out of any 3 consecutive days compared 
to baseline
3. ≥20% decrease in AM or PM PEF from baseline on 2 out of any 3 consecutive days 
compared to baseline
4. < 60% of personal best PEF compared to baseline 
5. Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights
6. Urgent unscheduled clinic visit due to asthma related deterioration
Note: The reference for the worsening of asthma during the screening epoch would be the 
FEV1 and PEF taken at Visit 1 (Screening). The Baseline FEV1 for the treatment epoch is 
taken at treatment Day 1 (Visit 101). The Baseline PEF (morning and evening) for the 
treatment epoch is calculated at Visit 99 and is the mean of the best of the three daily PEF 
measurements over the last 2 weeks of screening epoch (Visit 2 to 99).
If any of the above criteria (including the alert from e-Diary) are met while a patient is in the 
screening or treatment epoch, the investigator should assess the patient condition. If this 
occurs during screening epoch and it is considered a clinically significant asthma worsening
in the investigator’s opinion, the patient should be treat as appropriate and screen failed. Once 
the condition is resolved, if eligibility criteria are met, the patient may be reconsidered for 
rescreening.


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The alerts, which are trigged by above criteria, are in place to detect early onset of asthma
worsening at any time during the study and to help direct early intervention. Therefore the
investigator should do the following when alerts are received:

Reviewing alert trends over time, in particular PEF decreases

Calling the patient promptly when alerts are received when any one specific alert type (e.g.
PEF < 60%) is received on consecutive days to further assess the clinical status. This may
include urgent clinic visits as appropriate and/or immediate treatment.

Implementing prompt treatment as necessary
If patients believe their symptoms are worsening and/or receive alerts as outlined above, the 
patient should also notify the investigator and be evaluated by the investigator and treated as 
clinically appropriate.
Patients should also be withdrawn for safety reasons if, in the opinion of the investigators, it is 
appropriate to do so.
Worsening of asthma symptoms may require unscheduled evaluation between visits. Study
site personnel must be available to monitor and document patient's progress until asthma 
control is regained.


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6.4.6
Appropriateness of efficacy assessments
The measures described above are standard outcome measures in asthma trials.
6.5
Safety
The following safety assessments will be performed:

Medical history and physical examination including oropharyngeal examination

Vital signs


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
Hematology, chemistry, Urinalysis

Evening plasma cortisol

ECG

Adverse events including serious adverse events

Pregnancy (female patients); additional pregnancy testing might be performed if requested 
by local requirements

Serious asthma outcomes (asthma-related hospitalizations, intubations or deaths)
ECG and Laboratory assessments will be centralized.
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 at Visits 2, 
107, 111 and in case of early study treatment discontinuation visit as described in Table 6-1.
A short physical examination, including the examination of general appearances and vital 
signs (see Section 6.5.2), will be performed at all other clinic visits. 
An oropharyngeal examination will be performed at each clinic visit.
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 Medical History 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 sec interval), performed 
in the sitting position, will be recorded at scheduled visits as detailed in Table 6-1. At Visits 2, 
101, 102, 104, 107, 109, 111, or EOT if applicable, vital signs should be measured directly 
after the ECG assessments.
6.5.3
Height and weight
Height in centimeters (cm) will be measured at Visit 2. Body weight (to the nearest 
0.1 kilogram [kg] in indoor clothing, but without shoes) will be measured at Visit 2. BMI will 
be calculated based on height and weight.
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 
provided to investigators in the laboratory manual.
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 


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other than drug-related adverse experiences is identified, even after the medication has 
discontinued.
Safety Laboratory assessments (hematology, clinical chemistry) will be performed at Visits 2, 
101, 107, 111 and EOT if applicable.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential, and platelet count will be measured.
6.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, AST (SGOT), ALT (SGPT), bilirubin, creatinine, γGT, 
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
(ULN), total bilirubin should be differentiated into the direct and indirect reacting bilirubin.
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 study medication has 
discontinued.
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will be performed
at Visits 99, 107, 111, and EOT if applicable. Dipsticks are provided to investigators from the 
central laboratory.
If dipstick test is abnormal, the sample will be sent to central laboratory for additional testing, 
including assessment of microscopy and WBC and RBC sediments. The Central Laboratory 
will provide detailed procedures for the preparation and collection of these samples in the 
laboratory manual.
6.5.4.4
Plasma Cortisol
Evening plasma cortisol will be measured at Visits 101, 107, 111 and EOT (if applicable). 
The sampling point is as shown in Table 6-2.
6.5.5
Electrocardiogram (ECG)
Electrocardiograms (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 the blood 
draws but with enough time planned to ensure the spirometry is performed at the planned time 
point outlined in Table 6-2. Spirometry must be performed as close to the scheduled time 
point as possible.


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Centralized ECG equipment
At Visit 2, a screening ECG will be measured to test for eligibility for trial inclusion. (Patients 
whose ECG is abnormal at screening due to technical/mechanical faults may be re-screened.) 
At Visit 101, ECGs will be measured at 30 min pre-dose (evening dose) and 30 min post dose, 
at Visits 107, 111, and EOT if applicable, ECG will be measured pre-dose only as indicated in 
Table 6-2. All electrocardiograms should include 12 standard leads. An ECG tracing will be 
taken for those patients who prematurely discontinue from the study.
For each ECG performed original traces should be printed. Each ECG will be sent 
electronically for central review directly from the ECG machine. The print out will be kept at 
the investigator site and will be dated and signed. The subject's number, the date, actual time 
of the tracing, and study number 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 
event that the central cardiologist reports that an ECG is abnormal, the investigator must 
assess whether the ECG abnormality is clinically significant or not. A clinically significant 
abnormality should be reported as an AE. If necessary a cardiologist may be consulted.
Clinically significant ECG findings at baseline must be discussed with the sponsor before 
administration with investigational treatment.
If a patient experiences a clinically significant change in cardiac rhythm or other clinically 
significant cardiovascular abnormality, the investigator should consider withdrawing the 
patient from the study.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/AE eCRF page as appropriate.
New cases (not present during screening) of atrial fibrillation reported from the ECG 
measurements (or reported as an AE during the course of the study) will be adjudicated. 
Additional information regarding the Atrial Fibrillation/Atrial Flutter may be requested to be 
sent to the Adjudication Committee. All cases of atrial fibrillation, regardless of seriousness, 
will be reviewed by the Adjudication Committee.
6.5.6
Serious Asthma outcomes
Asthma-related hospitalizations, asthma-related intubations and asthma-related deaths over 
the 52 week treatment epoch will be recorded and will all be reviewed by the Adjudication 
Committee. Hospitalization is defined as an inpatient stay or a ≥24 hour stay in an 
observation area in an emergency department or other equivalent facility.
6.5.7
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. A 
serum or urine pregnancy test will be performed (tests provided by the Central Laboratory) 
per Assessment Schedule Table 6-1. If the urine pregnancy test at Visit 99 and Visit 107 is 
positive, a plasma testing is to be done to confirm the pregnancy. A positive pregnancy test at 
Visits 2 (Week -2), 99 (Week 0), 107 (Week 26), 111 (Week 52), EOT or at any time during 


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the study requires the patient to be discontinued from the study treatment. Refer to Section 
5.6.2 and Section 7.6 for more details.
6.5.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments
No additional tests will be performed on patients/subjects entered into this study.
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 
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. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
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


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
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 given 

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's 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.


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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 (specify what this includes)

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
general condition

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 patient has stopped study participation
(defined as time of last dose of study drug taken or last visit whichever is later) must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs 


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experienced after the 30 days period should only be reported to Novartis safety 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 each specific 
component of study treatment, 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, 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 
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
Pneumonia Reporting
Pneumonia will be defined as an event characterized by increased respiratory symptoms (e.g. 
increased cough, dyspnea, wheezing, purulent sputum), fever (i.e. body temperature greater 
than 38°C) or pleuritic chest pain or leukocytosis or other clinical signs consistent with 
pneumonia considered relevant in the opinion of the investigator and confirmed by X-ray. 
Any reported pneumonia will have to be confirmed by either X-ray or radiologist reading 
report of the X-ray (to be kept in the source documents). If not confirmed by X-ray, it should 
be reported as lower respiratory tract infection.
7.4
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. 


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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 Table 13-1 in Appendix 2 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 2 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 in Appendix 2.
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. 
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.
7.5
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.


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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 3 months after the birth, 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.
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 data capture requirements (i.e. eSource or eCRFs) 
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 data 
capture/data entry, 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.


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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 eCRF 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 data capture and/or data entry. 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 eCRF 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
The trial will be conducted in a fully validated Data Capture system which conforms to US
CRF 21 Part 11 requirements. Investigator site staff will not be given access to the system 
until they have been trained. Designated investigator staff will enter the data required by the 
protocol into the Data Capture system. Automatic validation programs within the system 
check for data discrepancies in the CRFs and by generating appropriate error messages, allow 
the data to be confirmed or corrected by the investigator staff. The investigator staff must 
certify that the data entered are complete and accurate. After database lock, the investigator 
will receive copies of the patient data for archiving at the investigational site.
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 
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. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.


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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(s), who will also manage the database. The database will be sent electronically to 
Novartis personnel.
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 Novartis 
IRT, who will also manage the database. The database will be sent electronically to 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 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
An independent adjudication committee will be established to assess serious asthma outcomes 
(asthma-related hospitalizations, intubations and deaths), serious cardiovascular and 
cerebrovascular (CCV) events, new onset of atrial fibrillation and flutter as well as all deaths. 
All serious CCV events occurring from the time of treatment start until the 30 days after the 
permanent discontinuation of study drug, where applicable, will be adjudicated.
The committee will consist of experts outside Novartis who are not involved in the study 
conduct, who will periodically review pertinent patient data and the supporting documentation 
to settle the specified adjudication objectives. Further details will be provided in the 
Adjudication Committee Charter.
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.


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9.1
Analysis sets
The Safety Set will consist of all patients who received at least one dose of study medication 
during this study.
Full Analysis Set (FAS) will consist of all patients who entered in this study and received at 
least one dose of study medication during this study.
Note that the Safety Sets and FAS are the same except that the Safety Set allows the inclusion 
of patients who are not intended to enter in this study but received study drug in error.
The Safety Set will be used in the analysis of all safety variables. The efficacy analysis 
population will be the FAS.
9.2
Patient demographics and other baseline characteristics
Demographic and baseline characteristics including age, sex, race, ethnicity, height, weight, 
body mass index (BMI), relevant medical history, screening spirometry parameters: (FEV1,
FVC, and FEV1/FVC), FEV1 reversibility, percentage of predicted FEV1, baseline PEF, 
duration of asthma, history of asthma exacerbations, smoking history, prior concurrent 
medications (asthma-related and non-asthma-related), vital signs (systolic and diastolic blood 
pressure, pulse rate), QTc using Fridericia's correction and baseline ACQ-7, will be 
summarized.
Continuous variables will be summarized using descriptive statistics (mean, median, standard
deviation, minimum, and maximum) and categorical variables will be summarized in terms of
the number and percentage of patients in each category for the Safety Set.
Baseline is defined as the last measurement before first dose of study drug.
9.3
Treatments
Study drug administration and concomitant medication data will be listed and summarized
using the Safety Set.
The duration of exposure and the number of patients who completed the study medication and 
who discontinued from the study medication will be summarized.
Medications started and stopped prior to study drug, and taken concomitantly will be
summarized for the Safety Set.
Concomitant therapies will be recorded, listed and summarized separately for asthma related
medications/non-drug therapies and other medications. Concomitant asthma related
medications will be summarized by route of administration, the recorded pre-specified drug 
subcategories (including types of combination) and preferred term. Concomitant medications 
not related to asthma will be summarized by route of administration and preferred term.
SABA usage (number of puffs) during the screening epoch will be summarized.
Treatment compliance with study medication over the study period will be summarized.


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9.4
Analysis of the primary variable(s)
9.4.1
Primary Variable(s)
The primary objective of this study is to assess the safety/tolerability of 52 weeks of treatment 
with QVM149 (150/50/160 µg, once daily), particularly with regard to treatment emergent 
adverse event reporting in Japanese patients with inadequately controlled asthma.
The primary variable is the number and percentage of patients who reported treatment 
emergent adverse events during the 52 week study period.
Adverse events will be summarized with descriptive statistics for the Safety Set.
All study emergent adverse events including asthma exacerbations will be summarized and
listed. Adverse events starting on or after the time of the first inhalation of study drug but not 
later than 7 days (30 days in the case of a SAE) after the last administration will be classified 
as a treatment emergent adverse event. Any adverse events that started during the study before 
the time of the first inhalation of study drug will be classified as a prior adverse event.
9.4.2
Statistical model, hypothesis, and method of analysis
The number and percentage of patients who reported treatment emergent adverse events will 
be summarized by primary system organ class, preferred term for

All adverse events

Serious adverse events

Adverse events by maximum severity

Adverse events suspected to be related to study drug

Adverse events leading to permanent study drug discontinuation

Adverse events of special interest
In addition, all adverse events reported in the study will be listed.
9.4.3
Handling of missing values/censoring/discontinuations
No imputation will be done for missing data. All available data will be summarized.
9.4.4
Sensitivity analyses
Not applicable.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The efficacy measurements during the study will be summarized for the FAS.
Baseline is defined as the last measurement before first dose of the study drug, unless 
otherwise specified. No imputation will be done for missing data.


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Spirometry
Spirometry measurements taken within 7 days of systemic corticosteroid use and/or 6 hours of
rescue use will be set to missing and not be imputed, unless specified otherwise.
For FEV1 and FVC, the baseline is defined as the mean of the values taken in the clinic at 45 
and 15 min prior to first dose at Visit 101.
Pre-dose FEV1 and FVC at Weeks 12, 26 and 52
The pre-dose FEV1 is defined as the mean of the pre-dose 45 and 15 min FEV1 values.
The pre-dose FEV1 and the change from baseline at 12, 26 and 52 weeks of the study 
treatment will be summarized with descriptive statistics. Summaries will be repeated for pre-
dose FVC.
In addition, the means in pre-dose FEV1 and FVC for each visit will be displayed graphically.
Peak Expiratory Flow Rate (PEF)
The morning/evening PEF (liters/min) will be averaged over the first 26 weeks and over the 
52 weeks.
e-Diary data recorded during the screening period will be used to calculate the baseline value.
The mean morning/evening PEF and the mean change from baseline will be summarized.
Rescue medication
The total number of puffs of rescue medication per day over the first 26 weeks and over the 
52 weeks will be calculated and divided by the total number of days to derive the mean daily 
number of puffs of rescue medication taken for the patient.
e-Diary data recorded during the screening period will be used to calculate the baseline value.
The mean daily number of puffs of rescue medication use over the first 26 weeks and over the 
52 weeks of treatment and the mean change from baseline will be summarized.
In addition, the mean number of puffs of rescue medication in the morning and in the evening,
and the percentage of 'rescue medication free days' (defined from diary data as any day where 
the patient did not use any puffs of rescue medication) will be summarized.
Asthma Control Questionnaire 7 (ACQ-7) at Weeks 26 and 52
ACQ-7 and the change from baseline at 26 and 52 weeks of the study treatment will be 
summarized.
The proportion of patients who achieve an improvement of at least 0.5 in ACQ-7 (i.e.
decrease of ACQ-7 score of at least 0.5 from baseline) at post-baseline visits will be 
summarized.
9.5.2
Safety variables
All safety variables will be summarized with descriptive statistics for the Safety Set.


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Baseline is defined as the last measurement before first dose of the study drug, unless 
otherwise specified. No imputation will be done for post-baseline missing data.
Electrocardiogram (ECG) and vital signs
Data from the ECG (including QT interval, RR interval, PR interval, QRS duration, heart rate,
Fridericia's QTc and Bazett's QTc) will be summarized at 30 min pre-dose, and at 30 min 
post-dose by visit. The baseline measurement will be the 30 min pre-dose measurement at 
Visit 101.
Vital signs (blood pressure, radial pulse rate) will also be summarized by visit.
The maximum (QTc, systolic blood pressure, radial pulse rate) or minimum (diastolic blood
pressure) post first dosing (i.e., post-baseline) value will be summarized. The changes from
baseline will also be summarized by visit.
All data will be included in the analysis regardless of rescue medication usage. 
The number and percentage of patients by the following classifications will be presented for
each visit.
The number (%) of patients with pulse rate of < 40 and > 90 bpm; systolic blood pressure of
< 90 and > 140 mmHg; diastolic blood pressure of < 50 and > 90 mmHg will be summarized.
Notable values for vital signs and the change from baseline will be summarized. A notable 
value is defined as follows:
Systolic blood pressure
“Low” criterion: < 75 mmHg, or ≤90 mmHg and decrease from baseline ≥20 mmHg
“High” criterion: > 200 mmHg, or ≥180 mmHg and increase from baseline ≥20 mmHg
Diastolic blood pressure
“Low” criterion: < 40 mmHg, or ≤50 mmHg and decrease from baseline ≥15 mmHg
“High” criterion: > 115 mmHg, or ≥105 mmHg and increase from baseline ≥15 mmHg
Pulse rate
”Low” criterion: < 40 bpm, or ≤50 bpm and decrease from baseline ≥15 bpm
“High” criterion: > 130 bpm, or ≥120 bpm and increase from baseline ≥15 bpm
Notable QTc values and the changes from baseline will be summarized. A notable value is
defined as a QTc interval of greater than 450 ms (male), 460 ms (female) and 500 ms (both) at 
baseline and the number of newly occurring or worsening notable QTc values for post
baseline time points. The categories used for the change from baseline in QTc are less than
30 ms, 30 to 60 ms and greater than 60 ms.
QTc will be calculated from the QT interval and RR (in seconds) by two methods:
1. using Fridericia's formula: QTc = QT ⁄ 3√RR, where 3√ denotes the cube root
2. using Bazett's formula: QTc = QT ⁄ √RR


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ECG and vital signs data measured more than 7 days after last inhalation of study drug is
regarded as post-treatment data and will not be summarized, only listed.
Laboratory data:
Evening plasma cortisol will be summarized by visit. The maximum evening plasma cortisol
post first dosing (i.e. post baseline value) will be summarized. The changes from baseline will 
also be summarized by visit.
All other laboratory data will be listed with abnormal values flagged. The laboratory values 
and the change from baseline for continuous laboratory parameters will be summarized at 
each visit. A frequency table of results for categorical laboratory parameters will be produced 
by visit. Shift tables relative to the normal reference ranges will be used to summarize the 
change from baseline to post-baseline by visit for each laboratory parameter.
All data will be included in the analysis regardless of rescue medication usage.
Laboratory data measured more than 7 days after last inhalation of study drug is regarded as
post-treatment data and will not be summarized, only listed.
9.5.3
Resource utilization
Not applicable.
9.5.4
Pharmacokinetics
Not applicable.
9.5.5
DNA
Not applicable.
9.5.6
Biomarkers
Not applicable.
9.5.7
PK/PD
Not applicable.


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9.7
Interim analyses
An interim analysis for 6-month data will be performed for the initial New Drug Application
submission in Japan (Section 3.2). This analysis will be performed after all patients have been
enrolled and completed Visit 107 (Week 26) or discontinued the study.
The cut-off date for each patient is defined as the Visit 107 date or study discontinuation date 
prior to Visit 107. All protocol specified analyses will be performed for all data on or prior to 
this cut-off date.
9.8
Sample size calculation
Since asthma is a chronic disease, and QVM149 is expected to be administered over a long 
period, safety in long-term treatment needs to be confirmed. “Regarding sample size and 
treatment period required to assess safety at the clinical study stage of a new drug anticipated 
to be administered for a non-fatal disease over a long period” (Notification No. 592 of the 
Pharmaceuticals and Cosmetics Division, Pharmaceutical Affairs Bureau, MHLW, dated 
24-May-1995), this notification requires to collect safety data of at least 100 patients who 
receive the drug over one year. CQVM149B2302 study was planned to collect efficacy and 
safety data of about 10 Japanese Asthma patients exposed to QVM149. Therefore this study, 
CQVM149B1304, is designed to obtain safety data of approximately 90 Japanese asthma 
patients exposed to QVM149. Since a 25% screening failure rate and a 10% dropout rate are 
expected, approximately 134 patients will need to be screened in order to collect 
approximately 100 patients who enter the treatment epoch and to collect a total of 
approximately 90 completed patients.
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 applicable
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. 


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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.
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, 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.


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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 
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
Adachi M, Hozawa S, Nishikawa M, et al. (2015) Asthma control, Quality of life and 
emotional feelings in a real life setting – a postal mail survey of adult asthma patients in Japan: 
the ACQUIRE study. Allergology&Immunology; 22:1446-60. (Article in Japanese)
Befekdadu E, Onofrei C, Colice GL (2014) Tiotropium in asthma, a systemic review. J 
Asthma Allergy; 7:11-21.
Global Initiative for Asthma (GINA) (2016) Global Strategy for Asthma Management and 
Prevention (Internet) Available from:
<http://ginasthma.org/> (Accessed 25 August 2016).
Juniper EF, O'Byrne PM, Guyatt GH, et al. (1999) Development and validation of the 
questionnaire to measure asthma control. Eur Resp J; 14(4):902-7.
Juniper EF, Svensson K, Mork AC, et al. (2005) Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med; 99:553-8.
Juniper EF, Bouquet J, Abetz L, et al. (2006) Identifying 'well-controlled' and 'not well-
controlled' asthma using the Asthma Control Questionnaire. Respir Med; 100(4):616-21.
Kerstjens HAM, Engel M, Dahl R, et al. (2012) Tiotropium in asthma poorly controlled with 
standard combination therapy. N Engl J Med; 367:1198-207.
Masoli M, Fabian D, Holt S, et al. (2004) The global burden of asthma: executive summary of 
the GINA Dissemination Committee Report. Allergy; 59:469-78.
Ohta K, Yamamoto M, Sato N, et al. (2010) One year treatment with omalizumab is effective 
and well tolerated in Japanese patients with moderate-to-severe persistent asthma.
Allergology International; 59(2):167-74.
Tohda Y, Adachi M, and Ohta K (2013) 日本人成人気管支喘息に対するフルチカゾン／
ホルモテロール配合剤（フルティフォーム®エアゾール）の長期投与時における安全
性及び有効性の検討—第III 相長期投与試験— Allergology&Immunology; 20:1686-704.
(Article in Japanese)
Vaidya S, Khindri S, Robinson J, et al. (2012) Pharmacokinetics (PK) of single doses of 
mometasone furoate (MF) delivered via the Breezhaler® (BH) and Twisthaler® devices in 
healthy subjects. Eur Respir J; 40, Suppl 56:P382.


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13
Appendices
13.1
Appendix 1: Clinically notable laboratory values and vital signs
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports.  Investigators are responsible for reviewing these abnormal values 
for clinical significance, signing the laboratory reports to indicate their review, and reporting 
values considered clinically significant in the appropriate CRF.
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.
See Appendix 2 for specific liver event and laboratory test trigger definitions and follow-
up requirements.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥450 msec for 
males or ≥460 msec for females – all such ECGs will be flagged by the Central CRO and 
require assessment for clinical relevance and continuance of the patient by the Investigator.
For vital signs, a notable value is defined as follows:
Systolic blood pressure
“Low” criterion: < 75 mmHg, or ≤90 mmHg and decrease from baseline ≥20 mmHg
“High” criterion: > 200 mmHg, or ≥180 mmHg and increase from baseline ≥20 mmHg
Diastolic blood pressure
“Low” criterion: < 40 mmHg, or ≤50 mmHg and decrease from baseline ≥15 mmHg
“High” criterion: > 115 mmHg, or ≥105 mmHg and increase from baseline ≥15 mmHg
Pulse rate
”Low” criterion: < 40 bpm, or ≤50 bpm and decrease from baseline ≥15 bpm
“High” criterion: > 130 bpm, or ≥120 bpm and increase from baseline ≥15 bpm
Investigators are responsible for reviewing these abnormal values for clinical relevance and 
reporting adverse events considered clinically significant in the appropriate CRF.


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13.2
Appendix 2: 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)
> 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)


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Criteria
Actions required
Follow-up monitoring
> 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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13.3
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, and no volume change for at least 1 second) or the subject cannot continue 
to exhale further. Overall acceptability will be determined by expert over-read by 
spirometry vendor.
Repeatability
The 2 largest FEV1 values from 3 acceptable maneuvers should not vary by more than 
0.150 L.
Recording of data 
The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).
Predicted normal
This study will utilize the spirometric predication equation standards from the ERS Global 
Lung Function Initiative2 or Japanese Respiratory Society3 for Japanese subjects 17 years of 
age or greater.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing1. A pre-bronchodilator spirometry assessment 
should be performed after a washout period of at least: 

6 h for short-acting β2-agonists

8 h short-acting anticholinergics

24 h for long-acting β2-agonists

7 days long-acting anticholinergic

7 days indacaterol

12 h for short-acting xanthines

24 h for long-acting xanthines
Administer 400 µg of salbutamol/albuterol (or equivalent) following the completion of the 
pre-bronchodilator assessment. Post-bronchodilator spirometry assessment is then performed 
within 15 to 30 minutes after administration of the salbutamol/albuterol.
Reversibility is calculated as:
100 x
FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)


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FEV1 (pre-bronchodilator) 
Subjects will be considered reversible if an increase of at least 12% (and 200 ml) is 
demonstrated after administration of the salbutamol/albuterol.
Following the reversibility testing assessment for post-bronchodilator FEV1, if patient has not 
met the above reversibility criteria after administration salbutamol/albuterol, then the patient 
may be rescreened or allow one spirometry retest.
References
1 Miller MR, Crapo R, Hankinson J, et al. (2005) Standardization of Lung Function Testing. 
Eur Resp J; 26:153-61.
2 Quanjer PH, Stanojevic S, Cole TJ, et al. (2012) 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 Resp J; 40(6):1324-43.
3 Kubota M, Kobayashi H, Quanjer PH, et al. (2014) 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 Investigation; 52:242-50.


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13.4
Appendix 4: Patient Asthma Control e-Diary
The following information will be captured:
In the MORNING
In the EVENING
Peak expiratory flow rate
How did you sleep last night?
Did you have asthma symptoms upon awakening 
in the morning?
Number of puffs of rescue medication during the 
past 12 hours
Peak expiratory flow
Did your respiratory symptoms stop you from 
performing your usual daily activities?
How severe was your shortness of breath today?
How was your wheeze during the past 12 hours?
How was your cough during the past 12 hours?
Did you have Chest tightness during the past 12 
hours?
Number of puffs of rescue medication during the 
past 12 hours


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Protocol No. CQVM149B1304
13.5
Appendix 5: Instruction for Use of Concept1
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

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.

The inhaler should be used for a maximum of 30 days, then replaced with a new inhaler

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.

SAP_001.pdf: 
Global Clinical Development - General Medicine
QVM149B (Indacaterol acetate/Glycopyrronium 
bromide/Mometasone furoate)
Clinical Trial Protocol CQVM149B1304 / NCT03100825
A multicenter, open-label, single arm, 52-week treatment 
study to assess the safety of QVM149 in Japanese patients 
with asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
01 (Clean)
Clinical trial phase:
III
Release date:
6-Apr-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


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Protocol No. CQVM149B1304
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 01 .........................................................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................18
2
Study objectives and endpoints .........................................................................................18
2.1
Objectives and related endpoints...........................................................................18
3
Investigational plan ...........................................................................................................19
3.1
Study design...........................................................................................................19
3.2
Rationale for study design .....................................................................................20
3.3
Rationale for dose/regimen, route of administration and duration of treatment....20
3.4
Rationale for choice of comparator .......................................................................21
3.5
Purpose and timing of interim analyses/design adaptations..................................21
3.6
Risks and benefits..................................................................................................21
4
Population..........................................................................................................................22
4.1
Inclusion criteria ....................................................................................................22
4.2
Exclusion criteria...................................................................................................23
5
Treatment...........................................................................................................................26
5.1
Study treatment......................................................................................................26
5.1.1
Investigational and control drugs..........................................................26
5.1.2
Additional treatment..............................................................................27
5.2
Treatment arms......................................................................................................27
5.3
Treatment assignment and randomization.............................................................27
5.4
Treatment blinding.................................................................................................27
5.5
Treating the patient................................................................................................27
5.5.1
Patient numbering .................................................................................27
5.5.2
Dispensing the study drug.....................................................................27
5.5.3
Handling of study and additional treatment..........................................28
5.5.4
Instructions for prescribing and taking study treatment........................28
5.5.5
Permitted dose adjustments and interruptions of study treatment ........29


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5.5.6
Rescue medication ................................................................................29
5.5.7
Concomitant medication .......................................................................30
5.5.8
Prohibited medication ...........................................................................30
5.5.9
Emergency breaking of assigned treatment code..................................33
5.6
Study completion and discontinuation...................................................................33
5.6.1
Study completion and post-study treatment..........................................33
5.6.2
Discontinuation of study treatment .......................................................33
5.6.3
Withdrawal of informed consent...........................................................36
5.6.4
Loss to follow-up ..................................................................................36
5.6.5
Early study termination by the sponsor.................................................36
6
Visit schedule and assessments .........................................................................................37
6.1
Information to be collected on screening failures..................................................40
6.2
Patient demographics/other baseline characteristics .............................................40
6.3
Treatment exposure and compliance .....................................................................41
6.4
Efficacy..................................................................................................................41
6.4.1
Spirometry.............................................................................................41
6.4.2
Electronic Diary ....................................................................................42
6.4.3
Asthma Control Questionnaire 7 (ACQ-7) ...........................................42
6.4.4
Worsening of asthma.............................................................................43
.44
6.4.6
Appropriateness of efficacy assessments..............................................45
6.5
Safety.....................................................................................................................45
6.5.1
Physical examination ............................................................................46
6.5.2
Vital signs..............................................................................................46
6.5.3
Height and weight .................................................................................46
6.5.4
Laboratory evaluations..........................................................................46
6.5.5
Electrocardiogram (ECG) .....................................................................47
6.5.6
Serious Asthma outcomes.....................................................................48
6.5.7
Pregnancy and assessments of fertility .................................................48
6.5.8
Appropriateness of safety measurements..............................................49
6.6
Other assessments..................................................................................................49
7
Safety monitoring..............................................................................................................49
7.1
Adverse events.......................................................................................................49
7.2
Serious adverse events...........................................................................................51
7.2.1
Definition of SAE .................................................................................51
7.2.2
SAE reporting........................................................................................51


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7.3
Pneumonia Reporting ............................................................................................52
7.4
Liver safety monitoring .........................................................................................52
7.5
Reporting of study treatment errors including misuse/abuse ................................53
7.6
Pregnancy reporting...............................................................................................54
8
Data review and database management.............................................................................54
8.1
Site monitoring ......................................................................................................54
8.2
Data collection.......................................................................................................55
8.3
Database management and quality control............................................................55
8.4
Data Monitoring Committee..................................................................................56
8.5
Adjudication Committee........................................................................................56
9
Data analysis......................................................................................................................56
9.1
Analysis sets ..........................................................................................................57
9.2
Patient demographics and other baseline characteristics.......................................57
9.3
Treatments .............................................................................................................57
9.4
Analysis of the primary variable(s) .......................................................................58
9.4.1
Primary Variable(s)...............................................................................58
9.4.2
Statistical model, hypothesis, and method of analysis..........................58
9.4.3
Handling of missing values/censoring/discontinuations.......................58
9.4.4
Sensitivity analyses ...............................................................................58
9.5
Analysis of secondary variables ............................................................................58
9.5.1
Efficacy variables..................................................................................58
9.5.2
Safety variables .....................................................................................59
9.5.3
Resource utilization...............................................................................61
9.5.4
Pharmacokinetics ..................................................................................61
9.5.5
DNA......................................................................................................61
9.5.6
Biomarkers............................................................................................61
9.5.7
PK/PD ...................................................................................................61
61
9.7
Interim analyses.....................................................................................................62
9.8
Sample size calculation..........................................................................................62
10 Ethical considerations........................................................................................................62
10.1
Regulatory and ethical compliance........................................................................62
10.2
Informed consent procedures.................................................................................62
10.3
Responsibilities of the investigator and IRB/IEC..................................................63
10.4
Publication of study protocol and results...............................................................63
10.5
Quality Control and Quality Assurance.................................................................63


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11 Protocol adherence ............................................................................................................64
11.1
Protocol amendments.............................................................................................64
12 References .........................................................................................................................65
13 Appendices ........................................................................................................................66
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................66
13.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................67
13.3
Appendix 3: Spirometry Guidance ........................................................................69
13.4
Appendix 4: Patient Asthma Control e-Diary .......................................................72
13.5
Appendix 5: Instruction for Use of Concept1........................................................73
List of tables
Table 1-1
Comparison of nominal MF doses in Asmanex Twisthaler, 
QMF149 and QVM149 drug products delivered by Concept1 
(Breezhaler)...........................................................................................17
Table 2-1
Objectives and related endpoints ..........................................................18
Table 5-1
Prohibited Asthma-related medications1...............................................30
Table 5-2
Prohibited Medications1........................................................................31
Table 5-3
Medications allowed under certain conditions1 ....................................31
Table 5-4
Table of assessment for the patients who discontinue 
investigational drug prematurely...........................................................35
Table 6-1
Assessment schedule.............................................................................38
Table 6-2
Timing of clinic visit procedures ..........................................................40
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................67
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers...67
List of figures
Figure 3-1
Study design..........................................................................................20


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List of abbreviations
ACQ
Asthma Control Questionnaire
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CCV
Cardiovascular and cerebrovascular
CFR
US Code of Federal Regulations
COPD
Chronic Obstructive Pulmonary Disease
CPO
Country Pharma Organization
CRO
Contract Research Organization
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
ePEF
electronic Peak Flow Meter
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in 1 second
FPM
Fine Particle Mass
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
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
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intra Uterine System
JGL
Asthma Prevention and Management Guideline
LABA
Long-Acting β2 Agonist
LAMA
Long-Acting Muscarinic Antagonist
LFT
Liver Function Test
MDDPI
Multi Dose Dry Powder Inhaler
MedDRA
Medical Dictionary for Regulatory Activities
MF
Mometasone Furoate
OC/RDC
Oracle Clinical/Remote Data Capture
OCS
Oral Corticosteroids
o.d.
once a day


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PC
Personal Computer
PEF
Peak Expiratory Flow
pMDI
pressurized Metered Dose Inhaler
RBC
Red Blood Cell
SABA
Short-Acting β2 Agonist
SAE
Serious Adverse Event
SAMA
Short-Acting Muscarinic Antagonist
SCS
Systemic Corticosteroids
SDDPI
Single Dose Dry Powder Inhaler
SUSAR
Suspected Unexpected Serious Adverse Reactions
ULN
Upper Limit of Normal range
WBC
White Blood Cell
WHO
World Health Organization


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Glossary of terms
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
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care.
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.”
Investigational treatment
All investigational drug(s) whose properties are being tested in the study 
as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination.
Investigational treatment generally does not include protocol-specified 
concomitant background therapies when these are standard treatments 
in that indication.
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system
Premature study
withdrawal (PSW)
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for 
progression and/or survival
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource.
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/investigational 
treatment discontinuation
Point/time when patient permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature patient withdrawal
Subject number
A number assigned to each patient who enrolls into the study
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


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Withdrawal of consent
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 
material


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Amendment 01
Amendment rationale
Modification of inclusion criteria for duration of baseline ICS/LABA requirements from 6 
months to 3 months. This is based on investigator feedback from real world asthma 
populations and intended to address evolving treatment patterns, whereby patient medications 
are more rapidly up-titrated in response to symptoms. This will help identify previously 
ineligible patients who may potentially benefit from treatment with LAMA as add-on therapy 
to existing ICS/LABA treatment.
Changes to the protocol
The described changes pertaining to the aforementioned amendment rationale are 
implemented throughout the protocol.
In addition, the following clarifications/additions are included in this protocol amendment:

Change the required pre-treatment period of ICS/LABA to 3 months prior to Visit 1 in
inclusion criteria 4 (Section 4.1)

Add the guidance of washout period in inclusion criteria 6 (Section 4.1)

Update the repeat spirometry test including reversibility in inclusion criterion 6, inclusion
criterion 7, and exclusion criterion 21 (Section 4.1 and Section 4.2)

Change the condition of spacer use for reversibility testing in inclusion 7 and excluding  
spacer use for rescue medication in exclusion criterion 30 (Section 4.1 and Section 4.2)

Add a clarification of Myocardial Infarction in exclusion criteria 16 and 19 (Section 4.2)

Correct the condition under antihistamines (except mizolastin) is permitted (Section 5.5.8)

Enhance importance of alert to have appropriate actions taken (Section 6.4.4).

Correct urinalysis item(Section 6.5.4.3)

Clarify SAE reporting (Section 7.2.2)

Remove ATC code for summarizing concomitant medication(Section 9.3)

Update the definition of repeatability in the spirometry guidance (Appendix 3)
An opportunity was also taken to make smaller changes such as some minor editorial changes 
that include correction of typographical errors and some clarifications and rewording to 
ensure consistency between protocol sections.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.


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The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein do NOT affect the trial specific model ICF.


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Protocol summary
Protocol number
CQVM149B1304
Full Title
A multicenter, open-label, single arm, 52-week treatment study to assess 
the safety of QVM149 in Japanese patients with asthma
Brief title
A long-term safety study of QVM149 in Japanese patients with asthma
Sponsor and Clinical 
Phase
Novartis Phase III
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to provide long term safety data of QVM149 in 
Japanese patients with asthma for the registration of QVM149 in Japan.
Primary Objective(s)
To assess the safety/tolerability of 52 weeks of treatment with QVM149 
(high dose) in Japanese patients with inadequately controlled asthma, by 
the incidence and severity of treatment emergent adverse events
Secondary Objectives

To assess the safety of QVM149 over 52 weeks of treatment, in terms 
of ECG, Vital signs, laboratory parameters, and plasma cortisol

To assess the efficacy of QVM149 in terms of lung-function in 
Japanese patients with inadequately controlled asthma after 26 and 52 
weeks of treatment

To assess the efficacy of QVM149 in terms of asthma control after 26 
and 52 weeks of treatment

To assess the efficacy of QVM149 in terms of rescue medication use 
during 52 weeks treatment
Study design
52 weeks multi-center, open-label, single arm study
Population
The study population will consist of approximately 100 Japanese males and 
females aged ≥18 years with asthma.
Key Inclusion criteria

Written informed consent must be obtained before any assessment is 
performed.

Male and female adult patient ≥18 years old.

Patients with a diagnosis of persistent asthma (GINA 2016) for a period 
of at least 1 year prior to Visit 1.

Patients who have used medium or high dose of ICS/LABA 
combinations for asthma for at least 3 months and at stable dose and 
regimen for at least 4 weeks prior to Visit 1.

An ACQ-7 score ≥1.5 at Visits 2.

Pre-bronchodilator FEV1 of ≥40% and ≤85% of the predicted normal 
value for the patient after withholding bronchodilators at Visit 2.

Repeating is allowed once only. Repeating 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 Visit 99.

Patients must demonstrate reversibility defined as an increase in FEV1
of ≥12% and 200 mL within 15 to 30 minutes after administration of 
400 µg of salbutamol at Visit 2. Spacer devices are permitted during 
reversibility testing only. The Investigator or delegate may decide 
whether or not to use a spacer for the reversibility testing.


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
If reversibility is not proven at Visit 2, patients may be permitted to 
enter the study with historical evidence of reversibility that was 
performed within 5 years prior to Visit 1.

Alternatively, patients may be permitted to enter the study with a 
historical positive bronchoprovocation test (defined as a provoked 
fall in FEV1 of 20% by bronchoconstriction agent e.g., 
methacholine, histamine) or equivalent test (e.g., astography) that 
was performed within 5 years prior to Visit 1.

If reversibility is not proven at Visit 2 and historical data is not 
available, reversibility should be repeated once in an ad-hoc visit 
scheduled as close as possible from the first attempt (but not on 
the same day).
Key Exclusion criteria

Patients who have had an asthma attack/exacerbation requiring 
systemic steroids or hospitalization or emergency room visit within 6-
weeks of Visit 1.

Patients who have ever required intubation for a severe asthma 
attack/exacerbation.

Patients who have a clinical condition which is likely to be worsened by 
ICS administration (e.g. glaucoma, cataract and fragility fractures) who 
are according to investigator's medical judgment at risk participating in 
the study.

Patients with narrow-angle glaucoma, symptomatic benign prostatic 
hyperplasia (BPH) or bladder-neck obstruction or severe renal 
impairment or urinary retention. BPH patients who are stable on 
treatment can be considered.

Patients who have had a respiratory tract infection or asthma 
worsening as determined by investigator within 4 weeks prior to Visit 1 
or between Visit 1 and Visit 99. Patients may be re-screened 4 weeks 
after recovery from their respiratory tract infection or asthma 
worsening.

Patients with a history of chronic lung diseases other than asthma, 
including (but not limited to) COPD, sarcoidosis, interstitial lung 
disease, cystic fibrosis, clinically significant bronchiectasis and active 
tuberculosis.

Patients with severe narcolepsy and/or insomnia

Pregnant or nursing (lactating) women

Women of child-bearing potential unless they are using highly effective 
methods of contraception during dosing and for 30 days after stopping 
of investigational medication
Study treatment
High dose QVM149 150/50/160 µg (indacaterol acetate/glycopyrronium 
bromide/MF) once daily delivered as powder in capsules via Concept1
Efficacy assessments

Spirometry

Peak Expiratory Flow

ACQ-7

Rescue Medication Use
Key safety 
assessments

Adverse events and serious adverse events

ECG

Vital signs

Laboratory findings


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
Evening plasma cortisol
Other assessments
Not applicable
Data analysis
The primary variable is the number and percentage of patients who 
reported treatment emergent adverse events during the 52 weeks study 
period.
Adverse events will be summarized with descriptive statistics for the Safety 
Set.
Key words
QVM149, asthma, Japanese


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1
Introduction
1.1
Background
Asthma is a chronic inflammatory disorder of the airways associated with airways hyper 
responsiveness 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 lung 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. Exacerbations 
of asthma are episodic whereas inflammation is chronic (GINA 2016).
Despite existing therapies there is still significant unmet medical needs in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years are lost annually due to asthma,
representing 1% of the total global burden. Annual worldwide deaths have been estimated at 
250 000 (Masoli et al 2004). In Japan, asthma death has been significantly decreased with the 
recent advance in asthma treatments and the widespread use of Asthma Prevention and 
Management Guideline (JGL). But then again, a nationwide survey conducted in Japanese 
adult asthma patients revealed that the proportion of patients with asthma control status of 
well-controlled, insufficiently-controlled and poorly-controlled were 9.1%, 73.6% and 17.3% 
respectively (Adachi et al 2015), indicating that there is still unmet needs for the new and 
better treatment option to improve asthma control.
GINA and JGL recommend similar diagnostic methods, treatment goals and treatment 
strategies and share the same treatment goal of long-term clinical asthma symptom control.
The current mainstay of asthma treatment is LABA/ICS-based, and the LAMA is expected to 
be an add-on option for patients whose asthma symptoms are poorly controlled. A clinical 
study of a LAMA (tiotropium) added to ICS or LABA/ICS in poorly controlled moderate to 
severe persistent asthma patients showed significant respiratory function improvements 
(forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF)) without a 
particular safety issue (Befekdadu et al 2014). Tiotropium was approved for asthma indication 
in Japan in 2014.
Following tiotropium regulatory approval in asthma, GINA 2016 guideline recommends 
tiotropium as a new add-on option on top of the preferred controller choice for steps 4 and 5 
in patients aged with a history of exacerbations. The preferred controller choice in asthma step 
4 is med/high ICS/LABA and in step 5 add-on treatment e.g. anti-IgE.
QVM149 is a fixed-dose combination of indacaterol acetate (inhaled LABA with 24 hour 
duration of action), glycopyrronium bromide (inhaled LAMA with 24 hours duration of 
action), and mometasone furoate (MF, ICS) in development 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. Novartis is developing QVM149 (LABA/LAMA/ICS) fixed dose 
combination (FDC) as a lactose-blended inhalation powder to be delivered via Concept1 


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(Breezhaler®), a single dose dry powder inhaler (SDDPI) for maintenance treatment for severe 
asthma (GINA 2016 Step ≥4).
In parallel, Novartis is developing QMF149, which is a fixed dose combination of 
mometasone furoate (MF) and indacaterol, in the Concept1 device.
Data from QVM149 monocomponents:
QVM149 is being developed in parallel with QMF149 (indacaterol acetate/MF) and existing 
efficacy and safety data for the three mono-components of the QVM149 FDC as well as for 
the two combinations indacaterol/mometasone (QMF149) and glycoppyronium/indacaterol 
(Ultibro®) support investigation in Phase III.
Indacaterol maleate, delivered via Concept1, a single dose dry powder inhaler (SDDPI) 
(Onbrez® Breezhaler®), is approved in over 110 countries worldwide for the once daily 
maintenance bronchodilator treatment of airflow obstruction in patients with COPD. 
Treatment guidelines state that LABAs are most effective when combined with an ICS 
(GINA 2016). The Phase III clinical development of indacaterol maleate that included studies 
in patients with asthma (who were receiving background ICS therapy), demonstrated that 
indacaterol maleate was effective and well-tolerated. A study in adolescent and adult patients 
with moderate to severe persistent asthma showed that doses of up to 600 µg o.d. over a 
26-week treatment period (when administered with concomitant ICS therapy) was well-
tolerated and resulted in effective bronchodilation which was superior to that provided by 
salmeterol (CQAB149B2338).
Studies comparing the indacaterol maleate salt with the acetate salt found that the alternative 
salts were associated with a lower incidence of post-inhalation cough (CQAB149B2102) with 
no impact on efficacy, safety or systemic exposure (CQAB149D2301). Indacaterol acetate 
dilates the bronchi quickly and continuously over 24 hours when administered once daily at 
150 µg in moderate to severe asthma patients (CQMF149E2203).
Glycopyrronium bromide (50 µg once daily in a lactose-based formulation) is registered in the 
EU since 2012 as Seebri®
Breezhaler®
(Concept1) for the treatment of COPD. 
Glycopyrronium bromide 50 µg has demonstrated clinically meaningful and statistically 
significant improvements in lung function in COPD patients which is sustained over 24 hours 
and provides significant symptomatic benefits with a favorable safety and tolerability profile.  
The fixed dose combination of indacaterol maleate and glycopyrronium bromide is also 
registered as Ultibro®, Breezhaler® in the EU and Japan (QVA149 110/50 µg with proven 
equivalent fine particle mass (FPM) of indacaterol maleate as obtained in indacaterol maleate 
150 µg) with the same doses as proposed for QVM149 (150/50/80 µg). Glycopyrronium 
bromide has been studied in adults and demonstrated optimal bronchodilation from the first 
dose and efficacy was maintained on once-daily dosing for treatment periods of up to a year, 
with good safety and tolerability.
MF is marketed in inhalation, nasal, cream, ointment and lotion formulations. The inhalation 
powder formulation which may be administered once or twice daily is marketed as a multi 
dose dry powder inhaler (MDDPI) called Asmanex® Twisthaler® for the treatment of asthma. 
Asmanex® Twisthaler® is currently approved in the United States for the treatment of asthma 


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in adults and children ≥4 years of age and is approved in over 55 countries world-wide for the 
treatment of asthma in adults and adolescents ≥12 years of age.
MF doses in QVM149
The MF doses in QMF149 program with Concept1 device are comparable to MF 200 µg, 
400 µg and MF 800 µg (400 µg twice a day) in Twisthaler® device as demonstrated in study 
(CQMF149E2101, Vaidya et al 2012) and after in-vitro fine particle mass adjustment. 
In a 4-week study in patients with persistent asthma (Study CQMF149E2201), MF doses of 
80 µg and 320 µg delivered once daily via Concept1 showed comparable efficacy and 
systemic exposure to MF doses of 200 µg and 800 µg (2 x 400 µg) delivered once daily via 
Twisthaler® confirming the selected doses for MF Concept1 are appropriate for further 
QMF149 Concept1 development.
The nominal doses of MF are 80 µg and 160 µg in the QVM149 FDC to ensure that the FPM 
(in-vitro aerosol performance) in the lactose blend formulation for the triple FDC is similar to 
the nominal MF doses of 160 µg and 320 µg for QMF149 Concept1 program, respectively. In 
this current study the medium and high doses of MF taken forward in QVM149 are 80 µg and 
160 µg which are comparable to the MF doses of 160 µg and 320 µg in the QMF149 products 
in QMF149B2301.
No adjustments to the doses of indacaterol acetate or glycopyrronium bromide in the FDC 
combinations were required.
Table 1-1
Comparison of nominal MF doses in Asmanex Twisthaler, QMF149 
and QVM149 drug products delivered by Concept1 (Breezhaler)
MF dose 
level
MF in Asmanex delivered 
by Twisthaler
MF in QMF149 delivered 
by Concept1
MF in QVM149 delivered 
by Concept1
Mid
400 µg
160 µg
80 µg
High
800 µg
320 µg
160 µg
The role of long-acting anticholinergics on top of medium and high dose ICS and LABA 
(FDC) as controller medication (QVM149) is supported based on the asthma clinical trial data 
with tiotropium on top of ICS and LABA/ICS in patients with severe persistent asthma 
(Kerstjens et al 2012).
Given that literature suggests that many asthma patients have poorly controlled disease 
despite currently available controller medications and there is increasing evidence of lung 
function benefit and improved control with triple combination therapy, further investigation of 
QVM149 triple therapy is supported.
On-going CQVM149B2302 is the pivotal study for regulatory submission, in which the 
superiority of QVM149 to QMF149 is evaluated and Japanese subjects are involved. Efficacy 
and safety data of 1 year treatment in Japanese patients will be obtained from this study.
The regulatory requirement for the long term safety data is to collect data for at least 100 
Japanese patients exposed to the study drug for one year. To comply with the requirement, 


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this study (CQVM149B1304) is intended to support the assessment of the long term safety 
and efficacy of QVM149 in Japanese population.
Additional information to QVM149 can be found in the QVM149 Investigator's brochure.
1.2
Purpose
The purpose of this study is to provide long term safety data of QVM149 in Japanese patients
with asthma for the registration of QVM149 in Japan.
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)

To assess the safety/tolerability of 52 weeks 
of treatment with QVM149 (150/50/160 µg, 
once daily) in Japanese patients with
inadequately controlled asthma
Endpoint(s) for primary objective(s) 

The incidence and severity of treatment 
emergent adverse events (AEs) over 52 
weeks of treatment
Secondary Objective(s)

To assess the safety of QVM149 over 
52 weeks of treatment
Endpoint(s) for secondary objective(s)

ECG, vital sign (blood pressure, pulse rate), 
laboratory parameters (hematology, clinical 
chemistry and urinalysis), plasma cortisol
over 52 weeks of treatment

To assess the efficacy of QVM149 in terms of 
lung-function in Japanese patients with 
inadequately controlled asthma

Change from baseline of pre-dose FEV1
measured after 26 and 52 weeks treatment

Change from baseline of morning and 
evening PEF during 52 weeks

To assess the efficacy of QVM149 in terms of 
asthma control

Change from baseline of ACQ-7 after 26 and 
52 weeks treatment

Responder rate of patients achieving the 
minimal important difference (MID) of ACQ-7
≥0.5 after 26 and 52 weeks treatment

To assess the efficacy of QVM149 in terms of 
rescue medication use

Change from baseline rescue medication 
use during 52 weeks treatment


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3
Investigational plan
3.1
Study design
This study uses a 52-week treatment, multicenter, open-label, single-arm design in Japanese 
patients with asthma (Figure 3-1). One interim analysis is planned after the last patient 
completed the assessments at Week 26 (Visit 107).
Screening epoch
All patients must have used medium or high dose ICS/LABA for at least 3 months and been 
on stable dose and regimen for at least 4 weeks prior to Visit 1. A screening epoch of 
maximum of 4 weeks (from Visit 1 to 99) will be used to assess eligibility and to taper 
patients off prohibited medications (Section 5.5.8). At Visit 1, all patients will be given 
salbutamol to use as rescue medication throughout the screening and treatment epochs and 
will be given an electronic diary to record asthma symptoms and rescue medication use. In 
addition, patients will be given an electronic Peak Flow meter to record PEF. The last 2 weeks 
of screening epoch (from Visit 2 to 99) will be used to assess eligibility of the patients to enter 
the treatment epoch and to collect baseline values for some variables.
Screening epoch must have a minimum of 2 weeks prior to start taking study medication at 
Visit 101 (Day 1).
Treatment epoch
Visits 99 and 101 take place sequentially on the same date. The assessments at Visit 99 should 
be performed prior to administration of the first dose of investigational drug; eligible patients 
will be assigned to QVM149 150/50/160 µg o.d. (high ICS dose), and enter 52-week 
treatment epoch. Patients will be required to inhale QVM149 150/50/160 µg via Concept1 
once daily in the evening throughout treatment epoch. The first dose of investigational drug
will be administered at the clinic in the evening (between 4:00 and 8:00 pm) at Visit 101. 
Subsequent clinic visits will be scheduled so that patients will be reassessed as close as 
possible to the same time relative to the evening doses. Patients will be instructed not to take 
their evening dose of investigational drug on the days of the clinic visits, as these doses will 
be administered at the clinic under the supervision of study personnel. Clinic visits to assess 
safety and efficacy are scheduled at weeks 4, 12, 26, 36 and 52.
Follow-up epoch
A safety follow-up (telephone contact, Visit 201) will be conducted at 30 days after the last 
treatment date (Visit 111 or early discontinuation). Investigator will prescribe appropriate 
asthma controller medication to the patients and investigational drug will not be given after 
the last treatment date.


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Figure 3-1
Study design
*Duration of screening epoch may vary from 2 to 4 weeks. Screening epoch must have a minimum of 
2 weeks prior to start taking study medication at Day 1. Visit 1 and Visit 2 may occur on the same day 
depends on concomitant medication and appropriate washout prior to spirometry testing. Please refer 
to Table 5-1, Table 5-2, and Table 5-3 for details.
3.2
Rationale for study design
The patient population will be described in more detail in the Section 4 below.
As stated in Section 1.2, this study is planned to fulfil the Japanese regulatory requirement for 
a registration of QVM149 (indacaterol acetate/glycopyrronium bromide/mometasone furoate) 
in Japan. 
 
 
 
 
 
 
 
An open-label design without comparator arm is considered adequate to evaluate Japanese 
long term safety for asthma and accepted by Japanese Health Authority previously (Ohta et al 
2010, Tohda et al 2013).
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
On-going Phase III study CQVM149B2302 is evaluating two doses of QVM149 
150/50/80 µg (medium ICS dose) o.d. inhalation and 150/50/160 µg once daily inhalation in 
asthma. The difference between the two doses of QVM149 is the dose of mometasone 
component (ICS). For the purpose of collecting additional long term safety data in Japanese 
patients, high dose of QVM149 150/50/160 µg o.d. is chosen on the basis that exposure of 
asthma patients to high (ICS) dose can generate supportive safety information for the 
lower/medium (ICS) dose in the fixed triple combination.


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Treatment duration of 52 weeks is chosen to comply with Japanese regulatory requirement 
(Section 3.2).
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
 
Details of statistical considerations are described in Section 9.6.
3.6
Risks and benefits
QVM149 is an orally inhaled fixed-dose combination of indacaterol acetate (a LABA), 
glycopyrronium bromide (a LAMA), and mometasone furoate (an ICS). All three 
mono-components
of QVM149, indacaterol maleate, glycopyrronium bromide and 
mometasone furoate have previously been developed and approved as individual drugs for 
COPD or asthma, respectively. QVM149 as a lactose-blended inhalation powder is delivered 
via Concept1 (Breezhaler®), a single dose dry powder inhaler (SDDPI). The favorable benefit-
risk ratio of a fixed-dose combination of indacaterol acetate and mometasone furoate 
(QMF149, in the Phase III development worldwide) in asthma and glycopyrronium bromide 
in COPD as well as the so far acquired knowledge about LAMA (tiotropium) on top of 
LABA/ICS in asthma (Kerstjens et al 2012) is a rationale to conduct this study.
Dual bronchodilation with ICS controller would be expected to achieve good symptom 
control, minimize airflow obstruction, minimize risk of exacerbations, and hospitalizations in 
asthma patients inadequately controlled on medium- or high-dose LABA/ICS. Use of multiple, 
often different devices represents a significant burden for asthma patients. Availability of 
three effective once-daily controller medications in a single device may offer advantages in 
terms of efficacy by improved adherence and convenience. Based on available data of 
components, it is expected that QVM149 will have a favorable benefit to risk profile in 
patients with asthma.
In line with current medical treatment guidelines, all patients participating in the study will 
receive active “controller” treatment for their asthma throughout the screening epoch and 52-
week treatment epoch. In addition, the patients will be provided with rescue medication for 
use as needed throughout study. At no time, will any patient be without treatment for asthma.
QVM149 is under development and therefore it is possible that unexpected safety issues may 
be identified. The risk will be minimized by compliance with the eligibility criteria and close 
clinical monitoring of patients. In addition, safety monitoring (e.g. symptom collection and 
rescue medication use via electronic diary) and daily PEF measurements at regular intervals 
throughout the study will help assess 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. The risks of side effects from the study 
medication are those known for the individual compounds indacaterol acetate, 


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glycopyrronium bromide and mometasone furoate. Up to now no additional risks have been 
identified which might occur when the three components are administered concurrently or 
from the same inhaler. Detailed risk-benefit information can be obtained from the QVM149 
Investigator's Brochure (IB).
There are concerns that LABA treatment used alone in asthma might cause severe asthma 
exacerbations. To address this safety concern all patients are treated with a FDC of 
LABA/LAMA/ICS in this study so LABA alone will not be allowed.
Potential risk of inappropriate use of inhaler devices will be mitigated by detailed instructions 
and trainings provided by the Investigators to patients.
Guidance to manage potential worsening of asthma symptoms will be provided to 
investigators consistent with guideline recommendations (GINA 2016 and JGL). Patients will 
receive well written instructions as to how to contact the investigator in the event of 
worsening of their asthma symptoms. The investigator should discontinue study treatment for 
a given patient and/or withdraw the patient from the study if, on balance, he/she believes that 
continuation would be detrimental to the patient's well-being. Patients are also instructed that 
they can withdraw from the study at any time, and for any reason.
In summary, based on available data of components, it is anticipated that QVM149 
150/50/160 µg once daily will have an acceptable benefit to risk profile in patients with 
asthma.
4
Population
The study population will consist of approximately 100 Japanese males and females aged ≥18
years with asthma, who are currently treated with or qualify for treatment with 
LABA/LAMA/ICS triple therapy. Since a 25% screening failure rate and a 10% dropout rate 
are expected, approximately 134 patients will be screened in order to collect a total of 
approximately 90 completed patients. Dropouts will not be replaced. This study is a single 
national trial to be conducted in Japan.
4.1
Inclusion criteria
Patients/subjects 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 patient ≥18 years old.
3. Patients with a diagnosis of persistent asthma (GINA2016) for a period of at least 1 year 
prior to Visit 1.
4. Patients who have used medium or high dose of ICS/LABA combinations for asthma for 
at least 3 months and at stable dose and regimen for at least 4 weeks prior to Visit 1.
5. An ACQ-7 score ≥1.5 at Visit 2.
6. Pre-bronchodilator FEV1 of ≥40% and ≤85% of the predicted normal value for the 
patient after withholding bronchodilators at Visit 2.

Withholding period of bronchodilators prior to spirometry:

SABA for ≥6 hrs,


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
LABA (or FDC of ICS/LABA) for ≥24 hrs,

Tiotropium for ≥7 days, 

SAMA for ≥8 hrs,

Short acting xanthines for ≥12 hrs,

Long acting xanthines for ≥24 hrs.

Washout period of each drug should be kept as close as possible as above and should
not be longer. If longer washout period is needed due to scheduling issues, please
contact Novartis Medical monitor.

Repeating is allowed once only. Repeating 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 Visit 99.
7. Patients must demonstrate reversibility defined as an increase in FEV1 of ≥12% and 
200 mL within 15 to 30 minutes after administration of 400 µg of salbutamol at Visit 2.
Spacer devices are permitted during reversibility testing only. The Investigator or delegate 
may decide whether or not to use a spacer for the reversibility testing.

If reversibility is not proven at Visit 2, patients may be permitted to enter the study 
with historical evidence of reversibility that was performed within 5 years prior to 
Visit 1.

Alternatively, patients may be permitted to enter the study with a historical positive 
bronchoprovocation test (defined as a provoked fall in FEV1 of 20% by
bronchoconstriction agent e.g., methacholine, histamine) or equivalent test (e.g.,
astography) that was performed within 5 years prior to Visit 1.

Where patient is assessed as eligible based on historical evidence, a copy of the 
original printed report must be available as source documentation.

If reversibility is not proven at Visit 2 and historical data is not available, reversibility 
should be repeated once in an ad-hoc visit scheduled as close as possible from the first 
attempt (but not on the same day).

If reversibility is not demonstrated at Visit 2 (or after repeated assessment at ad-hoc 
visit) and historical evidence of reversibility/bronchoprovocation/astography is not 
available, patients must be screen failed.
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. Use of other investigational drugs within 30 days or 5 half-lives of enrollment, or until the 
expected pharmacodynamic effect has returned to baseline, whichever is longer.
2. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes including untoward reactions to sympathomimetic amines or inhaled 
medication or any component thereof (including lactose).


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3. Patients who have a clinical condition which is likely to be worsened by ICS 
administration (e.g. glaucoma, cataract and fragility fractures) who are according to 
investigator's medical judgment at risk participating in the study.
4.
Patients with evidence upon visual inspection (laboratory culture is not required) of 
clinically significant (in the opinion of investigator) oropharyngeal candidiasis at Visit 99
or earlier, with or without treatment. Patients may be re-screened once their candidiasis 
has been treated and has resolved.
5. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH
patients who are stable on treatment can be considered) or bladder-neck obstruction or 
severe renal impairment or urinary retention.
6.
Patients who have smoked or inhaled tobacco products within the 6 month period prior to 
Visit 1, or who have a smoking history of greater than 10 pack years (Note:1 pack is 
equivalent to 20 cigarettes. 10 pack years = 1 pack/day x 10 yrs., or ½ pack/day x 20 yrs).
This includes nicotine inhalers such as e-cigarettes at time of Visit 1.
7.
Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients 
experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or 
emergency room visit between Visit 1 and Visit 99 they may be re-screened 6 weeks after 
recovery from the exacerbation.
8.
Patients who have ever required intubation for a severe asthma attack/exacerbation.
9. Patients who have had a respiratory tract infection or asthma worsening as determined by 
investigator within 4 weeks prior to Visit 1 or between Visit 1 and Visit 99. Patients may 
be re-screened 4 weeks after recovery from their respiratory tract infection or asthma 
worsening.
10. Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic 
sinusitis) which in the opinion of the investigator may interfere with the study evaluation 
or optimal participation in the study.
11. Patients with a history of chronic lung diseases other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, 
cystic fibrosis, clinically significant bronchiectasis and active tuberculosis.
12. 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.
13. Patients with Type I diabetes or uncontrolled Type II diabetes.
14. 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, New York Heart Association (NYHA) Class III/IV left ventricular 
failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric 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.


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15. Patients with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. 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 2 with 
a resting ventricular rate < 100/min.  At Visit 2 the atrial fibrillation must be confirmed by 
central reading.
16. Patients with a history of myocardial infarction (this should be confirmed clinically by 
the investigator) within the previous 12 months.
17. Concomitant use of agents known to prolong the QT interval unless it can be 
permanently discontinued for the duration of study.
18. Patients with a history of long QT syndrome or whose QTc measured at Visit 2
(Fridericia method) is prolonged (> 450 msec for males and > 460 msec for females) and 
confirmed by a central assessor (these patients should not be rescreened).
19. Patients who have a clinically significant ECG abnormality at Visit 2. ECG evidence of 
myocardial infarction at Visit 2 (via central reader) should be clinically assessed by the 
investigator with supportive documentation.
20. Patients who have a clinically significant laboratory abnormality at Visit 2.
21. Patients who have not achieved an acceptable spirometry result at Visit 2 in accordance 
with ATS/ERS criteria for acceptability and repeatability. A one-time repeat spirometry is
allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on 
the same day) if the spirometry did not qualify due to ATS/ERS criteria. If the patient fails 
the repeat assessment, the patients may be rescreened, provided the patient returns to the 
required treatment as per inclusion criteria 4.
22. Patients taking any asthma-related prohibited medications in the classes specified in
Table 5-1 unless they undergo the required washout period.
23. Patients in need of any prohibited medications listed in Table 5-2.
24. Patients taking medications listed in Table 5-3 should be excluded unless the medication 
has been stabilized for the specified period and the stated conditions have been met.
25. Patients on Maintenance Immunotherapy (desensitization) for allergies or less than 3 
months prior to Visit 1 or patients on Maintenance Immunotherapy for more than 3 
months prior to Visit 1 but expected to change throughout the course of the study.
26. Patients with severe narcolepsy and/or insomnia.
27. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
28. History of alcohol or other substance abuse.
29. Patients who are directly associated with any members of the study team or their family 
members.
30. Patients unable to use the Concept1 dry powder inhaler or a metered dose inhaler. Spacer 
devices are not permitted for rescue medication.
31. Patients with a known history of non-compliance to medication or who were unable or 
unwilling to complete a patient diary or who are unable or unwilling to use Electronic 
Peak Flow with e-Diary device.


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32. 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.
33. 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 investigational 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 6 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*.
*
Not approved in Japan.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
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), total hysterectomy or tubal ligation at least 6 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.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The investigational drug is as follows: 

QVM149 (indacaterol acetate/glycopyrronium bromide/mometasone furoate) 
150/50/160 µg o.d. delivered as powder in hard capsules via Concept1 (Appendix 5)
There is no control drug for this trial.


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5.1.2
Additional treatment
Starting at Visit 1, patients will receive short-acting β2 agonist (salbutamol) inhaler to use as 
rescue medication on an “as needed” basis.
More details regarding rescue medication are in Section 5.5.6.
5.2
Treatment arms
All eligible patients will be assigned to the investigational drug (Section 5.1.1) at Visit 101.
5.3
Treatment assignment and randomization
This study is a single-arm, non-randomized trial. For the purpose of the investigational drug 
accountability and tracking, Interactive Response Technology (IRT) will be used.
At Visit 101, 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 unique number to the 
patient, which will be used to link the patient to a unique medication number for the first 
package of study drug to be dispensed to the patient.
5.4
Treatment blinding
Not applicable.
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 must 
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 eCRF.
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 a specific visit. 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 


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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
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
The investigator should promote compliance by instructing the patient to take the study 
treatment (Section 5.1) exactly as prescribed and by stating that compliance is necessary for 
the patient's safety and the validity of the study. The patient should be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
At Visit 1 all patients will be instructed how to use a pMDI to administer rescue salbutamol 
correctly. At Visit 99 all patients will be fully trained in the correct use of the Concept1 to 
administer QVM149. Patients who are unable to use Concept1 correctly at Visit 99 will not be 
eligible to enter the treatment epoch. For this training purpose, training kits (placebo capsules 
of QVM149 and Concept1 inhalers) will be supplied to the investigator site. At each clinic 
visit the investigator should check the patient's use of the inhalational devices to ensure that 
they are using each device correctly. Additional device training should be provided if required.
Starting at Visit 101, all eligible patients will be instructed to take QVM149 150/50/160 µg 
via Concept1 once daily in the evening at approximately the same time of day. Patients will 
be instructed to rinse their mouth (e.g., 2 times with approximately 30 mL water) after 


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inhalation of QVM149. Water used for mouth rinsing should be spat out and should NOT be 
swallowed.
The study treatment can be taken without regard to sleep, meals, and other activities. On days 
of scheduled clinic visits, patients should take QVM149 at the clinic (approximately between 
4:00 to 8:00 pm) under the supervision of investigator or his/her delegate.
The duration of treatment epoch is 52 weeks, with the last dose of study treatment occurring 
in the evening of Day 365 (Visit 111).
All kits of investigational drug assigned by the IRT will be recorded in the IRT. All used and 
unused study medication/packaging must be returned by the patient at each study visit and/or 
at the time of discontinuation.
All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
If any faults are identified with either the device and/or the blisters, these should be returned 
to Novartis Drug Supply Management with the completed Device Return Form. The forms 
will be supplied to each investigator site by the Field Monitor.
5.5.5
Permitted dose adjustments and interruptions of study treatment
Dose adjustments and/or interruptions of QVM149 are not permitted unless the investigator 
considers an interruption is necessary for the treatment of an adverse event. Any interruption 
of QVM149 should be for the shortest time period possible and must be recorded on the 
Dosage Administration Record CRF.
5.5.6
Rescue medication
At Visit 1, all patients will be provided with a short-acting β2 agonist (100 µg salbutamol via 
pMDI) which they will be instructed to use throughout the screening and treatment epoch as 
rescue medication on an 'as needed' basis. Patients will be advised that between visits they can 
take their rescue medication for symptoms. The rescue salbutamol will be provided to the 
patients by the investigator site and reimbursed locally by Novartis or supplied to the 
investigator sites locally by Novartis. Nebulized salbutamol is not allowed as rescue 
medication and use of a spacer for rescue medication is not allowed at any time throughout 
the study.
In order to standardize measurements, patients will be instructed to abstain from taking rescue 
salbutamol within 6 hours of the start of each spirometry visit unless absolutely necessary. If 
rescue medication is taken within 6 hours prior to spirometry assessments, then the visit 
should be rescheduled to the next day if possible.
Bronchodilator medications that the patients used prior to Visit 1 must be recorded in the 
asthma-related prior/concurrent medication page of the CRF, with the stop date for these 
bronchodilators recorded as the date of Visit 1. The rescue salbutamol provided at Visit 1 for 
use during the study should NOT be recorded on the asthma-related prior/concurrent 
medication page of the eSource. From Visit 1, daily use of rescue medication (number of 
puffs taken in the previous 12 hours) will be recorded each morning and evening throughout 
the 52 week treatment epoch by the patient using their electronic diary.


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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' and 'Surgical and Medical Procedures' CRF.
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 
entering the treatment epoch or allowing a new medication to be started.
5.5.8
Prohibited medication
The class of medications listed in Table 5-1 and Table 5-2 are not permitted to be taken 
during the study. The medications in Table 5-3 are only permitted under the circumstances 
given. 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 
before allowing a new medication to be started.
If indicated for the treatment of an asthma exacerbation, any treatment deemed necessary by 
treating physician for the safety of the patient is allowed from the start of the asthma 
exacerbation event (defined as per protocol Section 6.4.5) until the asthma exacerbation event 
is resolved. Patients may NOT self-medicate (other than administration of rescue medication) 
or adjust therapy without permission/guidance from treating physician.
Table 5-1
Prohibited Asthma-related medications1
Medication
Minimum cessation prior to Screening (Visit 1) 
and Baseline (Visit 99)
Long-acting anticholinergics (LAMA)
Must not be used from 7days prior to Visit 2 
onwards.
Short-acting anticholinergics (SAMA)
Must not be used from 8 hours prior to spirometry 
at Visit 2 onwards.
Fixed dose combinations of β2-agonists and 
inhaled corticosteroids
Must be discontinued 24 hours prior to Visit 99. 
Must be withheld 24 hours prior to spirometry at 
Visit 2.
Long-acting β2-agonists (LABA)
Must be discontinued 24 hours prior to Visit 99. 
Must be withheld 24 hours prior to spirometry at 
Visit 2.
Inhaled corticosteroid
Must be discontinued one day prior to Visit 99 
(after the evening dose).
Short acting β2-agonists (SABAs) (other than 
Salbutamol provided at Visit 1 for rescue 
medication)
Must be discontinued at Visit 1
Salbutamol/albuterol (SABA) provided at Visit 1 
Must be withheld 6 hours prior to spirometry2
Parenteral corticosteroids (systemic 
corticosteroids are permitted for the treatment of 
asthma exacerbations)
Must be discontinued 4 weeks prior to Visit 1
Intra-muscular depot corticosteroids
Must be discontinued 3 months prior to Visit 1


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1 These tables are not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. These medications are also prohibited if administered 
for other indications.
2 Clinic visits may be rescheduled if rescue medication were taken less than 6 hours prior to the 
spirometry assessments.
Table 5-2
Prohibited Medications1
Medication
Minimum cessation prior to Visit 2
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
(Biologics and/or monoclonal antibody need to 
have a 6 month wash out period)
Non-selective systemic beta-blocking agents
7 days
Non-potassium sparing diuretics (unless 
administered as a fixed-dose combination with a 
potassium conserving drug)
7 days
Cardiac anti-arrhythmics Class Ia
7 days
Cardiac anti-arrhythmics Class III
7 days, amiodarone 3 months
Other drugs with potential to significantly prolong 
the QT interval
14 days or 5 half-lives, whichever is longer
Mizolastin
5 days
Tricyclic antidepressants (Please note that 
tetracyclics, which are similar in class with 
regards to drug interaction are also to be 
excluded)
14 days
All antipsychotic agents (first, second and third 
generation, inclusive of atypical antipsychotics). 
Combinations of antipsychotic agents with 
antidepressants are prohibited
14 days
Strong inhibitors of cytochrome P450 3A (e.g. 
ketoconazole) (may depend on compound) 
7 days
Serotonin Noradrenaline Reuptake Inhibitors
14 days
Monoamine-oxidase inhibitors
14 days
Noradrenaline reuptake inhibitors
7 days
Systemic anticholinergics
7 days
Live attenuated vaccine
30 days
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. The washout of these prohibited medications is not to 
be encouraged.
Table 5-3
Medications allowed under certain conditions1
Medication
Condition under which medication is permitted
Topical Corticosteroids for treatment of
eczema
Recommended doses and dosage regimens
Maintenance Immunotherapy for allergies
Stable dose for at least 3 months prior to 
screening (Visit 1) and unchanged throughout the 
study.


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Medication
Condition under which medication is permitted
Pure Selective Serotonin Reuptake Inhibitors 
(they must have no documented effect on any 
other neurotransmitters or other biological 
pathways. e.g. muscarinic pathway)
Stable regimen for at least 30 days prior to 
screening (Visit 1).
Intra-nasal corticosteroids
Stable dose for at least 4 weeks prior to screening
(Visit 1)
In the case of as needed, provided an established 
pattern of use has been documented.
Antihistamines (except mizolastin) (e.g. 
loratadine, cetirizine)
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1).
In the case of as needed, provided an established 
pattern of use has been documented.
Mucolytic agents not containing bronchodilators
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study.
Systemic mast cell stabilizers
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study.
Inactivated influenza vaccination, pneumococcal 
vaccination or any other inactivated vaccine
Not administered within 48 hours prior to a study 
visit
Rescue Short-acting β2 agonists
Not used within 6 hours prior to spirometry
Leukotriene Antagonist and leukotriene 
synthesis inhibitors
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study.
Long-acting theophylline
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study. Not administered within 24 hours prior 
to spirometry.
Short-acting theophylline
Stable dose/regimen for at least 4 weeks prior to 
the screening (Visit 1) and unchanged throughout 
the study. Not administered within 12 hours prior 
to spirometry.
Monoclonal antibodies for the treatment of 
asthma (e.g., omalizumab, mepolizumab)2
Stable dose for at least 3 months prior to 
screening (Visit 1)
Oral corticosteroids3
Stable dose for at least 30 days prior to screening 
(Visit 1) and throughout the study at prednisone 
equivalent dose of 5 mg daily to 10 mg every other 
day
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.
2 Omalizumab or mepolizumab may be discontinued at the investigator's discretion. Once 
discontinued, resuming omalizumab or mepolizumab is not permitted during the study. Omalizumab 
dosing should be guided by Japanese labelling.
3 Oral corticosteroids may be continued at a low stable dose after a course of steroid taper for
exacerbations at the discretion of the investigator (in doses not to exceed equivalent of prednisone 
5 mg daily). If steroids are continued beyond 7 to 10 day taper, the stable low dose (≤prednisone 
5 mg daily) should be maintained for at least 3 months prior to stopping. Otherwise patient must be 
discontinued from study treatment.


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5.5.9
Emergency breaking of assigned treatment code
Not applicable for this open-label 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 (Visit 111, Week 52) planned in the protocol.
Continuing care should be provided by investigator and/or referring physician based on 
patient availability for follow-up.
For all patients a safety follow-up visit (Visit 201) should be conducted (e.g. by telephone) 30 
days after last visit (Visit 111, Week 52). The information to be collected at this follow up 
visit includes serious adverse events, asthma exacerbations, and survival status.
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.
Patients may voluntarily discontinue study treatment for any reason at any time. In the case 
the patients would want to discontinue the treatment, it is particularly important to ask the 
reason and if they would be willing to remain in the trial to share their safety and vital status 
information (e.g., via telephone contact) until the scheduled final visit in order to ensure the 
scientific integrity of the trial.
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

Adverse events for which continued inhalation of the investigational drug would be 
detrimental

Abnormal test procedure results indicating risk for the patient on continued inhalation of 
the investigational drug 

Pregnancy (see Section 6.5.7 and Section 7.6)

If a patient develops a medical condition that requires use of prohibited treatment as per 
Section 5.5.8 or if patient exhibits a behavior of non-compliance regarding prohibited 
medications

Patients who experience 5 or more asthma exacerbations during the treatment epoch that 
required treatment with systemic corticosteroids

Patients with > 50% decrease in FEV1 from baseline (Visit 101) during treatment epoch

Any situation in which study participation might result in a safety risk to the patient
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of investigational drug, for a study treatment discontinuation visit. If the 


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patient fails to return for the study treatment discontinuation visit for unknown reasons, every 
effort (e.g., telephone, e-mail, letter) should be made to contact him/her as specified in 
Section 5.6.4. Treatment discontinuation visit assessments detailed in the “unscheduled 
treatment discontinuation visit” (UNS) in Table 5-4 and Table 6-1 should be completed and 
recorded in the eCRF. The investigator must determine the primary reason for the patient's
premature discontinuation of study treatment and record this information on the Dosage 
Administration eCRF.
The investigator and study staff must discuss with the patient the continued participation in 
the study by maintaining regular telephone contact with him/her or with a person pre-
designated by the patient. This telephone contact should preferably be done according to the 
study visit schedule. After study treatment discontinuation, the following data should to be 
collected via telephone visits:

Asthma exacerbation

Serious Adverse Events
The investigator must also contact the IRT to register the patient's discontinuation from study 
treatment.


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Table 5-4
Table of assessment for the patients who discontinue investigational 
drug prematurely
Assessment
Early study 
treatment 
discontinuation 
visit
Unscheduled 
safety follow-up 
visit
At time of 
scheduled 
clinic 
visit1
Early Study 
discontinuation 
(Premature study 
withdrawal)2
Follow-up 
Visit 201
Visit type
Clinic visit
Telephone
Telephone
Telephone
Telephone
Week
Discontinuation 
date
Discontinuation 
date + 4 weeks
56
Day
Discontinuation 
date
Discontinuation 
date + 30 days
395
IRT treatment discontinuation 
call
X
Vital signs
X
Physical exam
S
Oropharyngeal examination
S
Pregnancy test (serum)
X
Collect study medication
X
Record asthma/non-asthma 
related concomitant medication
X
X
Record interruption/changes in 
drug administration to assess 
compliance
X
Download/review e-Diary
S
Review rescue medication use
S
Review AEs
X
X
Review SAEs
X
X
X*
X*
X*
Review asthma exacerbations
X
X
X
X
X
Review surgery and procedures
X
X
Safety lab assessments 
(hematology, clinical chemistry, 
urinalysis)
X
Spirometry3
X
ECG3
X
ACQ-73, 4
X
Evening plasma cortisol3
X
Survival status
X
X
X
X
Record Healthcare visit for 
asthma worsening
X
X
Record end of treatment epoch 
disposition page
(Study Phase Completion)
X
X
S These assessments are source documentation only and will not be entered into the eCRF
X assessment to be reported in the clinical database
* If a subject experienced a serious adverse event (SAE), complete a corresponding AE CRF.
1 Refer to Table 6-1.
2 Refer to Section 5.6.3 and Section 5.6.5
3 Details of timed assessments are provided in Table 6-2.
4 ACQ assessed at clinic should be completed before any other assessment.


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5.6.3
Withdrawal of informed consent
Patients 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 the 
Table 5-4.
5.6.4
Loss 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 must 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.
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.


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6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients 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.
Patients will be contacted for safety evaluations during the 30 days following the last 
administration of study treatment.


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Table 6-1
Assessment schedule
Epoch
Screening
Treatment
Follow-up1
Visit number
1
2
99
101
102
103
104
105
106
107
108
109
110
111
EOT
Early 
treatment 
discontinuation
PSW
Early Study 
Discontinuation
201
Clinic (C)/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
C
T
C
C
T
T
Week
-4 to -2 -2
0
0
4
8
12
16
20
26
32
36
44
52
56
Obtain informed consent
X
Relevant Medical 
History/Demographics
X
History of Asthma exacerbation
X
Smoking History
X
Current asthma medication review
X
Inclusion/Exclusion criteria
X
X
X
Central pregnancy test (Serum)
X
X
X
Local pregnancy test (urine)
X
X
Urinalysis (dipstick)
S
S
S
S
Hematology/biochemistry
X
X
X
X
X
Evening plasma cortisol
X
X
X
X
Inhalation device training
S
Drug dispensing
X
X
X
X
X
Administer study drug at the visit
X
X
X
X
Reversibility test
X
Spirometry (centralized)
X
X
X
X
X
X
Issue and training on patient e-Diary
S
S
e-Diary, ePEF device training
S
S
S
Concomitant medication review
(for asthma & for non-asthma)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Epoch
Screening
Treatment
Follow-up1
Visit number
1
2
99
101
102
103
104
105
106
107
108
109
110
111
EOT
Early 
treatment 
discontinuation
PSW
Early Study 
Discontinuation
201
Clinic (C)/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
C
T
C
C
T
T
Week
-4 to -2 -2
0
0
4
8
12
16
20
26
32
36
44
52
56
Review and upload patient e-Diary
S
S
S
S
S
S
S
ACQ-7
X
X
X
X
X
X
Physical examination
S
S
S
S
S
S
S
S
Oropharyngeal examination
S
S
S
S
S
S
S
S
Vital sign: BP and pulse
X
X
X
X
X
X
X
X
Record height and weight
X
ECG
X
X
X
X
X
SAE recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review surgery and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record healthcare visits for asthma 
worsening
X
X
X
X
X
X
X
X
X
X
X
X
Survival status
X
X
Study Disposition (Screening)
X
X
Study Disposition (Study Phase 
Completion)
X
X
X
Record End of Treatment page
X
X
X
Study Disposition (Follow-up)
X
Early Study Discontinuation Visit should be used for Premature study withdrawal (PSW, please refer to Section 5.6.2) 
X = assessment to be recorded on clinical data base
S = these assessments are source documentation only and will not be entered into the eCRF
1 Information about patients’ survival will be obtained by a telephone call during the study treatment period and 30 days after the patient’s last dose of study drug for 
completed patients. For patients who withdraw early, please refer to discontinuation of study treatment and premature patient withdrawal section.


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Table 6-2
Timing of clinic visit procedures
Time 
Point1
ACQ-7
ECG
Vital Signs2 Hematology
Chemistry /Plasma 
cortisol/ Urinalysis3
Spirometry4
Visit 99/
Visit 101
Day 1
-50 min
X
-45 min
X
-30 min
X
X
X
-15 min
X
30 min
X
Visit 104
Week 12
-50 min
X
-45 min
X
-30 min
X
-15 min
X
Visit 107
Week 26
-50 min
X
-45 min
X
-30 min
X
X
X
-15 min
X
Visit 111
Week 52
Day 365
-50 min
X
-45 min
X
-30 min
X
X
X
-15 min
X
1: Time relates to the dose given from the device at visit. When multiple measurements are scheduled 
at a single time-point, they should wherever possible be done in the following order: ECG, vital signs 
and then samples for hematology/clinical chemistry/plasma cortisol and urinalysis.
2: Systolic and diastolic blood pressure and heart rate (radial pulse)
3: Urine analysis at central laboratory is to be done only if the urine dipstick is abnormal, and only 
done pre-dose.
4: A minimum 10 min rest period from the end of spirometry maneuvers and the beginning of ECG 
assessments must be observed at all times.
6.1
Information to be collected on screening failures
All patients 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

Sex

Race and ethnicity


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
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

ACQ-7

Prior concomitant medication (Both asthma related and non-asthma related)

Pre and post-bronchodilator spirometry (screening spirometry and reversibility testing).

Baseline PEF
6.3
Treatment exposure and compliance
The time of study treatment administration at each in-office dosing visit 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. While at home, the time of study 
treatment administration will be recorded by the patient in the e-Diary once a week. The data 
from the e-Diary will be reviewed at each visit.
Study treatment compliance should be assessed by the investigator and/or center personnel at 
all visits. In order to ensure compliance and safety follow-up, the patients will be requested to
record once per week in the e-Diary whether he/she missed any dosage in the evening from 
Visit 101 to 111. 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 102, 104, 107, 109, 111 (or at Early Treatment Discontinuation/end of 
treatment (EOT) Visit or Study Withdrawal visit if applicable). Study treatment compliance 
will be assessed from the capsule count from previously dispensed blister strips for the 
Concept1.
6.4
Efficacy
6.4.1
Spirometry
The following spirometric assessments will be made:

Forced expiratory volume in one second (FEV1)

Forced Vital Capacity (FVC)
Spirometric assessments will be measured at Visits 2, 101, 104, 107, 111 and EOT if 
applicable as indicated in Table 6-1.


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Pre-dose FEV1 is defined as the mean of the two FEV1 values measured at -45 min and -15 
min prior to evening dose taken at the site.
All clinic visits must occur in the evening. Please refer to Table 6-2 for full details of the 
scheduling of spirometry measurements. Equipment for spirometry assessments will be 
provided to all study sites by a Central Spirometry vendor, and all measurements will be 
reviewed by trained spirometry technicians at the central vendor.
Please refer to the latest version of Spirometry Guidance in Appendix 3 for full details on 
performing spirometry.
6.4.2
Electronic Diary
All patients will be provided with a patient electronic diary (referred to as e-Diary or 
e-Diary/ePEF) to record daily clinical symptoms, peak flow or rescue medication (salbutamol) 
use. The patients will be instructed to routinely complete the patient diary twice daily at the 
same time morning or evening (before taking the study drug) and 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 (see 
Appendix 4 for questions).
6.4.2.1
Number of inhalations of Rescue Medication
The total number of inhalation used of rescue medication (number of puffs taken in the 
previous 12 hours) will be recorded morning and evening by the patient, in the e-Diary.
The patient will input the number of puffs of rescue medication they have used during the 12 
hours previous. The patients mean evening and morning recue medication usage will be 
automatically be calculated by the e-Diary.  This SABA data collected by the patient during 
the last 7 days of screening will be used to set alerts to the patient to contact the investigator 
in case of worsening asthma (see Section 6.4.4 Asthma worsening criteria).
6.4.2.2
Peak expiratory flow (PEF)
An electronic Peak Flow Meter (ePEF) will be given to each patient at Visit 1 for the 
measurement of morning and evening PEF from Visit 1 until the end of the treatment epoch.
PEF will be measured at consistent times for a patient, in the morning and evening each day 
during the study from Visit 1 to 111. The measurements will be performed using an ePEF 
provided to the patients at Visit 1. PEF will be measured twice a day; in the evening just prior 
to taking study medication and again 12 hours later and as soon as possible after waking in the 
morning. Patients should be encouraged to perform morning and evening PEF measurements 
BEFORE the use of any rescue medication. At each time point, the patient should be 
instructed to perform 3 consecutive maneuvers within 10 minutes. These PEF values are 
captured in the e-Diary/ePEF. The best of 3 values will be used.
6.4.3
Asthma Control Questionnaire 7 (ACQ-7)
In this study, the ACQ-7 will be used to assess improvements in asthma symptom control. 
The ACQ-7 (Juniper et al 1999, Juniper et al 2005, Juniper et al 2006) is a seven-item disease-
specific instrument developed and validated to assess asthma control in patients in clinical 


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trials as well as in individuals in clinical practice. The ACQ-7 questionnaire will be provided 
to the site. The ACQ-7 questionnaire consists of five items to assess symptoms and activity 
limitations, one question to assess rescue medication use, and one question to assess airway 
caliber (FEV1% predicted). All seven items are scored on a 7-point Likert scale, with 0 
indicating total control and 6 indicating poor control. The questions are equally weighted and 
the total score is the mean of the seven items. The proportion of patients who achieve an 
improvement of at least 0.5 in ACQ-7 (i.e. decrease of ACQ-7 score of at least 0.5 from 
baseline) at post-baseline visits will also be analyzed.
The first 6 questions of the ACQ-7 should be completed by the patient based on one recall 
over the prior week. The last question should be completed by the investigator at the site 
using data from the Master Scope spirometer. The ACQ-7 should be completed at the 
investigators site at Visits 2, 101, 104, 107, 111 and EOT if applicable.
6.4.4
Worsening of asthma
Investigators and patients will be instructed how to deal with worsening of asthma symptoms. 
The data captured in the patient diary will also be used to alert the patient and/or investigator 
to possible signs of worsening asthma. The investigator must provide the patient with written 
instructions to contact the investigator if at any time during the trial from the screening
onwards one or more of the following criteria of worsening asthma develops:
Asthma Worsening Criteria
1. > 20% decrease in FEV1 from the baseline value (Criteria only be applicable to the 
investigator review at the time of study visit or possibly an alert setting if device is 
structured to capture)
2. > 50% increase in SABA use and > 8 puffs on 2 out of any 3 consecutive days compared 
to baseline
3. ≥20% decrease in AM or PM PEF from baseline on 2 out of any 3 consecutive days 
compared to baseline
4. < 60% of personal best PEF compared to baseline 
5. Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights
6. Urgent unscheduled clinic visit due to asthma related deterioration
Note: The reference for the worsening of asthma during the screening epoch would be the 
FEV1 and PEF taken at Visit 1 (Screening). The Baseline FEV1 for the treatment epoch is 
taken at treatment Day 1 (Visit 101). The Baseline PEF (morning and evening) for the 
treatment epoch is calculated at Visit 99 and is the mean of the best of the three daily PEF 
measurements over the last 2 weeks of screening epoch (Visit 2 to 99).
If any of the above criteria (including the alert from e-Diary) are met while a patient is in the 
screening or treatment epoch, the investigator should assess the patient condition. If this 
occurs during screening epoch and it is considered a clinically significant asthma worsening
in the investigator’s opinion, the patient should be treat as appropriate and screen failed. Once 
the condition is resolved, if eligibility criteria are met, the patient may be reconsidered for 
rescreening.


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The alerts, which are trigged by above criteria, are in place to detect early onset of asthma
worsening at any time during the study and to help direct early intervention. Therefore the
investigator should do the following when alerts are received:

Reviewing alert trends over time, in particular PEF decreases

Calling the patient promptly when alerts are received when any one specific alert type (e.g.
PEF < 60%) is received on consecutive days to further assess the clinical status. This may
include urgent clinic visits as appropriate and/or immediate treatment.

Implementing prompt treatment as necessary
If patients believe their symptoms are worsening and/or receive alerts as outlined above, the 
patient should also notify the investigator and be evaluated by the investigator and treated as 
clinically appropriate.
Patients should also be withdrawn for safety reasons if, in the opinion of the investigators, it is 
appropriate to do so.
Worsening of asthma symptoms may require unscheduled evaluation between visits. Study
site personnel must be available to monitor and document patient's progress until asthma 
control is regained.


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6.4.6
Appropriateness of efficacy assessments
The measures described above are standard outcome measures in asthma trials.
6.5
Safety
The following safety assessments will be performed:

Medical history and physical examination including oropharyngeal examination

Vital signs


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
Hematology, chemistry, Urinalysis

Evening plasma cortisol

ECG

Adverse events including serious adverse events

Pregnancy (female patients); additional pregnancy testing might be performed if requested 
by local requirements

Serious asthma outcomes (asthma-related hospitalizations, intubations or deaths)
ECG and Laboratory assessments will be centralized.
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 at Visits 2, 
107, 111 and in case of early study treatment discontinuation visit as described in Table 6-1.
A short physical examination, including the examination of general appearances and vital 
signs (see Section 6.5.2), will be performed at all other clinic visits. 
An oropharyngeal examination will be performed at each clinic visit.
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 Medical History 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 sec interval), performed 
in the sitting position, will be recorded at scheduled visits as detailed in Table 6-1. At Visits 2, 
101, 102, 104, 107, 109, 111, or EOT if applicable, vital signs should be measured directly 
after the ECG assessments.
6.5.3
Height and weight
Height in centimeters (cm) will be measured at Visit 2. Body weight (to the nearest 
0.1 kilogram [kg] in indoor clothing, but without shoes) will be measured at Visit 2. BMI will 
be calculated based on height and weight.
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 
provided to investigators in the laboratory manual.
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 


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other than drug-related adverse experiences is identified, even after the medication has 
discontinued.
Safety Laboratory assessments (hematology, clinical chemistry) will be performed at Visits 2, 
101, 107, 111 and EOT if applicable.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential, and platelet count will be measured.
6.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, AST (SGOT), ALT (SGPT), bilirubin, creatinine, γGT, 
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
(ULN), total bilirubin should be differentiated into the direct and indirect reacting bilirubin.
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 study medication has 
discontinued.
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will be performed
at Visits 99, 107, 111, and EOT if applicable. Dipsticks are provided to investigators from the 
central laboratory.
If dipstick test is abnormal, the sample will be sent to central laboratory for additional testing, 
including assessment of microscopy and WBC and RBC sediments. The Central Laboratory 
will provide detailed procedures for the preparation and collection of these samples in the 
laboratory manual.
6.5.4.4
Plasma Cortisol
Evening plasma cortisol will be measured at Visits 101, 107, 111 and EOT (if applicable). 
The sampling point is as shown in Table 6-2.
6.5.5
Electrocardiogram (ECG)
Electrocardiograms (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 the blood 
draws but with enough time planned to ensure the spirometry is performed at the planned time 
point outlined in Table 6-2. Spirometry must be performed as close to the scheduled time 
point as possible.


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Centralized ECG equipment
At Visit 2, a screening ECG will be measured to test for eligibility for trial inclusion. (Patients 
whose ECG is abnormal at screening due to technical/mechanical faults may be re-screened.) 
At Visit 101, ECGs will be measured at 30 min pre-dose (evening dose) and 30 min post dose, 
at Visits 107, 111, and EOT if applicable, ECG will be measured pre-dose only as indicated in 
Table 6-2. All electrocardiograms should include 12 standard leads. An ECG tracing will be 
taken for those patients who prematurely discontinue from the study.
For each ECG performed original traces should be printed. Each ECG will be sent 
electronically for central review directly from the ECG machine. The print out will be kept at 
the investigator site and will be dated and signed. The subject's number, the date, actual time 
of the tracing, and study number 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 
event that the central cardiologist reports that an ECG is abnormal, the investigator must 
assess whether the ECG abnormality is clinically significant or not. A clinically significant 
abnormality should be reported as an AE. If necessary a cardiologist may be consulted.
Clinically significant ECG findings at baseline must be discussed with the sponsor before 
administration with investigational treatment.
If a patient experiences a clinically significant change in cardiac rhythm or other clinically 
significant cardiovascular abnormality, the investigator should consider withdrawing the 
patient from the study.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/AE eCRF page as appropriate.
New cases (not present during screening) of atrial fibrillation reported from the ECG 
measurements (or reported as an AE during the course of the study) will be adjudicated. 
Additional information regarding the Atrial Fibrillation/Atrial Flutter may be requested to be 
sent to the Adjudication Committee. All cases of atrial fibrillation, regardless of seriousness, 
will be reviewed by the Adjudication Committee.
6.5.6
Serious Asthma outcomes
Asthma-related hospitalizations, asthma-related intubations and asthma-related deaths over 
the 52 week treatment epoch will be recorded and will all be reviewed by the Adjudication 
Committee. Hospitalization is defined as an inpatient stay or a ≥24 hour stay in an 
observation area in an emergency department or other equivalent facility.
6.5.7
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. A 
serum or urine pregnancy test will be performed (tests provided by the Central Laboratory) 
per Assessment Schedule Table 6-1. If the urine pregnancy test at Visit 99 and Visit 107 is 
positive, a plasma testing is to be done to confirm the pregnancy. A positive pregnancy test at 
Visits 2 (Week -2), 99 (Week 0), 107 (Week 26), 111 (Week 52), EOT or at any time during 


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the study requires the patient to be discontinued from the study treatment. Refer to Section 
5.6.2 and Section 7.6 for more details.
6.5.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
6.6
Other assessments
No additional tests will be performed on patients/subjects entered into this study.
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 
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. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
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


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
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 given 

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's 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.


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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 (specify what this includes)

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
general condition

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 patient has stopped study participation
(defined as time of last dose of study drug taken or last visit whichever is later) must be 
reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs 


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experienced after the 30 days period should only be reported to Novartis safety 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 each specific 
component of study treatment, 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, 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 
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
Pneumonia Reporting
Pneumonia will be defined as an event characterized by increased respiratory symptoms (e.g. 
increased cough, dyspnea, wheezing, purulent sputum), fever (i.e. body temperature greater 
than 38°C) or pleuritic chest pain or leukocytosis or other clinical signs consistent with 
pneumonia considered relevant in the opinion of the investigator and confirmed by X-ray. 
Any reported pneumonia will have to be confirmed by either X-ray or radiologist reading 
report of the X-ray (to be kept in the source documents). If not confirmed by X-ray, it should 
be reported as lower respiratory tract infection.
7.4
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. 


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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 Table 13-1 in Appendix 2 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 2 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 in Appendix 2.
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. 
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.
7.5
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.


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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 3 months after the birth, 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.
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 data capture requirements (i.e. eSource or eCRFs) 
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 data 
capture/data entry, 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.


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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 eCRF 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 data capture and/or data entry. 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 eCRF 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
The trial will be conducted in a fully validated Data Capture system which conforms to US
CRF 21 Part 11 requirements. Investigator site staff will not be given access to the system 
until they have been trained. Designated investigator staff will enter the data required by the 
protocol into the Data Capture system. Automatic validation programs within the system 
check for data discrepancies in the CRFs and by generating appropriate error messages, allow 
the data to be confirmed or corrected by the investigator staff. The investigator staff must 
certify that the data entered are complete and accurate. After database lock, the investigator 
will receive copies of the patient data for archiving at the investigational site.
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 
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. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.


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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(s), who will also manage the database. The database will be sent electronically to 
Novartis personnel.
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 Novartis 
IRT, who will also manage the database. The database will be sent electronically to 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 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
An independent adjudication committee will be established to assess serious asthma outcomes 
(asthma-related hospitalizations, intubations and deaths), serious cardiovascular and 
cerebrovascular (CCV) events, new onset of atrial fibrillation and flutter as well as all deaths. 
All serious CCV events occurring from the time of treatment start until the 30 days after the 
permanent discontinuation of study drug, where applicable, will be adjudicated.
The committee will consist of experts outside Novartis who are not involved in the study 
conduct, who will periodically review pertinent patient data and the supporting documentation 
to settle the specified adjudication objectives. Further details will be provided in the 
Adjudication Committee Charter.
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.


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9.1
Analysis sets
The Safety Set will consist of all patients who received at least one dose of study medication 
during this study.
Full Analysis Set (FAS) will consist of all patients who entered in this study and received at 
least one dose of study medication during this study.
Note that the Safety Sets and FAS are the same except that the Safety Set allows the inclusion 
of patients who are not intended to enter in this study but received study drug in error.
The Safety Set will be used in the analysis of all safety variables. The efficacy analysis 
population will be the FAS.
9.2
Patient demographics and other baseline characteristics
Demographic and baseline characteristics including age, sex, race, ethnicity, height, weight, 
body mass index (BMI), relevant medical history, screening spirometry parameters: (FEV1,
FVC, and FEV1/FVC), FEV1 reversibility, percentage of predicted FEV1, baseline PEF, 
duration of asthma, history of asthma exacerbations, smoking history, prior concurrent 
medications (asthma-related and non-asthma-related), vital signs (systolic and diastolic blood 
pressure, pulse rate), QTc using Fridericia's correction and baseline ACQ-7, will be 
summarized.
Continuous variables will be summarized using descriptive statistics (mean, median, standard
deviation, minimum, and maximum) and categorical variables will be summarized in terms of
the number and percentage of patients in each category for the Safety Set.
Baseline is defined as the last measurement before first dose of study drug.
9.3
Treatments
Study drug administration and concomitant medication data will be listed and summarized
using the Safety Set.
The duration of exposure and the number of patients who completed the study medication and 
who discontinued from the study medication will be summarized.
Medications started and stopped prior to study drug, and taken concomitantly will be
summarized for the Safety Set.
Concomitant therapies will be recorded, listed and summarized separately for asthma related
medications/non-drug therapies and other medications. Concomitant asthma related
medications will be summarized by route of administration, the recorded pre-specified drug 
subcategories (including types of combination) and preferred term. Concomitant medications 
not related to asthma will be summarized by route of administration and preferred term.
SABA usage (number of puffs) during the screening epoch will be summarized.
Treatment compliance with study medication over the study period will be summarized.


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9.4
Analysis of the primary variable(s)
9.4.1
Primary Variable(s)
The primary objective of this study is to assess the safety/tolerability of 52 weeks of treatment 
with QVM149 (150/50/160 µg, once daily), particularly with regard to treatment emergent 
adverse event reporting in Japanese patients with inadequately controlled asthma.
The primary variable is the number and percentage of patients who reported treatment 
emergent adverse events during the 52 week study period.
Adverse events will be summarized with descriptive statistics for the Safety Set.
All study emergent adverse events including asthma exacerbations will be summarized and
listed. Adverse events starting on or after the time of the first inhalation of study drug but not 
later than 7 days (30 days in the case of a SAE) after the last administration will be classified 
as a treatment emergent adverse event. Any adverse events that started during the study before 
the time of the first inhalation of study drug will be classified as a prior adverse event.
9.4.2
Statistical model, hypothesis, and method of analysis
The number and percentage of patients who reported treatment emergent adverse events will 
be summarized by primary system organ class, preferred term for

All adverse events

Serious adverse events

Adverse events by maximum severity

Adverse events suspected to be related to study drug

Adverse events leading to permanent study drug discontinuation

Adverse events of special interest
In addition, all adverse events reported in the study will be listed.
9.4.3
Handling of missing values/censoring/discontinuations
No imputation will be done for missing data. All available data will be summarized.
9.4.4
Sensitivity analyses
Not applicable.
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The efficacy measurements during the study will be summarized for the FAS.
Baseline is defined as the last measurement before first dose of the study drug, unless 
otherwise specified. No imputation will be done for missing data.


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Spirometry
Spirometry measurements taken within 7 days of systemic corticosteroid use and/or 6 hours of
rescue use will be set to missing and not be imputed, unless specified otherwise.
For FEV1 and FVC, the baseline is defined as the mean of the values taken in the clinic at 45 
and 15 min prior to first dose at Visit 101.
Pre-dose FEV1 and FVC at Weeks 12, 26 and 52
The pre-dose FEV1 is defined as the mean of the pre-dose 45 and 15 min FEV1 values.
The pre-dose FEV1 and the change from baseline at 12, 26 and 52 weeks of the study 
treatment will be summarized with descriptive statistics. Summaries will be repeated for pre-
dose FVC.
In addition, the means in pre-dose FEV1 and FVC for each visit will be displayed graphically.
Peak Expiratory Flow Rate (PEF)
The morning/evening PEF (liters/min) will be averaged over the first 26 weeks and over the 
52 weeks.
e-Diary data recorded during the screening period will be used to calculate the baseline value.
The mean morning/evening PEF and the mean change from baseline will be summarized.
Rescue medication
The total number of puffs of rescue medication per day over the first 26 weeks and over the 
52 weeks will be calculated and divided by the total number of days to derive the mean daily 
number of puffs of rescue medication taken for the patient.
e-Diary data recorded during the screening period will be used to calculate the baseline value.
The mean daily number of puffs of rescue medication use over the first 26 weeks and over the 
52 weeks of treatment and the mean change from baseline will be summarized.
In addition, the mean number of puffs of rescue medication in the morning and in the evening,
and the percentage of 'rescue medication free days' (defined from diary data as any day where 
the patient did not use any puffs of rescue medication) will be summarized.
Asthma Control Questionnaire 7 (ACQ-7) at Weeks 26 and 52
ACQ-7 and the change from baseline at 26 and 52 weeks of the study treatment will be 
summarized.
The proportion of patients who achieve an improvement of at least 0.5 in ACQ-7 (i.e.
decrease of ACQ-7 score of at least 0.5 from baseline) at post-baseline visits will be 
summarized.
9.5.2
Safety variables
All safety variables will be summarized with descriptive statistics for the Safety Set.


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Baseline is defined as the last measurement before first dose of the study drug, unless 
otherwise specified. No imputation will be done for post-baseline missing data.
Electrocardiogram (ECG) and vital signs
Data from the ECG (including QT interval, RR interval, PR interval, QRS duration, heart rate,
Fridericia's QTc and Bazett's QTc) will be summarized at 30 min pre-dose, and at 30 min 
post-dose by visit. The baseline measurement will be the 30 min pre-dose measurement at 
Visit 101.
Vital signs (blood pressure, radial pulse rate) will also be summarized by visit.
The maximum (QTc, systolic blood pressure, radial pulse rate) or minimum (diastolic blood
pressure) post first dosing (i.e., post-baseline) value will be summarized. The changes from
baseline will also be summarized by visit.
All data will be included in the analysis regardless of rescue medication usage. 
The number and percentage of patients by the following classifications will be presented for
each visit.
The number (%) of patients with pulse rate of < 40 and > 90 bpm; systolic blood pressure of
< 90 and > 140 mmHg; diastolic blood pressure of < 50 and > 90 mmHg will be summarized.
Notable values for vital signs and the change from baseline will be summarized. A notable 
value is defined as follows:
Systolic blood pressure
“Low” criterion: < 75 mmHg, or ≤90 mmHg and decrease from baseline ≥20 mmHg
“High” criterion: > 200 mmHg, or ≥180 mmHg and increase from baseline ≥20 mmHg
Diastolic blood pressure
“Low” criterion: < 40 mmHg, or ≤50 mmHg and decrease from baseline ≥15 mmHg
“High” criterion: > 115 mmHg, or ≥105 mmHg and increase from baseline ≥15 mmHg
Pulse rate
”Low” criterion: < 40 bpm, or ≤50 bpm and decrease from baseline ≥15 bpm
“High” criterion: > 130 bpm, or ≥120 bpm and increase from baseline ≥15 bpm
Notable QTc values and the changes from baseline will be summarized. A notable value is
defined as a QTc interval of greater than 450 ms (male), 460 ms (female) and 500 ms (both) at 
baseline and the number of newly occurring or worsening notable QTc values for post
baseline time points. The categories used for the change from baseline in QTc are less than
30 ms, 30 to 60 ms and greater than 60 ms.
QTc will be calculated from the QT interval and RR (in seconds) by two methods:
1. using Fridericia's formula: QTc = QT ⁄ 3√RR, where 3√ denotes the cube root
2. using Bazett's formula: QTc = QT ⁄ √RR


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ECG and vital signs data measured more than 7 days after last inhalation of study drug is
regarded as post-treatment data and will not be summarized, only listed.
Laboratory data:
Evening plasma cortisol will be summarized by visit. The maximum evening plasma cortisol
post first dosing (i.e. post baseline value) will be summarized. The changes from baseline will 
also be summarized by visit.
All other laboratory data will be listed with abnormal values flagged. The laboratory values 
and the change from baseline for continuous laboratory parameters will be summarized at 
each visit. A frequency table of results for categorical laboratory parameters will be produced 
by visit. Shift tables relative to the normal reference ranges will be used to summarize the 
change from baseline to post-baseline by visit for each laboratory parameter.
All data will be included in the analysis regardless of rescue medication usage.
Laboratory data measured more than 7 days after last inhalation of study drug is regarded as
post-treatment data and will not be summarized, only listed.
9.5.3
Resource utilization
Not applicable.
9.5.4
Pharmacokinetics
Not applicable.
9.5.5
DNA
Not applicable.
9.5.6
Biomarkers
Not applicable.
9.5.7
PK/PD
Not applicable.


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9.7
Interim analyses
An interim analysis for 6-month data will be performed for the initial New Drug Application
submission in Japan (Section 3.2). This analysis will be performed after all patients have been
enrolled and completed Visit 107 (Week 26) or discontinued the study.
The cut-off date for each patient is defined as the Visit 107 date or study discontinuation date 
prior to Visit 107. All protocol specified analyses will be performed for all data on or prior to 
this cut-off date.
9.8
Sample size calculation
Since asthma is a chronic disease, and QVM149 is expected to be administered over a long 
period, safety in long-term treatment needs to be confirmed. “Regarding sample size and 
treatment period required to assess safety at the clinical study stage of a new drug anticipated 
to be administered for a non-fatal disease over a long period” (Notification No. 592 of the 
Pharmaceuticals and Cosmetics Division, Pharmaceutical Affairs Bureau, MHLW, dated 
24-May-1995), this notification requires to collect safety data of at least 100 patients who 
receive the drug over one year. CQVM149B2302 study was planned to collect efficacy and 
safety data of about 10 Japanese Asthma patients exposed to QVM149. Therefore this study, 
CQVM149B1304, is designed to obtain safety data of approximately 90 Japanese asthma 
patients exposed to QVM149. Since a 25% screening failure rate and a 10% dropout rate are 
expected, approximately 134 patients will need to be screened in order to collect 
approximately 100 patients who enter the treatment epoch and to collect a total of 
approximately 90 completed patients.
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 applicable
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. 


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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.
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, 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.


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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 
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
Adachi M, Hozawa S, Nishikawa M, et al. (2015) Asthma control, Quality of life and 
emotional feelings in a real life setting – a postal mail survey of adult asthma patients in Japan: 
the ACQUIRE study. Allergology&Immunology; 22:1446-60. (Article in Japanese)
Befekdadu E, Onofrei C, Colice GL (2014) Tiotropium in asthma, a systemic review. J 
Asthma Allergy; 7:11-21.
Global Initiative for Asthma (GINA) (2016) Global Strategy for Asthma Management and 
Prevention (Internet) Available from:
<http://ginasthma.org/> (Accessed 25 August 2016).
Juniper EF, O'Byrne PM, Guyatt GH, et al. (1999) Development and validation of the 
questionnaire to measure asthma control. Eur Resp J; 14(4):902-7.
Juniper EF, Svensson K, Mork AC, et al. (2005) Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med; 99:553-8.
Juniper EF, Bouquet J, Abetz L, et al. (2006) Identifying 'well-controlled' and 'not well-
controlled' asthma using the Asthma Control Questionnaire. Respir Med; 100(4):616-21.
Kerstjens HAM, Engel M, Dahl R, et al. (2012) Tiotropium in asthma poorly controlled with 
standard combination therapy. N Engl J Med; 367:1198-207.
Masoli M, Fabian D, Holt S, et al. (2004) The global burden of asthma: executive summary of 
the GINA Dissemination Committee Report. Allergy; 59:469-78.
Ohta K, Yamamoto M, Sato N, et al. (2010) One year treatment with omalizumab is effective 
and well tolerated in Japanese patients with moderate-to-severe persistent asthma.
Allergology International; 59(2):167-74.
Tohda Y, Adachi M, and Ohta K (2013) 日本人成人気管支喘息に対するフルチカゾン／
ホルモテロール配合剤（フルティフォーム®エアゾール）の長期投与時における安全
性及び有効性の検討—第III 相長期投与試験— Allergology&Immunology; 20:1686-704.
(Article in Japanese)
Vaidya S, Khindri S, Robinson J, et al. (2012) Pharmacokinetics (PK) of single doses of 
mometasone furoate (MF) delivered via the Breezhaler® (BH) and Twisthaler® devices in 
healthy subjects. Eur Respir J; 40, Suppl 56:P382.


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13
Appendices
13.1
Appendix 1: Clinically notable laboratory values and vital signs
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports.  Investigators are responsible for reviewing these abnormal values 
for clinical significance, signing the laboratory reports to indicate their review, and reporting 
values considered clinically significant in the appropriate CRF.
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.
See Appendix 2 for specific liver event and laboratory test trigger definitions and follow-
up requirements.
For ECGs, a notable QTc value is defined as a QTcF (Fridericia) interval of ≥450 msec for 
males or ≥460 msec for females – all such ECGs will be flagged by the Central CRO and 
require assessment for clinical relevance and continuance of the patient by the Investigator.
For vital signs, a notable value is defined as follows:
Systolic blood pressure
“Low” criterion: < 75 mmHg, or ≤90 mmHg and decrease from baseline ≥20 mmHg
“High” criterion: > 200 mmHg, or ≥180 mmHg and increase from baseline ≥20 mmHg
Diastolic blood pressure
“Low” criterion: < 40 mmHg, or ≤50 mmHg and decrease from baseline ≥15 mmHg
“High” criterion: > 115 mmHg, or ≥105 mmHg and increase from baseline ≥15 mmHg
Pulse rate
”Low” criterion: < 40 bpm, or ≤50 bpm and decrease from baseline ≥15 bpm
“High” criterion: > 130 bpm, or ≥120 bpm and increase from baseline ≥15 bpm
Investigators are responsible for reviewing these abnormal values for clinical relevance and 
reporting adverse events considered clinically significant in the appropriate CRF.


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13.2
Appendix 2: 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)
> 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)


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Criteria
Actions required
Follow-up monitoring
> 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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13.3
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, and no volume change for at least 1 second) or the subject cannot continue 
to exhale further. Overall acceptability will be determined by expert over-read by 
spirometry vendor.
Repeatability
The 2 largest FEV1 values from 3 acceptable maneuvers should not vary by more than 
0.150 L.
Recording of data 
The greatest FEV1 and FVC from any of the acceptable curves are recorded. (The greatest 
FEV1 and FVC may not necessarily result from the same acceptable curve).
Predicted normal
This study will utilize the spirometric predication equation standards from the ERS Global 
Lung Function Initiative2 or Japanese Respiratory Society3 for Japanese subjects 17 years of 
age or greater.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing1. A pre-bronchodilator spirometry assessment 
should be performed after a washout period of at least: 

6 h for short-acting β2-agonists

8 h short-acting anticholinergics

24 h for long-acting β2-agonists

7 days long-acting anticholinergic

7 days indacaterol

12 h for short-acting xanthines

24 h for long-acting xanthines
Administer 400 µg of salbutamol/albuterol (or equivalent) following the completion of the 
pre-bronchodilator assessment. Post-bronchodilator spirometry assessment is then performed 
within 15 to 30 minutes after administration of the salbutamol/albuterol.
Reversibility is calculated as:
100 x
FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)


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FEV1 (pre-bronchodilator) 
Subjects will be considered reversible if an increase of at least 12% (and 200 ml) is 
demonstrated after administration of the salbutamol/albuterol.
Following the reversibility testing assessment for post-bronchodilator FEV1, if patient has not 
met the above reversibility criteria after administration salbutamol/albuterol, then the patient 
may be rescreened or allow one spirometry retest.
References
1 Miller MR, Crapo R, Hankinson J, et al. (2005) Standardization of Lung Function Testing. 
Eur Resp J; 26:153-61.
2 Quanjer PH, Stanojevic S, Cole TJ, et al. (2012) 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 Resp J; 40(6):1324-43.
3 Kubota M, Kobayashi H, Quanjer PH, et al. (2014) 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 Investigation; 52:242-50.


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13.4
Appendix 4: Patient Asthma Control e-Diary
The following information will be captured:
In the MORNING
In the EVENING
Peak expiratory flow rate
How did you sleep last night?
Did you have asthma symptoms upon awakening 
in the morning?
Number of puffs of rescue medication during the 
past 12 hours
Peak expiratory flow
Did your respiratory symptoms stop you from 
performing your usual daily activities?
How severe was your shortness of breath today?
How was your wheeze during the past 12 hours?
How was your cough during the past 12 hours?
Did you have Chest tightness during the past 12 
hours?
Number of puffs of rescue medication during the 
past 12 hours


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13.5
Appendix 5: Instruction for Use of Concept1
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

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.


Novartis
Confidential
Page 77
Amended Protocol Version 01 (Clean)
Protocol No. CQVM149B1304
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.

The inhaler should be used for a maximum of 30 days, then replaced with a new inhaler

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.