Clinical trial NCT02892344
Conditions: Mild Asthma
Keywords: Phase III, blinded, QMF149, Mometasone furoate (MF), mild asthma, Adolescent, adult
Sponsor: Novartis Pharmaceuticals
Start date: 2017-01-16; Completion date: 2018-11-30
Enrollment: 802 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the trial was to evaluate efficacy and safety of QMF149 150/80 microgram o.d.

delivered via Concept1 compared to MF 200 microgram o.d., delivered via Twisthaler® in terms of lung function and symptom control in poorly (ie inadequately) controlled asthma patients. This study was to assess contribution of LABA as an add-on therapy to low dose ICS monotherapy.

Detailed description:
The primary objective of this study was to demonstrate the superiority of QMF149 150/80 microgram o.d. (in the evening) delivered via Concept1 compared with MF 200 microgram o.d. (in the evening) delivered via Twisthaler® in terms of trough FEV1 after 12 weeks of treatment in adults and adolescents. The key secondary objective of this study was to demonstrate the superiority of QMF149 150/80 microgram to MF 200 microgram o.d. in terms of ACQ-7 after 12 weeks of treatment.

Arms: arm 1: QMF149 150/80 microgram o.d. delivered via Concept1 arm 2: MF 200 microgram o.d. delivered via Twisthaler®
Interventions: intervention 1: QMF149 150/80 μg intervention 2: MF 200 μg
Intervention descriptions: intervention 1: QMF149 150/80 μg o.d via Concept1 intervention 2: MF 200 μg o.d. via Twisthaler®

Protocol documents:
Prot_000.pdf: 
Global Clinical Development – General Medicine
CQVM149B (QMF149: Indacaterol acetate / Mometasone 
furoate) 
CQVM149B2303/ NCT02892344 
A multi-center, randomized, 12-week treatment, double-
blind study to assess the efficacy and safety of QMF149 
(150/80 microgram) compared with MF Twisthaler® (200 
microgram) in adult and adolescent patients with asthma 
Document type:
Clinical Trial Protocol 
EUDRACT number:
2016-000472-22
Version number:
Version 02 Clean (Amended protocol)  
Clinical trial phase:
III 
Release date:
20-Mar-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)
 


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 2 ....................................................................................................................10
Summary of amendments issued before this amendment: ................................................12
Protocol summary..............................................................................................................14
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................20
2
Study objectives and endpoints .........................................................................................20
2.1
Primary objective...................................................................................................20
2.2
Key Secondary objective .......................................................................................21
2.3
Other secondary objectives....................................................................................21
22
3
Investigational plan ...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale for study design .....................................................................................24
3.3
Rationale for dose/regimen, route of administration and duration of treatment....25
3.4
Rationale for choice of comparator .......................................................................25
3.5
Purpose and timing of interim analyses/design adaptations..................................25
3.6
Risks and benefits..................................................................................................25
4
Population..........................................................................................................................27
4.1
Inclusion criteria ....................................................................................................28
4.2
Exclusion criteria...................................................................................................29
5
Treatment...........................................................................................................................32
5.1
Study treatment......................................................................................................32
5.1.1
Investigational and control drugs..........................................................32
5.1.2
Additional treatment..............................................................................33
5.2
Treatment arms......................................................................................................33
5.3
Treatment assignment and randomization.............................................................33
5.4
Treatment blinding.................................................................................................34
5.5
Treating the patient................................................................................................34
5.5.1
Patient numbering .................................................................................34
 


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5.5.2
Dispensing the study drug.....................................................................34
5.5.3
Handling of study and additional treatment..........................................35
5.5.4
Instructions for prescribing and taking study treatment........................36
5.5.5
Permitted dose adjustments and interruptions of study treatment ........36
5.5.6
Rescue medication ................................................................................37
5.5.7
Concomitant medication .......................................................................37
5.5.8
Prohibited medication ...........................................................................37
5.5.9
Emergency breaking of assigned treatment code..................................40
5.6
Study completion and discontinuation...................................................................40
5.6.1
Study completion and post-study treatment..........................................40
5.6.2
Discontinuation of study treatment .......................................................40
5.6.3
Withdrawal of informed consent...........................................................43
5.6.4
Lost to follow up...................................................................................44
5.6.5
Early study termination by the sponsor.................................................44
6
Visit schedule and assessments .........................................................................................44
6.1
Information to be collected on screening failures..................................................52
6.2
Patient demographics/other baseline characteristics .............................................52
6.3
Treatment exposure and compliance .....................................................................53
6.4
Efficacy..................................................................................................................53
6.4.1
Spirometry.............................................................................................54
6.4.2
Asthma Control Questionnaire (ACQ-7) ..............................................54
6.4.3
Asthma Quality of Life Questionnaire (AQLQ-S +12) ........................54
6.4.4
Electronic Diary ....................................................................................55
6.4.5
Peak Expiratory Flow (PEF).................................................................55
6.4.6
Rescue Medication Usage.....................................................................55
6.4.7
Investigational Medication Usage.........................................................55
6.4.8
Worsening of asthma.............................................................................55
6.4.9
Asthma Exacerbation ............................................................................56
6.4.10
Appropriateness of efficacy assessments..............................................58
6.5
Safety.....................................................................................................................58
6.5.1
Physical examination ............................................................................58
6.5.2
Vital signs..............................................................................................59
6.5.3
Height and weight .................................................................................59
6.5.4
Laboratory evaluations..........................................................................59
6.5.5
Electrocardiogram (ECG) .....................................................................60
6.5.6
Serious asthma outcomes......................................................................61
 


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6.5.7
Pregnancy and assessments of fertility .................................................61
6.5.8
Appropriateness of safety measurements..............................................61
61
61
62
7
Safety monitoring..............................................................................................................62
7.1
Adverse events.......................................................................................................62
7.2
Serious adverse events...........................................................................................63
7.2.1
Definition of SAE .................................................................................63
7.2.2
SAE reporting........................................................................................64
7.2.3
Pneumonia reporting.............................................................................65
7.3
Liver safety monitoring .........................................................................................65
7.4
Pregnancy reporting...............................................................................................66
8
Data review and database management.............................................................................67
8.1
Site monitoring ......................................................................................................67
8.2
Data collection.......................................................................................................67
8.3
Database management and quality control............................................................67
8.4
Data Monitoring Committee..................................................................................68
8.5
Adjudication Committee........................................................................................69
8.6
Advisory Board......................................................................................................69
9
Data analysis......................................................................................................................69
9.1
Analysis sets ..........................................................................................................69
9.2
Patient demographics and other baseline characteristics.......................................70
9.3
Treatments .............................................................................................................70
9.4
Analysis of the primary variable............................................................................71
9.4.1
Primary variable....................................................................................71
9.4.2
Statistical model, hypothesis, and method of analysis..........................71
9.4.3
Handling of missing values/censoring/discontinuations.......................72
9.4.4
Multiplicity adjustment .........................................................................72
9.4.5
Supplementary analysis.........................................................................72
9.5
Key secondary variable..........................................................................................72
9.6
Analysis of secondary variables ............................................................................73
9.6.1
Efficacy variables..................................................................................73
9.6.2
Safety variables .....................................................................................76
9.6.3
Safety monitoring analysis....................................................................78
78
 


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79
9.7
Sample size calculation..........................................................................................79
10 Ethical considerations........................................................................................................79
10.1
Regulatory and ethical compliance........................................................................79
10.2
Informed consent procedures.................................................................................79
10.3
Responsibilities of the investigator and IRB/IEC..................................................80
10.4
Publication of study protocol and results...............................................................80
10.5
Quality control and quality assurance....................................................................80
11 Protocol adherence ............................................................................................................81
11.1
Protocol amendments.............................................................................................81
12 References .........................................................................................................................82
13 Appendices ........................................................................................................................83
Appendix 1: Instructions for Use of Concept1.........................................................................83
Appendix 2: Instructions for Use of Twisthaler®.....................................................................88
Appendix 3: How to Use an Accuhaler®/ Diskus®...................................................................91
Appendix 4:  Spirometry Guidance..........................................................................................95
Appendix 5: ACQ-7..................................................................................................................98
Appendix 6: AQLQ-S +12 .......................................................................................................99
Appendix 7: Patient Asthma Control eDiary..........................................................................103
Appendix 8: Liver Event and Laboratory Trigger Definitions and Follow-up 
Requirements...................................................................................................................104
Appendix 9: ICS Dose Level..................................................................................................106
List of tables
Table 5-1
Prohibited Asthma-Related Medications ..............................................38
Table 5-2
Prohibited Medications .........................................................................39
Table 5-3 
Medications Allowed Under Certain Conditions..................................39
Table 5-4
Table of Assessment for Patients who Discontinue Study 
Treatment Prematurely..........................................................................42
Table 6-1
Assessment schedule.............................................................................46
Table 6-2
Timed Assessment** ............................................................................51
Table 8-1
Liver Event and Laboratory Trigger Definitions ................................104
Table 8-2
Follow Up Requirements for Liver Events and Laboratory Triggers.104
Table 9-1
Low, Medium and High Daily Doses of Inhaled 
Glucocorticosteroids for Adults and Adolescents (12 years and 
older) (GINA 2016).............................................................................106
 


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List of figures
Figure 3-1
Study Design .........................................................................................24
 


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List of abbreviations
ACQ
Asthma Control Questionnaire
AE
Adverse Event
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AQLQ
Asthma Quality of Life Questionnaire
b.i.d.
twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CFR
Code of Federal Regulations
CHMP
Committee for Medicinal Products for Human Use
COPD
Chronic Obstructive Pulmonary Disease
CPO
Country Pharma Organization
CRO
Contract Research Organization
DALYS
Disability-Adjusted Life Years
DMC
Data Monitoring Committee
DS&E
Drug Safety and Epidemology
eCRF
Electronic Case Report/Record Form
eDiary
Electronic Diary
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA
European Medicines Agency
ER
Emergency Room
ERS
European Respiratory Society
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FEF
Forced Expiratory Flow
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GTL
Global Trial Leader
hCG
Human Chorionic Gonadotropin
HV
Healthy Volunteer
IgE
Immunoglobulin E
IB
Investigator Brochure
ICH
International Conference on Harmonization of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroid
 


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IEC
Independent Ethics Committee
i.v.
Intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra Uterine Device
IUS
Intra Uterine System
IVRS
Interactive Voice Response System
LABA
Long Acting Beta-2 Agonist
LAMA
Long Acting Muscarinic Antagonist
LFT
Liver Function Test
LTRA
Leukotriene Receptor Antagonist
LS Mean
Least squares mean
MDDPI
Multi dose dry powder inhaler
MDI
Metered Dose Inhaler
MF
Mometasone Furoate
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measurements
NYHA
New York Heart Association
OC/RDC
Oracle Clinical/Remote Data Capture 
o.d.
Once a day
p.o.
Oral(ly)
PDCO
Pediatric Committee of the European Medicines 
Agency
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PRO
Patient Reported Outcome
PSD
Premature patient discontinuation
QTc
Corrected QT interval
REB
Research Ethics Board
SABA
Short Acting Beta-2 Agonist
SAE
Serious Adverse Event
SAMA
Short Acting Anticholinergics
SCS
Systemic Corticosteroids
SDDPI
Single Dose Dry Powder Inhaler
SoC
Standard of Care
SMQ
Standard MEDRA Query
WHO
World Health Organization
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
WHO
World Health Organization
WoC
Withdrawal of Consent
 


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Glossary of terms
Dosage
Dose of the study treatment given to the patient in a time unit (e.g.,
100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g., prior to starting any of the procedures 
described in the protocol)
Epoch
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up
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
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Patient ID 
A unique number assigned to each patient upon signing the informed 
consent 
Protocol
A written account of all the procedures to be followed in a trial, which 
describes all the administrative, documentation, analytical and clinical 
processes used in the trial.
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug Run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Patient Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient 
does not want to participate in the study any longer, and does not want 
any further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained 
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Amendment 2
Amendment rationale
The assumptions for CQVM149B2303 key secondary endpoint,
Asthma Control 
Questionnaire-7 (ACQ-7) treatment difference, were originally based on data from 
CQMF149A2210. In study CQMF149A2210, the observed mean difference after 12 weeks of 
treatment (indacaterol acetate and mometasone furoate (QMF) combination therapy versus 
mometasone furoate (MF)
monotherapy) was -0.21 with 95% confidence interval 
(-0.28, -0.15). Based on the upper limit of the confidence interval, a treatment difference 
of -0.15 was chosen as a conservative estimate, which was used to determine the sample size of 
CQVM149B2303.
However, upon recent evaluation of the treatment difference of 
CQMF149A2210, it was decided to adopt an ACQ-7 treatment difference of -0.18. This 
treatment difference is the upper limit of the one-sided 80% confidence interval and more 
appropriately reflects the expected improvement in ACQ-7 for the patient population of 
CQVM149B2303. Reflecting the revised assumptions, the sample size re-estimation has 
allowed for a reduction from 1000 to approximately 750 patients.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The described changes pertaining to the aforementioned amendment rationale are implemented 
throughout the protocol.
In addition, the following clarifications/additions are included in this protocol amendment:
1. Section 3.1, clarified that starting with the Run-in epoch (Visit 101), patients will record 
Peak Expiratory Flow Rate (PEF) twice daily; clarified enrolled patients are randomized 
patients; clarified Visit 204 (Week 12) should take place within a 4 day window and if this 
is not possible, the sponsor should be notified.
2. Section 4, updated sample size to approximately 750 males and females with a diagnosis of 
asthma ≥ 12 and ≤ 75 years of age; updated adolescent sample size to approximately 50 
patients 
;
clarified that adolescents are ≥ 12 and < 18 years of age; updated anticipated number of 
patients to be screened to reach updated sample size with 1:1 randomization in the two 
treatment groups. 
3. Section 4.1, updated inclusion criterion 5 to clarify that adults must be symptomatic at V101 
and V102.
4. Section 4.2, updated exclusion criterion 2 for adolescents (≥ 12 and < 18) 
 
 to exclude adolescents that have had an asthma attack/exacerbation requiring 
systemic steroids or hospitalization (> 24 hours) or emergency room visit (≤24 hours)
requiring systemic corticosteroids within 6 months, prior to Visit 1.
5. Section 4.2, updated exclusion criterion 33 due to template changes for highly effective 
contraception.; this no longer includes barrier methods of contraception.
6. Section 6, clarified that sponsor should be notified if Visit 204 (Week 12) should take place 
outside of the 4 day window; clarified PEF measurements are recorded twice daily. 
 


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7. Table 6-1, clarified Visit 204 (Week 12) should take place within a 4 day window and if 
this is not possible, the sponsor should be notified.
8. Table 6-2, clarified that timed assessment windows are approximate.
9.
 
10. Section 6.3 & Section 6.4.4, clarified that the data from the electronic Diary (eDiary) will 
be reviewed by study site personnel at each visit.
11. Section 6.4.2, clarified that the ACQ-7 should be completed at the study site.
12. Section 6.5.5, clarified that electrocardiograms (ECG) should be recorded after 10 minutes 
rest in the supine position to ensure a stable Baseline.  Also clarified that only one printed 
copy needs to be kept by the study site. 
13.
 
14. Section 9, updated dosing time window to dosing time for clarity throughout this section. 
15. Section 9.2, clarified that percentage of predicted forced expiratory volume in one second 
(FEV1) 
will be summarized by treatment group.
16. Section 9.4.2, clarified that the between-treatment comparison will be carried out using the 
adjusted mean (least squares mean (LS mean)) difference based on the treatment main effect 
and the coefficient for the treatment-by-visit interaction for Day 85.
17. Section 9.4.5, updated section title from ‘supportive’ to ‘supplementary’ analysis and 
clarified that the same mixed model for repeated measure (MMRM) used in the primary 
analysis will be also performed on the Per-Protocol Set (PPS) to assess the treatment effect 
in protocol adherers.
18. Section 9.6.1.1, clarified that trough FEV1 at Day 2 visit will be analyzed using the same 
MMRM as specified for the primary analysis, i.e., the visit factor will include all available 
visits as a factor and between-treatment comparison will be carried out using the adjusted 
mean (least-square mean) difference based on the treatment main effect and the coefficient 
for the treatment-by-visit interaction for the respective visit and treatment.
19. Section 9.6.1.2, clarified that the analysis results for all post-baseline visits, obtained from 
the MMRM for the key secondary endpoint ACQ-7, will be displayed. In addition, analysis 
for change from baseline in the ACQ-7 will be performed.
20.
 
21. Section 9.7, updated secondary endpoint ACQ-7 treatment difference to -0.18 between 
QMF149 versus
MF, assuming a standard deviation of 0.80 based on study 
CQMF149A2210; updated sample size and power accordingly. 
22. Section 9.7, clarified sample size calculation is performed in PASS Software.
23. Section 9.7, removed reference to CQMF149E2201 and CQMF149E2203
24. Section 9.7 and References Section, removed references to Kerstjens HAM et al 2012 and 
Kerstjens et al 2015.
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.
 


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Summary of amendments issued before this amendment:
Amendment 1
Amendment rationale
1. Adjust the approach to asthma worsening eDiary alerts during the Run-in epoch (Section 
6.4.8). Currently, it is stated in the protocol, that if an asthma worsening alert is observed 
during the Run-in epoch, the patients must be discontinued regardless of clinical context 
and investigator judgment. This protocol amendment will allow investigators to use 
their discretion in determining the clinical significance of asthma worsening eDiary 
alerts during the Run-in epoch. This will allow the investigator to make the most 
appropriate decision as to whether patients may continue in the study or be discontinued. 
If asthma worsening alert is confirmed as clinically significant by the investigator, 
patients should be discontinued. A combination of eDiary alerts and investigator
judgment will help ensure that the most appropriate patients are enrolled in the study, 
while maintaining rigorous monitoring and assessment of patient safety.
2. Provide additional opportunity for patients to achieve reversibility. This includes a 
change to the text to allow spacer use for reversibility testing as well as increasing the 
time period for historical reversibility from 1 year to 2 years.
3. Provide more clarity in various sections of the protocol to address queries raised by 
various countries and health authorities.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The described changes pertaining to the aforementioned amendment rationale are implemented 
throughout the protocol.
In addition, the following clarifications/additions are included in this protocol amendment:

Updated “Other Secondary Objectives” for exacerbations to retain only the highest
level endpoints (Section 2.3).

Reference to GINA 2015 guidelines updated to GINA 2016 guidelines (Section 1.1, 
Section 3.1, Section 3.6, inclusion criterion 7 in Section 4.1, and exclusion criterion 20 
in Section 4.2) to allow repeat spirometry retest at both Visit 101 and 102, modified
timing for reversibility and modified the use of historical reversibility from 1 year to 2 
years.

Added clarification to inclusion criterion 7 that if patient fails spirometry repeatability 
at Visit 102, patient can be re-screened (Section 4.1).

Specified “severe” narcolepsy and/or insomnia in exclusion criterion 24 (Section 4.2).

Clarified spacer devices not permitted “for rescue medication” in exclusion criterion 28
(Section 4.2), however spacer devices are only permitted during reversibility testing 
based on investigator discretion (inclusion criterion 8, Section 4.1).

Adjusted wording from “completion” to “stopping” in exclusion criterion 33 (Section 
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
Clarified LAMA exclusion criteria: LAMA washout criteria in Table 5-1 removed and 
replaced with a new exclusion criterion 34 (Section 4.2) to exclude patients who were 
treated with LAMA 3 months prior to Visit 1.

Updated exclusion criterion 5 (Section 4.2) to clarify patient would be excluded if 
having respiratory tract infection or asthma worsening “as determined by investigator”.

Added clarification on myocardial infarction in exclusion criteria 13 and 16 (Section 
4.2).

Updated exclusion criterion 16 (Section 4.2) to clarify that patients having clinically 
significant abnormality in ECG at unscheduled visits between Visit 1 and Visit 102 will 
be excluded.

Clarified that countries who do not have fluticasone 100 µg b.i.d delivered by 
Accuhaler® or 125 µg b.i.d by MDI can use fluticasone propionate in an alternative 
formulation at an equivalent dose strength.

The word masterscope was replaced with “equipment provided by spirometry vendor”.

Clarified in Section 3.1 that screening period is to ensure wash-out of prior asthma 
medication as per protocol and that therefore the time between Visit 1 and Visit 101 
may be shorter than 2 weeks depending on the wash-out required.

Updated Section 5.5.4 for the purpose of drug accountability and clarified that study 
medication can be taken regardless of time of sleep, meals, and other activities.

Clarified wording and provided differentiation between monoclonal antibodies and IL-
5 inhibitors in Table 5-1.

Added a new safety criteria in Discontinuation of study treatment (Section 5.6.2).

Updated the visits where Survival Status eCRFs are visible (Table 5-4 and Table 6-1) 
to be in line with the clinical database.

Provided clarification in Section 5.6.3 regarding early study discontinuation visits for 
patients who withdrew consent from the study.

Provided clarification on ACQ-7 questionnaire (Section 6.4.2) regarding the questions 
that needs to be completed by the patient and those that need completion by investigator.

Clarified both exclusion criterion 5 (Section 4.2) and Section 6.4.8 to indicate that 
discontinuation is at the investigator’s discretion when the eDiary asthma worsening 
alert criteria are met during Run-in epoch in accordance with Section 6.4.8. This 
amendment will allow the investigator to incorporate clinical judgment into the context 
of eDiary alerts during Run-in epoch to assess clinical significance of the asthma 
worsening alert and decide on best course of action and the treatment for patient.

Aligned Section 9 with the statistical analysis plan.
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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Protocol summary
Protocol number
CQVM149B2303
Title
A multi-center, randomized, 12-week treatment, double-blind study 
to assess the efficacy and safety of QMF149 (150/80 microgram) 
compared with mometasone furoate (MF)
Twisthaler®
(200
microgram) in adult and adolescent patients with asthma
Brief Title
Efficacy and safety of low dose QMF149 (150/80 microgram) 
compared with MF Twisthaler® (200 microgram) in 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 demonstrate superiority of QMF149 
vs. MF monotherapy in terms of trough FEV1 at Week 12 in patients 
with asthma to demonstrate the contribution of the LABA 
component in the low dose QMF149 fixed dose combination.
Primary Objective 
The primary objective of this study is to demonstrate the superiority 
of QMF149 150/80 microgram o.d. (in the evening) delivered via 
Concept1 compared with MF 200 microgram o.d. (in the evening) 
delivered via Twisthaler® in terms of trough FEV1 after 12 weeks of 
treatment in patients with asthma, who are on low dose ICS 
monotherapy or low dose ICS/LABA.
Secondary Objectives
The key secondary objective of this study is to demonstrate the 
superiority of QMF149 150/80 microgram (µg) to MF 200
microgram (µg) o.d. in terms of ACQ-7 after 12 weeks of treatment.
The other secondary objectives include: lung function parameters 
(e.g., trough FEV1 at additional time points, peak FEV1, PEF) rescue 
medication use, days without symptoms, and asthma quality of life 
(AQLQ).
Study Design
A 12-week multi-center, randomized, double-blind, double-dummy, 
parallel-group, active controlled study.
Population
The study population will consist of approximately 750 males and 
females with asthma (approximately 50 adolescents). Patients will 
be stratified according to prognostic factors of age and region.
Key Inclusion Criteria
Adult patients with asthma who are symptomatic at screening
despite treatment with existing therapy. Patients must have ACQ-7 
score ≥1.5 at Visit 101 and at Visit 102 (i.e., inadequately 
controlled).
 


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Adolescent (≥12 to < 18 years old) patients with asthma:

Patients taking low dose ICS (without LABA), who are 
symptomatic at screening despite treatment with low dose 
ICS. These patients must have ACQ-7 score ≥1.5 at Visit 
101 and at Visit 102 (i.e., inadequately controlled).

Patients taking low dose ICS / LABA, may be included only 
if ACQ-7 score ≥1 and < 1.5 at Visit 101(i.e., adequately 
controlled). However, ACQ-7 score must be ≥1.5 at Visit 
102.
Pre-dose FEV1 ≥60% and < 90% of the predicted normal value.
FEV1 reversibility ≥12% and ≥ 200 mL.
Key Exclusion 
Criteria
Pregnant women/nursing mothers.
Women of child bearing potential (unless using adequate
contraception).
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.
Current smokers
who smoked or inhaled tobacco products 
(including electronic cigarettes) within the 6 month period prior to 
Visit 1 or ex-smoker with ≥10 pack years smoking history.
Patients who have had an asthma attack/exacerbation requiring
systemic steroids or hospitalization (> 24 hours) or emergency room
visit (≤24 hours) as follows:

For adults: within 6 weeks of Visit 1 (Screening). If patients 
experience an asthma attack/exacerbation requiring systemic 
steroids or emergency room visit between Visit 1 and Visit 
102 they may be re-screened 6 weeks after recovery from the 
exacerbation.

For 
adolescents: 
Severe 
asthma 
attack/exacerbation 
requiring systemic corticosteroids in the last 6 months, OR
hospitalization (>24 hours) due to severe asthma 
attack/exacerbation requiring systemic corticosteroids in the 
last 6 months, OR emergency room visit (≤24 hours) due to 
severe asthma attack/exacerbation requiring systemic 
corticosteroids within the last 6 months
Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption or with 
known intolerance to lactose or milk products. 
 


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Study Treatment

QMF149 150/80 µg Concept1 once-daily/ and Placebo to MF 
200 microgram Twisthaler® once-daily

MF 200 µg Twisthaler® once-daily/ and Placebo to QMF149 
150/80 microgram Concept1 once-daily
Key Efficacy 
Assessments
Spirometry
ACQ-7
AQLQ
Asthma symptoms based on electronic diary (eDiary)
Peak expiratory flow
Rescue medication use
Worsening of asthma
Asthma exacerbations
Key Safety 
Assessments
Physical examination, oropharyngeal examination 
Vital signs
Hematology, blood chemistry, urinalysis
Evening plasma cortisol 
Electrocardiogram (ECG)
Adverse events (AEs) including asthma exacerbations and serious 
adverse events (SAEs)
Pregnancy (female patients)
Serious 
asthma 
outcomes 
(asthma-related 
hospitalizations, 
intubations or deaths)
Data Analysis
The primary variable is trough FEV1 after 12 weeks of treatment.
The key secondary variable is ACQ-7 after 12 weeks of treatment. 
The primary variable will be analyzed using a mixed model for 
repeated measurement (MMRM) on the Full Analysis Set. 
The model will contain treatment, age (≥12 to < 18 or ≥18 years), 
region, visit (Days 2 and 85), and treatment-by-visit interaction as 
fixed effects with baseline FEV1 measurement, baseline-by-visit 
interaction, FEV1 prior to inhalation and FEV1 within 15 to 30 min 
post inhalation of salbutamol/albuterol (components of short acting 
beta-2 agonist reversibility) as covariates, and center nested within 
region as a random effect. The within-patient correlation will be 
 


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modeled using an unstructured covariance matrix in the mixed 
model. 
The same MMRM will be used for ACQ-7 except to include the 
appropriate baseline covariate. 
A hierarchical testing procedure will be applied to control the type-
I error rate for the primary and the key secondary endpoints, i.e., the 
key secondary endpoint ACQ-7 will be tested only if the primary 
endpoint (trough FEV1) is significant at the 2-sided 0.05 level.
Key Words
QMF149, Mometasone furoate (MF), Asthma, GINA
 


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1
Introduction
1.1
Background
Asthma is a chronic inflammatory disorder of the airways associated with hyper responsiveness 
of airways that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and 
coughing, particularly at night or in the early morning. These episodes are usually associated 
with widespread but variable airflow obstruction within the 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. Although exacerbations of 
asthma are episodic, inflammation is chronic (GINA 2016).
Despite existing therapies there is still significant unmet medical need in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years (DALYs) are lost annually due to asthma, 
representing 1% of the total global burden. Annual worldwide deaths have been estimated at 
250,000 (Masoli 2004).
Global Initiative for Asthma guidelines recommend use of low dose ICS (inhaled corticosteroid)
controller treatment for step ≥ 2 while preferred controller treatment for step ≥ 3 is the 
combination of ICS/LABA (inhaled corticosteroid / long-acting beta2-agonist) with a low dose 
ICS or mid/high dose ICS monotherapy (GINA 2016).
Fixed dose combination (FDC) products containing a LABA plus 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 a day (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 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 (Breezhaler®). Concept1 is the approved inhalation device for use with indacaterol 
maleate and other Novartis COPD inhalation therapies.
Background data for Indacaterol and Mometasone furoate monotherapies:
Indacaterol
Indacaterol maleate, a long-acting beta2-agonist, delivered via the Concept1 device in a single 
dose dry powder inhaler (SDDPI) (Onbrez® Breezhaler®) is approved in over 110 countries 
worldwide for the once daily maintenance bronchodilator treatment of airflow obstruction in 
patients with COPD. In addition to the extensive evidence for indacaterol maleate delivered via 
the Concept1 device in COPD, there are clinical data 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 acetate / MF) delivered by the 
Twisthaler® device in asthma patients. Indacaterol acetate delivered by Twisthaler® has been 
 


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studied in healthy volunteers (HV), adult patients with COPD and adult and adolescent patients 
with asthma. 
Two studies (CQMF149E2203 and CQAB149B2357) were conducted to support the selection 
of indacaterol 150 μg which is the proposed dose to be carried forward in the Phase III QVM 
program. Study CQMF149E2203 investigated two (2) doses of indacaterol acetate, 75 μg and 
150 μg delivered via Concept1 in adult patients with asthma and demonstrated superiority of 
treatment with indacaterol acetate 75 μg and 150 μg to placebo in terms of trough 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
PEF and rescue medication use compared with indacaterol acetate 75 μg. Both indacaterol 
acetate doses 150 μg and 75 μg treatments were safe and well tolerated.
A dose-ranging study CQAB149B2357 of indacaterol maleate in asthmatic patients 
demonstrated that a dose of 150 microgram o.d. was safe and effective. Furthermore, study 
CQAB149B2338, a 26-week study in asthmatic patients showed that indacaterol maleate at 
doses of 300 microgram and 600 microgram o.d. were 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 compared with the maleate salt without any impact on safety and 
comparable efficacy and systemic exposure (CQAB149D2301).
Mometasone furoate
Mometasone furoate (MF) is a corticosteroid and the active ingredient in the currently marketed 
product AsmanexTwisthaler® (mometasone furoate inhalation powder delivered via a multi-
dose dry powder inhaler (MDDPI)).
AsmanexTwisthaler® is currently indicated for the once or twice-daily maintenance treatment 
of persistent asthma in adults and adolescents > 12 years and, in the US, in children aged > 4 
years. AsmanexTwisthaler® is approved at doses of 100 µg, 200 µg and 400 µg (per delivered 
dose) up to a maximum daily dose of 800 µg for patients with severe disease, with preferred 
administration in the evenings. Merck is the Marketing Authorization Holder in 60 countries 
worldwide.
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 three 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 pharmacodynamic evaluation of efficacy in 
asthma patients in study CQMF149E2201 (Step 3). 
For Steps 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 microgram of 
MF in Concept1 device are comparable in strength to the approved doses of 200 microgram, 
400 microgram and 800 microgram (2 x 400 microgram) 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 microgram and 320 microgram delivered once daily via 
Concept1 showed comparable efficacy in trough FEV1 and slightly lower systemic exposure 
compared to MF doses of 200 microgram and 800 microgram (2 x 400 microgram) delivered 
once daily via Twisthaler® confirming the selected doses for MF Concept1 are appropriate for 
further QMF149 Concept1 development. 
Comparable MF Doses via Twisthaler® and Concept1
MF dose level
MF dose in Asmanex®
via Twisthaler®
MF dose in QMF149 
via Concept1 (Breezhaler®)
Low
200 µg
80 µg
Mid
400 µg
160 µg
High
800 µg
320 µg
1.2
Purpose 
The purpose of the trial is to evaluate efficacy and safety of QMF149 150/80 microgram o.d. 
delivered via Concept1 compared to MF 200 microgram o.d., delivered via Twisthaler® in terms 
of lung function and symptom control in poorly (i.e., inadequately) controlled asthma patients. 
This study will assess contribution of LABA as an add-on therapy to low dose ICS monotherapy.
2
Study objectives and endpoints
2.1
Primary objective
The primary objective of this study is to demonstrate the superiority of QMF149 150/80
microgram o.d. (in the evening) delivered via Concept1 compared with MF 200 microgram o.d. 
(in the evening) delivered via Twisthaler® in terms of trough FEV1 after 12 weeks of treatment
in adults and adolescents.
 


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2.2
Key Secondary objective
The key secondary objective is to demonstrate the superiority of QMF149 150/80 microgram
to MF 200 microgram o.d. in terms of ACQ-7 after 12 weeks of treatment.
2.3
Other secondary objectives
Other secondary objectives will evaluate the efficacy of QMF149 150/80 microgram versus MF 
200 microgram o.d. in terms of:
Lung function:

Trough FEV1 at Day 2 of treatment period (defined as the mean of 23 hours 15 min and 23 
hours 45 min FEV1 values post dose of Day 1)

Pre-dose FEV1 (defined as the mean of -45 min and -15 min FEV1 values pre-evening 
dose) at 4 weeks

Forced Vital Capacity (FVC) and Forced Expiratory Flow between 25% and 75% of FVC 
(FEF25-75) over 12 weeks

Morning and Evening Peak Expiratory Flow Rate (PEF) over 4 and 12 weeks of treatment
Symptoms and asthma control:

Percent of patients achieving the minimal important difference (MID) in ACQ-7 (i.e., at
least 0.5 improvement from baseline) at Week 12

Percentage of asthma symptoms free days, the percentage of nights without nighttime 
awakenings, and the percentage of mornings without symptoms on awakening as recorded 
by daily electronic Diary (eDiary) over 12 weeks of treatment

Asthma control as assessed by the Asthma Control Questionnaire (ACQ-7) at Week 4

Rescue salbutamol/albuterol usage (mean daily, nighttime and daytime use) from eDiary
recordings over 12 weeks of treatment

Percentage of rescue medication free days over 12 weeks of treatment period
Exacerbations:
The exacerbation data collected during 12 weeks of treatment period will be assessed with 
respect to the parameters described below. The exacerbation categories are: All exacerbations 
(mild, moderate, severe) and the combination of moderate or severe:

Time to first asthma exacerbation by exacerbation category

Annual rate of asthma exacerbations by exacerbation category

Quality of life as assessed by Asthma Quality of Life Questionnaire (AQLQ) over 12 
weeks of treatment period
The following safety and tolerability endpoints will be evaluated:

Cumulative incidence of the composite endpoint of serious asthma outcomes (i.e.,
asthma-related hospitalization, asthma-related intubation, or asthma-related death) 
over 12 weeks of treatment 

AEs, vital signs, electrocardiogram (ECG), and laboratory analysis (hematology, blood 
chemistry including glucose and potassium, urinalysis, evening plasma cortisol) over 
12 weeks of treatment 
 


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3
Investigational plan
3.1
Study design
This study uses a 12-week treatment, randomized, double-blind, double-dummy, parallel-group 
design. The 12 week treatment epoch will be followed by a 30 day Follow-up epoch. There is 
a screening visit (Visit 1) where informed consent is obtained and current asthma and other non-
asthma medications are reviewed. Where appropriate, concurrent asthma and other medications 
are adjusted at this visit and prohibited asthma medications are replaced with permitted asthma 
medications for use throughout the study.
All patients should have been on a stable dose of inhaled low dose corticosteroids (with or 
without LABA) for at least 1 month prior to Visit 1. Once the concurrent medications comply 
with the requirements of the study (Section 5.5.7 and Section 5.5.8) patients will enter a Run-
in epoch at Visit 101. 
At Run-in Visit 101 all patients will receive an open-label fluticasone propionate 100 µg b.i.d. 
delivered via Accuhaler® (if not available in a specific country, open-label fluticasone 
propionate 125 µg b.i.d. via MDI inhaler or fluticasone propionate in an alternative formulation 
at an equivalent dose strength ) for use throughout the Run-in epoch which will be stopped at
Visit 102 (end of Run-in epoch) (Figure 3-1).The screening epoch between Visit 1 and Visit 
101 is used to ensure washout of prior asthma medication. Depending on prior asthma 
medication and washout requirements, the period between Visit 1 and Visit 101 may be shorter 
than 2 weeks. At Visit 1 (Screening), all patients will be given salbutamol/albuterol to use as 
rescue medication throughout the study. They will be issued an electronic diary combined with 
Peak Flow (PEF) meter to record asthma symptoms and rescue medication use. After the end 
of the Screening epoch (maximum 2 weeks after Visit 1), starting with the Run-in epoch (Visit 
101), patients will record Peak Expiratory Flow Rate (PEF) twice daily. The Run-in epoch is 
three (3) weeks in duration and will be used to assess eligibility of the patients prior to entering
the treatment epoch and to collect baseline values for some variables.
Patient can enter the Run-in epoch provided inclusion criteria are met, including those for 
spirometry (pre-dose percent predicted FEV1, ATS/ERS criteria, and reversibility) as per 
spirometry equipment.
Patients who meet the eligibility criteria at Visit 102 will be randomized to one of following
two treatment groups with an equal (1:1) randomization ratio:

QMF149 150/80 microgram o.d. delivered via Concept1

MF 200 microgram o.d. delivered via Twisthaler®
 


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Randomized patients must have FEV1 between 60% and < 90% of predicted normal at both
Visit 101 and Visit 102 and they must qualify for treatment with low dose ICS plus LABA as 
per GINA 2016 guidelines. At Visit 102, all randomized patients must have ACQ-7 ≥1.5. Refer 
to Section 4.1 Inclusion Criteria for ACQ-7 requirements.
Visit 102 (end of Run-in) and Visit 201(Randomization) must take place sequentially on the 
same day. The assessments at Visit 102 should be performed prior to administration of the first 
dose of study medication (Visit 201). Reversibility should NOT be done at Visit 102 (Table 6-
1). Randomized patients will enter the 12-week Treatment epoch. All patients will receive both 
Concept1 and Twisthaler® inhalers (double-blind and double-dummy design). During the 
treatment epoch, patients will be instructed to inhale study medication once daily in the evening 
(between 5:00 pm and 8:00 pm).
Patients will be followed at regular intervals throughout the 12 week treatment epoch to assess 
the safety and efficacy of treatment, either by telephone or at clinic visits. Clinic visits are 
scheduled to take place after 4, and 12 weeks. All clinic visits should occur as scheduled per
Table 6-1. Patients will be required to attend the clinic visits to perform trough measurements 
of lung function (24 hours post dosing) after the first dose of study medication (Visit 201) and 
after the dose of study medication administered at the clinic after 12 weeks of treatment (Clinic 
Visit 204). In case of logistical issues, Visit 204 (Week 12) should take place within a 4 day 
window. If this is not possible, the sponsor should be notified. 
Pre-dose FEV1 measurements will be assessed at Week 4. Telephone reviews of patients’ status 
will be conducted after 8 weeks of treatment. Telephone contact with patients may indicate that 
a clinic visit is necessary, in which case an unscheduled clinic visit should be arranged as soon 
as possible and should include safety assessment (AEs, concomitant medications review and 
unscheduled laboratory exams as appropriate).
A final telephone contact must be conducted at 30-days after last treatment date (telephone Visit 
301 or unscheduled visit safety call for patients who discontinue treatment earlier than 12 
weeks).
The first dose of study medication will be administered at the clinic in the evening (between 
05:00 pm and 08:00 pm) at Visit 201 (Day 1). 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 study medication on the days of the 
clinic visits, as these doses will be administered at the clinic under the supervision of study 
personnel. 
 
 
 


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Figure 3-1
Study Design
1 Please refer to Table 5-1 for details of adjustments to concomitant asthma medications and specified 
minimum washout periods prior to Run-in (Visit 101) and/or Randomization (Visit 201). For Run-in
medication, fluticasone propionate 100 µg b.i.d should be delivered via Accuhaler® or fluticasone 
propionate 125 µg b.i.d. via Metered Dose Inhaler (MDI) will be accepted. In case it is not available in 
a particular country, fluticasone propionate in an alternative formulation at an equivalent dose strength
may be used.
3.2
Rationale for study design
In order to optimize the rigor of the study and minimize bias, a randomized, double-blind 
parallel group design is used. This design is appropriate to determine the benefit of the addition 
of a LABA in a fixed dose combination with low dose ICS as compared to low dose ICS 
monotherapy. The study design does not include a placebo control, as this would not be 
considered ethical in this population of asthmatic patients who are symptomatic.
The primary objective of the trial is to evaluate the efficacy and safety of QMF149 
150/80 microgram o.d. via Concept1 compared to MF 200 microgram via Twisthaler® in poorly 
(i.e., inadequately) controlled symptomatic patients as measured by trough FEV1. In addition, 
secondary endpoints will provide data related to asthma control (ACQ), rescue medication use, 
Treatment 
Epoch 
(12 weeks)
End of Run-in Visit 102
Randomization Visit 201
Screening
Epoch
(2 weeks)
Day 1 to Day 85
Run-in
Epoch1
(3 weeks) 
QMF149 150/80 µg o.d via Concept1 (and 
Placebo to MF 200 µg o.d. via Twisthaler®)
                         OR         
MF 200 µg o.d via Twisthaler® (and placebo 
to QMF149 150/80 µg o.d via Concept1)
Follow-up 
Epoch
(30 days)
Visit 1
Visit 
101
Visit 301
Fluticasone 
propionate 
100 µg b.i.d
Rescue Medication Available
Study completion Visit 204
Day -35 to 
Day -21
Day -21 to 
Day -1
 


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asthma exacerbations, quality of life, and safety of the studied QMF149 dose in this specific 
asthma patient population. 
The analyses will be performed in a sample size of approximately 750 patients. The patient 
population will be described in more detail in the Section 4.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
This study is a pivotal, multi-center, randomized, double-blind, double-dummy, parallel-group, 
Phase III study with a 12-week treatment epoch which is required to assess the safety and 
efficacy of QMF149 in asthma. The primary endpoint will be evaluated over 12 weeks. The 
dose regimen/route of administration of QMF149 selected (150/80 microgram delivered via 
Concept1) is based on the findings of previous studies identifying effective and safe doses of 
the individual components of the FDC, indacaterol and MF) (Section 1.1).
The 12 week duration is considered adequate to demonstrate improvements in the primary 
endpoint based on the known pharmacodynamic properties of the components of each fixed-
dose combination and precedent of other inhaled combination products in asthma.
3.4
Rationale for choice of comparator
MF was selected as the comparator as it is the ICS monocomponent in QMF149 combination 
formulation and is necessary in order to demonstrate the additional benefit of a LABA 
(indacaterol acetate 150 microgram) in the QMF149 combination (Appendix 9) as compared to 
MF monotherapy in patients whose asthma is inadequately controlled with ICS alone.
Furthermore, MF in Twisthaler® formulation is approved for treatment in asthma.
The MF inhalation powder formulation is marketed as a MDDPI called Asmanex® Twisthaler®
for the treatment of asthma and is currently approved in the Unites States for the treatment of 
asthma in adults and children ≥4 years of age and is approved in over 55 countries world-wide 
for the treatment of asthma in adults and adolescents ≥ 12 years old. The MF 200 microgram
o.d. delivered via Twisthaler® is comparable to MF 80 microgram o.d. delivered via Concept1 
(Section 1.1). 
3.5
Purpose and timing of interim analyses/design adaptations
No interim analysis for efficacy is planned. It is planned that the independent Data Monitoring 
Committee (DMC) will review semi-blinded (i.e., treatment groups names as A and B) safety 
data (Section 8.4). The details of the information flow, confidentiality and specific analysis will 
be available from the DMC Charter.
3.6
Risks and benefits 
ICS/LABA fixed dose combinations are frequently used as controller medications and are 
foundation therapy in GINA step ≥3 (GINA 2016).
QMF149 (indacaterol 150 microgram as an FDC with three doses of MF: 80 microgram, 160 
microgram or 320 microgram) is a new once daily ICS/LABA FDC in development for asthma 
for which a Phase II development was recently successfully completed.
 


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There is evidence of efficacy and safety of the mono components indacaterol and MF in asthma 
and COPD (indacaterol). In addition, supportive efficacy and safety information was gained 
from the early QMF149 development in the Twisthaler® device (see Section 1.1) and QMF149 
Investigator Brochure. To further investigate the overall risk and benefit evaluation of QMF149 
FDC delivered by Concept1, an MF 80 microgram dose in combination with indacaterol acetate 
(QMF149) is selected for further evaluation in Phase III. 
In one large Phase II event driven trial with a duration up to 68 weeks in over 1500 moderate 
to severe asthma patients including adolescents (12-17 years of age), indacaterol/mometasone 
500/400 microgram delivered by Twisthaler® comparable to indacaterol 150/160 microgram
delivered by Concept1 showed a favorable efficacy and safety profile over MF alone (Beasley 
et al 2015). 
Further efficacy and safety trials in Phase II included different indacaterol doses on background 
of MF in Concept1 in moderate to severe asthma (QMF149E2203), a device bridging study 
with MF in Concept1 (QMF149E2201) and an efficacy and safety study with QMF149 in 
Concept1 in moderate to very severe COPD patients (QMF149F2202). The studies showed 
statistically significant improvements in lung function and symptomatic endpoints including 
exacerbations and confirmed a favorable and robust efficacy and safety profile in Phase II.
In this Phase III study, randomized patients will receive either QMF149 or MF throughout the 
treatment epoch (12 weeks). Throughout the trial, patients will be given access to rescue 
medication (i.e., short acting beta-2agonist (SABA)), thus limiting the risk of significant 
asthmatic AEs. At no time during the study will any patient be without treatment for asthma.
The risk to the patients in participating in this study is that QMF149 is under development and 
therefore unexpected safety issues may be possible in patients randomized to QMF149 
treatment (Section 5.6.2). This risk will be minimized by adherence to the patient eligibility 
criteria as stated in the study protocol and by close clinical monitoring of all patients. 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 most current QMF149 Investigator’s Brochure.
There is evidence that LABA treatment used alone in asthma might cause asthma exacerbations 
(FDA warning, Advair® Diskus® prescription information). 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, depending on treatment arm).
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 12-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 (twice daily) 
 


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measurements at regular intervals throughout the study will help assess status of the patient’s 
asthma symptom control. eDiary data will be transmitted electronically from the device to the 
investigator daily. Therefore, investigators will be able to monitor the patients closely 
throughout the study in case of an early indication of worsening symptoms.
In the event of worsening asthma symptoms, guidance to manage potential worsening of asthma 
symptoms is available to the investigators in accordance with 6 guideline recommendations. 
Patients will be provided with clear written instructions on contacting the investigator in case 
of worsening of their symptoms.
The investigator must discontinue study treatment 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. Patients 
will be followed up for safety for 30 days after they have stopped study participation (defined 
as time of last dose of study drug taken or last visit whichever is later) 
In summary, based on the available data of QMF149 and the efficacy and safety data of the 
marketed monotherapy components, it is anticipated that QMF149 150/80 microgram will have 
a favorable benefit to risk profile in this patient population with asthma.
4
Population
The study population will consist of approximately 750 males and females with a diagnosis of 
asthma ≥12 and ≤75 years of age. Approximately 50 patients enrolled in the study will be 
adolescents (≥ 12 and < 18).
Adolescent patients with a diagnosis of asthma should be symptomatic on low dose ICS (ACQ-
7 ≥ 1.5). Patients more adequately controlled taking low dose ICS/LABA (ACQ-7 score ≥1 
and < 1.5) may also be included, however they can only be enrolled to double-blind treatment 
if ACQ-7 score is ≥1.5 at the time of randomization. The ACQ-7 thresholds for level of control 
are consistent with published literature (Juniper 2006). Although Juniper does not specifically 
define ‘adequate control’, it can be reasonably estimated to be around 1, which is considered 
the crossover point between ‘well controlled’ and ‘not well controlled’ asthma (Juniper 2006); 
therefore a range of ≥1 to < 1.5 is considered acceptable as an appropriate range for ‘adequately’ 
controlled asthma.
Adult patients with a diagnosis of asthma should be symptomatic on low dose ICS or low dose 
ICS/LABA with ACQ-7 score ≥ 1.5. 
It is anticipated 1370 patients will need to be screened in order to randomize approximately 750
patients into the two treatment groups with a randomization ratio of 1:1 (i.e., approximately 375
patients per treatment group). At least 676 randomized patients (338 per treatment group) are 
needed to complete the study.
Drop-outs after randomization will not be replaced. This study will enroll multi-nationally and 
patients will be stratified according to prognostic factors of age (≥ 12 to < 18 years or ≥18) and 
non-prognostic factor region to achieve improved homogeneity within each stratum.
 
 


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4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained from all patients before any study-related 
assessment is performed. Patients below the legal age of consent are required to have the 
Parental Informed Consent signed by the patient’s parent/legal guardian; adolescents are 
required to sign the Assent Form.
2. Male and female adolescents aged ≥12 to < 18 years old (depending upon regulatory and/or 
institutional Review Board (IRB)/Independent Ethics Committee (IEC)/REB approval 
and/or country participation) and male and female adults aged ≥ 18 years and ≤75 years
old.
3. Patients with a documented diagnosis of asthma for a period of at least 3 months prior to 
Screening (Visit 1).
4. Patients who have used low dose ICS (Appendix 9), with or without another controller
therapy (i.e., LABA, Leukotriene Receptor Antagonist (LTRA)) at stable dose for at least 1 
month prior to Screening (Visit 1).
5. Adult patients must be symptomatic despite treatment with existing therapy. Patients must 
have ACQ-7 score ≥1.5 at Visit 101 and at Visit 102 (i.e., inadequately controlled).
6. Adolescent patients:
If taking low dose ICS (without LABA), patients must be symptomatic despite treatment 
with low doses of ICS. These patients must have ACQ-7 score ≥1.5 at Visit 101 and at Visit 
102 (i.e., inadequately controlled).
If taking low dose ICS / LABA, patients may be included only if ACQ-7 score ≥1 and <1.5 
at Visit 101 (i.e., adequately controlled). However, ACQ-7 score must be ≥1.5 at Visit 102, 
directly prior to randomization.
7. Pre-bronchodilator FEV1 ≥60% and < 90% of the predicted normal value for the patient
according to ATS/ERS criteria after withholding bronchodilators at both Visits 101 and 102.
Withholding period of bronchodilators prior to spirometry: SABA for ≥6 hours and FDC 
or free combinations of ICS/LABA* for ≥48 hours (14 days for once daily combinations, 
i.e., indacaterol), short acting anticholinergics (SAMA) for ≥8 hours, xanthines ≥7 days.
*In case of combination ICS/LABA, ICS should be continued.
Washout period of each drug should be kept as close as possible as above and should not be 
longer. If washout period is considered to be longer, please contact your Novartis Medical 
Monitor.

A one-time repeat of percent predicted FEV1 (pre-bronchodilator FEV1) is allowed 
at Visit 101 as well as at Visit 102. Repeat of Visit 101 spirometry should be done 
in an ad-hoc visit to be scheduled on a date (preferably within 5 days of original 
Visit 101) that would provide sufficient time to receive confirmation from the 
spirometry data central reviewer of the validity of the assessment before 
randomization. Run-in medication should be dispensed only once the repeat 
spirometry was qualified by spirometry equipment, if all inclusion at Visit 101 are 
successful in case of necessary repeat of Visit 101.
 


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A one-time re-screen is allowed in case the patients fail to meet the criteria at the 
repeat, provided the patients return to their previous treatment until re-screened. In 
this circumstance, patients are not required to go back on prior medication for 1 full 
month duration as outlined in inclusion criterion 4.
8. Patients who demonstrate an increase in FEV1 of 12% and ≥200 mL within 15 to 30 
minutes after administration of 400 microgram salbutamol / 360 microgram albuterol (or 
equivalent dose) at Visit 101. Spacers may be used for reversibility testing.

All patients must perform a reversibility test at Visit 101.
If reversibility is not demonstrated at Visit 101:

Reversibility should be first repeated once.

If the retest does not show reversibility, patients may be permitted to enter the study 
with documented historical evidence of reversibility that was performed according 
to American Thoracic Society (ATS) / European Respiratory Society (ERS)
guidelines within 2 years prior to Visit 1.

Alternatively, patients may be permitted to enter the study with a historical positive
broncho-provocation test that was performed within 2 years prior to Visit 1.
If reversibility is not demonstrated at Visit 101 (or after repeated assessment at ad-hoc visit) 
and historical evidence of reversibility / broncho-provocation not available (or not performed 
according to ATS/ERS guidelines) patients will be noted as screen failure.
Spacer devices are ONLY permitted during reversibility testing. The decision whether or not to 
use a spacer for the reversibility testing will be taken by the study investigator.
4.2
Exclusion criteria
Patients 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.
1. Patients who have smoked or inhaled tobacco products (including electronic cigarettes)
within the 6 month period prior to Visit 1, or who have a smoking history of greater than or 
equal to 10 pack years (Note:1 pack is equivalent to 20 cigarettes. 10 pack years = 1 pack 
/day x 10 years, or ½ pack /day x 20 years.).
2. Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization (> 24 hours) or emergency room visit (≤24 hours) as follows:

For adults: within 6 weeks of Visit 1 (Screening). If patients experience an asthma 
attack/exacerbation requiring systemic corticosteroids or emergency room visit between 
Visit 1 and Visit 102 they may be re-screened 6 weeks after recovery from the exacerbation.

For adolescents: Severe asthma attack/exacerbation requiring systemic corticosteroids in 
the last 6 months, OR hospitalization (> 24 hours) due to severe asthma attack/exacerbation 
requiring systemic corticosteroids in the last 6 months, OR emergency room visit (≤24 
hours) due to severe asthma attack/exacerbation requiring systemic corticosteroids within 
the last 6 months. 
3. Patients who have ever required intubation for a severe asthma attack/exacerbation.
 


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4. 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).
5. Patients who have had a respiratory tract infection or asthma worsening as determined by 
the investigator within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and Visit 102. 
Patients may be rescreened 4 weeks after recovery from their respiratory tract infection or 
asthma worsening.
6. Patients with evidence upon visual inspection (laboratory culture is not required) of 
clinically significant (in the opinion of investigator) oropharyngeal candidiasis at Visit 102 
or earlier, with or without treatment. Patients may be rescreened once their candidiasis has 
been treated and has resolved.
7. 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.
8. Patients with a history of chronic lung diseases other than asthma, including (but not limited 
to) COPD, sarcoidosis, interstitial lung disease, cystic fibrosis, clinically significant 
bronchiectasis and active tuberculosis.
9. Patients with Type I diabetes or uncontrolled Type II diabetes.
10. Patients who have a clinically significant laboratory abnormality at Visit 101.
11. Use of other investigational drugs within 30 days of Visit 101 or 5 half-lives whichever is 
longer or until the expected pharmacodynamics effect has returned to baseline.
12. Patients who, either in the judgment of the investigator or the responsible Novartis 
personnel, have a clinically significant condition such as (but not limited to) unstable 
ischemic heart disease, New York Heart Association (NYHA), Class III/IV left ventricular 
failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric disease, 
neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and 
hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or 
ophthalmologic disorder or patients with a medical condition that might compromise patient 
safety or compliance, interfere with evaluation, or preclude completion of the study.
13. Patients with a history of myocardial infarction (clinical confirmation by the study
investigator required) within the previous 12 months.
14. Concomitant use of agents known to prolong the corrected QT (QTc) interval unless it can 
be permanently discontinued for the duration of study.
15. Patients with a history of long QT syndrome or whose QTc measured at Visit 101 (Fridericia 
method) is prolonged (> 450 msec for males and > 460 msec for females) and confirmed by 
a central assessor or inability to determine the QTcF interval (these patients should not be 
re-screened).
16. Patients who have a clinically significant ECG abnormality at Visit 101 (Start of Run-
in/Baseline epoch) and/or any time prior to randomization (Visit 102), including 
unscheduled ECG. ECG evidence of myocardial infarction at Visit 101 (via central reader) 
should be clinically assessed by the study investigator with supportive documentation.
17. 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.
 


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18. Patients with a history of hypersensitivity or intolerance to any of the study drugs (including 
excipients) or to similar drugs within the class including untoward reactions to 
sympathomimetic amines or inhaled medication or any component thereof. This criteria also 
applies to rescue and Run-in medications.
19. Patients with diagnosed rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption or with known intolerance to lactose or milk
products. 
20. Patients who have not achieved acceptable spirometry results at Visit 101 even after a re-
test, in accordance with American Thoracic Society/European Respiratory Society 
(ATS/ERS) criteria for acceptability and repeatability, repeat spirometry may be allowed in 
an ad-hoc visit which should be scheduled as close as possible to the first spirometry attempt 
(but not on the exact same day) if the spirometry did not qualify due to ATS/ERS criteria at 
Visit 101 and/or Visit 102. Should the patient fail the repeat assessment, he/she can be re-
screened once, provided the patient returns to the prior treatment until re-screened.
21. Patients receiving any asthma-related medications in the classes specified in Table 5-1
unless they undergo the required washout period prior to Visit 101 and Visit 201 and follow 
the adjustment to treatment program.
22. Patients receiving any medications in the classes listed in Table 5-2.
23. Patients receiving medications in the classes 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.
24. Patients with severe narcolepsy and/or insomnia.
25. Patients on Maintenance Immunotherapy (desensitization) for allergies for less than 3 
months prior to Visit 101 or patients on Maintenance Immunotherapy for more than 3 
months prior to Visit 101 but expected to change throughout the course of the study.
26. Patients, who are serving a custodial sentence, do not have a fixed residence or who are 
detained under local mental health legislation/regulations.
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, Twisthaler®, Accuhaler® or MDI.
Spacer devices are not permitted for rescue medication.
29. History of alcohol or other substance abuse in the last 10 years.
30. 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 eDiary device.
31. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
32. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
Chorionic Gonadotropin (hCG) laboratory test.
33. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 30 days after stopping medication. 
 


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Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. 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 patients on the 
study, the vasectomized male partner should be the sole partner for that patients

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before Visit 201 (Randomization/Start of treatment epoch).
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 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment is she considered not 
of child-bearing potential.
If requested by local authorities/ethics committees, additional and more frequent pregnancy 
testing might be performed. 
34. Use of Long Acting Muscarinic Antagonist (LAMA) within 3 months prior to Visit 1.
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
The Study drug is as follows:

QMF149 (indacaterol acetate/MF) 150/80 microgram o.d. (in the evening) delivered as 
powder in hard capsules via Concept1 inhaler
The Comparative treatment is:

MF 200 microgram o.d. (in the evening) delivered as powder via Twisthaler®
In addition, the following placebos will enable the double-dummy design of the study:

Placebo delivered as powder via Twisthaler® (in the evening)

Placebo delivered as powder in capsules via Concept1  (in the evening)
 


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Under no circumstances is an alternative inhalation device to be used for the administration of 
the investigational or reference therapies during the treatment period.
5.1.2
Additional treatment
The specified minimum washout periods prior to Run-in (Visit 101) are described in Table 5-1.
The low dose fluticasone propionate (100 microgram b.i.d. via Accuhaler or 125 microgram
b.i.d via MDI) should be used during the Run-in epoch. If these are not available in a particular 
country, fluticasone propionate in an alternative formulation at an equivalent dose strength can 
be used (Appendix 9). These will either be supplied to the investigator sites locally by Novartis 
or provided by the study center and reimbursed by Novartis.
At Visit 1 (Screening) patients will be provided with SABA (salbutamol/albuterol) inhaler to 
use as rescue medication on an “as needed” basis throughout the study. Please refer to Section 
5.5.6 for more details regarding rescue medication.
Salbutamol (100 microgram) or albuterol (90 microgram) will either be supplied to the 
investigator sites locally by Novartis or provided by the study center and reimbursed by 
Novartis.
5.2
Treatment arms
Patients will be assigned to one of the following two treatment arms (as per randomization ratio 
of 1:1):

QMF149 150/80 microgram o.d. delivered via Concept1 (in the evening) and Placebo 
to MF 200 microgram o.d. delivered via a Twisthaler® (in the evening)

MF 200 microgram o.d. delivered via a Twisthaler® (in the evening) and Placebo to 
QMF149 150/80 microgram o.d. delivered via Concept1 (in the evening)
5.3
Treatment assignment and randomization 
At Visit 201, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study drug to be dispensed 
to the patient. The randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
Randomization will be stratified by factors of age (≥12 to < 18 years or ≥18) and by region. 
 


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The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Group.
5.4
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods:

Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone (with the exception of bio-analyst) involved in the study

The identity of the treatment will be concealed by the use of study drugs that are all 
identical in packaging, labeling, and schedule of administration, appearance, taste, and 
odor.
During the study, the individual patient unblinding can occur in the case of patient emergencies, 
request from the DMC if needed for the safety interim analysis (Section 8.4) or as an outcome 
of their evaluation and at the conclusion of the study. Health authorities will be granted access 
to unblinded data if needed. Any patient whose treatment code has been broken inadvertently 
or for any non-emergency reason will be discontinued from the trial.
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 Patient 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 should select the 
electronic Case Report Form (eCRF) book with a matching Patient Number from the electronic 
data capture (EDC) system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the eCRF.
5.5.2
Dispensing the study drug
Each study site will be supplied by Novartis with study drug in packaging of identical 
appearance.
 


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The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the investigational drugs. 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 should 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 Country Pharma 
Organization (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 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. 
5.5.3.2
Handling of additional treatment 
The following non-study drug will be monitored as follows:
The non-study drug must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Clinical supplies are to be dispensed only in accordance with the 
protocol.
The investigator must maintain an accurate record of the shipment and dispensing of the non-
study drug in a drug accountability log. Monitoring of drug accountability will be performed 
by monitors during site visits or remotely and at the completion of the trial. Patients will be 
asked to return all unused non-study drug and packaging at the end of the Run-in for the Run-
in medication and at the end of the study or at the time of discontinuation of study drug for the 
rescue medication. 
These medications are:

Salbutamol (100 microgram) or albuterol (90 microgram) used as rescue medication from 
Visit 1 to Visit 204;

Fluticasone propionate (100 microgram b.i.d. or acceptable dose equivalent as outlined in 
Section 3.1 used as Run-in medication from Visit 101 to Visit 102.
 


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5.5.4
Instructions for prescribing and taking study treatment 
The investigator must promote compliance by instructing the patient to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed.
Patients will be provided with medication as described in Section 5.1.
All kits of study treatment assigned by the IRT will be recorded / databased 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. 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.
All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF page.
At Visit 1 all patients will be instructed how to use an MDI to administer rescue 
salbutamol/albuterol correctly. At Visit 101 patients will be trained to the use of the eDiary, 
peak flow meter and Accuhaler ® (Appendix 3). At Visit 102 all patients will be fully trained in 
the correct use of the Concept1 and Twisthaler® inhaler devices used to administer study 
medication. Patients who are unable to use either device correctly at Visit 102 will not be 
eligible to enter the treatment epoch. Additional training devices will be supplied for 
demonstration purposes. At clinic visits the investigator should check the patient’s use of the 
inhalational devices to ensure correct use of each device. If required, further device training 
should be provided. Patients will be instructed to contact the site if the device is not functioning 
properly.
Patients will be instructed to take their dose of study medication at approximately the same time 
every evening regardless of their time of sleep, meal or other activities. Patients will be 
instructed to rinse their mouth 2 times with approximately 30 mL of water after the last 
inhalation of the study drug following sequential inhalations from devices. Water used for 
mouth rinsing should NOT be swallowed. 
The study drugs must be taken in the evening (between 5:00 and 8:00 pm), and consist of 
sequential single inhalations from the following devices:
-
One inhalation from the Concept1 device containing either QMF149 or placebo 
-
One inhalation from the Twisthaler® device containing either MF or placebo 
The 2 inhalations should be taken as close together in time as possible. Instructions for use of 
the Concept1 inhaler and Twisthaler® are provided in Appendix 1 and Appendix 2.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
The Study drug dose adjustments and/or interruptions are not permitted unless the investigator 
considers an interruption is necessary for the treatment of an adverse event. Any interruption of 
study medication should be for the shortest time period possible and recorded in the Dosage 
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In case of blind broken, the study medication is to be permanently discontinued.
5.5.6
Rescue medication
At Visit 1, all patients will be provided with a SABA (100 microgram salbutamol or 
90 microgram albuterol via MDI) which they will be instructed to use throughout the study as 
rescue medication. Nebulized salbutamol/albuterol is not allowed as rescue medication 
throughout the entire trial. No other rescue treatment is permitted 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 
medication (salbutamol/albuterol) within 6 hours of the start of each visit where spirometry is 
being performed unless absolutely necessary. If rescue medication is taken within 6 hours prior 
to spirometry assessments, then the visit should be rescheduled to the next day if possible.
Bronchodilator medications that the patients used prior to Visit 1 must be recorded in the 
asthma-related prior/concurrent medication page of the eCRF, with the stop date for these 
bronchodilators recorded as the date of Visit 1. The rescue salbutamol/albuterol provided at 
Visit 1 for use during the study should NOT be recorded on the asthma-related prior/concurrent 
medication page of the eCRF. From Visit 101, patient should be instructed to record daily use 
of rescue medication (number of puffs taken in the previous 12 hours) each morning and 
evening throughout the 12 week treatment epoch in her/his electronic diary.
The rescue salbutamol/albuterol will be provided to the patients by the study center and 
reimbursed locally by Novartis or supplied to the investigator sites locally by Novartis.
5.5.7
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded in the concomitant 
medications/significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
5.5.8
Prohibited medication
Prohibited medications, as listed in Table 5-1, must not be taken during the study (unless for 
the treatment of asthma exacerbations). The specified minimum washout periods prior to Run-
in (Visit 101) and/or Randomization (Visit 201) are described in Table 5-1. The classes of 
medication listed in 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 medical monitor before randomizing a patient or 
allowing a new medication to be started. 
 


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If a patient takes systemic corticosteroids within 7 days prior to a study visit, the visit must be 
rescheduled to allow a washout of 7 days.
Table 5-1
Prohibited Asthma-Related Medications
Class of medication
Minimum washout period prior to Run-in (V101) 
1, 2, 3, 4
Short acting anticholinergics (SAMA)
Must be discontinued 8 hours prior to Visit 101 
Fixed combinations of β2-agonists and inhaled 
corticosteroids
Must be discontinued 48 hours prior to Visit 101;
Patients should continue with an ICS until Visit 101
when patients will be switched to fluticasone
propionate 100 μg b.i.d. (or equivalent dose) for Run-
in; the last dose of Run-in medication will be taken in 
the morning of visit 102
Inhaled corticosteroids1
All patients must be treated for asthma with 
fluticasone propionate 100 microgram b.i.d. (or 
equivalent dose) from Visit 101 to Visit 102 (Figure 3-
1); all other ICS must be discontinued at Visit 101
Fixed combinations of short-acting β2-agonist 
and short-acting anticholinergic
Must be discontinued 8 hours prior to Visit 101  
Leukotriene Receptor Antagonist (LTRA) and 
leukotriene synthesis inhibitors
Must be discontinued 7 days prior to Run-in
(Visit 101)
Long-acting β2-agonists (LABAs) 
LABAs b.i.d. must be discontinued 48 hours prior to 
Visit 101. LABAs o.d. (i.e., indacaterol) must be 
discontinued at Visit 1 (14 days prior to Visit 101). All 
patients will be provided with SABA at Visit 1 for use 
throughout the study 
Salbutamol/albuterol (SABA) provided at Visit 
1 and throughout study as required for rescue 
medication 
Must be withheld 6 hours prior to Visit 101 and 
Randomization (Visit 201)4
Short acting β2-agonists (SABAs) (other than 
Salbutamol/albuterol provided at Visit 1 for 
rescue medication)
Must be discontinued at Visit 1 and are not permitted 
during the study
Parenteral or oral corticosteroids (systemic 
corticosteroids are permitted for the treatment 
of asthma exacerbations)
Must be discontinued 4 weeks prior to Run-in
(Visit 101)
Intra-muscular depot corticosteroids
Must be discontinued 3 months prior to Run-in
(Visit 101)
Monoclonal Antibody: IgE inhibitors and other 
asthma-related biologics (i.e., omalizumab), 
IL-5 inhibitors (e.g., mepolizumab)
Must be discontinued 4 months prior to Run-in
(Visit 101)
Xanthines 
Must be discontinued 7 days prior to Run-in
(Visit 101)
Systemic mast cell stabilizers (e.g.,
cromoglycate, nedocromil, ketotifen)
Must be discontinued 7 days prior to Run-in
(Visit 101)
1 ICS must be discontinued at Visit 101. Treatment for recorded asthma exacerbation as defined in 
Section 6.4.9 is allowed ONLY until the asthma exacerbation is resolved (minimum wash-out of 7 days 
is required before scheduling a visit including spirometry assessment).
2 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria.
 


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3 These medications are also prohibited if administered for other indications.
4 SABA (salbutamol/albuterol rescue medication) should be withheld for at least 6 hours prior to 
spirometry measurements at clinic visits if possible. Clinic visits may be rescheduled if rescue 
medication were taken less than 6 hours prior to the spirometry assessments.
Table 5-2
Prohibited Medications
Class of medication
Minimum cessation period prior to Run-in
(Visit 101) 
Non-potassium sparing diuretics (unless 
administered as a fixed-dose combination with 
a potassium conserving drug
7 days
Non-selective systemic β-blocking agents
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
Strong inhibitors of cytochrome P4503A (e.g.,
ketoconazole)
7 days
Tricyclic antidepressants (tetracyclics which 
are similar in class with regards to drug 
interaction are also to be excluded)
14 days
Other investigational drugs 
30 days or 5 half-lives, whichever is longer
Noradrenaline reuptake inhibitors
7 days
Live attenuated vaccine
30 days
Table 5-3
Medications Allowed Under Certain Conditions
Class of medication
Condition
Mucolytic agents not containing 
bronchodilators
If stabilized for at least 4 weeks prior to Visit 1 and 
throughout the trial
Pure Selective Serotonin Reuptake Inhibitors 
(they must have no documented effect on any 
other neurotransmitters or other biological 
pathways, e.g., muscarinic pathway)
Treatment regimen is stable for at least one month at 
Visit 1
Inactivated influenza vaccination, 
pneumococcal vaccination or any other 
inactivated vaccine
Not administered within 48 hours prior to a study visit
Intra-nasal corticosteroids
Stable dose for at least 4 weeks prior to Visit 101;
In the case of as needed, providing an established 
pattern of use has been documented
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, 
providing an established pattern of use has been 
documented
Topical corticosteroids for the treatment of 
eczema
In recommended doses and dosage regimens
 


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Class of medication
Condition
Maintenance immunotherapy for allergies
Stable dose for at least 3 months prior to Visit 101 
and unchanged throughout study treatment
If indicated for the treatment of an asthma exacerbation, any treatment deemed necessary for 
the safety of the patient is allowed from the start of the asthma exacerbation event (Section 
6.4.9) until the asthma exacerbation event is resolved.
5.5.9
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation (TD) and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IRT. When the investigator contacts the system to break a treatment code for a patient, 
he/she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the
Novartis Clinical Trial Head that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

protocol number

study drug name (if available)

patient number
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding
can be performed at any time.
Study drugs must be discontinued after emergency unblinding. Study drugs must also be 
discontinued for any patient whose treatment code has been inadvertently broken. 
5.6
Study completion and discontinuation
5.6.1
Study completion and post-study treatment
Completion of the study will be when the last patient has completed Visit 301 and as close as 
possible to safety follow-up at Day 114 for serious adverse events (SAEs). 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.6.2
Discontinuation of study treatment 
Patients may voluntarily discontinue study drug (discontinue double-blind study medication but 
continue with study participation) at any time. Patients who wish to discontinue double-blind 
study medication will be asked to remain in the study and complete all study visits for 
 


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assessment of safety and vital status. Patients withdrawn from study drug will receive 
standard of care (SoC) asthma therapy according to investigator judgment.
The investigator should discontinue study treatment for a given patient and/or withdraw the 
patient from the study if, on balance, he/she believes that continuation would be detrimental to 
the patient’s well-being.
Study treatment must be discontinued under the following circumstances:

Patients who experience one “severe” asthma exacerbations (as defined in Section 6.4.9)
during the 12 week treatment epoch that requires treatment with systemic corticosteroids
or hospitalization (including intubation). 

Patients with > 50% decrease in FEV1 from Baseline (e.g., Visit 101) confirmed by a 
repeat measurement the same day during the Run-in or during the treatment epoch 
(Baseline being then Visit 201).

If a patient develops a medical condition that requires consistent use of prohibited 
treatment as per Section 5.5.8 or if patient is not compliant because of use of prohibited 
medications. Any other protocol deviation that results in a significant risk to the patient’s 
safety.

If a patient experiences paradoxical bronchospasm, as recommended in the QMF149
Investigator Brochure 

Any other protocol deviation that results in a significant risk to the patient’s safety.
Discontinuation of study treatment (but continued study participation) 
For this study it is very important to continue collecting data, especially vital status, on all 
patients whether or not he/she completes treatment to continue collecting safety information. 
The patient should NOT be considered withdrawn from the study due to study treatment 
interruption or discontinuation. 
If premature discontinuation of study treatment occurs, the patient should return to the clinic as 
soon as possible for a study Treatment Discontinuation (TD) visit. The investigator must 
determine the primary reason for the patient’s premature discontinuation of study treatment and 
record this information on the End of Study Treatment 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. This telephone contact should 
preferably be done according to the study visit schedule.
The data which must continue to be collected for all patients (including the patients 
discontinuing study treatment) are adverse event and serious adverse events for up to 30 days 
after drug discontinuation and survival status until the end of the study follow-up visit (Visit 
301). 
Any patient whose treatment code has been broken inadvertently or for any non-emergency 
reason should be discontinued from the double blind study medication. Patients can voluntarily 
stay in the study and complete all study visits for assessment of safety and vital status. The 
survival status also needs to be collected until the end of the study Follow-up visit (Visit 301)
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
He/she should return for the assessments indicated in Table 5-4. If he/she fails to return for 
 


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these assessments for unknown reasons, every effort (e.g., telephone, e-mail, and letter) should 
be made to contact them as specified in Section 5.6.4.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
Table 5-4
Table of Assessment for Patients who Discontinue Study Treatment 
Prematurely
Assessment
Early Study 
Treatment 
Discontinuation 
Visit
Unschedule
d Safety 
Follow-Up 
Visit
At time of 
Scheduled 
Visit 
Premature 
study
discontinuation
*
Follow-
up 
Visit 301
Clinic/Telephone
C
T
T
T
T
Week
Disc. Date
Disc.date +4 
weeks
16
Day 
Disc. Date
Disc.date +30 
days
114
IRT TD call
S
IRT Call for visit 
confirmation
S
S
S
S
Vital Signs
X
Physical exam
S
Record Height 
(Adolescent only)
X
Record Weight 
X
Oropharyngeal 
examination
S
Pregnancy test 
(serum)
X
Collect study 
medication
S
Concomitant 
medication
X
X
X
X
X
Record 
interruption/chang
es in Drug 
Administration to 
assess 
compliance
X
Download/review 
eDiary
S
Review rescue 
medication use
S
Review AEs 
X
X
X
X
X
Review SAEs
X
X
X
X
X
Review asthma 
exacerbations
X
X
X
X
 


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Clinical Trial Protocol (Version 02) Clean Version                                     Protocol No. CQVM149B2303
Assessment
Early Study 
Treatment 
Discontinuation 
Visit
Unschedule
d Safety 
Follow-Up 
Visit
At time of 
Scheduled 
Visit 
Premature 
study
discontinuation
*
Follow-
up 
Visit 301
Review surgery 
and procedures
X
X
X
X
X
Safety Lab 
assessments 
(hematology, 
clinical chemistry, 
urinalysis,
 
)
X
Spirometry1
X
ECG
X
ACQ-7 2
X
Evening Plasma 
cortisol 
X
Survival Status
X
X
Record 
Healthcare visit 
for asthma 
worsening
X
X
Record end of 
Study Treatment 
page
X
Record end of 
treatment epoch 
disposition
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
*Applicable for patients who withdrew consent or lost to follow-up or dead
1 Details of timed assessments are provided in Table 6-2
2 PRO assessments should be done before all other assessments. When a scheduled visit is planned 
on 2 consecutive days the PROs are to be completed on the first day.
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 occurs only 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.
If a patient withdraws consent, the investigator must make every effort (e.g., telephone, e-mail, 
and letter) to determine the primary reason for this decision and record this information. Study
treatment must be discontinued and no further assessments conducted. All biological material 
 


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that has not been analyzed at the time of withdrawal must not be used. Further attempts to 
contact the patient are not allowed unless safety findings require communicating or follow-up.
Patients who discontinued from study treatment and from the study simultaneously
For patients who decide to discontinue study treatment and immediately withdraw completely 
from the study (refuse any further study participation or contact), the Investigator should make 
every effort to perform the assessments detailed for the early study TD visit and enter on the 
eCRF as Early Study Discontinuation visit provided the patient gives consent for these 
assessments. The patient disposition status should be entered on the eCRF. The investigator 
should document an explanation of why the patient is withdrawing from the study. Following 
these assessments all study participation for that patient will cease and data to be collected at 
subsequent visits will be considered missing.
The investigator must also notify the IRT (Interactive Voice Response System(IVRS)/
Interactive Web Response System(IWRS)) of the premature discontinuation of study treatment.
Patients who prematurely discontinue study treatment and withdraw from the study will not be 
replaced.
5.6.4
Lost to follow up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw the investigator should allow “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 based on the Data Monitoring 
Committee advice, practical reasons (including slow enrollment), or for regulatory or medical 
reasons. Should this be necessary, the patient should be seen as soon as possible and treated as
a prematurely discontinued patient. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing the Institutional Review 
Board/Independent Ethics Committee (IRBs/IECs) of the early termination of the trial, unless 
otherwise required by local country regulations.
In addition, a Data Monitoring Committee will be used, which will evaluate safety data on a 
regular basis and can recommend adjustment to study conduct (including stoppage) at any time. 
Please see Section 8.4 for more details
6
Visit schedule and assessments
The study will consist of a Screening epoch, a Run-in epoch, a 12-week blinded treatment epoch 
and a Follow-up epoch of 30 days after the last treatment.
 


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Clinical Trial Protocol (Version 02) Clean Version                                     Protocol No. CQVM149B2303
Table 6-1 lists all the assessments to be performed for the study and indicates with an “X” the 
visits at which they will be performed. Patients should be seen for all visits on the designated
days or as close as possible to those dates. While Visit 102 (end of Run-in) and 
Visit 201(Randomization) must take place on the same day, a visit window of 4 days is allowed 
at Visit 204 as described in Section 3.1 (if this is not possible, the sponsor should be notified). 
All data obtained for these assessments must be supported in the patients’ source documentation.
At Visit 1, all patients will be issued an electronic diary to record asthma symptoms and rescue 
medication use and at Visit 101, a Peak Flow meter to record Peak Expiratory Flow Rate (PEF)
twice daily. The Run-in epoch will be used to assess eligibility of the patients to enter the 
treatment epoch and to collect baseline values for some variables.
Once patient’s eligibility is confirmed (at Visit 102), patient will be randomized to one of the 
two treatment groups with an equal (1:1) randomization ratio:

QMF149 150/80 microgram o.d delivered via Concept1

MF 200 microgram o.d. delivered via Twisthaler®
Visits 102 and 201 should take place sequentially on the same day and Visit 102 assessments
should be performed prior to administration of the first dose of study medication (Visit 201).
The scheduled assessments should be performed in the following order: Patient reported 
outcomes (PROs) (i.e., ACQ, AQLQ), ECG, radial pulse rate, blood pressure and blood /urine 
samples followed by spirometry (as per Table 6-2).
The details of spirometry assessments are indicated in Table 6-2. An approximate 3 min rest 
from start of ECG to the start of spirometry manoeuvres should be given. When an ECG is 
needed to be taken after spirometry, a 10 minute rest from the end of spirometry to start of ECG 
assessments should be considered.
If other assessments are scheduled at the same time-point, spirometry will take precedence (with 
the exception of PROs and blood tests) so that it occurs at/or as close as possible to the 
scheduled time points. 
 


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Table 6-1
Assessment schedule
Visit Number
1
101
102
201
202
203
5
20410
Early 
treatme
nt 
disconti
nuation
(TD)
Premat
ure 
study 
discont
inuatio
n (PSD)
3019
Epoch
Screen
Run-in
Treatment
PSD
Follow
-up
Clinic (C) 
/Telephone 
(T)
C
C
C
C
C
T
C
C
T
T
Week – Start 
of Week
-5 to
-3 
-3 
0
0
4
8
12
16
Day Number
-35 to -
21
-21
1
1/2
30
57
84/856
114
Obtain 
Informed 
Consent 
and/or assent 
(including for 
sub-group)
X11
Current 
medication 
review/
adjustment
X
Inclusion/excl
usion criteria
X
X
X
Randomizatio
n via IRT
S
Medical 
History, 
Demography 
X
History of 
Asthma 
exacerbation
X
Smoking 
history and 
status
X
Run-in
medication 
X
Pregnancy 
test (serum)1
X
X
X
X
Pregnancy 
test (urine) 1
X
X
 


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Clinical Trial Protocol (Version 02) Clean Version      
Protocol No. CQVM149B2303
Visit Number
1
101
102
201
202
203
5
20410
Early 
treatme
nt 
disconti
nuation
(TD)
Premat
ure 
study 
discont
inuatio
n (PSD)
3019
Epoch
Screen
Run-in
Treatment
PSD
Follow
-up
Clinic (C) 
/Telephone 
(T)
C
C
C
C
C
T
C
C
T
T
Week – Start 
of Week
-5 to
-3 
-3 
0
0
4
8
12
16
Day Number
-35 to -
21
-21
1
1/2
30
57
84/856
114
Urine analysis 
(dipstick)
S
S
S
S
Device 
training4
S
S
S
Concomitant 
medication 
review
X
X
X
X
X
X
X
X
X
X
Physical 
examination 
S
S
S
Oropharyngea
l examination
S
S
S
S
S
S
Record height 
(for adult 
patients only 
at Visit 101) 
and weight
X
X12
X12
ECG2
X
X
X
X
Vital signs2
X
X
X
X
X
X
Issue rescue 
medication as 
necessary 
S
S
S
S
Review 
rescue 
medication 
use
X
X
X
X
X
X
Spirometry 
Practice
(optional) 
S
 


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Clinical Trial Protocol (Version 02) Clean Version      
Protocol No. CQVM149B2303
Visit Number
1
101
102
201
202
203
5
20410
Early 
treatme
nt 
disconti
nuation
(TD)
Premat
ure 
study 
discont
inuatio
n (PSD)
3019
Epoch
Screen
Run-in
Treatment
PSD
Follow
-up
Clinic (C) 
/Telephone 
(T)
C
C
C
C
C
T
C
C
T
T
Week – Start 
of Week
-5 to
-3 
-3 
0
0
4
8
12
16
Day Number
-35 to -
21
-21
1
1/2
30
57
84/856
114
Screening 
spirometry 
and FEV1
reversibility 
test (SABA)
X
Spirometry2
X
X
X
X
X
Issue eDiary5
X
Issue Peak 
Flow meter
S
Review and 
upload eDiary
recordings5
S
S
S
S
Administer 
study drug at 
visit
X
X
X
Dispense 
study 
medication via 
IRT
X
X
Call IRT for 
visit 
confirmation
S
S
S
S
S
S
S
S
Collect 
unused study 
medication
S
S
S
Record 
interruption/ch
anges in Drug 
Administration 
to assess 
compliance
X
X
X
X
AE recordings X14
X
X
X
X
X
X
X
X
X
 


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Clinical Trial Protocol (Version 02) Clean Version      
Protocol No. CQVM149B2303
Visit Number
1
101
102
201
202
203
5
20410
Early 
treatme
nt 
disconti
nuation
(TD)
Premat
ure 
study 
discont
inuatio
n (PSD)
3019
Epoch
Screen
Run-in
Treatment
PSD
Follow
-up
Clinic (C) 
/Telephone 
(T)
C
C
C
C
C
T
C
C
T
T
Week – Start 
of Week
-5 to
-3 
-3 
0
0
4
8
12
16
Day Number
-35 to -
21
-21
1
1/2
30
57
84/856
114
SAE 
recording
X
X
X
X
X
X
X
X
X
X
Review 
Surgery and 
Procedures
X
X
X
X
X
X
X
X
X
Study 
Disposition 
(Screening)
X
Study 
disposition 
(Run-in)13
X
X
Study 
disposition 
End of 
Treatment 
epoch (end of 
study)
X
X
Study 
disposition 
(Follow-Up)
X
Survival 
Status
X
Review 
asthma 
exacerbations
X
X
X
X
X
X
X
X
Safety Lab 
assessments 
(hematology, 
clinical 
chemistry, 
urinalysis, 
 
X
X
X
X
 


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Clinical Trial Protocol (Version 02) Clean Version      
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Visit Number
1
101
102
201
202
203
5
20410
Early 
treatme
nt 
disconti
nuation
(TD)
Premat
ure 
study 
discont
inuatio
n (PSD)
3019
Epoch
Screen
Run-in
Treatment
PSD
Follow
-up
Clinic (C) 
/Telephone 
(T)
C
C
C
C
C
T
C
C
T
T
Week – Start 
of Week
-5 to
-3 
-3 
0
0
4
8
12
16
Day Number
-35 to -
21
-21
1
1/2
30
57
84/856
114
Evening 
plasma 
cortisol  2
X
X
X
ACQ-73
X
X
X
X
X
AQLQ-S+123
X
X
Telephone 
patient 1 day 
in advance of 
visit
S
S
S
Record 
healthcare 
visits for 
asthma 
worsening
X
X
X
X
X
TD = Study treatment discontinuation
S These assessments are source documentation only and will not be entered into the eCRF
X assessment to be reported in the clinical database
1 For females of child-bearing potential only. Additional pregnancy testing might be performed if 
requested by local requirements.
2 Details of timed assessments for randomized patients are provided in Table 6-2. 
3 PROs must be assessed before all other assessments. When a scheduled visit is planned on 2 
consecutive days the PROs are to be completed on the first day. 
4 Device training for peak flow meter and eDiary (electronic device for questionnaires and  
assessments based on asthma symptoms) and Accuhaler® at Visit 1 and/or 101 and for Concept1 and
Twisthaler® devices at Visit 102.  
5 Site to call patient at specified time points in between clinic visits to check if patient asthma 
symptoms have worsened, any treatment required and eDiary completed accordingly. In case of an
asthma exacerbation, the patient should be encouraged by the site to contact for advice. If necessary, 
an unscheduled visit to the site may be organized and should capture AEs/SAEs, concomitant 
medication and safety laboratory exams as appropriate. 
 


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6 The last dose of study medication will be taken on Day 84 (Visit 204).
9 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
10 Clinic Visit 204 (Week 12) should take place within a 4-day window. If this is not feasible, the 
sponsor should be notified.
11 Patients below the legal age of consent are required to have their parent/guardian sign the parental 
Informed Consent; adolescents must sign the Assent Form.
12 Height will be measured for adult patients only at Visit 101. Height will be measured for adolescent 
patients at Visits 101, 204 (or TD Visit if applicable). Weight will be measured for all patients at Visits
101, 204 (or TD if applicable).
13 Visit 101 disposition eCRF page should be completed in case the patient is a Run-in failure at Visit 
101. Visit 102 disposition eCRF page should be completed if the patient is a Run-in failure at this visit 
or if the patient is randomized in the study.
14 For randomized patients all AEs must be collected in the eCRF, however for screen failure patients,
AEs that are not SAEs must be collected in the source data
Table 6-2
Timed Assessment**
Visit 
(Day)
Time point1
Spirometry 
(FEV1, 
FVC)4
Hematology
Chemistry 
Urinalysis 5
Plasma 
cortisol  
ECG3
Vital 
signs2
Visit 201
(Day 1)7
-45 min
X
-35 min
X
-25 min
X
-20 min
X
X6
-15 min
X
0 min
Evening dosage (between 5:00 - 8:00 pm)
5 min
X
15 min
X
20 min
X
30 min
X
X5
1 h
X
X
X
Visit 201
(Day 2)
23h15 min
X
23h45 min
X
0 min
Evening dosage (between 5:00 - 8:00 pm)
Visit 202
(Day 30)
-45 min
X
-30 min
-25 min
-15 min
X
X
0 min
Evening dosage (between 5:00 - 8:00 pm)
5 min 
X
15 min
 


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Visit 
(Day)
Time point1
Spirometry 
(FEV1, 
FVC)4
Hematology
Chemistry 
Urinalysis 5
Plasma 
cortisol  
ECG3
Vital 
signs2
30 min
X
1 h
X
Visit 204
(Day 84)
-45 min
X
-35 min
X
-25 min
X
-20 min
X
X
-15 min
X
0 min
Evening dosage (between 5:00 - 8:00 pm)
5 min
X
15 min
20 min
X
30 min
X
X
1h
X
X
X
Visit 204
(Day 85)
23h15 min
X
23h45 min
X
X
X
**It is necessary that scheduled assessments follow this order: PROs, ACQ, AQLQ, ECG, radial PR, BP, blood /
urine samples and spirometry. Assessments in Table 6-2 are to be performed as close as possible to designated 
timeframes; however an approximate ± 5 min window is permitted.
1 Study drug time points. All study drug doses to be administered in the clinic. Time relates to the dose given from 
the first device at visit unless otherwise specified
2 Systolic and diastolic blood pressure and heart rate (radial pulse)
3 At time points requiring both spirometry and ECG, ECG should always be performed first. Approximately a 3 min 
rest period from the beginning of ECG assessments to the start of spirometry manoeuvres should be observed.
4 Approximately a 10 min rest period from the end of spirometry maneuvers to the beginning of ECG assessments 
should be observed. 
5 Blood/urine samples must always be taken in advance of spirometry measurements planned at the scheduled 
time points. Urine analysis is only to be performed if the urine dipstick is abnormal.
6 Baseline for the evening plasma cortisol
7 Assessments prior to randomization will be part of Visit 101 reporting.
6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the Screening epoch, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. AEs 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 
 


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
Gender

Race and ethnicity

Height and weight

Body mass index (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

Health status

Prior concomitant medication (asthma and non-asthma related)

Pre and post-bronchodilator spirometry (screening spirometry and reversibility testing).

6.3
Treatment exposure and compliance 
The time of study treatment administration at each 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 eDiary once a week. The data from the 
eDiary will be reviewed by study site personnel at each visit.
Study treatment compliance should be assessed by the investigator and/or center personnel at 
all visits. Where necessary, the Investigator will discuss compliance/documentation issues 
with the patient. The Investigator or designee will collect, from the patient, the used/unused 
investigational medication and packaging (unused capsules/blister strips and SDDPIs) at 
Visits 202 and 204 (or TD Visit or Study Withdrawal Visit if applicable). Compliance will be 
assessed based on the number of days where study drug was administered "As per protocol" 
as recorded on the Dosage Administration Record (DAR) Summary eCRF.
6.4
Efficacy
The following assessments of efficacy will be performed:

Spirometry

ACQ-7

AQLQ

Asthma symptoms based on eDiary

Peak expiratory flow

Rescue medication use

Asthma exacerbations
 


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6.4.1
Spirometry 
The following spirometry assessments will be made:

Forced Expiratory Volume in one second (FEV1)

Forced Vital Capacity (FVC)

Forced Expiratory Flow between 25% and 75% of Forced Vital Capacity (FEF25-75)
Spirometric assessments will be measured at Visit 201, 202, 204 and TD Visit (if applicable) 
as indicated in Table 6-2.
Trough FEV1 is defined as the mean of the two FEV1, values measured at 23 hours 15 min and 
23 hours 45 min after the evening dose taken at the site. 
Pre-dose FEV1 is defined as the mean of the two FEV1 values measured at -45 min and -15 min 
prior to evening dose.
Please refer to the Spirometry Guidance in Appendix 4 and Table 6-2 for full details on 
scheduling and performing spirometry.
6.4.2
Asthma Control Questionnaire (ACQ-7)
In this study, the ACQ-7 (Appendix 5) will be used to assess improvements in asthma symptom 
control. The ACQ-7 (Juniper et al 1999; Juniper et al 2005, and Juniper et al 2006) is a seven-
item disease-specific instrument developed and validated to assess asthma control in patients in 
clinical trials as well as in individuals in clinical practice. ACQ-7 will be provided to the site. 
All seven items are then scored on a 7-point Likert scale, with 0 indicating total control and 6 
indicating no control. The questions are equally weighted and the total score is the mean of the 
seven items. 
The proportion of patients who achieve an improvement of at least 0.5 in ACQ-7 (i.e., decrease 
of ACQ-7 score of at least 0.5 from Baseline) at post-baseline visits will also be analyzed.
The first 6 questions of the ACQ-7 are to be completed by the patient while the last question 
(question 7) is to be completed by the study investigator using spirometry data generated by the 
spirometry equipment. The ACQ-7 should be completed at the study site at Visits 101, 102, 202, 
204 and TD Visit if applicable.
6.4.3
Asthma Quality of Life Questionnaire (AQLQ-S +12)
The AQLQ-S +12 is a 32-item disease specific questionnaire designed to measure functional 
impairments that are most important to patients with asthma (Appendix 6). It consists of 4 
domains: symptoms, emotions, exposure to environmental stimuli and activity limitation.
Patients are asked to recall their experiences during the previous 2 weeks and to score each item 
on a 7-point scale. The overall AQLQ score is the mean response to all 32 questions (Juniper et 
al 1992, and Juniper et al 1993). Clinically important differences in scores between any two 
assessments have been determined by the authors of the AQLQ. Changes in scores of 0.5 are 
considered clinically meaningful; changes of 1.0 are considered as moderate and > 1.5 as large 
changes for any individual domain or for the overall summary score (Juniper et al 1994).
AQLQ should be completed at Visits 102 and 204.
 


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6.4.4
Electronic Diary
At Visit 1, all patients will be provided with an electronic diary (referred to as an eDiary) to 
record rescue medication (salbutamol/albuterol) use and clinical symptoms, the PEF and 
compliance with the study treatment (starting in Visit 101). The patients will be instructed to 
routinely complete the eDiary twice daily – at the same time each morning and again 
approximately 12 hours later in the evening. The eDiary is to be reviewed by study site 
personnel at each clinic visit until study completion. Sites and patients will receive appropriate 
training and guidance on the use of the eDiary device. A list of the asthma control eDiary
questions is provided in Appendix 7.
6.4.5
Peak Expiratory Flow (PEF)
An electronic Peak Flow Meter part of the eDiary device will be provided to each patient at 
Visit 101 for the measurement of morning and evening PEF during the Run-in and treatment 
periods. 
PEF will be measured at consistent times for a patient, in the morning and evening each day 
during the study from Visit 101 to 204 and TD Visit (if applicable). The measurements will be 
performed using an e-Peak Flow Meter provided to the patients at Visit 101. PEF will be 
measured twice a day; once in the morning and once approximately 12 hours later in the evening 
(prior to evening dose) from Run-in throughout the study. Patients should be encouraged to 
perform morning and evening PEF measurements BEFORE taking rescue medication. At each 
time point, the patient should be instructed to perform 3 consecutive maneuvers within 10 
minutes. These PEF values are captured in the e-PEF/diary. The best of 3 values will be used.
6.4.6
Rescue Medication Usage
The use of rescue salbutamol/albuterol should be recorded by patients in their eDiary twice each 
day in the morning and evening. In the morning patients should record the number of puffs of 
rescue medication they have taken during the night and since the last diary entry, and in the 
evening patients should record the number of puffs of rescue medication they have taken during 
the day since the morning diary entry.
6.4.7
Investigational Medication Usage
In order to ensure compliance and safety follow-up, the patients will be requested to record 
once per week in the eDiary whether he/she missed any dose and from which inhalation device.
6.4.8
Worsening of asthma
Investigators and patients will be instructed how to deal with worsening of asthma symptoms. 
The data captured in the eDiary will also be used to alert the patient and/or investigator to 
possible signs of worsening asthma and to possible asthma exacerbation. The investigator must 
provide the patient with written instructions to contact the investigator if at any time during the 
trial from the Run-in onwards if one or more of the following criteria of worsening asthma 
develop:
 


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Asthma Worsening Criteria alerts

> 20% decrease in FEV1 from Baseline value (this criterion applies to Investigator review 
at the time of a study visit or possibly an alert setting if device structured to capture)

> 50% increase in SABA use and > 8 puffs per day on 2 out of any 3 consecutive days 
compared to Baseline

≥20% decrease in am or pm PEF from Baseline on 2 out of any 3 consecutive days 
compared to Baseline

< 60% of PEF compared to Baseline

Nighttime awakenings requiring SABA use on at least 2 out of any 3 consecutive nights

Urgent unscheduled clinic visit due to asthma related deterioration
Note: The reference for the worsening of asthma during the Run-in epoch would be the FEV1
and PEF taken at Visit 101. The Baseline FEV1 for the treatment epoch is taken at treatment 
Day 1 (Visit 201). The Baseline PEF (morning and evening) for the treatment epoch is 
calculated at Visit 102 and is the mean of the best of the three daily PEF measurements over 
the Run-in period.
If any of the above criteria, including the alert from eDiary are met while a patient is in the Run-
in or treatment epoch, the investigator should assess the patient’s condition. If this occurs during 
the Run-in epoch, and it is considered a clinically significant asthma worsening in the 
investigator’s opinion, the patient should be treated for asthma worsening as appropriate and 
discontinued prior to randomization. Once the condition is resolved, if eligibility criteria are 
met, the patient may be considered for re-screening.
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:

Review alert trends over time, in particular PEF decreases.

Call the patient promptly to assess the clinical status when any specific alert type (e.g.,
PEF < 60%) is received on consecutive days. This may include urgent clinic visits as 
appropriate and/or immediate treatment.

Implement prompt clinical treatment as deemed necessary by the investigator.
If patient believes that his/her symptoms are worsening and/or has received alerts as outlined 
above the patient should notify the investigator in order to be evaluated and treated as clinically 
appropriate. Patient should be instructed to visit emergency room / hospital if deemed necessary.
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.
6.4.9
Asthma Exacerbation
A severe asthma exacerbation (Draft note for guidance on clinical investigation of medicinal 
products for treatment of asthma: CHMP/EWP/2922/01 Rev.1) is defined as an aggravation of 
 


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asthma symptoms (like shortness of breath, cough, wheezing, or chest tightness) that requires 
systemic corticosteroids (SCS) for at least three consecutive days and/or a need for an ER visit
or hospitalization due to asthma or death due to asthma.

Start date and end date:

In case of the use of SCSs for at least three days, the first day of treatment will 
determine the onset date of the event while the last day of treatment will define 
the stop date.

In the event that an ER visit and/or hospitalization due to asthma exacerbation 
were not associated with a course of SCSs as described above, start and end dates 
would be defined by the corresponding dates entered by the Investigator in the 
eCRF.
A moderate asthma exacerbation in this protocol is defined as the occurrence of two or more 
of the following: 
1. Progressive increase of at least one of the asthma symptoms like shortness of breath, 
cough, wheezing, or chest tightness. The symptoms should be outside the patient’s 
usual range of day-to-day asthma and should last at least two consecutive days.
2. Increased use of “rescue” inhaled bronchodilators defined by:
> 50% increase in SABA use and > 8 puffs on 2 out of any 3 consecutive days 
compared to Baseline captured.
Or
Nighttime awakenings requiring SABA use on at least 2 out of any 3 consecutive 
nights.
3. Deterioration in lung function, which last for two days or more but usually not severe 
enough to warrant SCSs for more than 2 days or hospitalization. This deterioration would 
be defined by:
> 20% decrease in FEV1 from baseline value.
Or
≥20% decrease in am or pm PEF from baseline on 2 out of any 3 consecutive days 
compared to baseline.
Or
< 60% of PEF compared to baseline.
A mild asthma exacerbation is defined as the occurrence of one of the following criteria:
1. Deterioration of at least one asthma symptoms like shortness of breath, cough, wheezing,
or chest tightness. 
2. Increased use of “rescue” inhaled bronchodilators.
3. Deterioration in lung function, which last for two days or more but usually not severe 
enough to warrant SCS or hospitalization. 
This deterioration would be defined by:
> 20% decrease in FEV1 from baseline value.
Or
 


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≥20% decrease in am or pm PEF from baseline on 2 out of any 3 consecutive days 
compared to Baseline.
Or
< 60% of PEF compared to Baseline.
“Start and end dates” of each reported event in the eCRF will be used to determine whether two 
consecutively reported events should be considered as separate events or as a prolonged.
If a second exacerbation is reported less than 7 days after the end date of a previous episode, 
then this will be assumed to be one continuous exacerbation with the start date taken from the 
first episode and the end date from the second or last episode. If two events are merged based 
on this “7 day rule”, the highest reported severity will be used to describe the overall severity 
of the prolonged event.
The treatment of asthma exacerbations including the initiation of systemic corticosteroids
should be done according to investigator’s or treating physician’s medical judgement and 
should be in line with national and international recommendations. 
6.4.10
Appropriateness of efficacy assessments 
The efficacy assessments selected are standard for this indication/patient population. 
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

AEs including asthma exacerbations and serious AEs

Pregnancy (female patients)

Serious asthma outcomes (asthma-related hospitalizations, intubations or deaths)
ECG and laboratory assessments will be centralized.
Additional pregnancy testing might be performed if requested by local requirements.
6.5.1
Physical examination
A physical examination will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, and 
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 101, 204 or TD 
visit (if applicable). 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 granted must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
 


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eCRF. Significant findings made after informed consent (Visit 1) is given which meet the 
definition of an AE must be recorded on the AE screen of the patient’s eCRF.
6.5.2
Vital signs 
Systolic and diastolic blood pressure and radial pulse rate (over a 30 second interval), performed 
in the sitting position, will be recorded at each scheduled clinic visits as detailed in Table 6-2. 
(at Visits 101, 102, 201, 202, 204 or TD Visit, if applicable). Vital sign should be measured 
directly after the ECG assessments.
6.5.3
Height and weight 
Height in centimeters (cm) will be measured at Visit 101 for all patients. In adolescents the 
height will additionally be measured at Visit 204 (or TD Visit if applicable). Body weight (to 
the nearest 0.1 kilogram in indoor clothing, but without shoes) will be measured at Visit 101, 
204 (or TD Visit if applicable). 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, urinalysis
 
) will be performed at Visit 101, 201, 204 and TD Visit if applicable.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured.
6.5.4.2
Clinical chemistry
Albumin, alkaline phosphatase, aspartate aminotransferase (AST) or Serum Glutamic-
Oxaloacetic Transaminase (SGOT), alanine aminotransferase (ALT) or Serum Glutamic 
Pyruvic Transaminase (SGPT), bilirubin, creatinine, gamma-glutamyl transferase (γ-GT), 
glucose, potassium, magnesium, blood urea nitrogen (BUN) and uric acid will be measured.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal range, 
total bilirubin should be differentiated into the direct and indirect reacting bilirubin.
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will be performed 
at Visits 101, 201, and 204, or TD (if applicable).
 


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If the urine dipstick result is abnormal at site, then the sample will be sent to central laboratory 
for additional testing, including assessment of WBC and RBC sediments.
6.5.4.4
Hepatotoxicity
Any liver event which meets the criteria for “medically significant” event as outlined in Table 
8-1 in Appendix 8 should follow the standard procedures for SAE reporting as described in 
Section 7.2.
6.5.4.5
Plasma Cortisol
Evening plasma cortisol will be measured at Visits 201, 204 and TD Visit if applicable. The 
sampling point is as shown in Table 6-1 and Table 6-2.
6.5.5
Electrocardiogram (ECG) 
ECGs should 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 101, 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 Visits 201, and 204, ECGs will be measured at -35min pre-dose (evening dose) 
and post dose 1 hour, as indicated in Table 6-2. All ECGs should include 12 standard leads. An
ECG tracing will be taken for those patients who prematurely discontinue from the study 
treatment.
For each ECG performed original trace should be printed. Each ECG will be sent electronically 
for central review directly from the ECG machine. One print-out will be generated and kept at 
the investigator site as source documentation and will be dated and signed. The patient's number, 
the date, actual time of the tracing, and Study Code must appear on each page of the tracing.
Full details of all procedures relating to the ECG collection and reporting will be contained in 
an investigator manual to be provided by the central laboratory to each investigator site. In the 
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 study drug.
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.
 


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Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/current medical conditions/AE eCRF page as appropriate.
6.5.6
Serious asthma outcomes
Asthma-related hospitalizations, asthma-related intubations or asthma-related deaths over the 
12-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 plasma 
and urine pregnancy test will be performed (tests provided by the Central Laboratory) per 
Assessment Table 6-1. A positive urine pregnancy test at Visit 1, Visit 102 and positive serum
pregnancy test at Visit 101 or Visit 202 or Visit 204 or TD Visit if applicable 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 7.4 for more details. 
Additional pregnancy testing might be performed if requested by local authorities.
6.5.8
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population.
 


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7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a patient or 
clinical investigation patient 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.
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient during 
or between visits or through physical examination, laboratory test, or other assessments.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

induce clinical signs or symptoms, 

considered clinically significant, 

require therapy. 
Clinically significant abnormal laboratory values or test results should 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 AEs.
AEs must be recorded in the AE eCRF 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 or No):
“No Relationship to study treatment or other investigational treatment” or
“Relationship to study treatment” or
“Relationship to other investigational treatment” or 
“Relationship to both study treatment and other investigational treatment or 
indistinguishable”.

Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
 


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
Whether it constitutes a SAE, as defined in Section 7.2 and which seriousness criteria 
have been met.

Action taken regarding the study treatment. All AEs should be treated appropriately. 
Treatment may include one or more of the following: 

no action taken (e.g., further observation only) 

[investigational] treatment dosage increased/reduced

[investigational] treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

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 AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should 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. Investigators should be familiar with known 
potential adverse events outlined in the IB as well as local labelling. If patients experience such 
AEs (or any AE), they should be treated as considered clinically appropriate. This may include 
discontinuation from treatment medication.
The investigator should 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 should 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 AE (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
 


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
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e., 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 more severe (Annex IV, ICH-E2D Guideline 2003).
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 (Annex IV, ICH-E2D Guideline 2003).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the eCRF. SAEs are also required for 
individual reporting to Drug Safety & Epidemiology DS&E) as per Section 7.2.2.
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 within 24 hours of the investigator learning of its occurrence / receiving follow up 
information. Any SAEs experienced after the 30 day period after the last study visit should only 
be reported to Novartis if the investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
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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, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study drug 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 drug 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 European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries.
7.2.3
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 a by radiologist's interpretation of a chest X-ray 
(to be kept in the source documents). If not confirmed by X-ray, it should be reported as lower 
respiratory tract infection. 
7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities/AEs 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 eCRF pages
 


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Please refer to Table 8-1 in Appendix 8 for complete definitions of liver laboratory triggers and 
liver events.
Every liver laboratory trigger or liver event as defined in Table 8-1 in Appendix 8 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 8-2 in Appendix 8.
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats should 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 should 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 should be reported on the Liver eCRF 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 should be recorded on appropriate eCRF pages, including the liver 
event overview eCRF pages.
7.4
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing of 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 following the birth of your child to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy 
follow up period can be increased if requested by health authorities.
Pregnancy should 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 investigational/study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
 


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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 eCRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the eCRFs, 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 Clinical Research Associate (CRA) organization. Additionally, a central analytics 
organization may analyze data and identify risks and 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, ECGs, and the results of any other tests or assessments. All 
information on eCRFs 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 eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the (OC/RDC)
system. Designated investigator site staff will not be given access to the system until they have 
been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the eCRFs 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 (or a designated Contract Research Organization (CRO)) staff will review the 
data entered into the eCRFs by investigational staff for completeness and accuracy and instruct 
the site personnel to make any required corrections or additions. Queries are sent to the 
 


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investigational site using an electronic data query. Designated investigator site staff is required 
to respond to the query and confirm or correct the data.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification (ATC) 
system. Concomitant procedures, non-drug therapies and AEs 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 (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to Novartis
(or a designated CRO).
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.
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
An independent, external data safety monitoring committee (DMC) will be set up to review all 
SAEs (including deaths and all hospitalizations). DMC members will review this data generated 
externally and independently of Novartis, at predetermined intervals. If significant safety issues 
arise in between scheduled meetings, ad-hoc meetings will be scheduled to review the data. 
Based on the safety implications of the data, the DMC may need to recommend modification 
or termination of the study. 
The details of the information flow, confidentiality and specific analyses required for the safety 
monitoring analysis will be documented in a DMC Charter. 
The DMC is the autonomous data and safety advisory group for Novartis. The DMC charter 
will be developed as a separate document. The charter will define: 
1. Membership of DMC 
2. Responsibilities of DMC and Novartis 
 


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3. Responsibilities of independent biostatistician and programmer 
4. The relationship of DMC with other trial components and data flow 
5. The purpose and timing of DMC meetings 
6. Procedures for ensuring proper confidentiality, addressing conflict of interest, and ensuring 
proper communication 
The charter complies with Novartis SOPs and is in accordance with the FDA guidance and 
CHMP guidelines on DMCs. 
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 randomization 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 blinded, pertinent patient data and the supporting 
documentation to settle the specified adjudication objectives.
Further details will be provided in the Adjudication Committee Charter.
8.6
Advisory Board
An Advisory Board will be established. This board will consist of a group of independent non-
sponsor clinical experts and clinical/medical/statistical sponsor representatives. 
In general, the functions of the advisory board may include:

Data interpretation 

Publications

Presentations
9
Data analysis 
The analysis will be conducted on all patient data at the time the trial ends. Measurements made 
after patients discontinue randomized treatment (off-treatment measures) will not be used for 
any efficacy evaluation.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
9.1
Analysis sets 
The following analysis sets are defined for data analysis.
The randomization (RAN) Set will consist of all patients who were assigned a randomization 
number, regardless of whether or not they actually received study medication.
 


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The Full Analysis Set (FAS) will consist of all patients in the RAN set who received at least 
one dose of study medication. Following the intent-to-treat principle, patients will be analyzed 
according to the treatment they were assigned to at randomization.
The Per-Protocol Set (PPS) will include all patients in the FAS who did not have any major 
protocol deviations. Major protocol deviations will be defined in the statistical analysis plan 
prior to database lock and the unblinding of the study. Patients will be analyzed according to 
the treatment they received.
The Safety Set will consist of all patients who received at least one dose of study medication. 
Patients will be analyzed according to the treatment they received.
 
 
The FAS will be used in the analysis of all efficacy variables. The RAN set will be used for a 
summary of patient disposition, demographics and baseline characteristics. The PPS will be 
used for supportive analysis of the primary analysis only. The Safety Set will be used in the 
analysis of all safety variables.
Note that the FAS and Safety Sets are the same except that the Safety Set allows the inclusion 
of non-randomized patients who received study drug in error. Also, the FAS assigned
randomized treatment and the Safety Set assigned received treatment.
9.2
Patient demographics and other baseline characteristics 
Demographic and baseline characteristics measured before randomization including age, 
gender, race, ethnicity, height, weight, BMI, relevant medical history, Screening spirometry 
parameters: (FEV1, FVC, FEV1/FVC and FEF25-75), FEV1 reversibility, percentage of predicted 
FEV1, 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, radial pulse rate), QTc using Fridericia’s correction and
baseline ACQ-7 and AQLQ will be summarized by treatment group.
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.
Baseline is defined as the last measurement before first dose of study drug.
No statistical analyses will be provided for baseline comparability among the treatment groups.
9.3
Treatments 
Study drug administration and concomitant medication data will be listed and summarized 
using Safety set. 
The duration of exposure and the number of patients randomized who completed the study and 
who discontinued from study medication will be summarized.
 


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Medications started and stopped prior to study drug, and taken concomitantly will be 
summarized by treatment group in separate tables in the Safety Set.
Concomitant therapies will be recorded, listed and summarized separately for asthma related
medications/non-drug therapies and other medications. Concomitant asthma related
medications will be summarized by the route of administration, the recorded pre-specified drug 
subcategories (including types of combination) and preferred terms. The summary will be 
repeated by showing ingredients instead of preferred terms. 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. 
Patients taking prohibited concomitant medications will be noted in the summary of protocol
deviations.
Treatment compliance with study medication over the study period will be summarized.
9.4
Analysis of the primary variable
9.4.1
Primary variable
The primary variable is trough FEV1 after 12 weeks of treatment. 
9.4.2
Statistical model, hypothesis, and method of analysis
The comparison of QMF149 150/80 microgram versus MF 200 microgram will be evaluated 
by testing the following null hypothesis (H0) versus the alternative hypothesis (Ha):
H0: QMF149 treatment group is equal to MF treatment group in trough FEV1 at Week 12
Ha: QMF149 treatment group is not equal to MF treatment group in trough FEV1 at Week 12
The primary variable will be analyzed using a mixed model for repeated measure (MMRM) on 
the FAS. The model will contain treatment, age (≥12 to < 18 or ≥18 years), region, visit (Days 
2 and 85), and treatment-by-visit interaction as fixed effects with baseline FEV1 measurement, 
baseline-by-visit interaction, FEV1 prior to inhalation and FEV1 within 15 to 30 min post 
inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates, and center 
nested within region as a random effect. The within-patient correlation will be modeled using 
an unstructured covariance matrix in the mixed model. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom (Kenward and Roger, 1997). If the model 
does not converge with unstructured covariance matrix, the compound symmetry covariance
matrix will be used in the mixed model. The restricted maximum likelihood method will be 
used. The between-treatment comparison will be carried out using the adjusted mean (least
squares mean (LS mean)) difference based on the treatment main effect and the coefficient for
the treatment-by-visit interaction for Day 85.
The estimated adjusted treatment difference (QMF149 – MF) will be displayed along with the 
associated standard error, 2-sided 95% confidence interval (CI), and p-value (2-sided). 
 


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9.4.3
Handling of missing values/censoring/discontinuations
If any of the 23 hours 15 min and 23 hours 45 min values contributing to the trough FEV1 is 
collected within 7 days of systemic corticosteroid use, within 6 hours of rescue medication, or 
if the actual measurement times are outside the 22-25 hour post-evening dose time then the 
individual FEV1 value will be set to missing.
If one of the two values is missing (or set to missing), then the remaining non-missing value 
will be taken as trough FEV1. If both values are missing, or if the patient withdrew from the 
study (regardless of the reason for discontinuation) then trough FEV1 will be regarded as 
missing in which case the missing value(s) of the patient at the particular visit(s) would not 
directly contribute to the primary analysis.
The MMRM which is used for the primary variable is based on missing at random mechanism 
for the missing values and assesses the treatment effects of trough FEV1 without explicit 
imputation.
9.4.4
Multiplicity adjustment
A hierarchical testing procedure will be applied to control the type-I error rate for the primary 
and the key secondary endpoints, i.e., the key secondary endpoint ACQ-7 will be tested only 
if the primary endpoint (trough FEV1) is significant at the 2-sided 0.05 level. 
9.4.5
Supplementary analysis 
As supplementary analysis, the same MMRM used in the primary analysis will be also 
performed on the PPS to assess the treatment effect in protocol adherers. The same primary 
MMRM on the FAS will be performed including all spirometric measures irrespective of 
systemic corticosteroid or rescue medication use but those measures taken outside of the 22-25
hour post-evening dose time will not be included.
The following exploratory subgroup analyses for trough FEV1 using MMRM will be performed 
(using the appropriate interaction term in the model and additional covariate as a fixed effect if 
necessary) for the FAS population to explore the treatment effect in:

Age group (≥12 to < 18 years, ≥18 years)

Race (Caucasian, Black, Asian, Other)

Gender (male, female)

History of asthma exacerbation in the 12 months prior to Screening (Yes, No)

Patients’ prior therapies before Run-in period (e.g., low dose ICS without LABA, low 
dose ICS with LABA)

FEV1 response according to percent predicted FEV1 range at Baseline (60% to < 70%, 
70% to < 90%, and < 60% or ≥ 90% in case of protocol deviations)

ACQ-7 Baseline (1 to < 1.5, 1.5 to < 2, 2 to < 2.5, ≥2.5)
9.5
Key secondary variable
The key secondary variable is ACQ-7 after 12 weeks of treatment. 
 


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It will be analyzed using the same MMRM (including all available visits) on the FAS as used 
for the primary analysis but will include Baseline ACQ-7 score instead of Baseline FEV1.
9.6
Analysis of secondary variables
9.6.1
Efficacy variables 
9.6.1.1
Spirometry
All spirometric efficacy variables will be analyzed for the FAS, unless otherwise specified.
Spirometry measurements taken within 7 days of systemic corticosteroid use within 6 hours of 
rescue medication use or if the actual measurement times are outside the 22-25 hour post 
evening dose time, then the individual FEV1 value will be set to missing and not be imputed, 
unless specified otherwise.
Spirometry data by visit
Trough FEV1 at Day 2 visit will be analyzed using the same MMRM as specified for the primary 
analysis, i.e., the visit factor will include all available visits as a factor and between-treatment 
comparison will be carried out using the adjusted mean (least-square mean) difference based 
on the treatment main effect and the coefficient for the treatment-by-visit interaction for the 
respective visit and treatment. Adjusted mean (LS mean) will be displayed for each treatment 
group along with the estimated treatment differences and the 95% confidence intervals and the 
two-sided p-values by visit.
Similar analyses will be performed for pre-dose trough FEV1, post-dose FEV1, pre and post-
dose FVC and pre and post-dose FEF25-75. 
9.6.1.2
ACQ-7
Analysis results for all post-baseline visits, obtained from the MMRM for the key secondary 
endpoint ACQ-7, will be displayed. In addition, analysis for change from baseline in the ACQ-
7 will be performed.
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 analyzed using a 
logistic regression model. The model will include terms for treatment, age (≥12 to < 18 years, 
≥18 years) , region, visit, and treatment-by-visit interaction as fixed effects, and Baseline ACQ-
7, Baseline-by-visit interaction, FEV1 prior to inhalation and FEV1 within 15 to 30 min post 
inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates. The 
estimated adjusted odds ratio will be displayed along with the associated 95% (2-sided) 
confidence interval and p-value.
9.6.1.3
Rescue medication
The number of puffs of the rescue medication use in the last 12-hour is recorded twice daily 
(morning/evening) by the patient in his/her eDiary. The mean daily number of puffs of rescue 
medication use over the 12 weeks of treatment will be summarized by treatment. The mean 
change from Baseline in the daily number of puffs of rescue medication use will be analyzed
 


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using an (ANCOVA) model. The model will contain treatment, age (≥ 12 to < 18, or ≥18), 
region as fixed effect factors with center nested within region as a random effect and, baseline 
rescue medication use, FEV1 prior to inhalation and FEV1 within 15 to 30 min post inhalation 
of salbutamol/albuterol (components of SABA reversibility) as covariates. No imputation will 
be done for missing data. The adjusted mean (LS mean) treatment difference along with the
corresponding two-sided 95% confidence interval and corresponding p-value will be presented. 
This analysis will be performed for morning (nighttime), evening (daytime), and daily (average 
of nighttime and daytime) rescue medication use.
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 by treatment and
analyzed the same way as described for the number of puffs of the rescue medication use with 
appropriate baseline as a covariate. 
In addition, the mean number of puffs of rescue medication per day, in the morning and in the 
evening and the percentage of ‘days with no rescue use’ will be summarized by 4 weekly (28 
days) intervals and analyzed using a similar MMRM as specified for the primary analysis with
the baseline FEV1 value replaced with the appropriate baseline rescue medication use.
9.6.1.4
Peak Expiratory Flow Rate (PEF)
All the patients are instructed to record PEF twice daily using an electronic Peak Flow Meter 
device, once in the morning and once approximately 12 hours later in the evening (prior to 
evening dose), from Run-in Visit 101 and throughout the study.
PEF (liters/min) will be averaged separately for morning and evening values with means over 
the 12 weeks treatment phase and the 3 weeks Baseline Run-in phase. 
Mean morning/evening PEF will be summarized by treatment. The between-treatment 
difference of the change from baseline in mean morning/evening PEF will be analyzed using 
the same model as specified for rescue medication data except that baseline rescue medication 
use will be replaced with baseline morning/evening PEF as the covariate. LS means and 
associated 95% confidence intervals will be presented for treatments and the treatment 
difference.
In addition, the mean morning/evening PEF will be summarized by 4 weekly intervals and 
analysed using a similar MMRM as specified for the primary analysis with baseline FEV1 value 
replaced with the appropriate baseline PEF.
9.6.1.5
Asthma symptoms based on eDiary
The eDiary data on asthma symptoms will be summarized for:

the mean daytime asthma symptom score

the total daily symptom score

percentage of days with no daytime symptoms

percentage of nights with no nighttime awakenings

percentage of mornings with no symptoms on rising
 


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
percentage of asthma symptoms free days, i.e., days with no daytime symptoms and no 
nighttime awakenings and no mornings with symptoms on rising
The same ANCOVA model as used for the analyses of rescue medication will be used with the 
appropriate baseline value as a covariate.
In addition, summarizations will be performed by 4 weekly intervals and analyzed using a 
similar MMRM as specified for the primary analysis but including the appropriate visits and 
baseline as a covariate.
9.6.1.6
Asthma exacerbations
The following asthma exacerbation-related parameters over the 12 weeks will be summarized 
by treatment (asthma exacerbation is defined in Section 6.4.9). The analysis will be performed 
by exacerbation category wherever specified. The exacerbation categories are: All (mild, 
moderate, severe) and the combination of either moderate or severe. 

Time to first asthma exacerbation by exacerbation category

The annual rate of asthma exacerbations by exacerbation category 
Time-to-event variables will be analyzed using a Cox regression model stratified by age (≥12 
to < 18 years, ≥18 years). The model will include treatment, region and history of asthma 
exacerbation in the 12 months prior to Screening (Yes, No) as fixed-effect factors, and FEV1
prior to inhalation and FEV1 within 15 to 30 min post inhalation of salbutamol/albuterol 
(components of SABA reversibility) as covariates. The estimated adjusted hazard ratio for 
QMF149 over MF will be displayed along with the associated two-sided 95% confidence 
interval and corresponding p-value.
Kaplan-Meier analysis stratified by treatment group will be also presented and displayed 
graphically.
Number of the asthma exacerbation will be analyzed using a generalized linear model assuming 
the negative binomial distribution including treatment, age (≥12 to < 18 years, ≥18 years), and 
region and history of asthma exacerbation in the 12 months prior to Screening (Yes, No) as 
fixed-effect factors, and FEV1 prior to inhalation and FEV1 within 15 to 30 min post inhalation 
of salbutamol/albuterol (components of SABA reversibility) as covariates. The log exposure in 
years will be included as an offset variable in the model. The estimated rate ratio along with 
two-sided 95% interval and corresponding p-value will be provided.
9.6.1.7
Asthma Quality of Life Questionnaire (AQLQ-S+12)
Asthma Quality of Life Questionnaire is a 32-item disease specific questionnaire designed to 
measure functional impairments that are most important to patients with asthma, with 7-point 
scale (1-totally limited/problems all the time, 7-not at all limited/no problems). It consists of 4 
domains: symptoms, emotions, exposure to environmental stimuli and activity limitation. Mean 
score will be calculated for the four domains, as well as the overall quality-of-life score defined 
as the mean score of all 32 items.
 


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For the overall score and each respective domain score measured at Week 12, treatment group 
comparison will be performed using the same ANCOVA model as specified for rescue 
medication use with baseline AQLQ as covariate.
The proportion of patients who achieve an improvement of at least 0.5 at Week 12 in the change 
from baseline in AQLQ (i.e., increase of AQLQ score of at least 0.5 from baseline) will be 
analyzed using a logistic regression model on the FAS. The model will include terms for 
treatment, age (≥12 to < 18 years, ≥18 years), region as fixed effects, and baseline AQLQ, 
FEV1 prior to inhalation and FEV1 within 15 to 30 min post inhalation of salbutamol/albuterol 
(components of SABA reversibility) as covariates.
9.6.2
Safety variables 
All safety variables will be summarized for the safety set.
9.6.2.1
Serious asthma outcomes
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 time of randomization 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. If a sufficient number 
of events will occur, similar analyses as described for asthma exacerbations will be performed. 
Otherwise, a purely descriptive analysis will be done only.
9.6.2.2
Adverse events
All treatment emergent AEs including asthma exacerbations will be summarized and listed. 
AEs 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 inhalation will be classified as a treatment emergent 
AE. Any AEs that started during the study before the time of the first inhalation of study drug 
will be classified as a prior AE. 
The following treatment emergent AE summaries will be produced, overall by system organ 
class and preferred term, overall by system organ class, preferred term and maximum severity, 
suspected drug-related AEs by system organ class and preferred term, SAEs by system organ 
class and preferred term, and AEs leading to permanent discontinuation of study-drug by system 
organ class and preferred term.
The number and percentage of patients with the most frequent AEs will be summarized by 
treatment. 
In addition, AEs will be summarized by standardized MedDRA query (SMQ) level. The 
Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify AEs of special interest which will be summarized too. 
Fatal AEs will be summarized by adjudicated reason for death.
 


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9.6.2.3
Electrocardiogram (ECG) and vital signs
ECG data, vital signs (systolic and diastolic blood pressure and radial pulse rate) data, and body 
weight will be summarized by treatment, visit, and time point, including changes from baseline.
The maximum (QTc, systolic blood pressure, radial pulse rate and heart rate) or minimum 
(diastolic blood pressure) post first dosing (i.e., post-baseline) value will also be summarized. 
All data will be included in the analysis regardless of rescue medication usage.
The number (%) of patients with radial 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 
by treatment group, visit and time point.
Notable values for vital signs and change from baseline will be summarized by treatment group, 
visit and time point. Additionally, the number and percentage of patients with notable values at 
any time on treatment considering all post-baseline data from scheduled, unscheduled and 
premature discontinuation visits 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
Radial 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 changes from baseline will be summarized in a similar way. A notable 
value is defined as a QTc interval of greater than 450 ms (male), 460 ms (female) and 500 ms
(both). The number of newly occurring or worsening notable QTc values will be shown for 
post-baseline time points and overall (i.e., at any time on treatment considering all post-baseline 
data from scheduled, unscheduled and premature discontinuation visits). 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) using Fridericia’s formula:
QTc = QT/3√RR, where 3√denotes the cube root
Vital signs and 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.
9.6.2.4
Laboratory data
The laboratory parameters (hematology, blood chemistry including glucose and potassium, 
urinalysis and evening plasma cortisol) will be summarized by treatment, visit and time point, 
including changes from baseline. The baseline measurement will be the 20 min pre-dose 
 


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measurement at Visit 201. The maximum blood glucose or minimum serum potassium post first 
dosing (i.e., post-baseline value) will also be summarized. 
All laboratory data will be listed with abnormal values flagged. 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.
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria will be 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. Similar analysis will be done for newly occurring or worsening 
abnormalities in liver function tests (LFT).
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.
9.6.2.5
Unscheduled primary and secondary care visits due to asthma 
worsening
Worsening of asthma symptoms may require unscheduled evaluation between visits. The on-
treatment data related to asthma worsening collected will be listed and summarized 
descriptively. 
9.6.3
Safety monitoring analysis
It is planned that the independent DMC will review semi-blinded (i.e., treatment group named 
as A or B) safety data. The details of the information flow, confidentiality and specific analyses 
required for the safety monitoring analysis will be documented in the DMC Charter. The 
Charter will be finalized prior to semi-blinding the data for the safety monitoring analysis. Since 
the purpose of the DMC is not based on efficacy (no interim analysis for efficacy has been 
planned) for stopping rule, there will be no alpha spent for the safety monitoring analysis. All 
analyses will be considered exploratory.
 


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9.7
Sample size calculation
The sample size calculation takes into account the following consideration:
1. To achieve at least 90% power for the primary endpoint trough FEV1 with a treatment 
difference of 100 mL between QMF149 vs. MF, assuming a standard deviation of 380 
mL based on internal studies CQMF149A2210, CQMF149E2201, CQMF149E2203 
and literature data, where  most observed treatment effects range approximately 80 mL 
to 120 mL.
2. To achieve at least 75% power (with multiplicity adjustment) for the secondary 
endpoint ACQ-7 with a treatment difference of -0.18 between QMF149 vs. MF, 
assuming a standard deviation of 0.80 based on study CQMF149A2210, where  
observed treatment difference was -0.21 with 95% confidence interval (-0.28, -0.15);
If 10% dropout rate is assumed, then calculation shows the sample size of 750 patients (i.e.,
375/arm) will provide approximately 93% power for item 1 and 77% power for item 2 with 
multiplicity adjustment.
The sample size calculation is performed in PASS Software.
10
Ethical considerations 
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.
Participation of patients and in particular adolescent patients in this study will be based on the 
local regulations and ethics committee requirements in various participating countries.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing (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. 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. Patients below the legal age of consent are required to have the 
 


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Parental Informed Consent signed by the patient’s parent/guardian; adolescents are required to 
sign the Assent Form.
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form.
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 should 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 
should 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, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made.
10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
10.5
Quality control and quality assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those involved 
 


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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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances, including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 
not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants. 
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 may be implemented immediately provided the health authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed.
 


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12
References
References are available upon request.
[Annex IV, ICH-E2D Guideline (2003)] Available from ich.org website
[Beasley R et al (2015)] Effect of once-daily indacaterol maleate/mometasone furoate on
exacerbation risk in adolescent and adult asthma: a double-blind randomized controlled trial; 
BMJ Open 2015;5:e006131. doi:10.1136/bmjopen-2014-006131.
[European Medicines Agency (2013)] Note for guidance on clinical investigation of medicinal 
products for treatment of asthma. CHMP/EWP/2922/01-Rev.1.
[FDA warning for Advair Diskus prescription information; ALERT [11/2005] Information for 
Healthcare Professionals - Fluticasone propionate; Salmeterol xinafoate (marketed as Advair 
Diskus.
[Global Initiative for Asthma (GINA) (2016)] Global Strategy for Asthma Management and 
Prevention. ‘Available from ginasthma.org website’
[Juniper EF, et al (1992)] Evaluation of impairment of health-related quality of life in asthma: 
development of a questionnaire for use in clinical trials. Thorax; 47: 76-83. 
[Juniper EF, et al (1993)] Measuring quality of life in asthma. Am Rev Respir Dis; 147: 832-
838. 
[Juniper EF et al (1994)]Determining a minimal important change in a disease-specific quality 
of life questionnaire. J Clin Epidemiol; 47: 81-87.
[Juniper EF et al (1999)] Development and validation of the questionnaire to measure asthma 
control. Eur Resp J; 14:‘902-7’.
[Juniper EF et al (2005)] Measurement properties and interpretation of three shortened versions 
of the asthma control questionnaire. Respir Med 99:553-8.
[Juniper EF et al (2006)] Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using 
the Asthma Control Questionnaire. Respir Med; 100: 616-621.
[Kenward MG and Roger JH (1997)] Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics 53(3):983-97.
[Vaidya S, et al (2012)] Pharmacokinetics (PK) of single doses of mometasone furoate (MF) 
delivered via the Breezhaler® (BH) and Twisthaler® (TH) devices in healthy subjects. Eur 
Respir J; 40 (Suppl 56): P382.
 


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13
Appendices
Appendix 1: Instructions 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
The study drug package consists of both the inhaler and one or more blister-packaged 
capsules.

Capsules are supplied in blisters.

Inhaler consists of a cap, mouthpiece and a base.
Your inhaler is designed to deliver the medicine contained within the capsules.
Do not use the study medication capsules with any other capsule inhaler, and do not use the 
inhaler to take any other capsule medicine.
How to use your inhaler
Pull off cap.
 


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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.
Close the inhaler:
You should hear a “click” as the mouthpiece closes onto the 
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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.
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 
 


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


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After you have finished taking your medicine:

You may be directed by your physician to rinse mouth 
with water and spit it out; do not swallow the water.

Open the mouthpiece again, and remove the empty 
capsule by tipping it out of the capsule chamber. Put the 
empty capsule in your household waste.

Close the inhaler and replace the cap.
Do not store the capsules in the inhaler.
REMEMBER:

Do not swallow capsules.

Only use the inhaler contained in this pack.

Capsules must always be stored in the blister, and only removed immediately before use.

Never place a capsule directly into the mouthpiece of the inhaler.

Do not press the side buttons more than once.

Never blow into the mouthpiece of the inhaler.

Always release the push buttons before inhalation.

Never wash the inhaler with water. Keep it dry. See “How to clean your inhaler”.

Never take the inhaler apart.
Always use the new inhaler that comes with your new medication pack. Dispose the inhaler 
after maximum 30 days of use.

Do not store the capsules in the inhaler.

Always keep the inhaler and capsules in a dry place, and avoid very hot or cold 
temperatures.
How to clean your inhaler

Clean your inhaler once a week.

Wipe the mouthpiece inside and outside to remove any powder with a clean, dry lint-free 
cloth.

Do not wash your inhaler with water. Keep it dry.

Do not take the inhaler apart.
 


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Appendix 2: Instructions for Use of Twisthaler®
HOW TO USE
Before first use, remove the TWISTHALER® from its foil pouch.
Step 1.Open inhaler
Hold the inhaler straight up with the portion (the base) on the bottom (Figure 1). It is important 
that you remove the cap of the TWISTHALER® while it is in this upright position to make sure 
that you get the correct dose.
Figure 1-Cap Removal
Holding the base, twist the cap in a counterclockwise direction to remove it. As you lift off the 
cap, the dose counter on the base will count down by one. (If you began with the dose counter 
reading "60", this action will cause it to now read "59".) This action loads the device with the 
dose that you are now ready to inhale.
IT IS IMPORTANT TO NOTE that the indented arrow (located on the portion of the 
TWISTHALER®, directly above the base) is pointing to the dose counter (Figure 2).
Figure 2
 


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Step 2.  Inhale dose
Exhale fully. Then bring the TWISTHALER® up to your mouth with the mouthpiece facing 
toward you. Place it in your mouth, holding it in a horizontal position as illustrated (Figure 3). 
Firmly closing your lips around the mouthpiece, take in a fast, deep breath. Since it is a very 
fine powder, you may not be able to feel or taste it after inhalation.
Figure 3-Inhalation
Remove the TWISTHALER® from your mouth and hold your breath for about 10 seconds or 
as long as you comfortable can.
IMPORTANT: DO NOT BREATHE OUT THROUGH THE INHALER.
After you use your inhaler, it is important that you wipe the mouthpiece dry, if necessary, and 
immediately replace the cap firmly closing the TWISTHALER® (Figures 4 and 5).
This is the only way to be sure that your next dose is properly loaded. Be sure that the arrow is 
in line with the dose-counter window. The cap needs to be put back on and turned in a clockwise 
direction, as you gently press down. You'll hear a distinctive "click" to let you know that the 
cap is fully closed.
Figure 4 -Closing the Inhaler
 


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Figure 5 -Closed inhaler
IT IS IMPORTANT TO REPEAT STEPS 1 AND 2 EACH TIME YOU INHALE. Rinse your 
mouth after using.
STORING YOUR INHALER
Keep your inhaler clean and dry at all times. If the device needs cleaning, gently wipe the 
mouthpiece with a dry cloth or tissue as needed. Do not wash the inhaler. Avoid contact with 
any liquids.
Store in a dry place. Avoid storing it in damp or hot conditions such as a bathroom or in your 
car.
Keep your inhaler out of the reach of young children. 
HOW TO KNOW WHEN YOUR INHALER IS EMPTY
The inhaler has a dose indicator window on the base. It is a dose counter which displays the 
number of doses remaining. When the unit reads "01", this indicates the last remaining dose. 
After dose "01", the counter will read "00", and the cap will lock and no additional dose will be 
delivered.
WHAT TO DO WITH YOUR USED INHALER
Please return all used TWISTHALER® device to the study site
 


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Appendix 3: How to Use an Accuhaler®/ Diskus®
Instructions for use
Follow the instructions below for using your Diskus® inhalation device. You will breathe in 
(inhale) the medicine from the Diskus. Do not use the Diskus unless your healthcare provider 
has taught you, and you understand everything. If you have any questions, ask the doctor, nurse 
or pharmacist personnel at the study site.
Figure 1
Parts of the Diskus
Take the Diskus out of the medication pack given to you. The Diskus will be in the closed 
position. The dose indicator on the top of the Diskus tells you how many doses are left. The 
dose indicator number will decrease each time you use the Diskus. After you have used 55 doses 
from the Diskus, the numbers 5 to 0 will appear in red to warn you that there are only a few 
doses left (see Figure 2).
Figure 2
Dose Indicator for the Diskus®
Taking a dose from the Diskus® requires the following 3 steps: Open, Click, Inhale.
1. OPEN
Hold the Diskus® in one hand and put the thumb of your other hand on the thumbgrip.  Push 
your thumb away from you as far as it will go until the mouthpiece appears and snaps into 
position (see Figure 3).
 


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Figure 3
Opening the Mouthpiece Cover
2. CLICK
Hold the Diskus® in a level, flat position with the mouthpiece towards you. Slide the lever away 
from you as far as it will go until it clicks (see Figure 4). The Diskus® is now ready to use. 
Figure 4
Sliding the Lever Until It Clicks
Every time the lever is pushed back, a dose is ready to be inhaled. This is shown by a decrease 
in numbers on the dose counter. To avoid releasing or wasting doses once the Diskus® is 
ready:

Do not close the Diskus.

Do not tilt the Diskus.

Do not play with the lever.

Do not move the lever more than once.
3. INHALE
Before inhaling your dose from the Diskus®, breathe out (exhale) fully while holding the 
Diskus® level and away from your mouth (see Figure 5). Remember, never breathe out into 
the Diskus® mouthpiece.
 


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Figure 5
Exhaling
Put the mouthpiece to your lips (see Figure 6). Breathe in quickly and deeply through the 
Diskus®. Do not breathe in through your nose.
Figure 6
Inhaling
Remove the Diskus® from your mouth. Hold your breath for about 10 seconds, or for as long 
as is comfortable. Breathe out slowly. The Diskus® delivers your dose of medicine as a very 
fine powder. Most patients can taste or feel the powder. Do not use another dose from the 
Diskus® if you do not feel or taste the medicine.
4. CLOSE
Close the Diskus® when you are finished taking a dose so that the Diskus® will be ready 
for you to take your next dose. Put your thumb on the thumbgrip and slide the thumbgrip back 
towards you as far as it will go (see Figure 7). The Diskus® will click shut. The lever will
automatically return to its original position. The Diskus® is now ready for you to take your next 
scheduled dose, due in about 12 hours. (Repeat steps 1 to 4 at that time).
 


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Figure 7
Closing the Mouthpiece Cover
Remember:

Never breathe into the Diskus®.

Never take the Diskus® apart.

Always ready and use the Diskus® in a level, flat position.

Do not use the Diskus® with a spacer device.

Never wash the mouthpiece or any part of the Diskus®. Keep it dry.

Always keep the Diskus® in a dry place.
Never take an extra dose, even if you did not taste or feel the medicine
 


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Appendix 4:  Spirometry Guidance
Equipment
Spirometers must meet the specifications and performance criteria recommended in the 
ATS/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 patient
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 patient’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 patient. The technician should ensure a good seal 
around the mouthpiece, and confirm that the patient’s posture is correct. The patient 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 
patient is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued. 
Acceptability
An acceptable maneuver has the following characteristics: 
 


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
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 patient 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 highest FEV1 and FVC from any of the acceptable curves are recorded. (The highest FEV1
and FVC may not necessarily result from the same acceptable curve).
Predicted normal
This study will utilize the spirometric predication equation standards for the European 
Community for Coal and Steel2, Nhanes3, ERS Global Lung Function Initiative (GLI)2 or 
Japanese Respiratory Society3.
Reversibility
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing
Administer 400 microgram of salbutamol/albuterol following the completion of the baseline 
assessment. A second spirometry assessment is then performed within 15 to 30 minutes after 
administration of the salbumatol/albuterol. 
Reversibility is calculated as: 
100 x       FEV1 (post β2-agonists) – FEV1 (baseline)
                                     FEV1 (baseline)
Patients will be considered reversible if an increase of at least 12% (and 200 mL) is 
demonstrated after administration of the bronchodilator. 
Predicted normal values will be calculated according to ECSC
For height measured in meters
Males: FEV1 predicted (L)=4.30x(height(meters))-0.029xage(years)-2.49
Females: FEV1 predicted (L)=3.95x(height(meters))-0.025xage(years)-2.60
 


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


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Appendix 5: ACQ-7
For illustrative purposes only:  
 


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Appendix 6: AQLQ-S +12
For illustrative purposes only:  
 


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Appendix 7: Patient Asthma Control eDiary
(For illustrative purposes only)
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 rate
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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Appendix 8: Liver Event and Laboratory Trigger Definitions and 
Follow-up Requirements
Table 8-1
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 8-2
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 eCRF
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 eCRF
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 eCRF
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
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc
(frequency at investigator 
discretion)
 


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Criteria
Actions required
Follow-up monitoring
If elevation persists for more than 2 
weeks, discontinue the study drug
Establish causality
Complete liver eCRF
> 3 × ULN 
accompanied by 
symptomsb
Discontinue the study treatment 
immediately
Hospitalize if clinically appropriate
Establish causality
Complete liver eCRF
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 eCRF
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 eCRF
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 eCRF
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 eCRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
 


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Appendix 9: ICS Dose Level 
Table 9-1
Low, Medium and High Daily Doses of Inhaled Glucocorticosteroids 
for Adults and Adolescents (12 years and older) (GINA 2016)
Drug
Total Daily Dose (microgram/day)
Low
Medium
High
Beclomethasone dipropionate – CFC*
200 - 500
> 500 - 1000
> 1000 
Beclomethasone dipropionate – HFA
100 - 200
> 200 - 400
> 400
Budesonide – DPI
200 - 400
> 400 - 800
> 800 
Ciclesonide – HFA
80 - 160
> 160 - 320
> 320 
Fluticasone propionate – DPI
100 - 250
> 250 - 500
> 500 
Fluticasone propionate – HFA
100 - 250
> 250-500
> 500
Mometasone furoate
110 - 220
> 220 - 440
≥440
Triamcinolone acetonide
400 - 1000
> 1000 - 2000
> 2000
Fluticasone Furoate - DPI**
N/A
100
200
CFC: chlorofluorocarbon propellant; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant
*Beclomethasone dipropionate CFC is included only for comparison with older literature
**As per Relvar SmPC 
 

SAP_001.pdf: 
Clinical Development
QVM149B (QMF149: Indacaterol acetate/Mometasone furoate)
CQVM149B2303/ NCT02892344
A multi-center, randomized, 12-week treatment, double-
blind study to assess the efficacy and safety of QMF149 
(150/80 microgram) compared with MF Twisthaler® (200 
microgram) in adult and adolescent patients with asthma 
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Trial Statistician (CRO), 
Document type:
SAP Documentation
Document status:
Amendment 2
Release date:
2-Jan-2019
Number of pages:
47
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Page 2
SAP Amendment 2
CQVM149B2303
Document History - Changes compared to previous final version
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
10-Mar-
2017
Prior 
to 
FPFV
Creation 
of 
final version
N/A – First version
NA
11-Sep-
2017
Before DB 
lock
Creation 
of 
amendment 1
Asthma exacerbation endpoints updated to 
be consistent with protocol amendment1
Section 
2.7.6 
Asthma 
exacerbation
11-Sep-
2017
Before DB 
lock
Creation 
of 
amendment 1
Baseline definition for few endpoints 
Section 2.1.1.2 Baseline 
definition
Section 
2.7.3 
Rescue 
medication
11-Sep-
2017
Before DB 
lock
Creation 
of 
amendment 1
 
11-Sep-
2017
Before DB 
lock
Creation 
of 
amendment 1
 
 summary statistics for predicted FEV1 
excluded
Section 
2.3.2 
Patient 
demographics
and
baseline characteristics
05-Oct-
2017
Before DB 
lock
Creation 
of 
amendment 1
Text updated 
Section 2.5.4 Supportive 
and sensitivity analysis
05-Oct-
2017
Before DB 
lock
Creation 
of 
amendment 1
Text updated to clarify the analyses to be 
performed
Section 2.7.1 Spirometry 
data 
other 
than 
the 
primary endpoint
05-Oct-
2017
Before DB 
lock
Creation 
of 
amendment 1
Analyses, that will be performed slightly 
differently from protocol mentioned way, 
has been updated
Section 4 Change to 
protocol 
specified 
analyses
05-Oct-
2017
Before DB 
lock
Creation 
of 
amendment 1
Updated criteria for Hy’s law as per current 
guideline
Section 6.4 Laboratory 
parameter-direction 
of 
interest and definition of 
clinically notable values
16-Oct-
2017
Before DB 
lock
Creation 
of 
amendment 1
Subgroup category ‘1-<1.5’ has been 
removed from baseline ACQ-7. Subgroup 
category <60% and >=90% has been 
removed for % predicted FEV1
Section 2.2.1 Subgroup 
of interest
14-Nov-
2017
Before DB 
lock
Creation 
of 
amendment 1
Analyses for ACQ-5 included
Section 
2.7.2 
Asthma 
control 
questionnaire 
(ACQ)
24-Nov-
2017
Before DB 
lock
Creation 
of 
amendment 1
Exclusion flags for protocol deviations
included
Section 
6.7
Rule 
of 
exclusion 
criteria 
of 
analysis sets
24-Nov-
2017
Before DB 
lock
Creation 
of 
amendment 1
Term ‘study treatment’ clarified
Section 2.1.1 General 
definitions
5-Dec-
2017
Before DB 
lock
Creation 
of 
amendment 1
Sub-group analyses for adverse events of 
special interest removed except for age-
group
Section 2.8.2.2 Adverse 
events of special interest
18-Apr-
2018
Before DB 
lock
Creation 
of 
amendment 1
Removed analyses for medical history by 
status.
Section 2.3.2
18-Apr-
2018
Before DB 
lock
Creation 
of 
amendment 1
Removed compliance analyses by inhaler.
Section 2.4.1


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Page 3
SAP Amendment 2
CQVM149B2303
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
18-Apr-
2018
Before DB 
lock
Creation 
of 
amendment 1
Added clarification on imputation of 
missing ACQ-7 items.
Section 2.6.3
18-Apr-
2018
Before DB 
lock
Creation 
of 
amendment 1
Updated sample size and sample size 
calculation 
according 
to 
Protocol 
amendment.
Section 1.1 and 3
18-Apr-
2018
Before DB 
lock
Creation 
of 
amendment 1
Removed Sodium 
Section 6.4
18-Apr-
2018
Before DB 
lock
Creation 
of 
amendment 1
Updated multiple imputation.
Section 2.5.4 and 6.6
8-May-
2018
Before DB 
lock
Creation 
of 
amendment 1
Removed shift tables by visit and time 
point.
Section 2.8.4 and 2.8.5
29-May-
2018
Before DB 
lock
Creation 
of 
amendment 1
Updated baseline definition of PEF and 
other eDiary data.
Section 2.1.1.2 and 2.7.3
29-May-
2018
Before DB 
lock
Creation 
of 
amendment 1
Analyses that will be reported outside of 
CSR, have been mentioned
Section 5
30-May-
2018
Before DB 
lock
Creation 
of 
amendment 1
Notable value for magnesium included
Section 6.4
31-Jul-
2018
Before DB 
lock
Creation 
of 
amendment 2
Subgroups for race combined..
Section 2.2.1
31-Jul-
2018
Before DB 
lock
Creation 
of 
amendment 2
Added further details to actions in case
model fails to converge.
Section 2.5.2 and 6.6
30-Aug-
2018
Before DB 
lock
Creation 
of 
amendment 2
Changed notable criteria for Magnesium to 
SI unit
Section 6.4
28-Sep-
18
Before DB 
lock
Creation 
of 
amendment 2
Added exclusion of implausible spirometry 
values
Section 2.5.1
28-Sep-
18
Before DB 
lock
Creation 
of 
amendment 2
Added non-parametric test exploration in 
case of non-convergence or highly skewed 
data.
Section 2.7.3 and 2.7.5.
21-Dec-
18
Before DB 
lock
Creation 
of 
amendment 2
Updated major PDs.
Section 6.7
26-Dec-
18
Before DB 
lock
Creation 
of 
amendment 2
Shift tables for urinalysis parameters 
removed
Section 2.8.4


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SAP Amendment 2
CQVM149B2303
Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
1.2.1
Primary objective ....................................................................................8
1.2.2
Key secondary objective .........................................................................9
1.2.3
Other secondary objectives .....................................................................9
.10
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................12
2.2.1
Subgroup of interest ..............................................................................12
2.3
Patient disposition, demographics and other baseline characteristics ...................13
2.3.1
Patient disposition.................................................................................13
2.3.2
Patient demographics and baseline charecteristics ...............................13
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment / compliance................................................................14
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint...................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................16
2.5.4
Supportive and Sensitivity analyses......................................................17
2.6
Analysis of the key secondary objective ...............................................................18
2.6.1
Key secondary endpoint........................................................................18
2.6.2
Statistical hypothesis, model, and method of analysis..........................18
2.6.3
Handling of missing values/censoring/discontinuations.......................18
2.6.4
Multiplicity adjustment .........................................................................19
2.7
Analysis of secondary efficacy objective(s)..........................................................19
2.7.1
Spirometry data other than the primary endpoint .................................19
2.7.2
Asthma control questionnaire (ACQ) ...................................................20
2.7.3
Rescue medication ................................................................................21
2.7.4
Peak Expiratory Flow Rate (PEF).........................................................22


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SAP Amendment 2
CQVM149B2303
2.7.5
Asthma symptoms based on e-Diary.....................................................22
2.7.6
Asthma Exacerbations...........................................................................24
2.7.7
Quality of life as assessed by Asthma Quality of Life 
Questionnaire (AQLQ-S+12)................................................................25
2.8
Safety analyses.......................................................................................................25
2.8.1
Serious asthma outcome........................................................................26
2.8.2
Adverse events (AEs)............................................................................26
2.8.3
Deaths....................................................................................................28
2.8.4
Laboratory data .....................................................................................28
2.8.5
Other safety data ...................................................................................29
31
32
2.11
Interim analysis......................................................................................................32
3
Sample size calculation .....................................................................................................32
4
Change to protocol specified analyses ..............................................................................33
5
Analyses to be reported outside of CSR............................................................................33
5.1
Subgroup analyses .................................................................................................33
6
Appendix ...........................................................................................................................34
6.1
Imputation rules.....................................................................................................34
6.1.1
Study treatment .....................................................................................34
6.1.2
AE date imputation ...............................................................................34
6.1.3
Concomitant medication date imputation .............................................34
6.2
AEs coding/grading ...............................................................................................34
6.3
Data pooling and assessment windows..................................................................34
6.4
Laboratory parameters – direction of interest and definition of clinically 
notable values ........................................................................................................36
6.5
Vital signs and ECG – definition of clinically notable values...............................38
6.6
Statistical methodology and assumptions..............................................................40
6.7
Rule of exclusion criteria of analysis sets..............................................................43
7
Reference...........................................................................................................................46


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SAP Amendment 2
CQVM149B2303
List of abbreviations
ACQ
Asthma Control Questionnaire
AE
Adverse Event
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AQLQ
Asthma Quality of Life Questionnaire
b.i.d
twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CCV
Cardio-/Cerebro-vascular
CRF
Case Report/Record Form (paper or electronic)
DMC
Data Monitoring Committee
eDiary
Electronic Diary
ECG
Electrocardiogram
ER
Emergency Room
FAS
Full analysis set
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FEF
Forced Expiratory Flow
FVC
Forced Vital Capacity
IgE
Immunoglobulin E
ICS
Inhaled Corticosteroid
LABA
Long Acting Beta-2 Agonist
LFT
Liver Function Test
MF
Mometasone Furoate
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measurements
o.d.
Once a day
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PPS
Per protocol set
QTc
Corrected QT interval
RAN
Randomized set
SAE
Serious Adverse Event
SAF
Safety analysis set
SCS
Systemic Corticosteroids
SOC
System Organ Class
SMQ
Standard MEDRA Query
TD
Study Treatment Discontinuation
TFL
Table Figure Listing


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1
Introduction
This document contains details of the statistical methods that will be used in the phase III 
clinical trial CQVM149B2303. This study is designed to evaluate the efficacy and safety of 
QMF149 150/80 microgram o.d. delivered via Concept1 compared with MF 200 microgram 
o.d. delivered via Twisthaler® in patients with asthma as determined by pulmonary function 
testing and effects on asthma control.
Data will be analyzed according to Section 9 of the study protocol.
Important information is given in the following sections and details are provided, as applicable, 
in section 6: Appendix.
1.1
Study design
This study uses a randomized, double-blind, double-dummy, parallel-group design to  assess 
the efficacy and safety of QMF149 150/80 microgram o.d. delivered via Concept1 compared 
with MF 200 microgram o.d. delivered via Twisthaler® in adult and adolescent patients with 
mild asthma (figure 1)
Approximately 750 patients (including approximately 50 adolescent patients) will be 
randomized into the two treatment groups with a randomization ratio of 1:1 ( i.e. approximately 
375 patients per treatment group). At least 676 randomized patients (338 per treatment group) 
are needed to complete the study treatment. Detailed information regarding sample size 
calculation is provided in section 3.
This study will enroll multi-nationally and patients will be stratified according to prognostic 
factors of age (12 to 17 years or ≥ 18) and non-prognostic factor region to achieve improved 
homogeneity within each stratum.
No interim analysis for efficacy is planned. It is planned that the independent Data Monitoring 
Committee (DMC) will review semi-blinded (i.e., treatment groups names as T01 and T02) 
safety data (as described in Section 8.4 of the protocol). The details of the information flow, 
confidentiality and specific analysis will be available from the DMC Charter.


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Figure 1     Study design
1.2
Study objectives and endpoints
Section 2 of the study protocol lists the following primary, key secondary, other secondary 
 objectives.
1.2.1
Primary objective
The primary objective of this study is to demonstrate the superiority of QMF149 150/80 
microgram o.d. (in the evening) delivered via Concept1 compared with MF 200 microgram o.d. 
(in the evening) delivered via Twisthaler® in terms of trough FEV1 after 12 weeks of treatment 
in adults and adolescents.
Treatment Epoch 
(12 weeks)
End of Run-in Visit 102
Randomization Visit 201
Screening
Epoch
(2 weeks)
Day 1 to Day 85
Run-in
Epoch1
(3 weeks) 
QMF149 150/80 µg o.d via Concept1 (and 
Placebo to MF 200 µg o.d.via Twisthaler®)
                         OR         
MF 200 µg o.d via Twisthaler®   (and placebo 
to QMF149 150/80 µg o.d via Concept1) 
Follow-up
Epoch
(30 days)
Visit 1
Visit 
101
Visit 301
Low dose ICS
(e.g. 
Fluticasone 
propionate 
100 µg b.i.d)
Rescue Medication Available
Study completion Visit 204
Day -35 to 
Day -21
Day -21 to 
Day -1


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1.2.2
Key secondary objective
The key secondary objective is to demonstrate the superiority of QMF149 150/80 microgram 
to MF 200 microgram o.d. in terms of ACQ-7 after 12 weeks of treatment.
1.2.3
Other secondary objectives
Other secondary objectives will evaluate the efficacy of QMF149 150/80 microgram versus MF 
200 microgram o.d. in terms of:
Lung function:

Trough FEV1 at Day 2 of treatment period (defined as the mean of 23 h15 min and 23 h 
45min FEV1 values post dose of Day 1.)

Pre-dose FEV1 (defined as the mean of -45 min and -15 min FEV1 values pre-evening dose) 
at 4 weeks

Forced Vital Capacity (FVC) and Forced Expiratory Flow between 25% and 75% of FVC 
(FEF25-75) over 12 weeks

Morning and Evening Peak Expiratory Flow Rate (PEF) over 4 and 12 weeks of treatment.
Symptoms and asthma control:

Percent of patients achieving the minimal important difference (MID) in ACQ-7 (i.e. at least 
0.5 decrease from baseline) at Week 12

Percentage of asthma symptoms free days, the percentage of nights without nighttime 
awakenings, and the percentage of mornings without symptoms on awakening as recorded 
by daily electronic Diary (e-Diary) over 12 weeks of treatment

Asthma control as assessed by the Asthma Control Questionnaire (ACQ-7) at Week 4

Rescue salbutamol/albuterol usage (mean daily, nighttime and daytime use) from e-Diary 
recordings over 12 weeks of treatment

Percentage of rescue medication free days over 12 weeks of treatment period.
Exacerbations:

To evaluate the efficacy in terms of asthma exacerbation-related parameters described 
below during 12 weeks of treatment. The analysis will be performed by exacerbation 
category wherever specified. The exacerbation categories are: All (mild, moderate, severe)
and the combination of moderate or severe:

Time to first asthma exacerbation by exacerbation category.

Annual rate of asthma exacerbations by exacerbation category.

Quality of life as assessed by Asthma Quality of Life Questionnaire (AQLQ) over 12
weeks of treatment period.
The following safety and tolerability endpoints will be evaluated:


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
Cumulative incidence of the composite endpoint of serious asthma outcomes (i.e. asthma-
related hospitalization, asthma-related intubation, or asthma-related death) over 12 weeks 
of treatment.

AEs, vital signs, electrocardiogram (ECG), and laboratory analysis (hematology, blood 
chemistry including glucose and potassium, urinalysis, evening plasma cortisol) over 
12weeks of treatment.
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by 
. The most recent version of SAS available 
in the statistical programming environment of 
will be used for the analysis. 
2.1.1
General definitions 
The terms ‘study treatment’ which has been used in this document actually refer to ‘double-
blind treatment’. 
2.1.1.1
Study day
Study day will be defined as the number of days since the date of first dose of study treatment. 
The date of first dose of study treatment will be defined as Day 1 and the day before the first 
dose of study treatment will be 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 treatment,
Study day = Assessment date – Date of first dose of study treatment + 1;

for dates prior to the first date of study treatment,
Study day = Assessment date – Date of first dose of study treatment.
If a patient has no study treatment, the randomized date will be used instead of the date of first 
dose of study treatment. Then, the randomized date is defined as Day 1 and the day before the 
randomization was defined as Day -1.


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2.1.1.2
Baseline definition
In general, baseline is defined as the last measurement before the first dose of study treatment
at the evening of  Day 1.
Parameter
Baseline assessment
Detail
Post-dose FEV1,  
Pre-dose trough FEV1, 
Trough FEV1
45 min and 15 min pre-dose 
FEV1 at Day 1
The average of the values 
taken at -45 and -15 min
Post-dose FVC,
Pre-dose trough FVC, 
Trough FVC
45 min and 15 min pre-dose 
FVC at Day 1
The average of the values 
taken at -45 and -15 min
Post-dose FEF25-75,
Pre-dose trough FEF25-75, 
Trough FEF25-75
45 min and 15 min pre-dose 
FEF25-75 at Day 1
The average of the values 
taken at -45 and -15 min
ACQ-7
Prior to first dose of study 
treatment at Day 1
The average of responses of 7 
questions
ACQ-5
Prior to first dose of study 
treatment at Day 1
The average of responses of 
first 5 questions
Diary data (PEF, symptoms, 
and rescue medication use)
Last 21 days of run-in period 
between run-in Visit 101 and 
up to one day before first 
dose of study treatment
The average from all non-
missing 
records
or 
percentage of days free of 
symptoms 
or 
rescue 
medication use
Laboratory data
(hematology, biochemistry, 
urinalysis, and plasma 
cortisol)
20 min pre-dose at Day 1
Vital signs 
(pulse rate and systolic and 
diastolic blood pressures)
25 min pre-dose at Day 1
Height and weight
Run-in Visit 101
ECG
35 min pre-dose at Day 1
Detail descriptions for calculating baseline values are provided in the latter sections.
2.1.1.3
Post-baseline measurement
Post-baseline measurements are defined as those assessments after the first dose of study 
treatment.


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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.
Detail descriptions for calculating post-baseline values are provided in the latter sections.
2.2
Analysis sets
The following analysis sets are defined:

The randomized (RAN) set will consist of all patients who were assigned a randomization 
number, regardless of whether or not they actually received study treatment. Patients in 
RAN will be analyzed according to the treatment they were randomized to. The RAN set 
will be used for a summary of patient disposition, demographics and baseline characteristics.

The Full Analysis Set (FAS) will consist of all patients in the RAN set who received at least 
one dose of study treatment. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they were assigned to at randomization. The FAS will 
be used in the analysis of all efficacy variables.

The Per-Protocol set (PPS) will include all patients in the FAS who did not have any major 
protocol deviations. The list of major protocol deviations will be available in Appendix 6.7
prior database lock. Patients will be analyzed according to the treatment they received. The 
PPS will be used for supportive analysis of the primary analysis only.

The Safety Set will consist of all patients who received at least one dose of study treatment
including non-randomized patients who received study treatment in error. Patients will be 
analyzed according to the treatment they received. If patients switch double-blind treatment 
during the study, they will be counted and analyzed only once according to their initial 
treatment. The safety set will be used in the analysis of all safety variables.

 
 
2.2.1
Subgroup of interest
Subgroup analyses of primary, key and other secondary, 
 objectives will be 
performed for adolescent patients (12 - 17 years old). These analyses will be identified in the 
TFL shells. For tables presenting results from statistical models, the treatment effects in 
adolescent patients will be derived from the treatment x age subgroup interaction term by 
including all patients in the analysis. 
At week 12, the following subgroups will be used for supporting analyses of primary endpoint 
trough FEV1:

Age group (12 to 17 years, ≥18 years)

Race (Caucasian, Asian, Black and other)

Gender (male, female)


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
History of asthma exacerbation in the 12 months prior to Screening (Yes, No)

Patients’ prior therapies before Run-in period (eg. low dose ICS without LABA, low dose 
ICS with LABA)

FEV1 response according to % predicted FEV1 range at Baseline (60 %-< 70%, 70% to < 
90%)

ACQ-7 Baseline (1.5- < 2, 2-< 2.5, ≥2.5)
2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The number of patients will be summarized by region (i.e., Eastern Europe, Western Europe, 
India, Japan, Asia (other than India and Japan), rest of world), country and treatment group for 
the RAN set. Further, for each study epoch (i.e., screening, run-in, 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.
Time to premature treatment discontinuation will be displayed graphically for each treatment 
group using a Kaplan-Meier curve for the safety analysis set. The date of premature treatment 
discontinuation is defined as the date of last dose of study treatment. Patients who completed 
the study treatment will be censored at the date of last dose of study treatment. 
Number of patients with protocol deviations will be tabulated by deviation category (e.g., 
selection criteria not met, prohibited concomitant medication).
The number of patients included in each analysis set will be tabulated, as well as the reasons 
for exclusions from analysis sets.
2.3.2
Patient demographics and baseline charecteristics
Demographic and baseline characteristics measured before randomization including age, 
gender, race, ethnicity, height, weight, BMI, relevant medical history, Screening spirometry 
parameters: (FEV1, FVC, FEV1/FVC and FEF25-75), FEV1 reversibility, percentage of predicted 
FEV1, duration of asthma, history of asthma exacerbations, smoking history, prior asthma 
treatment (ICS low dose, ICS/LABA low dose and in case of protocol deviation ICS other than 
low dose, ICS/LABA other than low dose will be included), prior concurrent medications 
(asthma-related and non-asthma related) baseline ACQ-7, 
will be 
summarized by treatment group using the RAN set.
Continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, standard deviation, median, first and third quartiles, minimum, and maximum) and 
categorical variables will be summarized in terms of the number and percentage of patients in 
each category including a category for missing data if any.


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No statistical analyses will be provided for baseline comparability among the treatment groups.
In addition, the following categorizations of continuous variables will be done:

Age into 12 – 17 years, 18 - 64 years, and ≥65 years;

BMI into ≤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 
treatment into 0, 1, > 1

pre-bronchodilator FEV1 into < 60%, 60 - < 70%, 70% - < 90%, and ≥90% of predicted 
FEV1 (< 60% and ≥90% will be included in case of protocol deviation)

ACQ-7 into <1.5, 1.5- < 2, 2-< 2.5, ≥ 2.5 (<1.5 will be included in case of protocol deviation)
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 
History/conditions will be summarized for the RAN set by primary system organ class and 
preferred term. 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.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
2.4.1.1
Duration of exposure
Duration of exposure 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 by treatment 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 treatment for each 1 – 29 days, 30 – 85 
days and > 85 days.
The number of patients who completed the 12-week study treatment and who discontinued the 
study treatment prematurely will be shown including the reasons for discontinuation of study 
treatment.
2.4.1.2
Compliance
Compliance will be calculated by counting the days where study treatment was administered 
"As per protocol" according to the records on the Dosage Administration Record (DAR) 


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Summary eCRF. The percentage of days divided by the days of exposure will be analyzed. To 
be counted as a day of compliance with study treatment, two administrations, i.e., the Twisthaler 
and the Concept 1 inhaler in the evening, have to be taken as per protocol. 
Compliance will be categorized into < 80 % and 80 % - 100 % and summarized by treatment 
for the safety set.
2.4.2
Prior, concomitant and post therapies
Each medication, either an asthma or non-asthma medication, will have the start and end dates 
recorded on the eCRF. Separate tables will be provided for medications which were started and 
stopped prior to the first dose of study treatment and medications which were taken 
concomitantly to the study treatment (regardless of whether continued or started after the first 
dose of study treatment).
Asthma medications will be summarized by the route of administration, the recorded 
prespecified drug subcategories (including types of combination) and the coded preferred terms. 
The summary will be repeated by showing ingredients instead of preferred terms. Non-asthma 
medications will be summarized by route of administration and preferred term. 
Surgical and medical procedures (non-drug therapies) will be coded using MedDRA and 
presentations will be done by MedDRA primary system organ class and preferred term, 
separately for prior procedures and those after start of study treatment.
Short acting beta2 agonist (SABA) rescue medication usage (mean number of puffs) during the 
screening epoch will be summarized.
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations.
All summarizations will be by treatment group in the Safety Set.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary objective is to demonstrate the superiority of  QMF149 150/80 μg to MF 200 μg 
in terms of trough FEV1 after 12 weeks of treatment.
Trough FEV1 is defined as the average of the two FEV1 measurements taken 23 hr 15 min and 
23 hr 45 min post-evening dose. Trough measurements will be done at Day 2 and Day 85 (Week 
12, the primary endpoint).
For trough FEV1, the baseline value is defined as the average of the values taken at -45 and -15 
min prior to first dose of study treatment at the evening of Day 1. Checks will be performed to 


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ensure both values were indeed taken prior to the first dose of study treatment. 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 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 run-in Visits 
101 and 102 or at unscheduled run-in visits will be used as the baseline. If the FEV1, FVC or 
FEF25-75 measurements are missing both on Day 1 and at run-in visits, the respective baseline 
values will be set to missing. Measurements taken within 6 hours of rescue use or within 7 days 
of systemic corticosteroid use will be set to missing.
For all spirometry measurements, implausible values will be excluded. If a patient has 
implausible FEV1 value (defined as > 7 L) at an assessment, all spirometry measurements 
related to that assessment will be excluded. The threshold of 7 L was chosen because according 
to ERS/ECCS 1993 regressions, the maximum normal predicted FEV1 is 5.17 L, we set 7 L as 
the implausible cutoff to allow for some fluctuation around the maximum mean.
2.5.2
Statistical hypothesis, model, and method of analysis
The comparison of QMF149 150/80 microgram versus MF 200 microgram will be evaluated
by testing the following null hypothesis (H0) versus the alternative hypothesis (Ha):
H0: QMF149 treatment group is equal to MF treatment group in trough FEV1 at Week 12
Ha: QMF149 treatment group is not equal to MF treatment group in trough FEV1 at Week 12
The primary variable will be analyzed using a mixed model for repeated measure (MMRM) on 
the FAS. The model will contain treatment, age (12 to 17 or ≥ 18 years), region, visit (Days 2 
and 85), and treatment-by-visit interaction as fixed effects with baseline FEV1 measurement, 
baseline-by-visit interaction, FEV1 prior to inhalation and FEV1 within 15 to 30 min post 
inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates, and center 
nested within region as a random effect. The within-patient correlation will be modeled using 
an unstructured covariance matrix in the mixed model. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom (Kenward and Roger, 1997). If the model 
does not converge, with unstructured covariance matrix, the compound symmetriy covariance 
matrix will be used in the mixed model, if the model still does not converge the random effect 
will be removed, if the model converges after removing the random center effects, the original 
model without random center effects will be re-assessed. The restricted maximum likelihood 
method will be used. The between-treatment comparison will be carried out using the adjusted 
mean (least-squares mean(LS mean)) difference based on the treatment main effect and the 
coefficient for the treatment-by-visit interaction for Day 85 and treatment.
The estimated adjusted treatment difference (QMF149 – MF) will be displayed along with the 
associated standard error, 2-sided 95% confidence interval (CI), and p-value (2-sided).
2.5.3
Handling of missing values/censoring/discontinuations
If any of the 23 hr. 15 min and 23 hr. 45 min values contributing to the trough FEV1 is collected 
within 7 days of systemic corticosteroid use, within 6 hours of rescue medication, or if the actual 


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measurement times are outside the 22-25 hour post-evening dose time window then the 
individual FEV1 value will be set to missing.
If one of the two values is missing (or set to missing), then the remaining non -missing value 
will be taken as trough FEV1. If both values are missing, or if the patient withdrew from the 
study (regardless of the reason for discontinuation) then trough FEV1 will be regarded as 
missing in which case the missing value(s) of the patient at the particular visit(s) would not 
directly contribute to the primary analysis.
Post-dose spirometry measurements which were actually taken pre-dose will be set to missing 
and not used for by time point assessments. Similarly, any pre-dose spirometry measurements 
which were actually taken post-dose will be set to missing and not used for by time point 
assessments.
The MMRM which is used for the primary variable is based on missing at random mechanism 
for the missing values and assesses the treatment effects of trough FEV1 without explicit 
imputation.
2.5.4
Supportive and Sensitivity analyses
As supportive analysis, the same MMRM used in the primary analysis will be also performed 
on the PPS to assess the treatment effect in protocol adherers. 
In addition, the same primary MMRM on the FAS will be performed including all spirometric 
measures irrespective of systemic corticosteroid or rescue medication use but those measures 
taken outside of the 22 – 25 hour post-evening dose time window will not be included.
As a sensitivity analysis, a so-called 'tipping point analysis' will be performed for the primary 
endpoint to evaluate the impact of a deviation from the MAR assumption of missing data. The 
delta-adjusting approach described in Ratitch et al (2013) will be used to find the tipping point, 
in a spectrum of conservative missing not at random (MNAR) assumptions, at which 
conclusions change from being favorable to QMF149 to being unfavorable. After such a tipping 
point is determined, clinical judgment can be applied as to the plausibility of the assumptions 
underlying this tipping point. This methodology would provide a good picture of what it would 
take to overturn study conclusions on the basis of varying assumptions about missing data. The 
basic idea is to first impute the missing values using a regression based multiple imputation 
(MI) method based on the MAR assumption. The imputed Week 12 values for the QMF149 
arms are then adjusted by a delta value. A detailed description of the analysis steps are provided 
in Section 6.6.
The exploratory subgroup analyses for trough FEV1 using MMRM will be performed (using the 
appropriate interaction term in the model and additional covariate as a fixed effect, if necessary) 
for the FAS population to explore the treatment effect in key demographic and disease related 
subgroups (See Section 2.2.1 for the details of subgroups).


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2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoint
The key secondary objective is to demonstrate the superiority of QMF149 150/80 μg to MF 200 
μg in terms of ACQ-7 after 12 weeks of treatment.
The ACQ-7 measures asthma symptom control and consists of seven items: five on symptom 
assessment, one on rescue bronchodilator use and one on airway calibre (FEV1 % predicted). 
Patient recall is one week. All 7 questions of the ACQ-7 are equally weighted. Items 1-5 are 
scored along a 7-point response scale, where 0 = good controlled and 6 = poor controlled. Item 
6 is scored between 0 = no rescue medication and 6 = More than 16 puffs/inhalations most days. 
The 7th item will be scored by the investigator based on the FEV1 % predicted from the 
masterscope at the site (i.e., Score = 0 means > 95% of predicted FEV1, 1 = 90 95%, 2 = 80 –
89%, 3 = 70 – 79%, 4 = 60 – 69%, 5 = 50 – 59%, and Score = 6 means < 50% of predicted 
FEV1). The total score is calculated as the mean of all questions. The mean will be calculated 
as the sum of scores divided by the number of questions that were answered, as long as there 
were at least 6 questions answered and the missing question is neither Question 1 ('On average, 
during the past week, how often were you woken by your asthma during the night?') nor 
Question 7. In case of one missing response (not Question 1 or Question 7), first that missing 
response will be imputed as per the method given in Section 2.6.3 and then the ACQ score will 
be calculated.
ACQ-7 measurements are scheduled for Days -21, 1, 30 and 84.
For the ACQ-7 score, the baseline value is defined as the score obtained at Day 1 prior to first 
dose of study treatment. If the value is missing, the last measurements from run-in visit 101 or 
unscheduled run-in visits will be used.
2.6.2
Statistical hypothesis, model, and method of analysis
It will be analyzed using the same MMRM (including all available visits) on the FAS as used 
for the primary analysis but will include Baseline ACQ-7 score instead of Baseline FEV1.
2.6.3
Handling of missing values/censoring/discontinuations
For a missing individual item while on-treatment, the interpolation method using either previous 
or subsequent completions of the questionnaire (ACQ User Guide, 2004) will be used. For 
instance, 
Item
Visit 1
Visit 2
1
4
6
2
3
5
3
0
0
4
4
4


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5
0
0
6
2
Missing
7
5
6
Total visit 1 score for items answered on both visits is 4+3+0+4+0+5=16 (A)
Total visit 2 score for items answered on both visits is 6+5+0+4+0+6=21 (B)
Item 6 score at visit 1=2
Item 6 score at visit 2= B/A * 2=21/16*2=2.63
The ACQ score for visit 1 is (4+3+0+4+0+2+5)/7=2.57
The ACQ score for visit 2 is (6+5+0+4+0+2.63+6)/7=3.38
For post-baseline visits, missing items will be imputed by using data from subsequent visit first, 
if these are not available, data from previous visit will be used for imputation of the missing 
item. For baseline, missing item at Day 1 will be imputed by using Day -21 data or data from 
any unscheduled run-in visit, whichever is later. To clarify, for imputation of the first post-
baseline value, if the second post-baseline assessment is not available, the value of the baseline 
assessment will be used. If there are two assessments from the same day, the first will be used 
only and the second ignored even for imputation.
If more than one individual item is missing, then ACQ-7 score will set to be missing. The 
MMRM which is used for analysis of ACQ-7 score, is based on missing at random mechanism 
for the missing values and assesses the treatment effects of ACQ-7 without explicit imputation.
2.6.4
Multiplicity adjustment
A hierarchical testing procedure will be applied to control the type-I error rate for the primary 
and the key secondary endpoints, i.e., the key secondary endpoint ACQ-7 will be tested only if 
the primary endpoint (trough FEV1) is significant at the 2-sided 0.05 level.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Spirometry data other than the primary endpoint
Pre-dose trough is defined as the average of the two measurements taken 45 min and 15 min 
pre-evening dose. FEF25-75 is defined as forced expiratory flow between 25% and 75% of Forced 
Vital Capacity (FVC).
For all FEV1, FVC, and FEF25-75 endpoints, the baseline value is defined in a similar way as 
defined for trough FEV1 (See Section 2.5.1). 
For FEV1, FVC and FEF25-75 measurements, missing values will be handeled similarly as 
mentioned for trough FEV1 (See Section 2.5.3). Additionally for pre-dose trough, pre-dose 
measurements will be set to missing when they are actually taken post-dose. However, the post-


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evening dose time window of 22 – 25 hours can not be applied here since the time of evening 
dose of the previous day will not be recorded. 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 used as 
average pre-dose value.
Trough FEV1 at Day 2 visit will be analyzed using the same MMRM as specified for the primary 
analysis, i.e., the visit factor will include all available visits as a factor and between treatment 
comparison will be carried out using the adjusted mean (least-squares mean) difference based 
on the treatment main effect and the coefficient for the treatment-by-visit interaction for the 
respective visit and treatment. Adjusted mean (LS mean) will be displayed for each treatment 
group along with the estimated treatment differences and the 95% confidence intervals and the 
two-sided p-values by visit.
Similar analyses will be performed for pre-dose trough FEV1 at days 30 and 84. 
Post-dose FEV1 (Day 1, Day 30 and Day 84) measurements will be analyzed separately by visit 
using the same MMRM as trough FEV1 with time point as repeat variable (i.e. in statistical 
model visit will be replaced by timepoint).
Pre- and post-dose FVC and FEF25-75 will be analyzed similar to FEV1 with respective baseline 
values (See Section 2.1.1.2).
Change from Baseline in the spirometry values will be also analyzed using the same MMRM.
For additional details of statistical models, please refer to Section 5.6.
2.7.2
Asthma control questionnaire (ACQ)
Results for ACQ-7 at day 30, obtained from MMRM for the key secondary endpoint ACQ-7 
at day 84, will be displayed.
Change from baseline in the ACQ-7 will be also analyzed using the same MMRM model.
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 analyzed using a 
logistic regression model. First missing ACQ-7 values will be imputed using a regression based 
Multiple Imputation (MI) method under missing at random (MAR) assumption, based on 
continuous ACQ values. Then continuous ACQ values will be converted into binomial 
responses and generalized estimating equation (GEE) method will be used to analyze the 
datasets and then the results from GEE method will be combined for the inference. The GEE 
model will include terms for treatment, age (12 to 17 or ≥ 18 years), region, visit, and treatment-
by-visit interaction as fixed effects, and Baseline ACQ-7, Baseline-by-visit interaction, FEV1 
prior to inhalation and FEV1 within 15 to 30 min post inhalation of salbutamol/albuterol 
(components of SABA reversibility) as covariates. The estimated adjusted odds ratio will be 
displayed along with the associated 95% (2 -sided) confidence interval and p-value.


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Additionally, the number of patients will be summarized by response relative to baseline ACQ-
7 with the following categories: Response (decrease of >= 0.5 units in ACQ-7), No change (-
0.5 < change in ACQ-7 < 0.5), Worsening (increase of >= 0.5 units in ACQ-7), Net response 
(response – worsening) and Total.
In addition to ACQ-7, average of first 5 questions in ACQ (ACQ-5) will be calculated and all 
the analyses described for ACQ-7 will be repeated for ACQ-5.
2.7.3
Rescue medication
The number of puffs of the rescue medication use in the last 12-hour is recorded twice daily 
(morning/evening) by the patient in his/her e-Diary. For rescue medication use, the baseline 
values are defined as the average from all non-missing records taken over the last 21 days in 
the run-in period between run-in Visit 101 and up to one day before first dose of study treatment
Missing diary data will not be imputed.
If for the value over the whole day (24 hours) the number of puffs is missing for part of the day 
(either day-time or night-time) then a half day will be used in the denominator to calculate the 
average value. Any values > 30 for the number of puffs of rescue medication in a 12 hour period 
will be set to missing. These high numbers are not realistic and could impact the analyses. If a 
patient has less than 7 days with non-missing data, then the baseline value will be set to missing.
Post-baseline measurements start with the morning recordings at Day 2 and end with the 
evening recordings one day after the last evening dose. Summary data (i.e., mean values and 
percentage of days with) will be calculated for 4-weekly intervals (defined as 28 days), and for 
Weeks 1 – 12 (defined as the whole treatment period up to Visit 204, Day 85). Similar 
calculations as for baseline diary data will be done. 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 period. For Weeks 
1 – 12, 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.
The mean daily number of puffs of rescue medication use over the 12 weeks of treatment will 
be summarized by treatment. The change from Baseline in the mean daily number of puffs of 
rescue medication use will be analyzed using an ANCOVA model. The model will contain 
treatment, age (12 to 17, or ≥ 18), region as fixed effect factors with center nested within region 
as a random effect and baseline rescue medication use, FEV1 prior to inhalation and FEV1 within 
15 to 30 min post inhalation of salbutamol/albuterol (components of SABA reversibility) as 
covariates. No imputation will be done for missing data. The adjusted mean (LS mean) 
treatment difference along with the corresponding two-sided 95% confidence interval and 
corresponding p-value will be presented. This analysis will be performed for morning 
(nighttime), evening (daytime), and daily (average of nighttime and daytime) rescue medication 
use.
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 during daytime and nighttime) will be 
summarized by treatment and analyzed the same way as described for the number of puffs of 


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the rescue medication use with baseline percentage of ‘rescue medication free days’ as a 
covariate instead of baseline rescue medication use.
In addition, the mean number of puffs of rescue medication per day, in the morning and in the 
evening and the percentage of ‘days with no rescue use’ will be summarized by 4 weekly (28 
days) intervals and the change from baseline in mean number of puffs of rescue medication will 
be analyzed using a similar MMRM as specified for the primary analysis with the baseline FEV1 
value replaced with the appropriate baseline rescue medication use. In case of non-convergence
or evidence of highly skewed data, non-parametric tests such as Wilcoxon Rank Sum Test will 
be explored.
2.7.4
Peak Expiratory Flow Rate (PEF)
All the patients are instructed to record PEF twice daily using an electronic Peak Flow Meter 
device, once in the morning and once approximately 12 hours later in the evening (prior to 
evening dose), from Run in visit 101 and throughout the study. PEF (liters/min) will be averaged 
separately for morning and evening values with means over the 12 weeks treatment phase and 
the 3 weeks Baseline Run-in phase.
Baseline values are defined similarly as rescue medication in Section 2.7.3
For post-baseline measurements, similar procedure will be followed, as mentioned for rescue 
medication use.
Mean morning/evening PEF over 12 weeks of treatment phase will be summarized by treatment. 
The between-treatment difference of the change from baseline in mean morning/evening PEF 
will be analyzed using the same model as specified for rescue medication data except that 
baseline rescue medication use will be replaced with baseline morning/evening PEF as the 
covariate. LS means and associated 95% confidence intervals will be presented for treatments 
and the treatment difference.
In addition, the mean morning/evening PEF will be summarized by 4 weekly intervals and the 
change from baseline in mean morning/evening PEF will be analysed using a similar MMRM 
as specified for the primary analysis with baseline FEV1 value replaced with the appropriate 
baseline PEF.
2.7.5
Asthma symptoms based on e-Diary
The night-time symptom score consists of one question 'How did you sleep last night?' which 
has to be answered with scores from 0 = 'I did not wake up because of any breathing problems.' 
up to 4 = 'I had difficulty sleeping because of my breathing problems even though I used my 
rescue medication.' The morning score consists of the question 'Did you have asthma symptoms 
upon awakening in the morning?' which has to be answered with scores from 0 = 'None' up to 
4 = 'Very Severe'. There are 5 questions including the today's severity of shortness of breath, 


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wheeze, cough, and chest tightness during the past 12 hours, and 'Did your respiratory 
symptoms stop you from performing your usual daily activities?' which are part of the daytime 
symptom score. All have to be answered with a score from 0 = 'None / Not at all' up to 4 = 'Very 
Severe / Completely'.
Daily e-Diary recordings will be used to derive: 

the mean daytime asthma symptom score i.e., the mean score over the 5 evening questions 
with respect to shortness of breath, wheeze, cough, chest tightness, and 'Did your respiratory 
symptoms stop you from performing your usual daily activities?', each with scores from 0 
(no problems) to 4 (very severe problems)

the total daily symptom score, defined as the sum of the nighttime score ('How did you sleep 
last night?' with scores from 0 - 4), the morning awakening score ('Did you have asthma 
symptoms upon awakening in the morning?' with scores from 0 - 4) and the mean daytime 
asthma symptom score. The sum will be in the range of 0 – 12.

day with no daytime symptoms, i.e., all 5 evening questions must have a score = 0.

night with no night-time awakenings, i.e., the question 'How did you sleep last night?' must 
be answered with 'I did not wake up because of any breathing problems'.

morning with no symptoms on awakening, i.e., the question 'Did you have asthma 
symptoms upon awakening in the morning?' to be answered with 'None'.

asthma symptoms free days, i.e., days with no daytime symptoms and no night-time 
awakenings and no symptoms on awakening.
Baseline values are defined similarly as rescue medication in Section 2.7.3. Additionally, the
baseline total daily symptom score will be obtained in the first step by adding the nighttime 
symptom score, the morning score, and the mean daytime symptom score for each single day. 
In the second step, these daily symptom scores will be averaged over the days of the run-in 
period with non-missing data. The score is in the range from 0 to 12. For the derivation of the 
total daily symptom score, all 3 scores have to be available at that day. Otherwise a total daily 
symptom score will not be calculated for that day. If a patient has less than 7 days with non-
missing data, then the baseline value will be set to missing.
For post-baseline measurements, similar procedure will be followed, as mentioned for rescue 
medication use.
Daily scores will be averaged for each patient over the days of the run-in period (which will be 
used as the baseline value), 12 weeks double-blind period, and over 4 weekly intervals (from 
Weeks 1-4 up to Weeks 9-12). Days with no daytime symptoms, nights with no night time 
awakenings, mornings with no symptoms on awakening and days with no asthma symptoms 
will be expressed in percentage of days with data during the respective periods. The same 
periods as for average scores will be analyzed for percentage of days. In case of non-
convergence or evidence of highly skewed data, non-parametric tests such as Wilcoxon Rank 
Sum Test will be explored.For post baseline periods only the days on double-blind treatment 
will be considered. ANCOVA and MMRM will be performed on changes from baseline similar 
to the analysis of PEF with the appropriate baseline symptom score value as a covariate.


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2.7.6
Asthma Exacerbations
All analyses will base on data as reported on the "Asthma Exacerbation Episodes" eCRF. The 
following asthma exacerbation-related parameters will be summarized considering the whole 
12 weeks of double-blind treatment. The analysis will be performed by exacerbation category 
wherever specified. The exacerbation categories are: All (mild, moderate, severe) , and the 
combination of moderate or severe. The data for categories mild, moderate and severe will be 
collected as a part of Asthma Exacerbation Episode CRF and an additional category moderate 
or severe will be added for analysis.

Time to first asthma exacerbation by exacerbation category

The annual rate of asthma exacerbations by exacerbation category
In patients with multiple exacerbations, if the start date of an exacerbation was less than 7 days 
after the end date of a previous episode, then this will be assumed to be one continuous 
exacerbation with the start date taken from the first episode and the end date from the second 
or last episode. The worst severity of these episodes will be taken as the severity of the collapsed 
exacerbation. Collapsing of exacerbation episodes will only be done for efficacy analyses but 
not for safety analyses of adverse events which includes asthma exacerbations.
Asthma exacerbations starting after the first dose and not later than one day after the date of
last dose will be included in the analyses of efficacy.
Time-to-event variables will be analyzed using a Cox regression model stratified by age (12 to 
17 or ≥ 18). The model will include treatment, region and history of asthma exacerbation in the 
12 months prior to screening (Yes, No) as fixed-effect factors, and FEV1 prior to inhalation and 
FEV1 within 15 to 30 min post inhalation of salbutamol/albuterol (components of SABA 
reversibility) as covariates. The estimated adjusted hazard ratio for QMF149 over MF will be 
displayed along with the associated two-sided 95% confidence interval and corresponding p-
value. Kaplan-Meier analysis stratified by treatment group will be also presented and displayed 
graphically. Patients without any asthma exacerbation will be censored at the earliest date of 
(last dose of study treatment + 1, death, last visit).
The annual rate of asthma exacerbations will be analyzed using a generalized linear model 
assuming the negative binomial distribution including treatment, age (12 to 17 or ≥ 18), and 
region and history of asthma exacerbation in the 12 months prior to screening (Yes, No) as 
fixed-effect factors, and FEV1 prior to inhalation and FEV1 within 15 to 30 min post inhalation 
of salbutamol/albuterol (components of SABA reversibility) as covariates. The log exposure in 
years will be included as an offset variable in the model. The estimated rate ratio along with 
two-sided 95% interval and corresponding p-value will be provided.
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2.7.7
Quality of life as assessed by Asthma Quality of Life Questionnaire 
(AQLQ-S+12)
AQLQ is a 32-item disease specific questionnaire designed to measure functional impairments 
that are most important to patients with asthma, with a recall time of two weeks and each 
question to be answered on a 7-point scale (1-totally limited/problems all the time, 7-not at all 
limited/no problems). It consists of 4 domains:

Symptoms = Mean of Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 (12 items)

Activity limitation = Mean of Items 1, 2, 3, 4, 5, 11, 19, 25, 28, 31, 32 (11 items)

Emotional function = Mean of Items 7, 13, 15, 21, 27 (5 items)

Environmental stimuli = Mean of Items 9, 17, 23, 26 (4 items)

Overall Score = Mean of Items 1 to 32 (32 items)
Dr. Juniper, developer of AQLQ questionnaire suggests no more than 10% of missing data. 
This means that for a questionnaire of 32 items, no more than 3 items should be missing.  Further, 
for the activity and symptom domains, the recommendation is no more than 1 missing value 
per domain, and for the emotional function and environmental stimuli domains, no missing 
responses at all. Missing individual items will be imputed similarly to missing items for ACQ-
7.
For the overall score and each respective domain score measured at Week 12, treatment group 
comparison will be performed using the same ANCOVA model as specified for rescue 
medication use with baseline AQLQ as covariate.
The proportion of patients who achieve an improvement of at least 0.5 at Week 12 in the change 
from baseline in AQLQ (i.e. an increase of AQLQ score of at least 0.5 from baseline) will be 
analyzed using a logistic regression model via GEE on the FAS as specified for ACQ-7 analysis 
except that the GEE model will include terms for treatment, age (12 to 17 or ≥ 18 years), region 
as fixed effects, and baseline AQLQ, FEV1 prior to inhalation and FEV1 within 15 to 30 min 
post inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates. The 
handling of missing data will also be the same as for ACQ-7, i.e., first missing continuous 
AQLQ values will be imputed using a MI method under MAR assumption. Then continuous 
AQLQ values will be converted into binomial responses and GEE method will be used to 
analyze the datasets and then the results from GEE method will be combined for the inference.
2.8
Safety analyses
All safety evaluation will be based on the safety set.
The study will be reviewed for safety issues by an independent, external data safety monitoring 
board (DMC), as described in Section 2.11 Interim analysis.
For safety data, post-baseline measurements comprise recordings up to the last dose of study 
treatment + 7 days for laboratory, ECG, vital signs. ECG, vital signs and laboratory values 


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which have complete date and time values are assigned to pre or post-dose assessment based 
on the actual date/time. However, values with missing date/time are assigned to their respective 
scheduled visit date and time given the visit number and time point are non-missing. If a 
measurement scheduled as pre-dose is actually performed post-dose, or vice versa, the data will 
not be used for by time point assessments but will be included in the summaries of the notable 
values and extreme values.
2.8.1
Serious asthma outcome
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 time of randomization until the 30 days after permanent 
discontinuation of study treatment 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. If a sufficient number 
of events will occur, similar analyses as described for asthma exacerbations will be performed. 
Otherwise, a purely descriptive analysis will be done only.
2.8.2
Adverse events (AEs)
All adverse events including asthma exacerbations, coded with MedDRA using the most actual 
version at the time of database lock, will be listed. In general, summaries will include treatment-
emergent adverse events only, i.e., those starting on or after the time of the first administration 
of study treatment but not later than 7 days (30 days in the case of a SAE) after the last 
administration. Any AEs that started during the study before the time of the first inhalation of 
study treatment will be classified as a prior AE.
The number and percentage of patients who reported treatment-emergent adverse events will 
be summarized by primary system organ class (SOC), preferred term (PT), and treatment for

all adverse events

all adverse events by maximum severity

adverse events suspected to be related to study treatment

adverse events leading to permanent study treatment discontinuation

all adverse events by standardized MedDRA query (SMQ) level

serious adverse events

fatal adverse events
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the QMF149 150/80 μg treatment group. 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 in the QMF149 150/80 μg treatment group.
2.8.2.1
AE reporting for CT.gov and EudraCT
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 2% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2.2
Adverse events of special interest
The number and percentage of patients who reported treatment-emergent adverse events of 
special interest will be summarized by risk name, preferred term and treatment groups..
Risk names will be sorted alphabetically and, within each risk name, the preferred terms will 
be sorted in descending order of frequency in the QMF149 150/80 μg treatment group. 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 
risk, the patient will be counted only once at that risk.
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.
Adverse events of special interest will also be analyzed for the following selected subgroups:
- Age group (12 to 17 years, ≥ 18 years)


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2.8.3
Deaths
A summary of deaths will be presented by primary system organ class, preferred term, and 
treatment groups regardless of study treatment relationship. In addition, deaths will be 
summarized by adjudicated primary cause and treatment group.
All the deaths in the clinical database will be listed with both the investigator-reported principal 
cause and the adjudicated primary cause presented side by side. If adverse events (including 
asthma exacerbations) leading to death start between the first study treatment and (the last dose 
+ 30 days), then those deaths will be included in summary tables..
2.8.4
Laboratory data
All laboratory samples will be processed through the central laboratory. Laboratory data consist 
of hematology, biochemistry and urinalysis measurements, including plasma cortisol. All data 
will be listed with abnormal values flagged.
Baseline laboratory data is defined as the assessment taken 20 minutes pre-dose at Day 1. 
Checks will be performed to ensure the assessments were indeed taken prior to the first dose of 
study treatment on Day 1. If this assessment is missing or not confirmed to be pre-dose, the last 
value taken at the run-in Visit 101 (applicable for hematology, biochemistry and urinalysis) or 
at an unscheduled visit before the first administration of study treatment will be used for 
baseline. Otherwise, the baseline laboratory data will be set to missing without imputation.
Laboratory data measured more than 7 days after last inhalation of study treatment are regarded 
as post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use.
The following analyses will be performed by treatment:

absolute values and change from baseline summarized for continuous laboratory parameters 
by visit and time point, including the minimum/maximum post-baseline value

frequency table of results for categorical laboratory parameters by visit and time point, 
including the worst post-baseline value

shift tables relative to the normal reference ranges summarizing the change from baseline 
to the most extreme post-baseline value for each continuous laboratory parameter (except 
urinalysis parameters)

shift tables from baseline to the worst post-baseline value for categorical laboratory 
parameters (except urinalysis parameters)

the number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (see Section 6.4 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.


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The worst case post-baseline values and the most extreme post baseline values will be  
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 hematology and 
biochemistry parameters in Section 6.4. 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. 
A listing of all patients with notable laboratory values will be provided.
Maximum change from baseline laboratory result for liver parameters will be summarized. 
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) will be summarized by treatment and 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 visit (if not measured 
more than 7 days after last dose) based on the criteria mentioned in the section 5.4.
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 patients with clinically notable LFT values will be provided.
2.8.5
Other safety data
2.8.5.1
ECG
ECG measurements include ventricular rate, QT interval, RR interval, PR interval, QRS 
duration, and Fridericia’s QTc (calculated as QTcF = QT / 3√ RR(in seconds), where 3√denotes 
the cube root). Furthermore, an overall interpretation of the central cardiologist will be provided 
as well as a specification of abnormal findings.
Baseline ECG is defined as ECG measured 35 minutes prior to the first dose of study treatment
on Day 1. Checks will be performed to ensure the ECG was indeed assessed prior to the first 
dose of study treatment. If it is missing (or not confirmed to be pre-dose), then the last 
assessment taken at the run-in Visit 101 or at an unscheduled visit before the first administration 
of study treatment will be used. Otherwise, the ECG baseline will be set to missing without 
imputation.


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ECG data measured more than 7 days after last inhalation of study treatment are regarded as 
post treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use.
The following analyses will be performed by treatment:

absolute values and change from baseline summarized by parameter, visit and time point

the number and percentage of patients with newly occurring or worsening notable QTcF 
values (see Section 6.5 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 

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 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 QTc value and a worsening notable QTc value.
A listing of all patients with notable QTc values and changes will be provided.
2.8.5.2
Vital signs
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), pulse 
rate, height (for adolescents only) and body weight (at selected visits only).
Baseline vital signs (systolic and diastolic blood pressure (SBP and DBP), pulse rate) are 
defined as the assessment taken 25 minutes pre-dose at Day 1. Checks will be performed to 
ensure the assessments were indeed taken prior to the first dose of study treatment on Day 1. If 
this assessment is missing or not confirmed to be pre-dose, the last value taken at the run-in 
Visit 101 or at an unscheduled visit before the first administration of study treatment will be 
used for baseline. Baseline height and weight are defined as the measurements taken at the run-
in Visit 101. Missing baseline values will not be imputed.
Vital signs data measured more than 7 days after last inhalation of study treatment 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.


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The following analyses will be performed by treatment:

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 mm Hg, 90 – 140 mm Hg, and > 140 mm Hg
- DBP < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg

the number and percentage of patients with newly occurring or worsening notable vital signs 
values (see Section 6.5 for definition of notable values) summarized by parameter (except 
height), 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.
2.8.5.3
Unscheduled primary and secondary care visits due to asthma 
worsening
Worsening of asthma symptoms may require unscheduled evaluation between visits. The on-
treatment data related to asthma worsening collected will be listed and summarized 
descriptively. 
Number of hospitalizations, number of unscheduled health care provider visits (office and home 
visit combined),  number of visits in emergency room <=24 hours and number of other type of 
facility will be summarized for asthma related reason. Here “asthma related” reason will 
combine both asthma related and asthma exacerbation related reason. 
Data of the adjudicated hospitalization reports will be used to derive the number of 
hospitalizations. Asthma – Healthcare Resource Utilization – Outpatient Visits CRF data will 
be used for summarization of all other type of facilities.


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2.11
Interim analysis
An independent, external data safety monitoring board (DMC), comprising experts (as defined 
in the Charter) will be set up to review all serious adverse events (including deaths and all 
hospitalizations) and pneumonia. DMC members will review this data generated externally and 
independently of Novartis, at predetermined intervals. If significant safety issues arise in 
between scheduled meetings, ad-hoc meetings will be scheduled to review the data. Based on 
the safety implications of the data, the DMC may recommend modification or termination of 
the study.
No interim analysis for efficacy is planned. It is planned that the independent DMC will review 
semi-blinded (i.e., treatment group named as T01 and T02) safety data. The details of the 
information flow, confidentiality and specific analyses required for the safety monitoring 
analysis will be documented in the DMC Charter. The Charter will be finalized prior to semi-
blinding the data for the safety monitoring analysis. Since the purpose of the DMC is not based 
on efficacy for stopping rule, there will be no alpha spent for the safety monitoring analysis. 
All analyses will be considered exploratory.
3
Sample size calculation
The sample size calculation takes into account the following consideration:
1. To achieve at least 90% power for the primary endpoint trough FEV1 with a treatment 
difference of 100 mL between QMF149 vs. MF, assuming a standard deviation of 380 
mL based on internal studies CQMF149A2210, CQMF149E2201, CQMF149E2203 


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and literature data, where most observed treatment effects range approximately 80 mL 
to 120 mL.
1. To achieve at least 75% power (with multiplicity adjustment) for the secondary endpoint 
ACQ-7 with a treatment difference of -0.18 between QMF149 vs. MF, assuming a 
standard deviation of 0.80 based on study CQMF149A2210, where observed treatment 
difference was -0.21 with 95% confidence interval (-0. 28, -0.15);
If 10% dropout rate is assumed, then calculation shows the sample size of 750 patients (ie 
375/arm) will provide approximately 93% power for item 1 and 77% power for item 2 with 
multiplicity adjustment.
The sample size calculation was performed in PASS software.
4
Change to protocol specified analyses
Section 2.7.2 Asthma control questionnaire (ACQ) : All the analyses described for ACQ-7 has 
been included for ACQ-5.
5
Analyses to be reported outside of CSR
5.1
Subgroup analyses
Subgroup analyses for Japanese patients will be performed for the FAS to explore the treatment 
effect in this sub population. These analyses will only include patients of the respective country.
The following endpoints will be summarized and/or analyzed using similar methods as 
described in previous sections, if not marked with special symbol.

Patient disposition

Protocol deviations

Analysis sets

Demographics

Disease characteristics

Spirometry at run-in visits and at baseline

Trough FEV1

ACQ-7

Pre-dose trough FEV1

Trough FVC

Pre-dose trough FVC

Mean morning/evening PEF

Asthma symptom based on e-diary


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
Rescue medication

Asthma exacerbations

Asthma Quality of Life Questionnaire (AQLQ-S+12)*

 

Exposure

Concomitant asthma medications

Laboratory data

Vital signs

ECG

Adverse events
The specific outputs for the sub population under each endpoint will be specified in the TFLs.
6
Appendix
This appendix gives details about statistical methods in addition to the report text. All analyses 
will be performed by using SAS Version 9.4.
6.1
Imputation rules
6.1.1
Study treatment
Missing/partial start date or end date of study treatment will not be imputed.
6.1.2
AE date imputation
Rules for imputing AE end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
6.1.3
Concomitant medication date imputation
Rules for imputing the CM end date or start date will be provided in Programming Dataset 
Specification (PDS) document in details.
6.2
AEs coding/grading
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events.
6.3
Data pooling and assessment windows


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Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed. For patients who do not complete the study treatment, the treatment 
discontinuation visit will be an unscheduled visit.
Clinical laboratory measurements, vital signs and ECG data from unplanned or unscheduled 
visits will only be included in the summaries of the notable values and extreme values. All 
efficacy data (including spirometry data) from these visits will not be used for missing data 
imputation unless specified otherwise.
Laboratory, vital signs, and ECG values that have complete data and time values will be slotted 
into pre- or post-dose assessment based on the actual date/time. For values with missing 
date/time, scheduled visit date and time will be used. This rule will be applied to data from 
scheduled visits only. If a measurement scheduled as pre-dose is actually performed post-dose, 
or vice versa, the data will not be used for by time point assessments.


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6.4
Laboratory parameters – 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. 
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
WBC
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
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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Laboratory parameter (unit)
Lower bound of 
clinically notable range
Upper bound of 
clinically notable range
Hematology
Hematocrit (v/v)
     Male
     Female
0.37
0.32
Hemoglobin (g/L)
    Male
    Female
115
95
Platelets (x10E9/L)
75 
700
WBC (x109/L)
2.8
16.0
Chemistry
Albumin (g/L)
25
-
Alkaline Phosphatase (U/L)
-
3xULN
ALT/SGPT (U/L)
-
3xULN
AST/SGOT (U/L)
-
3xULN
Bilirubin Total (mcmol/L)
-
34.2
BUN (mmol/L)
-
9.99
Creatinine (mcmol/L)
-
176.8
Glucose (mmol/L)
2.78
9.99
Gamma GT (U/L)
-
3 x ULN
Potassium (mmol/L)
3
6
Magnesium (mmol/L)
0.51
1.07
v = volume, ULN = upper limit of normal 
Notable liver function test values


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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.
6.5
Vital signs and ECG – definition of clinically notable values
The following table shows the clinical notable criteria for vital signs.


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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
The following table shows the clinical notable criteria for QTcF.
Clinical notable criteria for QTcF (Fridericia's formula)
ECG parameter (unit)
Clinically notable range
Notable value considering newly occurring or worsening cases
QTc (msec)
> 450 (male)
QTc (msec)
> 460 (female)
QTc (msec)
> 500 (both)
Notable change from baseline
QTc
30 – 60
QTc
> 60
Combined criterion
QTc (msec)
> 500 & increase from baseline > 60


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6.6
Statistical methodology and assumptions
SAS codes for all statistical methodology described in this section will be included as 
programming note in TFL Shells.

Mixed Model Repeated Measures (MMRM)
The following MMRM ANCOVA will be used for trough FEV1, ACQ-7, and other data:
Dependent variable = intercept + treatment + age group + region + baseline value + FEV1 prior 
to inhalation + FEV1 within 15 to 30 min post inhalation + visit + treatment*visit + baseline
value*visit + random effect of center nested within region + error.
The within-patient correlation will be modeled using an unstructured covariance matrix in the 
mixed model. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom (Kenward and Roger, 1997). 
For the final analysis, if the model does not converge with unstructured covariance matrix, the 
compound symmetry covariance structure will be used, if the model still does not converge the 
random effect will be removed, if the model converges after removing the random center effects, 
the original model without random center effects will be re-assessed
The SAS procedure PROC MIXED will be used for analysis. Results will be presented with 
least squares mean (LSM) and standard error (SE) for treatment effects and LSM, SE, associated 
two-sided 95% confidence interval, and two-sided p-value for the treatment contrast.
In the analysis of laboratory data 
, the covariates FEV1 prior to 
inhalation and FEV1 15 to 30 min post inhalation will not be included in the MMRM.

Tipping point analysis for trough FEV1 at Week 12
As a sensitivity analysis to evaluate the impact of missing data, a tipping point analysis will be 
performed for the primary endpoint trough FEV1 at Week 12. The delta-adjusting approach 
described in Ratitch et al (2013) will be used to find the tipping point, in a spectrum of 
conservative missing not at random (MNAR) assumptions, at which conclusions change from 
being favorable to QMF149 to being unfavorable. The basic idea is to impute the missing values 
using a regression based multiple imputation (MI) method based on the MAR assumption. The 
imputed Week 12 values for the QMF149 arms are then adjusted by a delta value.
The endpoint is assumed to have a normal distribution at Day 2 and Week 12. The primary 
analysis is performed on the delta-adjusted datasets to see if the conclusions change. If not, a 
larger delta is chosen and the process is repeated until the conclusion is overturned. The tipping 
point is the delta value which will cause the QMF149 vs. MF comparison on the primary 
endpoint to be no longer statistically significant. A series of analyses on a range of delta values 
will be performed to find the tipping point. For each delta value, the following steps will be 
performed.


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1. Impute missing covariates (baseline FEV1, FEV1 prior to inhalation and FEV1 15 to 30 
min post inhalation value) and missing values at Day 2 and/or Week 12 using the MI 
approach based on the fully conditional specification (FCS) method for 100 times and 
obtain 100 imputed datasets. Missing baseline FEV1, FEV1 prior to inhalation and FEV1
15 to 30 min post inhalation value will be imputed separately for each treatment group 
using a model with age group, geographic region, and the respective other covariates 
(baseline FEV1, FEV1 prior to inhalation and FEV1 15 to 30 min post inhalation value) 
as predictors. Missing Day 2 values will be imputed separately for each treatment group 
using a model with the imputed values of age group, geographic region, baseline FEV1, 
FEV1 prior to inhalation and FEV1 15 to 30 min post inhalation value as predictors. 
Missing Week 12 values will be imputed separately for each treatment group using a 
model with the imputed values of age group, geographic region, baseline FEV1, FEV1
prior to inhalation, FEV1 15 to 30 min post inhalation, and Day 2 value as predictors. 
2. After the imputation obtained in above step, for subjects in the QMF149 treatment arms 
only, make the imputed value at Week 12 worse by a value of delta (i.e., subtract delta 
from the imputed value at Week 12). Note: delta = 0 represents the standard missing at 
random (MAR) based MI.
3. The final multiply-imputed dataset where all missing values are filled will be analyzed 
(by imputed dataset) using a linear mixed model with treatment, age group, geographic 
region, baseline FEV1, FEV1 prior to inhalation, and FEV1 within 15 to 30 min post 
inhalation as predictors.
4. The results for the treatment effect from the 100 datasets will then be combined using 
Rubin’s rule. If the combined results does not change the conclusion (i.e., the QMF149 
treatment effect is still statistically significantly superior to MF), a larger delta will be 
chosen and Steps 1-4 will be repeated using the datasets from Step 2 until the tipping 
point is found (when p > 0.05).

Logistic regression analysis
The analysis of 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 
performed using the following steps:
1. Impute missing covariates (baseline ACQ-7, FEV1 prior to inhalation and FEV1 15 to 
30 min post inhalation value) and missing continuous ACQ-7 values at Day 30 and/or 
Week 12 using the MI approach based on the fully conditional specification (FCS) 
method for 100 times and obtain 100 imputed datasets. Missing baseline ACQ-7, FEV1
prior to inhalation and FEV1 15 to 30 min post inhalation value will be imputed 
separately for each treatment group using a model with age group, geographic region, 
and the respective other covariates (baseline ACQ-7, FEV1 prior to inhalation and FEV1
15 to 30 min post inhalation value) as predictors. Missing Day 30 values will be imputed 
separately for each treatment group using a model with the imputed values of age group, 
geographic region, baseline ACQ-7, FEV1 prior to inhalation and FEV1 15 to 30 min 


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post inhalation value as predictors. Missing Week 12 values will be imputed separately 
for each treatment group using a model with the imputed values of age group, 
geographic region, baseline FEV1, FEV1 prior to inhalation, FEV1 15 to 30 min post 
inhalation, and Day 30 value as predictors.  
The SAS procedure PROC MI will be used and this will result in 100 copies of the 
original dataset.
2. Then continuous ACQ values will be converted into binomial responses (1= an 
improvement of at least 0.5, 0= no improvement) and generalized estimating equation 
(GEE) method will be used to analyze the dataset. The GEE model will include terms 
for treatment, age (12 to 17 or ≥ 18 years), region, visit, and treatment-by-visit 
interaction as fixed effects, and Baseline ACQ-7, Baseline-by-visit interaction, FEV1 
prior to inhalation and FEV1 within 15 to 30 min post inhalation of salbutamol/albuterol 
(components of SABA reversibility) as covariates.
The SAS procedure PROC GENMOD will be used.
Combining results from X copies of original dataset:
3. In the next step, results from each copy, obtained from GEE method will be combined 
for the inference using Rubin’s rule. The SAS procedure PROC MIANALYZE will be 
used for combining the results considering the linear scale and then we will take 
exponential of combined result to obtain the odds ratio.
The estimated adjusted odds ratio will be displayed along with the associated 95% confidence 
interval and p-value (two-sided).
The proportion of patients who achieve an improvement of at least 0.5 at Week 12 in the change 
from baseline in AQLQ (i.e. increase of AQLQ score of at least 0.5 from baseline) will be 
analyzed using the same procedure as mentioned above for ACQ-7, with the following changes:
Replace ACQ-7 in all steps by AQLQ. Change step 1 as follows.
1. In Step 1, Impute missing covariates (baseline AQLQ, FEV1 prior to inhalation and 
FEV1 15 to 30 min post inhalation value) and missing continuous AQLQ values at Week 
12 using the MI approach based on the fully conditional specification (FCS) method for 
100 times and obtain 100 imputed datasets. Missing baseline AQLQ, FEV1 prior to 
inhalation and FEV1 15 to 30 min post inhalation value will be imputed separately for 
each treatment group using a model with age group, geographic region, and the 
respective other covariates (baseline AQLQ, FEV1 prior to inhalation and FEV1 15 to 
30 min post inhalation value) as predictors. Missing Week 12 values will be imputed 
separately for each treatment group using a model with the imputed values of age group, 
geographic region, baseline AQLQ, FEV1 prior to inhalation, FEV1 15 to 30 min post 
inhalation.  

Linear Mixed Model Analysis of Covariance (ANCOVA)


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The following linear mixed ANCOVA model will be used for diary data summarized over 12
weeks:
Dependent variable = intercept + treatment + age group + region + baseline value + FEV1 prior 
to inhalation + FEV1 within 15 to 30 min post inhalation + random effect of center nested within
region + error.
The SAS procedure PROC MIXED will be used for analysis. Results will be presented with 
LSM and SE for treatment effects and LSM, SE, associated two-sided 95% confidence interval, 
and two-sided p-value for the treatment contrast.
Cox regression analysis
A Cox proportional hazards regression model stratified by age (12 to 17, ≥ 18 years) will be 
applied in time-to-event analyses to test the null-hypothesis H0: λQMF(t) / λControl(t) = 1, where 
λ(t) is the hazard function for the failure time of patients treated with QMF and the control 
group, respectively.
The SAS procedure PHREG will be used for analysis. Results will be presented with adjusted 
hazard ratio for the treatment group comparison and associated 95% confidence interval and 
two-sided p-value. P-value will be obtained from the Wald chi-squared statistic testing the null-
hypothesis that the parameter estimate for the respective treatment effect is 0 (then the hazard 
ratio is exp(0) = 1).
No check for the validity of proportional hazards assumptions will be done.

Generalized linear model assuming a negative binomial distribution
The annual rate of asthma exacerbations (by exacerbation category) will be analyzed using a 
generalized linear model assuming a negative binomial distribution.
The time at risk for a patient is defined as the duration of exposure in days + 1 day and the 
log(time at risk in years) will be used as the offset variable in the model.
The SAS procedure GENMOD will be used for analysis. Treatment group ratio of exacerbation 
rate will be presented together with 95% confidence interval and two-sided p-value.
6.7
Rule of exclusion criteria of analysis sets 
The following table provides the protocol deviations (PD) and other criteria leading to partial 
or complete exclusion from analyses sets


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Deviation 
ID
Description of Deviation
Deviations leading to exclusion from all analyses sets
INCL01A
Informed consent not obtained
EXCL22A
Patient with custodial sentence. Do not have permanent residence or detained under local 
mental health legislation/regulation
Deviations leading to exclusion from RAN, FAS, PPS
 analysis set
OTH05A
Patient received study drug but was not randomized
Deviations leading to exclusion from FAS, PPS, Safety 
 analysis set
OTH04A
Patient randomized but did not receive study drug
Deviations leading to exclusion from FAS and PPS
OTH03A
Patient Randomized more than once in this study or randomized in another study
Deviations leading to exclusion from PPS
INCL02A
Age < 12 years or > 75 years or missing
INCL03A
No documented diagnosis of Asthma for at least 3 months prior to Visit 1
INCL04A 
Patients who are not treated with low dose ICS, with or without controller (ie, LABA, 
Leukotriene Receptor Antagonist (LTRA) at stable dose for at least 1 month (=30 days) prior 
to Visit 1
INCL05A
Adult patients with ACQ-7 score < 1.5 at visit 101 and/or visit 102
INCL06A
Adolescent patient on ICS only (without LABA), have ACQ -7 < 1.5 at visit 101 and/or visit 
102
INCL06B
Adolescent patient on ICS+LABA have ACQ-7 score < 1 or >= 1.5 at visit 101
INCL06C
Adolescent patient on ICS+LABA have ACQ-7 score < 1.5 at visit 102
INCL07A
Pre Bronchodilator FEV1 < 60% or >= 90% of predicted normal after withholding 
bronchodilator both at visit 101 and 102
INCL08A
Patients for whom increase in FEV1 < 12% and/or < 200 ml within 30 minutes after 
administration of 400  microgram salbutamol/360  microgram albuterol (or equivalent dose) at 
Visit 101
INCL08B
Patient has not achieved an acceptable spirometry result does not have historical reversibility 
INCL08C
Patient has not achieved assessments according to ATS/ERS criteria
EXCL01A
Patients who have smoked or inhaled tobacco products (including electronic ciggarettes) within 
6 months prior to visit 1
EXCL01B
Patient has a smoking history of >= 10 pack years or missing
EXCL02A
Adults: who had an asthma attack or exacerbation requiring systemic steroids or hospitalization 
or emergency room visit within 6 weeks of visit 1
EXCL02B
Adults: who had an asthma attack or exacerbation requiring systemic steroids or hospitalization 
or emergency room visit between visit 1 and 102


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Deviation 
ID
Description of Deviation
EXCL02C
Adolescents: who had an asthma attack or exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 6  months prior to visit 1
EXCL02D
Adolescents: who had an asthma attack or exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within: between Visit 1 and 102
EXCL03A
History of Intubation for severe asthma attack or exacerbation
EXCL05A
Patients with respiratory tract infection or asthma worsening between Visit 1 and Visit 102
EXCL05B
Patients with respiratory tract infection or asthma worsening within: 4 weeks prior to visit 1
EXCL06A
Clinically significant oropharyngeal candidiasis at Visit 102 or earlier, with or without 
treatment.
EXCL07A
Patient with chronic condition affecting upper respiratory tract (eg. chronic sinusitis)
EXCL08A
Patient have a medical history of chronic lung diseases other than asthma
EXCL11A
Other investigational drugs used within 30 days of visit 1 or 5 half lives or untill return of 
baseline pharmacodynamic effect whichever is longer.
EXCL21A
Patient on Maintenance Immunotherapy (desensitization) for allergies less than 3 months prior 
to Visit 101
EXCL21B
Patient on Maintenance Immunotherapy for allergies more than 3 months prior to Visit 101 but 
expected to change therapy throughout the study
EXCL21C
Monoclonal antibodies: IgE inhibitors and other asthma related biologics (e.g. omalizomab) 
IL-5 inhibitors (e.g. mepolizomab) taken within 4 months prio to run-in 101.
EXCL23A
Patient associated with any member of study team
EXCL24A
Patient unable to use the dry powder inhalers
EXCL25A
Patient has history of alcohol or other substance abuse since last 10 years
EXCL34A
LAMA taken less than 3 months prior to Visit 101
COMD09A
Parenteral or oral corticosteroids taken within 4 weeks prior to run in 101
COMD10A
Intra-muscular depot corticosteroids taken within 3 months prior to Run in 101
COMD12A
Xanthines taken within 7 days prior to Run In 101
COMD13A
Systemic mast cell stabilizers taken within7 days prior to Run in visit 101
OTH01A
Patient not having correct run in medication (i.e. 100mcg accuhaler or 125 mcg via MDI 
inhaler) or dose eqivalent
OTH07A
Patient took study treatment not as per protocol (i.e not inhaled the study medication)
OTH12A
Compliance failure of the patient influencing the safety and efficacy data as per investigator 
judgement
OTH14A
Patient receiving investigational drug other than study drug during the course of the study
COMD02A
SAMA taken less than 8 hours prior to visit 101
COMD03A
Fixed combinations of β2-agonists and inhaled corticosteroids taken within 48 hours prior to 
Visit 101


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Deviation 
ID
Description of Deviation
COMD04A
Fixed combinations of short-acting β2-agonist and short-acting anticholinergic taken within 8 
hours prior to Visit 101
COMD05A
Leukotriene Receptor Antagonist (LTRA) and leukotriene synthesis inhibitors taken within 7 
days prior to Run-in (Visit 101)
COMD06A
LABA b.i.d taken within 48 hours prior to visit 101
COMD07A
LABA o.d continuing at visit 1
COMD08A
Short Acting B2 Agonist, other than rescue medication is continuing after visit 1
WTH01A
Patient still on study treatment even after having 1 severe asthma exacerbation requiring 
treatment with systemic corticosteroids or hospitalizations
WTH06A
Blind broken and study treatment not permanently discontinued
COMD16A
Banned asthma related concomitant Medications used during the study*
Deviations leading to exclusion of data collected after occurence of that event, from all 
analyses set
WTH07A
Study procedures performed after withdrawing of informed consent
7
Reference
Elizabeth Juniper (2004). Asthma Control Questionnaire: Background, Administration and 
Analysis
Frank B. Hu; Jack Goldberg; Donald Hedeker; Brian Ft. Flay; Mary Ann Pentz (1998). 
Comparison of Population-Averaged and Subject-Specific Approaches for Analyzing 
Repeated Binary Outcomes. American Journal of Epidemiology
Kenward MG and Roger JH (1997). Small sample inference for fixed effects from restricted
maximum likelihood. Biometrics 53(3):983-97
Scott L. Zeger; Kung Yee Liang; Paul S. Albert (1988). Models for Longitudinal Data: A 
generalized Estimating Equation Approach. Biometrics, Volume 44, Issue 4, 1049-1060


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