Clinical trial NCT03100500
Conditions: Asthma
Keywords: QVM149, Asthma, Japanese, Allergic asthma, Allergy triggered asthma, Reactive asthma, Asthma attack, Difficulty breathing
Sponsor: Novartis Pharmaceuticals
Start date: 2017-04-25; Completion date: 2019-02-12
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to provide long term safety data of QMF149 in Japanese participants with inadequately controlled asthma for the registration of QMF149 in Japan.

Detailed description:

Arms: arm 1: All eligible patients take QMF149 150/320 μg once daily over 52 weeks.
Interventions: intervention 1: QMF149
Intervention descriptions: intervention 1: QMF149 150/320 μg once daily, delivered as powder in hard capsules via Concept1 inhaler

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine
QVM149B (QMF149: Indacaterol acetate/Mometasone furoate)
Clinical Trial Protocol CQVM149B1305 / NCT03100500
A multicenter, open-label, single arm, 52-week treatment 
study to assess the safety of QMF149 in Japanese patients 
with asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
01 (Clean)
Clinical trial phase:
III
Release date:
15-Mar-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 1 ...........................................................................................................................10
Protocol summary..............................................................................................................12
1
Introduction .......................................................................................................................15
1.1
Background............................................................................................................15
1.2
Purpose ..................................................................................................................17
2
Study objectives and endpoints .........................................................................................18
2.1
Objectives and related endpoints...........................................................................18
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
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 ....................................................................................................23
4.2
Exclusion criteria...................................................................................................24
5
Treatment...........................................................................................................................27
5.1
Study treatment......................................................................................................27
5.1.1
Investigational and control drugs..........................................................27
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.....................................................................28
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...................................................................34
5.6.1
Study completion and post-study treatment..........................................34
5.6.2
Discontinuation of study treatment .......................................................34
5.6.3
Withdrawal of informed consent...........................................................37
5.6.4
Loss to follow-up ..................................................................................37
5.6.5
Early study termination by the sponsor.................................................37
6
Visit schedule and assessments .........................................................................................38
6.1
Information to be collected on screening failures..................................................42
6.2
Patient demographics/other baseline characteristics .............................................42
6.3
Treatment exposure and compliance .....................................................................43
6.4
Efficacy..................................................................................................................43
6.4.1
Spirometry.............................................................................................43
6.4.2
Electronic Diary ....................................................................................44
6.4.3
Asthma Control Questionnaire (ACQ)-7 ..............................................44
6.4.4
Worsening of asthma.............................................................................45
46
6.4.6
Appropriateness of efficacy assessments..............................................47
6.5
Safety.....................................................................................................................47
6.5.1
Physical examination ............................................................................48
6.5.2
Vital signs..............................................................................................48
6.5.3
Height and weight .................................................................................48
6.5.4
Laboratory evaluations..........................................................................48
6.5.5
Electrocardiogram (ECG) .....................................................................49
6.5.6
Serious Asthma outcomes.....................................................................50
6.5.7
Pregnancy and assessments of fertility .................................................50
6.5.8
Appropriateness of safety measurements..............................................50
6.6
Other assessments..................................................................................................50
7
Safety monitoring ..............................................................................................................51
7.1
Adverse events.......................................................................................................51
7.2
Serious adverse events...........................................................................................52
7.2.1
Definition of SAE .................................................................................52
7.2.2
SAE reporting........................................................................................53


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7.3
Pneumonia Reporting ............................................................................................54
7.4
Liver safety monitoring .........................................................................................54
7.5
Reporting of study treatment errors including misuse/abuse ................................55
7.6
Pregnancy reporting...............................................................................................56
8
Data review and database management.............................................................................56
8.1
Site monitoring ......................................................................................................56
8.2
Data collection.......................................................................................................57
8.3
Database management and quality control............................................................57
8.4
Data Monitoring Committee..................................................................................58
8.5
Adjudication Committee........................................................................................58
9
Data analysis......................................................................................................................58
9.1
Analysis sets ..........................................................................................................58
9.2
Patient demographics and other baseline characteristics.......................................58
9.3
Treatments .............................................................................................................59
9.4
Analysis of the primary variable(s) .......................................................................59
9.4.1
Primary Variable(s)...............................................................................59
9.4.2
Statistical model, hypothesis, and method of analysis..........................59
9.4.3
Handling of missing values/censoring/discontinuations.......................60
9.4.4
Sensitivity analyses ...............................................................................60
9.5
Analysis of secondary variables ............................................................................60
9.5.1
Efficacy variables..................................................................................60
9.5.2
Safety variables .....................................................................................61
9.5.3
Resource utilization...............................................................................62
9.5.4
Pharmacokinetics ..................................................................................62
9.5.5
DNA......................................................................................................62
9.5.6
Biomarkers ............................................................................................62
9.5.7
PK/PD ...................................................................................................63
63
9.7
Interim analyses .....................................................................................................63
9.8
Sample size calculation..........................................................................................63
10 Ethical considerations........................................................................................................63
10.1
Regulatory and ethical compliance........................................................................63
10.2
Informed consent procedures.................................................................................64
10.3
Responsibilities of the investigator and IRB/IEC..................................................64
10.4
Publication of study protocol and results...............................................................64
10.5
Quality Control and Quality Assurance.................................................................65


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11 Protocol adherence ............................................................................................................65
11.1
Protocol amendments.............................................................................................65
12 References .........................................................................................................................65
13 Appendices ........................................................................................................................67
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................67
13.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements .........................................................................................................68
13.3
Appendix 3: Spirometry Guidance ........................................................................70
13.4
Appendix 4: Patient Asthma Control e-Diary .......................................................73
13.5
Appendix 5: Instruction for Use of Concept1........................................................74
List of tables
Table 1-1
Comparable MF monocomponent doses between Asmanex,
Twisthaler and QMF149 Concept1.......................................................17
Table 2-1
Objectives and related endpoints ..........................................................18
Table 5-1
Prohibited Asthma-related medications1...............................................30
Table 5-2
Prohibited Medications1........................................................................32
Table 5-3
Medications allowed under certain conditions1 ....................................33
Table 5-4
Table of assessment for the patients who discontinue 
investigational drug prematurely...........................................................35
Table 6-1
Assessment schedule.............................................................................39
Table 6-2
Timing of clinic visit procedures ..........................................................42
Table 7-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................55
Table 13-1
Liver Event and Laboratory Trigger Definitions ..................................68
Table 13-2
Follow Up Requirements for Liver Events and Laboratory Triggers ...68
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
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
FDC
Fixed Dose Combination
FEV1
Forced Expiratory Volume in 1 second
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
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
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
PEF
Peak Expiratory Flow
RBC
Red Blood Cell
SABA
Short-Acting β2 Agonist
SAE
Serious Adverse Event
SAMA
Short-Acting Muscarinic Antagonist


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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 
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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 1 
Amendment rationale
Modification of inclusion criteria for duration of baseline ICS plus at least one controller 
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 medium or high dose ICS 
plus at least one controller.
Changes to the protocol
The described changes pertaining to
the aforementioned amendment rationale are 
implemented throughout the protocol.
The following clarifications/additions are included in this protocol amendment:

Change the required pre-treatment period of medium or high dose ICS plus at least one 
controller 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). Add an exclusion 
criteria 32 to exclude any patients treated with LAMA within the last 3 months before
Visit1 (Section 4.2)

Update the repeat spirometry test/reversibility test in inclusion criterion 6, inclusion 
criterion 7, and exclusion criterion 19 (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 28 (Section 4.1 and Section 4.2)

Add a clarification of Myocardial Infarction in exclusion criteria 14 and 17 (Section 4.2)

Clarify wording on Table 5-1

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 the specific sections of the protocol are shown by track changes in the track 
changes version of the protocol using strike through (for deletions) and underlining (for 
insertions).


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
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
CQVM149B1305
Full Title
A multicenter, open-label, single arm, 52-week treatment study to assess 
the safety of QMF149 in Japanese patients with asthma
Brief title
A long-term safety study of QMF149 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 QMF149 in 
Japanese patients with inadequately controlled asthma for the registration 
of QMF149 in Japan.
Primary Objective(s)
To assess the safety/tolerability of 52 weeks of treatment with QMF149 
(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 QMF149 over 52 weeks of treatment, in terms 
of ECG, Vital signs, laboratory parameters, and plasma cortisol

To assess the efficacy of QMF149 in terms of lung-function in 
Japanese patients with inadequately controlled asthma after 26 and 52 
weeks of treatment.

To assess the efficacy of QMF149 in terms of asthma control after 26 
and 52 weeks of treatment.

To assess the efficacy of QMF149 in terms of rescue medication use
during 52 weeks treatment.
Study design
52 weeks multicenter, open-label, single-arm study
Population
The study population will consist of approximately 66 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 ICS plus at least 1
controller for asthma for at least 3 months and at stable dose and 
regimen for at least 4 weeks prior to Visit 1.

Patients must have ACQ-7 score ≥1.5 at Visits 2 and qualify for 
treatment with high dose ICS/LABA

Pre-bronchodilator FEV1 of ≥50% 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 


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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.

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 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) chronic obstructive pulmonary disease,
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 QMF149 150/320 µg (indacaterol acetate/ mometasone furoate)
once daily delivered as powder in capsules via Concept1
Efficacy assessments

Spirometry

Peak Expiratory Flow

Asthma Control Questionnaire-7

Rescue Medication
Key safety 
assessments

Adverse events and serious adverse events

ECG

Vital signs

Laboratory findings

Evening plasma cortisol


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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 week study 
period.
Adverse events will be summarized with descriptive statistics for the Safety 
Set.
Key words
QMF149, 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.
Fixed dose combination (FDC) products containing a Long acting beta-2 agonist (LABA) plus 
Inhaled corticosteroids (ICS) have been shown to be safe and effective in the management of 
asthma. 
However, 
most 
of 
currently 
available 
FDC
products 
(e.g. 
salmeterol 
xinafoate/fluticasone propionate) require twice-daily (b.i.d.) dosing to achieve an optimum 
therapeutic effect in asthma.
Novartis is developing QMF149, an inhaled FDC of indacaterol acetate, a LABA with a 
24-hour duration of action and mometasone furoate (MF) an ICS, as a once daily (o.d.)
maintenance treatment of asthma. QMF149 is formulated as a lactose-blended inhalation
powder, hard capsule, delivered by a single dose dry powder inhaler (SDDPI), referred to as
the Concept1 device (also known in some regions as the Breezhaler® device), the approved
inhalation device for use with indacaterol maleate and other Novartis Chronic Obstructive 
Pulmonary Disease (COPD) inhalation therapies.
QMF149 
is 
developed 
under 
the 
QVM149 
(indacaterol 
acetate/glycopyrronium
bromide/mometasone furoate) program and therefore all the studies are coded as QVM149.
Background data for the monotherapies:
Indacaterol
Indacaterol maleate, delivered via the Concept1 device, a SDDPI (Onbrez® Breezhaler®), is 
approved in over 110 countries worldwide for the once daily maintenance bronchodilator 
treatment of airflow obstruction in patients with COPD. In addition to the extensive evidence 
for indacaterol maleate delivered via the Concept1 device in COPD, there AE are clinical data 


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to support the efficacy and safety of indacaterol (as acetate salt) in asthma both as 
mono-component (as add-on to existing ICS) as well is in the fixed dose combination 
QMF149 (indacaterol maleate/MF) delivered by the Twisthaler® device in asthma patients. 
Indacaterol maleate delivered by Twisthaler® has been studied in healthy volunteers, adult 
patients with COPD and adult and adolescent patients with asthma.
Two studies (CQMF149E2203 and CQAB149B2357) were conducted to support the selection
of indacterol 150 µg which is the proposed dose to be carried forward in the Phase III QVM
project for asthma indication. In study CQMF149E2203, two doses of indacaterol acetate, 
75 µg and 150 µg delivered via Concept1 were investigated in adult patients with asthma and 
this study demonstrated superiority of treatment with indacaterol acetate 75 µg and 150 µg to 
placebo in terms of trough forced expiratory volume in 1 second (FEV1) after 12 weeks of 
treatment. Although the study was not powered to show a statistically significant difference 
between indacaterol acetate 150 µg and 75 µg for the efficacy objectives, it demonstrated 
positive trends in favor of indacaterol acetate 150 µg in terms of trough FEV1, Peak expiratory 
flow (PEF) and rescue medication use compared with indacaterol acetate 75 µg. The 
treatments of both indacaterol acetate doses 150 µg and 75 µg were safe and well tolerated.
A dose-ranging study CQAB149B2357 of indacaterol maleate in asthmatic patients
demonstrated that a dose of 150 µg o.d. was safe and effective. Furthermore, study
CQAB149B2338, a 26 week study in asthmatic patients showed that indacaterol maleate at
doses of 300 µg and 600 µg o.d. was also well-tolerated in this population.
In the QVM149 program, the indacaterol acetate salt will be used. Indacaterol maleate salt has
been associated with post-inhalational cough, both as a monotherapy and part of a fixed-dose
combination with MF (in the Twisthaler®), without any negative impact on safety, efficacy or
tolerability in patients with COPD or asthma. The acetate salt of indacaterol was chosen
following demonstration of a significantly lower incidence of post-inhalational (PI) cough
with acetate and xinafoate salts than that with the maleate salt without any impact on safety
and comparable efficacy and systemic exposure (CQAB149D2301).
Mometasone furoate
Mometasone furoate (MF) is marketed in inhalation, nasal, cream, ointment and lotion
formulations. MF in the Twisthaler® device, a multi dose dry powder inhaler (MDDPI),
(Asmanex®) is approved for the once daily or twice daily treatment in over 55 countries
world-wide in patients with asthma. The inhalation powder formulation which may be
administered once or twice daily is marketed as an MDDPI called Asmanex® Twisthaler® for
the treatment of asthma. Asmanex® Twisthaler® is currently approved in the United States for
the treatment of asthma in adults and children ≥4 years of age and is approved in over 60
countries world-wide for the treatment of asthma in adults and adolescents ≥12 years of age.
In adult and adolescent patients 12 years of age and older, MF (Asmanex ® Twisthaler®) was
studied in 10 placebo-controlled clinical trials of 8 to 12 weeks duration with a total of 1750
patients receiving Asmanex® Twisthaler®. There were also 3 trials with a total of 475 patients
receiving Asmanex® Twisthaler® for 1 year. In the 8 to 12-week clinical trials, the population
was 12 to 83 years of age. In 3 long-term safety trials (two 9-month extensions of efficacy
trials and one 52-week active-controlled safety trial), 475 patients with asthma received
various doses of Asmanex® Twisthaler® for 1 year.


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Comparison of MF doses in Asmanex® Twisthaler® and Concept1
The fixed dose combination of mometasone and indacaterol, QMF149 will be delivered by
Concept1 device in the current study. Based on existing data for the MF component in the
Twisthaler® device, a 3 step bridging approach was conducted to determine MF dose for 
Concept1 which is comparable to each of the registered daily doses of Asmanex® Twisthaler®
(mometasone 
furoate, 
inhalation 
powder). 
Pharmacokinetic 
bridging 
utilizing 
pharmacokinetic characterization in study CQMF149E2101 (step 1) (Vaidya et al 2012) 
followed by in-vitro fine particle mass adjustment (step 2) and finally pharmacodynamics 
evaluation of efficacy in asthma patients in study CQMF149E2201 (step 3).
For Step 1 and 2, the data of study CQMF149E2101 (Vaidya et al 2012), along with in vitro
fine particle mass adjustments have determined that doses of 80, 160, and 320 µg of MF in 
Concept1 device are comparable in strength to the approved doses of 200 µg, 400 µg and 
800 µg (2 × 400 µg) MF in Twisthaler®.
For Step 3, two of the MF doses in Twisthaler® and Concept1 were further evaluated for 
pharmacodynamics and clinical comparability in a 4-week study (CQMF149E2201) in 
patients with persistent asthma. MF doses of 80 µg and 320 µg delivered once daily via 
Concept1 showed comparable efficacy in trough FEV1 and slightly lower systemic exposure 
compared to MF doses of 200 µg and 800 µg (2 × 400 µg) delivered once daily via 
Twisthaler® confirming the selected doses for MF Concept1 are appropriate for further 
QMF149 Concept1 development.
Table 1-1
Comparable MF monocomponent doses between Asmanex,
Twisthaler and QMF149 Concept1
MF dose level
MF dose in Asmanex®
delivered by Twisthaler®
MF dose in QMF149
delivered by Concept1 (Breezhaler®)
Low
200 µg
80 µg
Mid
400 µg
160 µg
High
800 µg
320 µg
On-going CQVM149B2301 and B2302 are the pivotal study for regulatory submission, in 
which the superiority of QMF149 is evaluated and Japanese subjects are involved. Efficacy 
and safety data of 1 year treatment in Japanese patients will be obtained from these studies.
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,
this study (CQVM149B1305) is intended to support the assessment of the long term safety 
and efficacy of QMF149 in Japanese population.
Additional information to QMF149 can be found in the QMF149 Investigator's Brochure.
1.2
Purpose
The purpose of this study is to provide long term safety data of QMF149 in Japanese patients
with inadequately controlled asthma for the registration of QMF149 in Japan.


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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 QMF149 (150/320 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 QMF149 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 QMF149 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 treatment

To assess the efficacy of QMF149 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
1) To assess the efficacy of QMF149 in terms of 
rescue medication use
1. Change from baseline of rescue medication 
use during 52 weeks treatment
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 plus at least one controller (e.g. LABA, 
LTRA, Theophylline, or anti-allergics) for at least 3 months and been on stable dose and 


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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 washout 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.
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 QMF149 150/320 µg o.d. (high ICS dose), and enter 52-week treatment 
epoch. Patients will be required to inhale QMF149 150/320 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
Screening epoch*
Open label treatment epoch (52 weeks)
Follow-up epoch
Day -28 to -1
Day 1 to 365
30 days
M-H ICS
QMF149 150/320 µg via Concept1 once daily
LABA**, LTRA, Theophylline, or anti-allergics
Visit 1*
Visit 2*
Interim Analysis
Visit 201
Visit 99 (End of Screening)
Visit 101 (day1)
          Visit 111(Study completion)
Rescue SABA (as needed)
*Duration of screening epoch may vary from 2 to 4 weeks. 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.
**LABA must be discontinued 24 hours prior to Visit 99.
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 QMF149 (indacaterol acetate/ mometasone furoate) in Japan. At the End-of-
Phase II meeting 
 
 
 
 
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 CQVM149B2301 and CQVM149B2302 are evaluating two doses of 
QMF149 150/160 µg (medium ICS dose) o.d. inhalation and 150/320 µg o.d. inhalation in 
asthma. In addition, CQVM149B2303 is evaluating of low dose QMF149 (150/80 µg o.d.
inhalation) in asthma. The difference between the three doses of QMF149 is the dose of
mometasone (ICS) component. For the purpose of collecting additional long term safety data 
in Japanese patients, high dose of QMF149 150/320 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 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
LABA/ICS FDC is frequently used as controller medication and is foundation therapy in 
GINA step ≥3 (GINA 2016).
QMF149 (indacaterol 150 µg as a FDC with MF 80 µg, 160 µg or 320 µg) is a new once daily 
LABA/ICS FDC for which a Phase II development was recently successfully completed.
There is evidence of the efficacy and safety of the mono components of QMF149 indacaterol 
and MF in asthma and COPD (indacaterol). In addition, there is supportive efficacy and safety
information from the early QMF149 development in the Twisthaler® device (see Section 1.1
Background and QMF149 Investigator Brochure). QMF149 FDC of indacaterol acetate and 
mometasone furoate delivered by Concept1 is further investigated in Phase III.
In one large Phase II event driven trial with a duration up to 68 weeks in over 150 0 moderate 
to severe asthma patients including adolescents (12 to 17 years old). In this study QMF149 
500/400 µg o.d. via Twisthaler® (comparable to QMF149 150/160 µg o.d. via Concept1) was 
compared with MF alone 400 µg o.d. via Twisthaler® and showed a favorable efficacy and 
safety profile over MF (Beasley et al 2015).
Further efficacy and safety trials in Phase II included different indacaterol acetate doses on 
background of MF in Concept1 in moderate to severe asthma (CQMF149E2203), a device 
bridging study with MF in Concept1 (CQMF149E2201) and an efficacy and safety study with 
QMF149 in Concept1 in moderate to very severe COPD patients (QMF149F2202). These
studies showed statistically significant improvements in lung function and symptomatic 
endpoints including exacerbations (CQMF149F2202) and confirmed a favorable efficacy and 
safety profile in Phase II.
In summary, the QMF149 Twisthaler® program in Phase II along with further Phase II studies 
with QMF149 delivered by the Concept1 inhaler suggests a favorable efficacy and safety 
profile of the compound.
In this safety study (QVM149B1305) with an open-label QMF149 150/320 µg once daily, 
single arm design, the patients must be symptomatic (defined by ACQ-7 mean score ≥1.5) 
despite treatment according to the current GINA guideline as of year 2016. The patients need 
to have persistent asthma with a ≥50% FEV1 ≤85% of predicted normal (at Visit 1) under 


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ongoing asthma medication. All patients will be treated with one dose of QMF149
150/320 µg). Throughout the trial all patients will have free access to rescue medication (i.e. 
short-acting β2 agonist), thus limiting the risk for patients with a significant asthmatic adverse 
events.
The risks of side effects from the study medication are those known for the individual 
compounds indacaterol and MF, and no additional risks have been identified that might occur 
when the two components are administered concurrently or from the same inhaler. Further 
information can be obtained from the QMF149 Investigator's Brochure. This risk will be 
minimized by compliance with the eligibility criteria and close clinical monitoring.
There is evidence that LABA treatment used alone in asthma might cause asthma
exacerbations. This risk is mitigated by the fact that all patients will have a minimum
background therapy of low dose ICS (monotherapy or in combination with LABA). The 
potential benefit for the patient includes an improvement in the pulmonary function testing 
and a potential translation into better asthma control, such as reductions in symptoms and 
rescue medication use, and improved quality of life. A thorough medical evaluation of the 
patient's disease and close clinical monitoring for the duration of the study may be considered
as additional benefit to the patient.
Frequent and regular contacts between the patient and site staff will occur in terms of clinic
visits and telephone contacts to each patient throughout the 52-week treatment epoch. In
addition, safety monitoring (e.g. symptom collection and rescue medication use via electronic
diary), assessment of compliance with the study medication regimen, and PEF (daily)
measurements at regular intervals throughout the study will help assess status of the patient's
asthma symptom control. Diary data will be transmitted electronically from the device to the
investigator daily. Therefore, investigators may have an early indication of worsening
symptoms and will be able to monitor the patient closely throughout the study.
Guidance to manage potential worsening of asthma symptoms will be provided to
investigators consistent with guideline recommendations (GINA 2016, JGL), as well as to 
patients via written instructions to contact the investigator in the event of worsening asthma 
symptoms.
The investigator should discontinue study treatment for a given patient and/or withdraw the
patient from the study if, 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 the available data of QMF149 and the safety and efficacy data of t he
marketed monotherapy components, it is anticipated that QMF149 150/320 µg will have an 
acceptable benefit to risk profile in patients with asthma.
4
Population
The study population will consist of approximately 66 Japanese males and females aged ≥18 
years, used medium or high dose ICS plus at least one controller (LABA, LTRA, 
Theophylline, or anti-allergics) for asthma. It is anticipated that approximately 88 patients will 
need to be screened in order to collect approximately 66 patients who enter the treatment 


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epoch. It is intended that at least 59 patients will complete the study (i.e. a 25% screening 
failure rate and a 10% dropout rate are expected). Dropouts after enrollment in treatment 
epoch 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 (GINA 2016) for a period of at least 1 year 
prior to Visit 1.
4. Patients who have used medium or high dose ICS plus at least one controller (LABA, 
LTRA, Theophylline, or anti-allergics) for asthma for at least 3 months and at stable dose 
and regimen for at least 4 weeks prior to Visit 1.
5. Patients must have ACQ-7 score ≥1.5 at Visits 2 and qualify for treatment with high dose 
ICS/LABA
6. Pre-bronchodilator FEV1 of ≥50% 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,

FDC or free combination* of ICS/LABA for ≥24 hrs,

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 wash-out period is considered to be longer, please contact your 
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.
* In case of combination ICS/LABA, ICS should be continued.
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.


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
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).
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 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.
6. 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.
7. Patients who have ever required intubation for a severe asthma attack/exacerbation.
8. 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.
9. 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.


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10. 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.
11. 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.
12. Patients with Type I diabetes or uncontrolled Type II diabetes.
13. 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, hyper adrenergic 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.
14. Patients with a history of myocardial infarction (this should be confirmed clinically by the 
investigator) within the previous 12 months.
15. Concomitant use of agents known to prolong the QT interval unless it can be permanently 
discontinued for the duration of study.
16. 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).
17. 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.
18. Patients who have a clinically significant laboratory abnormality at Visit 2.
19. Patients who have not achieved an acceptable spirometry result at Visit 2 in accordance 
with ATS/ERS criteria for acceptability and repeatability. Repeat spirometry may be 
allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on 
the same day) if the spirometry was not qualified due to ATS/ERS criteria. If the patients 
fail the repeat assessment, the patients may be rescreened, provided the patients return to 
their treatment prior until rescreened.
20. Patients taking any asthma-related prohibited medications in the classes specified in Table 
5-1 unless they undergo the required washout period.
21. Patients in need of any prohibited medications listed in Table 5-2.
22. 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.
23. 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.
24. Patients with severe narcolepsy and/or insomnia.


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25. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
26. History of alcohol or other substance abuse.
27. Patients who are directly associated with any members of the study team or their family 
members.
28. Patients unable to use the Concept1 dry powder inhaler or a metered dose inhaler. Spacer 
devices are not permitted for the inhalation rescue medication.
29. 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.
30. 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.
31. 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.
32. LAMA use within 3 months prior to Visit 1
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.


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5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The investigational drug is as follows: 

QMF149 (indacaterol acetate/ mometasone furoate) 150/320 µg o.d. delivered as powder 
in hard capsules via Concept1 inhaler (Appendix 5)
There is no control drug for this trial.
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.


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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 
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.


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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 QMF149. 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 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 QMF149 150/320 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 inhalation 
of QMF149. 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 QMF149 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 QMF149 are not permitted unless the investigator 
considers an interruption is necessary for the treatment of an adverse event. Any interruption 
of QMF149 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 SABA (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 
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 


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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 eCRF, 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 eCRF. 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.
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’ eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
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)
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 12 hours prior to Visit 99 


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Medication
Minimum cessation prior to Screening (Visit 1) 
and Baseline (Visit 99)
(e.g. evening dose can be taken prior next 
morning Visit 99/101).
Short acting β2-agonists (SABAs) (other than 
Salbutamol provided at Visit 1 for rescue 
medication)
Must be discontinued at Visit 1
Salbutamol (SABA) provided at Visit 1
Must be withheld 6 hours prior to spirometry2
Parenteral or oral 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
Monoclonal antibodies for the treatment of 
asthma (e.g., omalizumab, mepolizumab)
Must be discontinued 4 months prior to Visit 1
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.
Patients using LAMA within 3 months prior to Visit 1 are not allowed in the trial as per exclusion 32.


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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
Tricyclic antidepressants (Please note that 
tetracyclics, which are similar in class with 
regards to drug interaction are also to be 
excluded)
14 days
Strong inhibitors of cytochrome P450 3A (e.g. 
ketoconazole) (may depend on compound)
7 days
Noradrenaline reuptake inhibitors
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.


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Table 5-3
Medications allowed under certain conditions1
Medication
Condition under which medication is 
permitted
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.
Antihistamines (e.g. loratadine, cetirizine)
If stabilized for at least 4 weeks prior to Visit 1 
and throughout the trial.
In the case of as needed, provided an established 
pattern of use has been documented.
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.
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.
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
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.
5.5.9
Emergency breaking of assigned treatment code
Not applicable for this open-label study.


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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 
patient fails to return for the study treatment discontinuation visit for unknown reasons, every 


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effort (e.g., telephone, e-mail, and 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.
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 eDiary
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


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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
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 Tale 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 
assessment table below.
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 t hat 
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 po ssible. 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 eDiary
S
S
Device training, e-Diary, ePEF
S
S
S
Prior and Concomitant non-indication 
Medications
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
Prior and Concomitant Asthma 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review and upload patient eDiary
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


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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 be done wherever possible 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/subjects who have signed informed consent but not entered into the next epoch 
will have the study completion page for the screening epoch, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all patients include:

Year of birth

Age 

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 Visit (EOT) 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 eDiary or 
eDiary/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 eDiary 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 eDiary 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 eDiary. 
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 eDiary. 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 eDiary/ePEF. The best of 3 values will be used.
6.4.3
Asthma Control Questionnaire (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 ACQ7 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 ACQ7 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 eDiary) 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 worsening in the
investigator’s opinion, the patient should be treated as appropriate and discontinued prior to
Visit 99. 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 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 

Call the patient promptly 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

Hematology, Blood 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


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
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 
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.


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6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count (RBC), 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.
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.


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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 (Week52), EOT or at any time during 
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.


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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

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


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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 Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient's personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator's source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)]
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)


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
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 
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. 


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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.
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.


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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.
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


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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.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the 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 CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients/subjects will be disclosed.


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8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained.
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
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.
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.


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8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
An independent external adjudication committee will be established to assess serious asthma 
outcomes (asthma-related hospitalizations, intubations and deaths). All serious asthma
outcomes, and deaths 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.
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.


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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 administrations, the recorded pre-specified drug 
subcategories (including type of combinations) 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.
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 QMF149 (150/320 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.


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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.
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.


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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.
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.
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


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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
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.


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9.5.7
PK/PD
Not applicable.
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 QMF149 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 24, 1995), this notification requires to collect safety data of at least 100 patients who 
receive the drug over one year. CQVM149B2301 and 2302 study were planned to collect 
efficacy and safety data of about 41 Japanese Asthma patients exposed to QMF149. Therefore 
this study, CQVM149B1305, is designed to obtain safety data of approximately 59 Japanese 
asthma patients exposed to QMF149. Since a 25% screening failure rate and a 10% dropout 
rate are expected, approximately 88 patients will need to be screened in order to collect 
approximately 66 patients who enter the treatment epoch and to collect a total of 
approximately 59 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 


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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. 
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.


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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.
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.
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)


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Beasley R, Donohue F, Mehta R, et al (2015) Effect of once-daily indacaterol 
maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-
blind randomised controlled trial. BMJ Open; 5(2):e006131. doi: 10.1136/bmjopen-2014-
006131
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.
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, 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 (11): 1686-
1704. (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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Protocol No. CQVM149B1305
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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Protocol No. CQVM149B1305
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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Protocol No. CQVM149B1305
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 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.


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Protocol No. CQVM149B1305
Reversibility is calculated as:
100 x
FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator)
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; 26:153-161.
2 Quanjer PH, Stanojevic S, Cole TJ, et al (2012), ERS Global Lung Function Initiative, Multi 
thnic 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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Protocol No. CQVM149B1305
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. CQVM149B1305
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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Protocol No. CQVM149B1305
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.
This image cannot currently be displayed.


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Protocol No. CQVM149B1305
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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Protocol No. CQVM149B1305
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_000.pdf: 
Clinical Development 
QVM149B (QMF149: Indacaterol acetate/Mometasone furoate) 
CQVM149B1305 / NCT03100500
A multicenter, open-label, single arm, 52-week treatment 
study to assess the safety of QMF149 in Japanese patients 
with asthma 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician,  
 
Document type: 
SAP Documentation 
Document status: 
Amendment1  
Release date: 
17-Aug-2018
Number of pages: 
25 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP 
 
CQVM149B1305 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
13Feb2017 
Prior 
to 
FPFV 
Creation of 
Final 
Version 
NA 
17Aug2018 Prior 
to 
DB lock 
for IA 
Protocol 
amendment, 
consistency 
with 
protocol 
and pivotal 
studies and 
dry 
run 
review 
 Updated defenition of categories for 
pre-bronchodilator FEV1 in % of 
predicted FEV1 at screening Visit 2 in 
Section2.2.1, and conducted same 
upadate in Section 2.3 and section 2.5.4 
 Removed ATC code for summarizing 
concomitant medication in Section 2.4.2 
 Removed list of special interest AEs in 
Section 2.5.2 
 Updated definition of baseline in PEF in 
Section 2.6.2 
 Added summary in PEF by 4 weekly 
interval and definition for post baseline 
in Section 2.6.2 
 Added summary in ACQ-7 at week 12 
in Section 2.6.2   
 Removed a category, “QTc  <30”, in 
section 2.7.3.1  
 Replaced notable criterion for Sodium 
with one for Magnesium in section 5.3 


Novartis 
For business use only 
Page 3 
SAP 
 
CQVM149B1305 
 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................ 6 
1.2 
Study objectives and endpoints ............................................................................... 6 
2 
Statistical methods ............................................................................................................... 7 
2.1 
Data analysis general information ........................................................................... 7 
2.1.1 
General definitions .................................................................................. 7 
2.2 
Analysis sets ............................................................................................................ 8 
2.2.1 
Subgroup of interest ................................................................................ 8 
2.3 
Patient disposition, demographics and other baseline characteristics ..................... 8 
2.3.1 
Patient disposition ................................................................................... 9 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 10 
2.4.1 
Study treatment / compliance ................................................................ 10 
2.4.2 
Prior, concomitant and post therapies ................................................... 10 
2.5 
Analysis of the primary objective .......................................................................... 11 
2.5.1 
Primary endpoint ................................................................................... 11 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 11 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 12 
2.5.4 
Supportive analyses ............................................................................... 12 
2.6 
Analysis of secondary efficacy objective(s) .......................................................... 12 
2.6.1 
Secondary endpoints ............................................................................. 12 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 14 
2.7 
Safety analyses....................................................................................................... 14 
2.7.1 
Adverse events (AEs) ............................................................................ 14 
2.7.2 
Laboratory data ..................................................................................... 15 
2.7.3 
Other safety data ................................................................................... 18 
2.8 
Pharmacokinetic endpoints .................................................................................... 20 
2.9 
PD and PK/PD analyses ........................................................................................ 20 
2.10 
Patient-reported outcomes ..................................................................................... 20 
2.11 
Biomarkers ............................................................................................................. 20 
 
 20 
2.13 
Interim analysis ...................................................................................................... 21 


Novartis 
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Page 4 
SAP 
 
CQVM149B1305 
 
 
3 
Sample size calculation ..................................................................................................... 21 
4 
Change to protocol specified analyses .............................................................................. 22 
5 
Appendix ........................................................................................................................... 22 
5.1 
Imputation rules ..................................................................................................... 22 
5.2 
AEs coding/grading ............................................................................................... 22 
5.3 
Laboratory parameters derivations ........................................................................ 22 
Direction of interest and definition of clinically notable values ....................................... 22 
5.4 
Statistical models ................................................................................................... 24 
5.4.1 
Primary analysis .................................................................................... 24 
5.4.2 
Key secondary analysis ......................................................................... 24 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 24 
6 
Reference ........................................................................................................................... 25 


Novartis 
For business use only 
Page 5 
SAP 
 
CQVM149B1305 
 
 
List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


Novartis 
For business use only 
Page 6 
SAP 
 
CQVM149B1305 
 
 
1 
Introduction 
This document contains details of the statistical methods that will be used in the phase III 
clinical trial CQVM149B1305. This study is designed to provide long term safety data of 
QMF149 in Japanese patients with asthma for the registration of QMF149 in Japan. 
Data will be analyzed according to Section 9 of the study protocol. 
Important information and details are given in the following sections. 
1.1 
Study design 
This study uses a 52-week treatment, multicenter, open-label, single-arm design in Japanese 
patients with asthma. One interim analysis is planned after the last patient completed the 
assessments at Week 26 (Visit 107). 
This study is designed to obtain safety data of QMF149 in 59 Japanese asthma patients. 
Details of sample size are described in Section 3 in this document. 
No randomization is planned in this study. 
The primary objective of this study is to assess the safety/tolerability of 52 weeks of treatment 
with QMF149 (150/320 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. 
An interim analysis for 6-month data will be performed for the initial New Drug Application 
submission in Japan. This analysis will be performed after all patients have been enrolled and 
completed Visit 107 (Week 26) or discontinued the study. Details of the interim analysis are 
described in Section 2.13 in this document. 
1.2 
Study objectives and endpoints 
 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
 To assess the safety/tolerability of 52 weeks of 
treatment with QMF149 (150/320 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 QMF149 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 QMF149 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 treatment 


Novartis 
For business use only 
Page 7 
SAP 
 
CQVM149B1305 
 
 
Objective(s) 
Endpoint(s) 
 To assess the efficacy of QMF149 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 QMF149 in terms of 
rescue medication use 
 Change from baseline of rescue medication 
use during 52 weeks treatment 
 
2 
Statistical methods 
2.1 
Data analysis general information 
All data analysis will be performed by Novartis according to the data analysis section 9 of the 
study protocol using the most actual version of SAS at the time of database lock.  
General descriptive statistical rules to summarize quantitative or qualitative parameter are: 
continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, median, standard deviation, first and third quartiles, minimum, and maximum) 
and categorical variables will be summarized in terms of the number and percentage of 
patients in each category including a category for missing data if any. 
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.  
2.1.1 
General definitions  
Study day is defined as the number of days since the date of first dose of study medication. 
The date of first dose of study medication was defined as Day 1 and the day before the first 
dose of study medication was defined as Day -1.  
Therefore, for a particular date, study day will be calculated as follows: 
 
for dates on or after the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication + 1; 
 
for dates prior to the first date of study medication, 
Study day = Assessment date – Date of first dose of study medication. 


Novartis 
For business use only 
Page 8 
SAP 
 
CQVM149B1305 
 
 
In general, baseline is defined as the last measurement before the first dose of study drug at  
Day 1. Refer to the baseline definitions for each analysis described in the later sections.  
When change from baseline is of interest the following formula will be used for each 
scheduled visit and time-point where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value 
Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed. For patients who do not complete the study, the treatment discontinuation visit 
will be an unscheduled visit. Clinical laboratory measurements, vital signs and ECG data from 
unplanned or unscheduled visits will only be included in the summaries of the notable values 
and extreme values. All efficacy data (including spirometry data) from these visits will not be 
used for missing data imputation unless specified otherwise. Laboratory, vital signs, and ECG 
values that have complete data and time values will be slotted into pre- or post-dose 
assessment based on the actual date/time. For values with missing date/time, their respective 
scheduled visit date and time will be used. This rule will be applied to data from scheduled 
visits only. If a measurement scheduled as pre-dose is actually performed post-dose, or vice 
versa, the data will not be used for by time point assessments but will be included in the 
summaries of the notable values and extreme values. 
2.2 
Analysis sets 
The Safety Set will consist of all patients who received at least one dose of study medication 
during this study. The Safety Set will be used in the analysis of all safety variables. 
Full Analysis Set (FAS) will consist of all patients who entered in the treatment epoch of this 
study and received at least one dose of study medication during this study. The efficacy 
analysis will be based on FAS. 
Note that the Safety Set and FAS are the same except that the Safety Set allows the inclusion 
of patients who are not intended to enter in the treatment epoch of this study but received 
study drug in error.  
2.2.1 
Subgroup of interest 
- 
Age (18 - < 65years, ≥ 65years) 
- 
Sex (male, female) 
- 
Pre-bronchodilator FEV1 in % of predicted FEV1 at screening Visit 2 (< 50%, 50% - < 
60%, 60% - ≤ 85%, > 85%) 
Refer to the Section 2.5.4 in this document. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographics 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 


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pressure, pulse rate), QTc using Fridericia's correction and baseline ACQ-7, will be 
summarized on safety set. 
 
Baseline is defined as the last measurement before first dose of study drug. Missing baseline 
will not be imputed, unless otherwise specified. 
In addition, the following categorizations of continuous variables will be done:  
 Age into 18 - 39 years, 40 - 64 years, and ≥ 65 years; 
 BMI into < 25.0 kg/m2, 25.0 - 30.0 kg/m2, and > 30.0 kg/m2;  
 Duration of asthma into < 1 year, 1 - 5 years, > 5 - 10 years, > 10 - 15 years, > 15 - 20 
years, and > 20 years;  
 Number of asthma exacerbations in the 12 months prior to the start of the study that 
required medical care into 1, 2, 3, ≥ 4; 
 pre-bronchodilator FEV1 into < 50 %, 50% - < 60%, 60% - ≤ 85%, > 85% of predicted 
FEV1; 
 ACQ-7 into < 1.5, 1.5 - < 2, 2 - < 2.5, ≥ 2.5. 
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most actual version at the time of database lock. 
History/conditions will be summarized for the Safety Set by primary system organ class and 
preferred term. Verbatim recorded history/conditions will be listed together with the coded 
terms, date of diagnosis/surgery and whether the problem was ongoing at start of the study.  
In addition, medical histories/current medical conditions will be summarized by their status at 
baseline (current medical conditions, past medical conditions) and primary system organ class. 
Current medical conditions are defined as those which were reported as "Ongoing" at baseline. 
2.3.1 
Patient disposition 
For each study epoch (i.e., screening, treatment phase, post treatment follow-up), the overall 
number of patients who entered, completed, and discontinued that phase will be summarized 
including the reasons for discontinuation. 
The number of patients included in each analysis set will be tabulated, as well as the reasons 
for exclusions from analysis sets. Patient exclusion from analysis sets will be listed for all 
patients with reasons for exclusion (including both CSR-reportable and non CSR-reportable 
protocol deviations). 
The number of patients with protocol deviations will be tabulated by category (e.g., selection 
criteria not met, prohibited concomitant medication, key procedures not performed as per 
protocol) and deviation for the Safety Set. Protocol deviations will be listed with date and 
study day of occurrence, deviation and analysis populations from which patients are excluded. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
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. Duration of exposure to 
study treatment will be calculated as the number of days starting from the first dose date up to 
and inclusive the last dose date. The duration of exposure will be summarized for the Safety 
Set as a continuous variable with the standard descriptive statistics. In addition, the duration 
of exposure will be summarized with total patient years and the number (%) of patients who 
were exposed to study drug for each 1 - 29 days, 30 - 86 days, 87 - 183 days, 184 - 254 days, 
255 - 365 days, and > 365 days. The number of patients who completed the 52-week study 
treatment and who discontinued prematurely will be shown including the reasons for 
discontinuation of study treatment. 
Treatment compliance with study medication over the study period will be summarized. 
Compliance will be calculated by counting the days where study drug was administered "As 
per protocol" according to the records on the Dosage Administration Record (DAR) Summary 
eCRF. The percentage of days divided by the days of exposure will be analyzed. Compliance 
will be categorized into < 80% and 80% - 100% and summarized for the Safety Set. 
2.4.2 
Prior, concomitant and post therapies 
Medications started and stopped prior to study drug, and taken concomitantly will be 
summarized for the Safety Set. Prior medications are defined as drugs taken and stopped prior 
to first dose of study medication. Any medication given at least once between the day of first 
dose of study medication and last day of study visit will be a concomitant medication, 
including those which were started pre-baseline and continued into the treatment period. 
Concomitant therapies will be recorded, listed and summarized separately for asthma related 
medications/non-drug therapies and other medications.  
Separate tables will be provided for medications which were started and stopped prior to the 
first dose of study drug and medications which were taken concomitantly to the study drug 
(regardless of whether continued or started after the first dose of study drug).  
Asthma medications will be summarized by the route of administration, the recorded pre-
specified drug subcategories (including types of combination) and the coded preferred terms. 
The summary will be repeated by showing ingredients instead of preferred terms.  
Non-asthma medications will be summarized by route of administration and the coded 
preferred terms.  
Surgical and medical procedures (non-drug therapies) will be coded using MedDRA and 
presentations will be done by MedDRA primary system organ class and preferred term, 
separately for prior procedures and those after start of study drug. 


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Short acting beta2 agonist (SABA) rescue medication usage (number of puffs) during the 
screening epoch will be summarized. 
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations. 
2.5 
Analysis of the primary objective 
The primary objective of this study is to assess the safety/tolerability of 52 weeks of treatment 
with QMF149 (150/320 µg, once daily), particularly with regard to treatment emergent 
adverse event reporting in Japanese patients with inadequately controlled asthma. 
2.5.1 
Primary endpoint 
The primary variable is the number and percentage of patients who reported treatment 
emergent adverse events during the 52 week study period for the Safety set. 
All treatment 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. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Adverse events will be summarized with descriptive statistics for the Safety Set. 
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 
 All adverse events by time at onset (≤ 12 weeks, > 12 - ≤ 26 weeks, > 26 weeks) 
 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 
All adverse events including asthma exacerbations, coded with MedDRA using the most 
actual version at the time of database lock, will be listed.  
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency. If a patient reported more than one adverse event with the same preferred term, 
the adverse event will be counted only once. If a patient reported more than one adverse event 
within the same primary system organ class, the patient will be counted only once at the 
system organ class level. 


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In addition, the most frequent adverse events will be presented by preferred term in 
descending order of frequency.  
For AEs by maximum severity, missing severity will be assumed to be severe in the summary 
table. 
A composite endpoint of serious asthma outcomes is defined as a) asthma-related 
hospitalization, b) asthma-related intubation, or c) asthma-related death. All serious asthma 
outcomes and deaths occurring from the treatment epoch until the 30 days after permanent 
discontinuation of study drug will be adjudicated by an independent external committee to 
determine their asthma relatedness. 
The composite endpoint as well as each single component of it will be analyzed for the 
number of patients with the event, the time to event and the annual rate of events. 
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of special interest. The most recent list of adverse events 
of special interest at the time of database lock will be used. 
2.5.3 
Handling of missing values/censoring/discontinuations 
No imputation will be done for missing data. All available data will be summarized. 
2.5.4 
Supportive analyses 
Adverse events of special interest will also be analyzed for the following selected subgroups:  
- 
Age (18 - < 65years, ≥ 65years) 
- 
Sex (male, female) 
- 
Pre-bronchodilator FEV1 in % of predicted FEV1 at screening Visit 2 (< 50%, 50% - < 
60%, 60% -  ≤85%, > 85%) 
2.6 
Analysis of secondary efficacy objective(s) 
2.6.1 
Secondary endpoints 
The secondary efficacy measurements (Spirometry, PEF, Rescue medication and ACQ-7) 
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. 
Measurements made after patients discontinue study treatment (off-treatment measures) will 
not be used for any efficacy evaluation. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Spirometry 
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. If one of the -45 and -15 min values is missing (or 
is not confirmed to be pre-dose) then the remaining non-missing value will be taken as the 


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baseline. If both values are missing (or not confirmed to be pre-dose), then the last out of the 
pre-bronchodilator measurements taken at the screening Visits 2 or at unscheduled screening 
visits will be used as the baseline. If the FEV1, FVC measurements are missing both on Day 1 
and at screening visits, the respective baseline values will be set to missing. 
The pre-dose FEV1 is defined as the mean of the pre-dose 45 and 15 min FEV1 values. The 
pre-dose FVC is defined as for the pre-dose FEV1. If any of the pre-dose 45 and 15 min 
values contributing to the pre-dose value are collected within 7 days of systemic 
corticosteroid use, 6 hours of rescue medication use, or actual measurement times are post-
dose will be set to missing. If one of the two values is missing (or set to missing) then the 
remaining non-missing value will be taken as pre-dose value. If both values are missing, then 
pre-dose value will be missing. 
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 pre-dose FVC for each visit will be displayed 
graphically.  
Peak Expiratory Flow Rate (PEF) 
PEF(liters/min) will be analysed separately for morning and evening values. 
The baseline values are defined as the average from all non-missing records taken in the 
screening period for 14 days before Day 1 administration (in case they were measured before 
the first intake of study drug as scheduled in the study protocol). When calculating the 
baseline value there is no limitation to the 14 days immediately prior to Day 1 administration. 
If a patient has less than 7 days with non-missing data, then the respective baseline value will 
be set to missing. 
The post-baseline measurements start with the morning recordings at Day 2 and end with the 
evening recordings at the day of last dose. Similar calculations as for baseline data will be 
done. For the first 26 weeks and the whole 52 weeks, summary values will only be calculated 
if a patient has at least 30% of their diary days and at least 20 diary days with evaluable data 
for that variable in the period of interest. For 4-week intervals (defined as 28 days), summary 
values will only be calculated if a patient has at least 50% of their diary days (i.e. 14 days) of 
non-missing data. If there will be less than 14 days with data in a 4-week period, then the data 
should collapse with the previous 4-week interval. The mean morning/evening PEF and the 
mean change from baseline will be summarized for the first 26 weeks (defined as up to Visit 
107), and for the whole 52 weeks of treatment period (defined as up to Visit 111), and will be 
summarized by 4 weekly interval. 
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. 
The baseline and post-baseline valuses are defined in the same way as for the PEF.  


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The mean daily number of puffs of rescue medication use will be calculated for each patient 
over the first 26 weeks of treatment period, over the whole 52 weeks of treatment peroid and 
over the screening period (which will be used as the baseline value) as described for the PEF. 
This will be done separately for morning (night-time), evening (daytime), and daily (night-
time plus daytime) rescue medication use. If for the value over the whole day (24 hours) the 
number of puffs is missing for part of the day (either day-time or night-time) then a half day 
will be used in the denominator to calculate the average value. Any values > 30 for the 
number of puffs of rescue medication in a 12 hour period will be set to missing. These high 
numbers are not realistic and could impact the analyses. Where the number of puffs of rescue 
medication is missing but the rest of the e-diary has non-missing data, the number of puffs 
will be assumed to be zero. 
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 as any day where the patient did 
not use any puffs of rescue medication during daytime and night-time) will be summarized. 
Asthma Control Questionnaire 7 (ACQ-7) 
The baseline value is defined as the score obtained at Day 1. If the value is missing, the last 
measurements from screening visit 2 or unscheduled screening visits will be used. 
ACQ-7 and the change from baseline at 12, 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., a 
decrease of ACQ-7 score of at least 0.5 from baseline) at 26 and 52 weeks visits will be 
summarized. 
2.6.3 
Handling of missing values/censoring/discontinuations 
No imputation will be done for missing data. 
2.7 
Safety analyses 
All safety variables will be summarized with descriptive statistics for the Safety Set. 
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. 
Post-baseline measurements comprise recordings up to the last dose of study drug + 7 days for 
laboratory, ECG, vital signs, non-serious AE and up to the last dose of study drug + 30 days 
for SAEs and death. 
2.7.1 
Adverse events (AEs) 
Refer to the AEs analyses described in Section 2.5 in this document. 


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2.7.1.1 
Adverse events of special interest / grouping of AEs 
Refer to the AEs analyses described in Section 2.5 in this document. 
Deaths 
A summary of deaths according to the affected primary system organ class and preferred term 
for the investigator-reported principal cause of death and for the adjudicated cause of death 
will be separately presented regardless of study drug relationship.  
All the deaths in the clinical database will be listed with both the investigator-reported 
principal cause and the adjudicated cause presented side by side, but only those between the 
first treatment and (the last dose + 30 days) will be included in summary tables.  
See Section 2.5 in this document as well. 
2.7.2 
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 laboratory data will be listed with abnormal values flagged.  
Baseline laboratory data is defined as the assessment taken 30 minutes pre-dose at Day 1. If 
this assessment is missing or not confirmed to be pre-dose, the last value taken at the 
screening Visit 2 or at an unscheduled visit before the first administration of study drug will 
be used for baseline. Otherwise, the baseline laboratory data will be set to missing. 
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. 
The following analyses will be performed: 
 absolute values and change from baseline summarized with standard descriptive statistics 
for continuous laboratory parameters by visit and time point 
 frequency table of results for categorical laboratory parameters by visit and time point 
 shift tables relative to the normal reference ranges summarizing the change from baseline 
to post-baseline by visit and time point for each continuous laboratory parameter 
 shift tables from baseline to post-baseline by visit and time point for categorical laboratory 
parameters 
 the number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (see Section 5.3 in this document for 
definition of notable values) summarized by laboratory parameter, scheduled post-baseline 
visit and time point and additionally at any time on treatment considering all post-baseline 
data from scheduled, unscheduled and premature discontinuation visits 
The by-visit/time point summaries will include the worst case post-baseline values 
(determined from all post-baseline data even if from unscheduled and premature 
discontinuation visits, if not measured more than 7 days after last dose). To determine the 
worst case, the direction of interest (maximum and/or minimum value) is tabulated for 


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hematology and biochemistry parameters in Section 5.3. For continuous urinalysis parameters 
the direction of interest is always "High" (maximum value). 
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value that is not clinically notable for that parameter. For a patient to 
meet the criterion of a worsening clinically notable value, the patient needs to have a baseline 
value that is clinically notable and also have a worse post-baseline value. For patients with 
missing baseline value, any post-baseline notable value will be considered as newly occurring.  
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) at any time post-baseline will be summarized based 
on the following criteria: 


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 
Notable liver function test values 
Criterion   
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin > 1 x ULN 
Total bilirubin > 1.5 x ULN 
Total bilirubin > 2 x ULN 
Total bilirubin > 3 x ULN 
ALP > 1.5 x ULN 
ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP ≤ 2 x ULN (Hy's law) 
ALT or AST > 3 x ULN and (nausea or vomiting or fatigue or general malaise or abdominal pain or (rash and 
eosinophilia))* 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
*  Based on the signs/symptoms information as recorded on the liver events eCRF, not the adverse events eCRF. 
When a criterion contains multiple laboratory parameters, the criterion will only be 
considered to have been met when all conditions occur at the same time (i.e., within the same 
sample). A case where all criteria are met at a post-baseline time point will be considered as 
newly occurring if the criteria are not met at baseline and will be considered as worsening if 
the criteria are met at baseline and at least one component is worsening from baseline 
irrespective of whether the other(s) are better. 
Listings of all patients with notable laboratory values and also with clinically notable LFT 
values will be provided. 


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2.7.3 
Other safety data 
2.7.3.1 
ECG and cardiac imaging data 
Data from the ECG (including ventricular rate, QT interval, RR interval, PR interval, QRS 
duration , Fridericia's QTc and Bazett’s QTc) will be summarized at 30 min pre-dose, and at 
30 min post-dose (at selected visits only). 
Furthermore, an overall interpretation of the central cardiologist will be provided as well as a 
specification of abnormal findings. For qualitative assessments, if multiple ECG values were 
taken, the worst case will be chosen for all summaries. 
ECG 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. All data will be included in the 
analysis regardless of rescue medication usage. 
Baseline ECG is defined as ECG measured 30 minutes prior to the first dose of study drug on 
Day 1. If it is missing (or not confirmed to be pre-dose), then the last assessment taken at the 
screening Visit 2 or at an unscheduled visit before the first administration of study drug will 
be used. Otherwise, the ECG baseline will be set to missing without imputation. 
QTc will be calculated from the QT interval and RR (in seconds) by two methods: 
1. using Fridericia's formula: QTcF = QT ∕ 3√RR, where 3√ denotes the cube root 
2. using Bazett's formula: QTcB = QT ∕ √RR 
The following analyses will be performed: 
 absolute values and change from baseline summarized by parameter, visit and time point 
 the number and percentage of patients with newly occurring or worsening notable QTcF 
/QTcB values (see bellow for definition of notable values) summarized by scheduled post-
baseline visit and time point and additionally at any time on treatment considering all 
post-baseline data from scheduled, unscheduled and premature discontinuation visits 
 frequency table of results for overall ECG interpretation (normal, abnormal) by visit and 
time point and with shift tables from baseline to the worst interpretation during treatment 
 the number and percentage of patients with ECG abnormalities summarized by evaluation 
type, abnormality finding, visit and time point. In addition, the number and percentage of 
patients with newly occurring or persistent/recurrent ECG abnormalities at any time point 
over the treatment period (considering all post-baseline data from scheduled, unscheduled 
and premature discontinuation visits) will be summarized by evaluation type and 
abnormality finding 
The by-visit/time point summaries will include the maximum QTcF/QTcB and maximum 
ventricular rate (even if from post-baseline unscheduled and premature discontinuation visits, 
if not measured more than 7 days after last dose). 
The same approach as for notable laboratory values will be used to define a newly occurring 
notable QTcF/QTcB value and a worsening notable QTcF/QTcB value. 
A listing of all patients with notable QTcF/QTcB values and changes will be provided.  
The following table shows the clinical notable criteria for QTcF/QTcB. 


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Clinical notable criteria for QTcF and QTcB 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTc (ms) 
> 450 (male) 
QTc (ms) 
> 460 (female)  
QTc (ms) 
> 500  
Categories used for the change from baseline 
QTc 
30 – 60 
QTc 
> 60 
 
2.7.3.2 
Vital signs 
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), and 
pulse rate.  
Vital signs data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
Baseline vital signs are defined as the assessment taken 30 minutes pre-dose at Day 1. If this 
assessment is missing or not confirmed to be pre-dose, the last value taken at the screening 
Visit 2  or at an unscheduled visit before the first administration of study drug will be used for 
baseline. 
The following analyses will be performed: 
 absolute values and change from baseline summarized by parameter, visit and time point 
 the number and percentage of patients by parameter, visit and time point with 
- pulse rate < 40 bpm, 40 – 90 bpm, and > 90 bpm 
- SBP < 90 mmHg, 90 – 140 mmHg, and > 140 mmHg 
- DBP < 50 mmHg, 50 – 90 mmHg, and > 90 mmHg 
 the number and percentage of patients with newly occurring or worsening notable vital 
signs values (see bellow for definition of notable values) summarized by parameter, 
scheduled post-baseline visit and time point and additionally at any time on treatment 
considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits 
The by-visit/time point summaries will include the maximum and minimum post-baseline 
SBP, DBP, and pulse rate values (even if from post-baseline unscheduled and premature 
discontinuation visits, if not measured more than 7 days after last dose). 
The same approach as for notable laboratory values will be used to define a newly occurring 
notable vital sign value and a worsening notable vital sign value. 
A listing of all patients with notable vital sign values and changes will be provided. 
The following table shows the clinical notable criteria for vital signs. 


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Clinical notable criteria for vital signs 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of clinically 
notable range 
Notable value considering newly occurring or worsening cases 
Systolic blood pressure (mmHg) 
< 75 
> 200 
Diastolic blood pressure (mmHg) 
< 40 
 
> 115 
Pulse rate (bpm) 
< 40 
> 130 
Notable change from baseline 
Systolic blood pressure (mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20  
≥ 180 and increase from 
baseline by ≥ 20 
Diastolic blood pressure (mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase from 
baseline by ≥ 15 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase from 
baseline by ≥ 15 
 
2.8 
Pharmacokinetic endpoints   
Not applicable.  
2.9 
PD and PK/PD analyses 
Not applicable. 
2.10 
Patient-reported outcomes 
Not applicable. 
2.11 
Biomarkers 
Not applicable. 


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2.13 
Interim analysis 
 
 
   
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. 
3 
Sample size calculation 
Since asthma is a chronic disease, and QMF149 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 24, 1995), this notification requires to collect safety data of at least 100 patients who 
receive the drug over one year. CQVM149B2301 and 2302 study were planned to collect 


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efficacy and safety data of about 41 Japanese Asthma patients exposed to QMF149. Therefore 
this study, CQVM149B1305, is designed to obtain safety data of approximately 59 Japanese 
asthma patients exposed to QMF149. Since a 25% screening failure rate and a 10% dropout 
rate are expected, approximately 88 patients will need to be screened in order to collect 
approximately 66 patients who enter the treatment epoch and to collect a total of 
approximately 59 completed patients. 
4 
Change to protocol specified analyses 
No change from protocol specified analysis is made. 
5 
Appendix 
5.1 
Imputation rules 
No imputation is planed in this study. 
5.2 
AEs coding/grading 
Refer to the AEs analyses described in Section 2.5 in this document. 
5.3 
Laboratory parameters derivations 
Direction of interest and definition of clinically notable values 
The following table shows the direction of interest when analyzing worst case values in form 
of maximum and/or minimum post-baseline values. If the direction of interest is given as 
"High" the maximum value will be calculated and used as worst value, if the direction is given 
as "Low" the minimum value will be taken, and if it is given as "Low and high", both the 
minimum value and the maximum value will be calculated and presented in summary tables. 


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Direction of interest for worst case value for laboratory parameters 
Laboratory Parameter 
Direction of interest for worst case value 
A. Hematology 
Hemoglobin 
Low 
Hematocrit 
Low 
Erythrocytes 
Low 
Leukocytes 
Low and high 
Basophils 
High 
Eosinophils 
High 
Lymphocytes 
Low and high 
Monocytes 
High 
Neutrophils 
Low and high 
Platelets 
Low and high 
B. Chemistry 
 
Albumin 
Low 
Alkaline Phosphatase 
High 
ALT/SGPT 
High 
AST/SGOT 
High 
Bilirubin Total 
High 
Blood Urea Nitrogen (BUN)  
High 
Creatinine 
High 
Glucose 
Low and high  
Gamma GT 
High 
Potassium 
Low and high 
Sodium 
Low and high 
Magnesium 
Low and high 
Uric acid 
High 
Plasma cortisol 
Low and high 
 
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined.  


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Clinical notable criteria for selected laboratory tests 
Laboratory parameter (unit) 
Lower bound of clinically notable 
range 
Upper bound of clinically notable 
range 
Hematology 
 
 
Hematocrit (v/v)) 
     Male 
     Female 
 
0.37 
0.32 
 
- 
- 
Hemoglobin (g/L) 
    Male 
    Female 
 
115 
95 
 
- 
- 
Platelets (x10E9/L) 
75  
700 
Leukocytes (x109/L) 
2.8 
16.0 
Chemistry 
 
 
Albumin (g/L) 
25 
- 
Alkaline Phosphatase (U/L) 
- 
3 x ULN 
ALT/SGPT (U/L) 
- 
3 x ULN 
AST/SGOT (U/L) 
- 
3 x ULN 
Bilirubin Total (µmol/L) 
- 
34.2 
BUN (mmol/L) 
- 
9.99 
Creatinine (µmol/L) 
- 
176.8 
Glucose (mmol/L) 
2.78 
9.99 
Gamma GT (U/L) 
- 
3 x ULN 
Potassium (mmol/L) 
3 
6 
Magnesium (mmol/L) 
0.51 
1.07 
v = volume, ULN = upper limit of normal  
5.4 
Statistical models 
5.4.1 
Primary analysis 
Not applicable. 
5.4.2 
Key secondary analysis 
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets  
The following protocol deviations will be considered as major and will lead to exclusion of 
patients from the FAS or the Safety Set:  
 Patient received study drug but not intended to enter in the treatment epoch of this study 
(excludes from FAS) 
Note: The list will be completed when the major PDs are defined and will be updated shortly 
before database lock. 
Protocol deviations will lead to patient classification into the analysis sets as follows: 


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Analysis set exclusions based on population codes  
Analysis set 
Population codes that cause a subject to be excluded 
SAF 
2, 3 
FAS 
1, 3 
Population code text 
Population Code  
Population code - text  
0 
INCLUDE IN EVERYTHING 
1 
EXCLUDE FROM FULL ANALYSIS SET (FAS) 
2 
EXCLUDE FROM SAFETY 
3 
EXCLUDE FROM FAS AND SAFETY 
Note that the population codes will be derived in the analysis datasets and are not part of the 
source data.  
Unless otherwise stated, summary tables, figures and listings will be on all subjects included 
in the analysis set under consideration. 
Protocol deviations that cause subjects to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
TRT01 
Patient was entered treatment epoch 
but no study drug was taken 
Excluded 
form 
FAS 
and 
Safety Set analysis 
TRT02 
Patient received wrong treatment or 
expired drug 
Excluded form FAS analysis 
 
6 
Reference 
Not applicable.