Conditions: Asthma
Keywords: QMF149, Mometasone furoate (MF), asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2216
Healthy volunteers: no

Brief summary:
The purpose of the trial is to evaluate the efficacy and safety of two different doses of QMF149 (QMF149 150/160 µg and QMF149 150/320 µg via Concept1) over two respective MF doses (MF 400 µg and MF 800 µg via Twisthaler® (total daily dose)) in poorly controlled asthmatic participants as determined by pulmonary function testing, and effects on asthma control

Detailed description:

Arms:
arm 1: QMF149 (Indacaterol acetate/Mometasone furoate) 150/160 μg was delivered once daily (o.d) via Concept1 inhaler in the evening. arm 2: QMF149 (Indacaterol acetate/Mometasone furoate) 150/320 μg was delivered o.d via Concept1 inhaler in the evening. arm 3: Mometasone furoate (MF) 400 μg was delivered o.d via Twisthaler® in the evening arm 4: Salmeterol xinafoate/fluticasone propionate 50/500 μg was delivered twice daily (in the morning and in the evening) via Accuhaler®. arm 5: MF 800 μg of total daily dose (400 μg twice daily, in the morning and in the evening) was delivered via Twisthaler®.

Interventions: intervention 1: Indacaterol acetate/Mometasone furoate intervention 2: Mometasone furoate intervention 3: Salmeterol xinafoate/fluticasone propionate
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_000.pdf: 
Global Clinical Development - General Medicine
QVM149B (QMF149: Indacaterol acetate/Mometasone furoate) 
CQVM149B2301 / NCT02554786
A multi-center, randomized, 52 week treatment, double-
blind, triple-dummy, parallel-group study to assess the 
efficacy and safety of QMF149 compared with mometasone 
furoate in patients with asthma
Authors:
 
Document type:
Clinical Trial Protocol
EUDRACT number:
2015-002529-21
Version number:
v05 clean version
Development phase:
III
Release date:
17-Jan-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0, November, 2013


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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
Protocol summary..............................................................................................................17
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.2
Purpose ..................................................................................................................25
2
Study objectives.................................................................................................................25
2.1
Primary objective...................................................................................................25
2.2
Key Secondary objective .......................................................................................25
2.3
Secondary Objectives ............................................................................................25
27
3
Investigational Plan ...........................................................................................................28
3.1
Study design...........................................................................................................28
3.2
Rationale of study design.......................................................................................30
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....31
3.4
Rationale for choice of comparator .......................................................................32
3.5
Purpose and timing of interim analyses/design adaptations..................................32
3.6
Risks and benefits..................................................................................................33
4
Population..........................................................................................................................35
4.1
Inclusion criteria ....................................................................................................35
4.2
Exclusion criteria...................................................................................................37
5
Treatment...........................................................................................................................40
5.1
Protocol requested treatment .................................................................................40
5.1.1
Investigational treatment.......................................................................40
5.1.2
Additional study treatment....................................................................40
5.1.3
Treatment arms......................................................................................41
5.2
Treatment assignment, randomization...................................................................41
5.3
Treatment blinding.................................................................................................42
5.4
Treating the patient................................................................................................42
5.4.1
Patient numbering .................................................................................42
5.4.2
Dispensing the investigational treatment ..............................................43
5.4.3
Handling of study treatment..................................................................43
5.4.4
Instructions for prescribing and taking study treatment........................44


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5.4.5
Permitted dose adjustments and interruptions of study treatment ........46
5.4.6
Rescue medication ................................................................................46
5.4.7
Concomitant treatment..........................................................................47
5.4.8
Prohibited Treatment.............................................................................47
5.4.9
Discontinuation of study treatment .......................................................49
5.4.10
Withdrawal of consent ..........................................................................52
5.4.11
Lost to follow-up...................................................................................52
5.4.12
Emergency breaking of assigned treatment code..................................53
5.4.13
Study completion and post-study treatment..........................................53
5.4.14
Early study termination.........................................................................53
6
Visit schedule and assessments .........................................................................................54
6.1
Information to be collected on screening failures..................................................63
6.2
Patient demographics/other baseline characteristics .............................................63
6.3
Treatment exposure and compliance .....................................................................64
6.4
Efficacy..................................................................................................................64
6.4.1
Spirometry.............................................................................................65
6.4.2
Health Status (Patient Reported Outcomes)..........................................65
6.4.3
Electronic Diary ....................................................................................66
6.4.4
Worsening of asthma.............................................................................67
6.4.5
Asthma Exacerbation ............................................................................68
6.4.6
Appropriateness of efficacy assessments..............................................70
6.5
Safety.....................................................................................................................70
6.5.1
Physical examination ............................................................................70
6.5.2
Vital signs..............................................................................................71
6.5.3
Height and weight .................................................................................71
6.5.4
Laboratory evaluations..........................................................................71
6.5.5
Electrocardiogram (ECG) .....................................................................72
6.5.6
Serious Asthma outcomes.....................................................................73
6.5.7
Pregnancy and assessments of fertility .................................................73
6.5.8
Appropriateness of safety measurements..............................................73
73
73
73
74
7
Safety monitoring..............................................................................................................74
7.1
Adverse events.......................................................................................................74
7.2
Serious adverse events...........................................................................................75


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7.2.1
Definition of SAE .................................................................................75
7.2.2
SAE reporting........................................................................................76
7.2.3
Pneumonia Reporting............................................................................77
7.3
Liver safety monitoring .........................................................................................77
7.4
Pregnancy reporting...............................................................................................78
8
Data review and database management.............................................................................79
8.1
Site monitoring ......................................................................................................79
8.2
Data collection.......................................................................................................79
8.3
Database management and quality control............................................................80
8.4
Data Monitoring Committee..................................................................................80
8.5
Adjudication Committee........................................................................................81
8.6
Advisory Board......................................................................................................81
9
Data analysis......................................................................................................................81
9.1
Analysis sets ..........................................................................................................82
9.2
Patient demographics and other baseline characteristics.......................................82
9.3
Treatments .............................................................................................................83
9.4
Analysis of the primary variable(s) and key secondary variables .........................83
9.4.1
Variable(s).............................................................................................83
9.4.2
Statistical model, hypothesis, and method of analysis..........................83
9.4.3
Handling of missing values/censoring/discontinuations.......................84
9.4.4
Multiplicity Adjustment........................................................................84
9.4.5
Key secondary variable.........................................................................85
9.4.6
Supportive analyses...............................................................................85
9.5
Analysis of secondary variables ............................................................................86
9.5.1
Efficacy variables..................................................................................86
9.5.2
Safety variables .....................................................................................90
92
93
93
9.6
Interim Analysis.....................................................................................................93
9.7
Safety Monitoring Analyses ..................................................................................93
9.8
Sample size calculation..........................................................................................93
10 Ethical considerations........................................................................................................94
10.1
Regulatory and ethical compliance........................................................................94
10.2
Informed consent procedures.................................................................................94
10.3
Responsibilities of the investigator and IRB/IEC..................................................95
10.4
Publication of study protocol and results...............................................................95


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11 Protocol adherence ............................................................................................................95
11.1
Protocol Amendments ...........................................................................................95
12 References .........................................................................................................................96
13 Appendices ........................................................................................................................98
Appendix 1: Instruction for Use of Concept1 ...................................................................98
Appendix 2: Instructions for use of Twisthaler®.............................................................103
Appendix 3 How to Use an Accuhaler®/ Diskus®...........................................................105
Appendix 4: Spirometry Guidance..................................................................................109
Appendix 5: ACQ-7 ........................................................................................................112
Appendix 6: AQLQ-S +12 ..............................................................................................113
118
Appendix 8: Patient Asthma Control e-Diary .................................................................121
Appendix 9: Liver event definitions and follow-up requirements ..................................122
 
.125
Appendix 11: ICS Dose level..........................................................................................127
Appendix 12: Estimation of non-inferiority margin of comparing QMF149 versus 
active control (salmeterol xinafoate /fluticasone propionate) .............................128
List of tables
Table 1-1
Comparable MF monocomponent doses between Asmanex 
Twisthaler and QMF149 Concept1.......................................................24
Table 5-1
Study Treatments ..................................................................................45
Table 5-2
Prohibited asthma-related medications .................................................47
Table 5-3
Prohibited Medications .........................................................................48
Table 5-4 
Medications allowed under certain conditions......................................49
Table 5-5
Table of Assessment for Patients who Discontinue Study 
Treatment prematurely..........................................................................51
Table 6-1
Table of assessment...............................................................................55
Table 6-2
Timed Assessment** ............................................................................62
Table 13-1
Liver Event Definitions.......................................................................122
Table 13-2
Liver Event Follow Up Requirements ................................................123
Table 13-3
Low, medium and high Daily Doses of Inhaled 
Glucocorticosteroids for Adults and adolescents (12 years and 
older)* (GINA 2015)...........................................................................127
Table 13-4
Historical evidence of sensitivity of drug effect of active control 
fixed-dose combination (FDC) for trough FEV1 in patients with 
persistent asthma.................................................................................128


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Table 13-5
Summary of studies HZA106827 and HZA113091 for trough FEV1
from Relvar® asthma program ............................................................129
List of figures
Figure 3-1
Study design..........................................................................................30


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List of abbreviations
ACQ
Asthma Control Questionnaire
AE / SAE
Adverse event / Serious adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification
AQLQ
Asthma Quality of Life Questionnaire
b.i.d.
Twice a day
BMI
Body Mass Index
BUN
Bilirubin Unit Normalized
CFR
US Code of Federal Regulations 
eCRF
Case Report/Record Form (electronic)
COPD
Chronic Obstructive Pulmonary Disease
CPO
Country Pharma Organization
CRO
Contract Research Organization
CSR
Clinical Study Report
DALYS
    Disability–adjusted life years
DMC
Data Monitoring Committee
DPI
Dry powder inhaler
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
EDC
Electronic Data Capture
EOT
Early Treatment Discontinuation 
FAS
Full analysis set
FDC
Fixed dose combination
FEF
Forced expiratory flow
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HV
Healthy volunteer


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ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
i.v.
Intravenous
IQS
Integrated quantitative drug development sciences.
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intra uterine device
IUS
Intra uterine system
LABA
Long acting beta-2 agonist
LAMA
Long acting muscarinic antagonist
LFT
Liver function test (raised serum transaminases and/or bilirubin levels)
MDDPI
Multi dose dry powder inhaler
MF
Mometasone furoate
MedDRA
Medical dictionary for regulatory activities 
OC/RDC
Oracle Clinical/Remote Data Capture o.d. once a day
Pbo
Placebo
PEF
Peak expiratory flow
PI
Post inhalation
PK
Pharmacokinetics
PPS
Per protocol set
PRO
Patient reported outcome
p.o.
Oral (ly)
RAN
Randomization set
SABA
Short acting beta-2 agonist
SCS
Systemic corticosteroids
SDDPI
Single dose dry powder inhaler
SUSAR
Suspected Unexpected Serious Adverse Reactions
WHO
World Health Organization 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the 
trial
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol)
Epoch 
A portion of the study which serves a specific purpose. Typical 
Epochs are: screening/recruitment, wash-out, treatment, and 
follow-up
Investigational drug
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.”
Investigational treatment
All investigational drug(s) whose properties are being tested in 
the study as well as their associated treatment controls. 
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination. 
Investigational treatment generally does not include protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication
Medication number
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT 
system
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.
Premature subject/patient 
withdrawal
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless 
the patient will be followed for progression and/or survival
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), active drug run-ins or background 
therapy 
Study/investigational 
treatment discontinuation
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal
Subject Number 
A number assigned to each patient who enrolls into the study 
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study


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Amendment 5
Amendment Rationale: 
Conduct primary analysis after all patients have completed at least 26 weeks treatment 
(V207): 
The primary and key secondary endpoints of CQVM149B2301 study are trough FEV1 and 
ACQ-7, respectively after 26 weeks of treatment, while the entire study treatment period is 52 
weeks. Novartis has decided to perform primary analysis (see CSR I below) once all patients 
have completed 26 weeks of treatment (Visit 207) or prematurely withdrawn from the study. 
The analysis will be used for internal decision making prior to study completion at 52 weeks. 
Importantly, the study will continue as originally planned in a blinded manner, for full 52 weeks 
period (plus 30 days of safety follow-up). This will be conducted by a distinct and separate 
study team who are not involved in the primary analysis.
In terms of reporting, two separate CSRs will be written:

CSR I: will be completed for the primary analyses once all patients have completed the 
assessments after 26 weeks of treatment (Visit 207) or prematurely withdrawn from the 
study. This will consist of primary and key secondary objectives as well as other pre-
specified objectives up to and including Week 26. The CSR will be based on variable 
duration of exposure with minimum of 26 weeks and maximum of 52 weeks. It will 
consist of:

All data in all patients up to 26 weeks (Visit 207)

Data for the subset of patients who have completed 52 weeks treatment plus follow up 
(Visit 214 and 301) or prematurely withdrawn from the study.

Data up to last available visit for patients who have already completed 26 weeks (Visit 
207) but have not yet completed 52 week treatment plus follow up (Visit 214/301)

CSR II: will be completed once all patients have completed 52 weeks of treatment (Visit 
214) plus 30 day follow up (Visit 301) or prematurely withdrawn from the study. CSR II 
will consist of primary and secondary objectives analyzed in CSR I in addition to all other 
objectives evaluated after 26 weeks and up to 52 weeks (plus follow up). 
Since the primary analysis (CSR I) will be performed prior to all patients completing the study,
a dedicated unblinded team will be involved in CSR I related activities. In order to maintain the 
integrity of the study data, a separate blinded team will continue the study until its completion. 
The details outlining this process including appropriate firewalls will be maintained in a
separate charter.
Modification of analysis of key secondary endpoint, ACQ-7: The key secondary objective 
has been modified to demonstrate the benefit of indacaterol (QAB149) 150 µg monotherapy on 
ACQ-7. This will be achieved by demonstrating superiority of combined medium and high 
QMF149 doses to combined medium and high MF doses, respectively in terms of ACQ-7 after 
26 weeks of treatment. The analysis will be performed only if the individual treatment 
comparisons are significant for the primary endpoint, trough FEV1 at week 26 (i.e., there is an 
evidence of efficacy of both doses of QMF149 over respective MF doses in terms of trough 
FEV1). Sample size has been re-calculated based on updated objective and multiplicity 
adjustment. Assuming 10% dropout, the calculation shows that a sample size of approximately 


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2000 patients (i.e., 400/arm) will provide 94% power for primary endpoint trough FEV1 and 
85% power for key secondary endpoint ACQ-7.
Changes to the protocol
The described changes pertaining to the aforementioned amendment rationale are implemented 
throughout the protocol.
In addition, the following clarifications/additions are included in this protocol amendment:

Add an explanation for primary read-out when all patients have completed 26 weeks of 
treatment as above (Section 3.5, Section 5.3, Section 8.2 and Section 9.6)

Revise the key secondary objective to demonstrate the superiority of add-on indacaterol 
(QAB149) 150 µg by demonstrating superiority of QMF149 (150/160 and 150/320 µg 
combined) to mometasone furoate doses (MF, 400 µg and 800 µg combined) in terms of 
ACQ-7 after 26 weeks of treatment (Section 2.2, Section 9.4).

Changed the multiple testing strategy to reflect updated key secondary objective.

Reduction in sample size to approximately 2000 (Section 4, Section 9.8)

Add the clarification that the treatment for adverse events (including asthma 
exacerbations) is permitted (Section 5.4.8)

Change the requirement for duplicate trace of ECG. Duplicated trace was printed out as a 
back-up (e.g. in case of data transmission error). However currently ECG central vendor 
accepts an electronic back up only (Section 6.5.5)

Clarify the handling of missing data in terms of the duration of post-dosing spirometry 
with respect to b.i.d. regimen (Section 9.4.3, Section 9.4.6)

Align to the analysis plan for the analysis of glucose and potassium value (Section 9.5.2). 
This was mentioned in the last version of amendment (Amendment 4); however, the text 
deletion was not done

Revised targeted number of adolescents from 10% of sample size to approximately 5%.
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).
Additional changes were made in the protocol to reflect the US local amendment which took 
place between the global amendment 4 and amendment 5 in Section 5.4.13.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein do NOT affect the trial specific model ICF.


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Summary of amendments issued before this amendment:
Amendment 4 (14-Feb-2017)
Amendment rationale:
1. Modification of inclusion criteria for baseline ICS and ICS/LABA requirements and 
upper limit of FEV1 threshold. This is based on investigator feedback of real world 
asthma populations and intended to address variability in baseline FEV1 as well as 
evolving treatment patterns, whereby patient medications are more rapidly up-titrated 
in response to symptoms.  This will help identify previously ineligible patients who may 
potentially benefit from treatment with medium to high fixed dose combination of 
ICS/LABA. 
2. Revision of the sample size based on the re-estimation of drop-out rate at Week 26 at 
which time the primary and key secondary objectives are evaluated (Section 4 and 
Section 9.7).
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:

Change in inclusion 3 the required pre-treatment period of ICS or LABA /ICS from 1 year 
to 3 months prior to Visit 1 in inclusion criteria 4 (Section 4.1)

Update inclusion criteria 6, inclusion criteria 7 in Section 4.1, and exclusion criteria 19 in 
Section 4.2 to allow repeat spirometry retest at Visit 101 and 102, modify timing for 
reversibility and modify the use of historical reversibility from 1 year to 2 years 

Update inclusion criteria 6 on the FEV1 upper range limit from <80% to <85%, allow a 
one-time rescreen in Section 4.1 and enhance the importance of complying with the 
asthma medication wash-out as per protocol

Take out LAMA wash-out on criteria 6 of Section 4.1 and Table 5-2 in Section 4.2. Add 
an exclusion criteria to exclude any patients treated with LAMA within the last 3 months 
before Visit 101

Add a clarification on myocardial infarction (MI) in exclusion criteria 13 and 16 (Section 
4.2)

Change the condition of spacer use for reversibility testing in inclusion 7 in Section 4.1
and excluding spacer use for rescue medication in exclusion criterion 27 in Section 4.2

Update the definition of repeatability in the spirometry guidance in Appendix 4

Add for run in medication that countries who do not have fluticasone 100 µg b.i.d by
Accuhaler® or 125 µg b.i.d by MDI can use fluticasone low dose equivalent as per 
Appendix 11

Add fluticasone furoate in Appendix 11, definition of dose of ICS
 


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
Enhance importance of alert to have appropriate actions taken in Section 6.4.4

Clarify 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.

Clarify wording on Table 5-2

Align 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).
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein do NOT affect the trial specific model ICF.
Amendment 3 (08-Sep-2016)
The amendment rationale was to modify the e-diary alert handling during the run-in. 
In addition, the following clarifications or updates from Standards were included in this protocol 
amendment

Clarify that smoking exclusion also pertains to the use of e-cigarettes in the exclusion 
criteria #01.

Removing GINA reference from inclusion  # 03  and # 05 as it is reflected in 
inclusion # 04  

Clarify the exclusion criteria #05 and in Section 6.4.4 that the discontinuation is at 
investigator’s discretion when the e-diary asthma worsening alert criteria are met 
during run-in epoch in accordance with Section 6.4.4. The current text states that 
discontinuation is mandatory regardless of investigators discretion. This amendment 
will allow the investigator to incorporate clinical judgment into the context of e-diary 
alerts during run-in epoch to assess clinical significance of the asthma worsening alert 
and decide on best course of treatment for patient.

Clarify that the FEV1 assessment in inclusion criteria #06 also needs to comply to 
ATS/ERS criteria

Clarify the ECG prior to randomization (Visit 102) in exclusion criterion #16, 
although no ECG is scheduled at Visit 102, any clinically significant abnormal ECG 
before Visit 102 (including unscheduled ECG) should lead to exclusion.


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
Include lactose as an example of hypersensitivity in the exclusion #18 since study 
drug is formulated using lactose blended dry powder.

Clarify that repeat spirometry is permitted in cases where the spirometry did not meet 
ATS/ERS criteria at Visit 101 in inclusion #07 and exclusion #19.

Specify “severe” narcolepsy and/or insomnia in exclusion criteria #23.

Exclusion criteria #32

Adjust the wording from “effective” to “highly effective” because the listed 
methods are actually “highly effective” contraception methods.

Under ‘total abstinence’, the following text has been added. “if allowed as 
effective method of contraception by local regulations”.

Clarify that contraception requirement includes both treatment epoch and 30 days 
follow-up epoch after end of study treatment.

Add IL-5 inhibitor (e.g., mepolizumab) in the Prohibited asthma-related medications 
(Table 5-2).

Clarify the conditions in which anti-histamine use is permitted in Table 5-4.

Clarify when pregnancy test is required in Section 6.5.7.

Add the maximum duration of device usage in Appendix 1 (to address questions 
received in some countries).

Specify that time between Visit 1 and Visit 101 can be adapted according to the 
required wash-out from previous medication as per Table 6-1.

Clarify timing of urine analysis in Table 6-2.

Numbering on exclusion criteria was entered.

Update in Section 7.4  the follow-up period “up to 3 months after birth” in case a
female patient is pregnant during the study.

As Visit 299 does not have a specific eCRF visit page, but only summary pages to fill 
in, the numbering was replaced by the term Early Study Discontinuation to avoid 
misunderstanding.

The word masterscope was replaced with “equipment provided by spirometry 
vendor”.

Update of Section 7.2.1 for Serious Adverse Event reporting.
Amendment 2 (01-Oct-2015)
The amendment rationale was to modify ACQ score inclusion from ACQ>2 to ACQ≥1.5
In addition, the following minor clarifications were included in this protocol amendment:

Additional pregnancy testing might be performed if requested by local requirements
(added on the footnote of Table 6-1 Table of Assessment, Section 6.5 Safety and Section 
6.5.7 Pregnancy and Assessment of Fertility)

Differentiate the reversibility and the pre-bronchodilator spirometry assessments on Table 
6-1 to clarify that the reversibility is only done at Visit 101


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
Clarify that asthma worsening criteria in Section 6.4.4 as defined by PEF is based on a 
decrease of more than 60% of PEF compared to baseline. The terms ‘predicted’ and 
‘personal best’ to describe PEF measurements have been removed to avoid confusion. 
This is also reflected in the asthma exacerbation definition in Section 6.4.5. Baseline PEF 
definition for the treatment period is added as being calculated at visit 102 as the mean of 
the best of the three daily PEF efforts over the past 14 days.

Clarify the wording for ECG timing to be done at Visit 210 in Section 6.5.5

Add footnote on Table 6-1 to specify that historical reversibility or bronchoprovocation 
are acceptable as inclusion criteria. 

Clarify on Section 6 the order of the PROs completion

Remove the visit window between Visit 102 to Visit 201 Day 1 in Section 3.1 and Table 
6-1

Insert the whole questionnaire on Appendix 7
 

Add clarification on analysis timepoint in Section 9.4.6, Section 9.5.1.3, Section 9.5.1.4
and statistical method used in Section 9.5.1.6.
Amendment 1 (30-Jul-2015)
This amendment is in order to comply with the Health Authorities requirements received after 
finalization of the protocol version 00 regarding the pediatric population before finalization of 
the Pediatric Investigational Plan. 
As this protocol includes adolescent patients, the following changes were made:

Modify the Section 5.4.9 in order to permanently discontinue study drug for any 
adolescent patients after one asthma exacerbation requiring hospitalization.

Modify inclusion criteria number 4 and 5 in Section 4.1 and in the protocol summary to 
change the requirement of previous treatment of “any” dose of LABA/ICS to “low” dose 
of LABA/ICS. Also patients should qualify for treatment with medium or high dose 
LABA/ICS (GINA 2015 step≥3). The Section 9.4.6 was modified accordingly for the 
subgroup analysis.
The opportunity was taken to also make the following changes and revisions:

Change ACQ-5 to be given to the patients and site to ACQ-7 on Table 5-5, Table 6-1,
Section 6.4.2 and Section 9.5.1.2. Derivation of rescue medication from e-diary ( 6th item 
on ACQ) and FEV1 (07th item on ACQ) will not be performed

Specification in Section 6.3 that the patient will have to enter on the e-diary the
compliance of study drug once a week.

Update on Section 6.4.3 in order to be aligned with Section 6.3.

Update on Section 6.4.3.1 in order to clarify the PEF measurement start and update Table 
6-1 accordingly


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
Update of the questions of Appendix 8 for the Patient Asthma diary in order to align to the 
exacerbations definitions.
The described changes in the aforementioned amendment rationale are implemented throughout 
the protocol.
The following minor omission and clarification are additionally included in this protocol
amendment:

Specifying on Section 4 the recruitment of approximately 10% adolescents in the trial to 
be consistent with the Protocol Summary

Adding the ACQ-7 in Appendix 5 and AQLQS+12 questionnaire in Appendix 6


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Protocol summary
Protocol number
CQVM149B2301
Title
A multi-center randomized 52-week treatment, double-blind, triple-
dummy, parallel-group study, to assess the efficacy and safety of 
QMF149 compared with mometasone furoate in patients with asthma 
Brief title
Safety and Efficacy study of QMF149 in asthmatic patients 
Sponsor and Clinical 
Phase
Novartis Phase III
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of the trial is to evaluate the efficacy and safety of two 
different doses of QMF149 (QMF149 150/160 µg and QMF149 
150/320 µg via Concept1) over two respective MF doses (MF 400 µg and 
MF 800 µg via Twisthaler® (total daily dose)) in poorly controlled 
asthmatic patients as determined by pulmonary function testing and 
effects on asthma control. 
Primary Objective(s) 
The primary objective is to demonstrate the superiority of QMF149 
delivered via Concept1 to MF delivered via Twisthaler® in terms of trough 
FEV1 after 26 weeks of treatment in patients with asthma.
Key Secondary 
Objective
The key secondary objective is to demonstrate the superiority of QMF149
(150/160 and 150/320 µg combined) to mometasone furoate doses (MF, 
400 and 800 µg combined)in terms of ACQ-7 after 26 weeks of treatment
in patients with asthma.
Study design
52 weeks Multi-center, randomized, double-blind, triple-dummy, parallel-
group, active controlled study
Population
The study population will consist of approximately 2000 males and 
females with asthma (5% adolescents) and patients will be stratified 
according to prognostic factors of age (12 to 17 years or ≥18) and region. 
Key Inclusion criteria

Patients with a diagnosis of asthma for a period of at least 1 year 
prior to Visit 1 (Screening)

Patients who have used medium or high dose ICS (please refer to 
Appendix 11 for guidance) or low dose of LABA/ICS combinations 
for asthma for at least 3 months and at stable doses for at least 1 
month prior to Visit 1

Patients must be symptomatic at screening despite treatment with 
mid or high stable doses of ICS and/or low dose combinations of 
ICS with long-acting beta adrenergic agent. Patients must have 
ACQ-7 score ≥1.5 at Visit 101 and at Visit 102 (prior to double-blind 
treatment) and qualify for treatment with medium or high dose 
LABA/ICS

In case that the spirometry is repeated due to a failure of meeting 
criterion 7, ACQ-7 should be repeated as well.

Pre-bronchodilator ≥50% FEV1 and < 85 % of the predicted normal 
value for the patient after withholding bronchodilators (see Table 5-
2) at both Visit 101 and 102.
Withholding period of bronchodilators prior to spirometry:

SABA for ≥6 hours


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
FDC or free combinations of ICS*/LABA for ≥48 hours

SAMA for ≥8 hours

Xanthines ≥7 days
Washout period of each drug should be kept as close as possible as 
above and should not be longer. If wash-out period is considered to be 
longer, please contact your Novartis Medical Monitor
A one-time repeat of percent predicted FEV1 (pre-bronchodilator 
FEV1) is allowed at Visit 101 and/or Visit 102 Repeat spirometry
should be done in an ad-hoc visit to be scheduled on a date that 
would provide sufficient time to receive confirmation from the 
spirometry data central reviewer of the validity of the assessment 
before randomization in case of repeat at Visit 101.
* in case of combination LABA/ICS, ICS should be continued.
A one time rescreening is allowed provided the patient returned to 
the required treatment as per inclusion 4.

Patients who demonstrate an increase in FEV1 of 12% and 200 
mL within 15 to 30 minutes after administration of 400 µg 
salbutamol/360 µg albuterol (or equivalent dose) at Visit 101

All patients must perform a reversibility test at Visit 101
If reversibility is not demonstrated at Visit 101:

Reversibility should be repeated once

Patients may be permitted to enter the study with historical evidence 
of reversibility that was performed according to ATS/ERS guidelines 
within 2 years prior to Visit 1

Alternatively, patients may be permitted to enter the study with a 
historical positive bronchoprovocation test that was performed within 
2 years prior to Visit 1.
Spacer devices are permitted during reversibility testing only. The 
Investigator or delegate may decide whether to use spacer or not for 
the reversibility testing.
Key Exclusion criteria

Patients who have had an asthma attack/exacerbation requiring 
systemic steroids or hospitalization or emergency room visit within 6 
weeks of Visit 1 (Screening).

Patients who have ever required intubation for a severe asthma 
attack/exacerbation.

Patients who have a clinical condition which is likely to be worsened 
by ICS administration (e.g. glaucoma, cataract and fragility 
fractures) who are according to investigator's medical judgment at 
risk participating in the study).Patients who have had a respiratory 
tract infection or asthma worsening as determined by investigator 
within 4 weeks prior to Visit 1 (Screening) or between Visit 1 and 
Visit 102. Patients may be re-screened 4 weeks after recovery from 
their respiratory tract infection or asthma worsening.

Patients with a history of chronic lung diseases other than asthma, 
including (but not limited to) COPD, sarcoidosis, interstitial lung 
disease, cystic fibrosis, clinically significant bronchiectasis and 
active tuberculosis .Patients with severe narcolepsy and/or 
insomnia.

Patients on Maintenance Immunotherapy (desensitization) for 
allergies for less than 3 months prior to Visit 101 or patients on 


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Maintenance Immunotherapy for more than 3 months prior to Visit 
101 but expected to change throughout the course of the study.
Investigational and 
reference therapy
The Investigational treatments are as follows:

QMF149 (indacaterol acetate/MF) 150/160 µg o.d. (in the evening) 
delivered as powder in hard capsules via Concept1 inhaler.

QMF149 (indacaterol acetate/MF) 150/320 µg o.d. (in the evening) 
delivered as powder in hard capsules via Concept1 inhaler.
The Comparative treatments are:

MF 400 µg o.d. (in the evening) delivered via Twisthaler®

MF 800 µg total daily dose (administered as 400 µg b.i.d.) delivered 
via Twisthaler®)

Salmeterol/fluticasone 50/500 µg b.i.d. delivered as powder via 
Accuhaler®
In addition the following placebo will be provided to enable the triple-
dummy design of the study:

Placebo, b.i.d. or o.d. delivered via Twisthaler®

Placebo o.d. delivered as powder in capsules via Concept1 inhaler 
(evening)Placebo b.i.d. delivered as powder via Accuhaler®
Efficacy assessments

Spirometry

Health Status (PROs)

e-Diary

Peak Expiratory Flow

Rescue Medication Use
Safety assessments

Medical history and physical examination oropharyngeal 
examination and height measurements for adolescents

Vital signs

Hematology, Blood chemistry, Urinalysis

Evening plasma cortisol 

ECG

Adverse events including asthma exacerbations and serious 
adverse events

Pregnancy (female patients)

Serious asthma outcomes (asthma-related hospitalizations, 
intubations or deaths)
Other assessments

Asthma exacerbation
 
 

PROs (ACQ-7, AQLQ-S+12, 
) 
Data analysis
The primary objective is to demonstrate the superiority of either 
QMF149 150/160 µg delivered via Concept1 o.d. (in the evening) to MF 
400 µg delivered via Twisthaler® or QMF149 150/320 µg delivered via 
Concept1 o.d. (in the evening) to MF 800 µg delivered via Twisthaler®
(delivered as 400 µg b.i.d.) in terms of trough FEV1 after 26 weeks of 
treatment in patients with asthma.


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The comparisons of QMF149 150/160 µg versus MF 400 µg and QMF149 
150/320 µg versus MF 800 µg 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 26
Ha: QMF149 treatment group is not equal to MF treatment group in trough 
FEV1 at Week 26
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, 184, and 365), 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 the 
unstructured covariance matrix in the mixed model. 
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).
The key secondary objective is to demonstrate the superiority of 
QMF149 (150/160 and 150/320 µg combined) to mometasone furoate 
doses (MF, 400 µg and 800 µg combined) in terms of ACQ-7 after 26
weeks of treatment in patients with asthma.
The key secondary variable ACQ-7 will be analyzed using the same
MMRM model (including the appropriate visits) on the FAS as used for
the primary analysis but will include baseline ACQ-7 score instead of 
baseline FEV1. To demonstrate the add-on effect of indacaterol over MF, 
the average of following treatment contrasts will be computed:
QMF149 (150/160 µg) vs. MF 400 µg
QMF149 (150/320 µg) vs. MF 800 µg.
Multiplicity handling:
To control the family-wise type-I error rate at the two-sided 5% 
significance level, a multiple testing procedure based on the trimmed 
Simes test in Brannath et al (2009) is used. The family for the overall type-
I error rate control contains three hypotheses including:

Two hypotheses for the primary endpoint trough FEV1

One hypotheses for the key secondary endpoint ACQ-7. 
Denote the two hypotheses for the primary endpoint as H1 and H2 for 
comparing QMF149 150/160 µg vs. MF 400 µg and QMF149 150/320 
µg vs. MF 800 µg respectively. Similarly, denote the hypothesis as H3 
for comparing QMF149 vs. MF in terms of ACQ-7.
Below is a brief description of the testing procedure based on the trimmed 
Simes test in Brannath et al (2009).
Let p1, p2, p3 be the corresponding p-values (2-sided) of the three 
hypotheses of H1, H2, and H3. 
Step 1: Retain both H1 and H2 if pi ≤ 0.05 AND the observed treatment 
difference for the corresponding pi is in the wrong direction (i.e. MF is 


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performing better than QMF) for ANY i = 1, 2, stop here; otherwise go to 
Step 2;
Step 2: Reject H1 and H2 if pi < 0.05 for BOTH i = 1, 2 and go to Step 3; 
otherwise go to Step 4;
Step 3: Reject H3 if p3 < 0.05 and stop;
Step 4: If neither Step 1 nor Step 2 applies, perform the Bonferroni test to 
H1 and H2. Thus reject H1 if p1 < 0.025 or reject H2 if p2 < 0.025 and stop.
Key words
QMF149, Mometasone furoate (MF), asthma 


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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 2015).
Despite existing therapies there is still significant unmet medical need in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years (DALYs) are lost annually due to asthma, 
representing 1% of the total global burden. Annual worldwide deaths have been estimated at 
250,000 (Masoli, 2004).
Global Initiative for Asthma guideline (GINA 2015) recommends as preferred controller 
treatment for step ≥3 the combination of LABA/ICS with a low dose ICS in step 3, increasing 
the ICS dose to medium and high in step 4 and addition of monoclonal antibodies i.e. anti-IgE) 
or referral to specialist investigation in step 5 (GINA 2015). Alternative controller treatment for 
step ≥3 is medium/high dose ICS.
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-daily (b.i.d.) dosing to 
achieve an optimum therapeutic effect in asthma. 
Novartis is developing QMF149, an inhaled FDC of indacaterol acetate, a LABA with a 24-
hour duration of action and mometasone furoate (MF) an ICS, as a once daily (o.d.) maintenance 
treatment of asthma QMF149 is formulated as a lactose-blended inhalation powder, hard 
capsule, delivered by a single dose dry powder inhaler (SDDPI), referred to as the Concept1 
device (also known in some regions as the Breezhaler® device), the approved inhalation device 
for use with indacaterol maleate and other COPD inhalation therapies.
QMF149 
is 
developed 
under 
the 
QVM149 
(indacaterol 
acetate/glycopyrronium 
bromide/mometasone furoate) program and therefore all the studies are coded as QVM149.
Background data for the monotherapies:
Indacaterol
Indacaterol maleate, delivered via the Concept1 device, a 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 monotherapy (as add-on to existing ICS) as well is in the fixed dose 
combination QMF149 (indacaterol maleate/MF) delivered by the Twisthaler® device in asthma 


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patients. Indacaterol maleate delivered by Twisthaler® has been studied in healthy volunteers 
(HV), adult patients with COPD and adult and adolescent patients with asthma. 
Study CQMF149E2203 investigated two 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.
QMF149 (mometasone/indacaterol) in Twisthaler device in asthma
Phase II study CQMF149A2210 - an event driven study up to 68 weeks - 1508 asthmatic 
patients were treated (66 patients 12-17 years old). In this study QMF149 500/400 µg o.d. via 
Twisthaler® (comparable to QMF149 150/160 µg o.d. via Concept1) was compared with MF 
alone 400 µg o.d. via Twisthaler®. The findings of this study demonstrated that both QMF149 
resulted in greater reductions in asthma exacerbations compare to MF and had beneficial effects
in terms of the time to first exacerbation and the cumulative incidence of serious asthma 
exacerbations (with treatment differences in favor of QMF149 over MF). Furthermore, the 
differences between treatments for efficacy parameters, in terms of lung function and asthma 
symptoms were all statistically significant in favor of QMF149 throughout the treatment period
(Beasley R et al, 2015).
Mometasone furoate
Mometasone furoate (MF) is marketed in inhalation, nasal, cream, ointment and lotion 
formulations. MF in the Twisthaler® device, a multi dose dry powder inhaler (MDDPI), 
(Asmanex®) is approved for the once daily or twice daily treatment in over 55 countries world-
wide in patients with asthma. The inhalation powder formulation which may be administered 
once or twice daily is marketed as a multi dose dry powder inhaler (MDDPI) called Asmanex®
Twisthaler® for the treatment of asthma. Asmanex® Twisthaler® is currently approved in the 
United States for the treatment of asthma in adults and children ≥4 years of age and is approved 
in over 60 countries world-wide for the treatment of asthma in adults and adolescents ≥12 years 
of age. 
In addition, MF in combination with formoterol fumarate as Dulera® (inhalation aerosol) has 
been approved in the United States and as Zenhale® (HFA) in Canada as a maintenance 
treatment for asthma in adults and children who are at least 12 years old.
In adult and adolescent patients 12 years of age and older, MF (Asmanex® Twisthaler®) was 
studied in 10 placebo-controlled clinical trials of 8 to 12 weeks duration with a total of 1750 
patients receiving Asmanex® Twisthaler®. There were also 3 trials with a total of 475 patients 
receiving Asmanex® Twisthaler® for 1 year. In the 8 to 12-week clinical trials, the population 
was 12 to 83 years of age. In 3 long-term safety trials (two 9-month extensions of efficacy trials 
and one 52-week active-controlled safety trial), 475 patients with asthma received various doses 
of Asmanex® Twisthaler® for 1 year.


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In pediatric patients 4 to 11 years of age, Asmanex® Twisthaler® was studied in 3 placebo 
controlled clinical trials of 12 weeks duration with a total of 630 patients receiving Asmanex®
Twisthaler® and a 52-week, active-controlled safety trial with a total of 152 patients receiving 
Asmanex® Twisthaler®.
In the QMF149 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).
In this study, the fixed dose combination of mometasone and indacaterol, QMF149 will be 
delivered by Concept 1 device. Since existing data for the MF component exists in the 
Twisthaler® device, a 3 step bridging bridging approach was conducted to determine MF dose 
for Concept 1 which is comparable to each of the registered daily doses of Asmanex Twisthaler®
(mometasone furoate, inhalation powder). Step 1: pharmacokinetic bridging utilizing 
pharmacokinetic characterization in study CQMF149E2101 (Vaidya S 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 Step 1 and 2, the data of study CQMF149E2101 (Vaidya S et al, 2012), along with in-vitro 
fine particle mass adjustments have led to the selection of 80, 160 and 320 µg as doses of MF 
in Concept1 device that are comparable to the approved doses 200 µg, 400 µg and 800 µg 
(2x400 µg) MF in Twisthaler®.
For Step 3, two of the MF doses in Twisthaler® and Concept1 were further evaluated for 
pharmacodynamic and clinical comparability in a 4-week study (CQMF149E2201) in patients 
with persistent asthma. MF doses of 80 μg and 320 μg delivered once daily via Concept1 
showed comparable efficacy in trough FEV1 and slightly lower systemic exposure compared to 
MF doses of 200 μg and 800 μg (2 x 400 μg) delivered once daily via Twisthaler® confirming 
the selected doses for MF Concept1 are appropriate for further QMF149 Concept1 development. 
Table 1-1
Comparable MF monocomponent doses between Asmanex Twisthaler
and QMF149 Concept1
MF dose level
MF dose in Asmanex 
delivered by Twisthaler®
MF dose in QMF149 
delivered by Concept1 
(Breezhaler®)
Mid
400 µg 
160 µg
High
800 µg 
320 µg
In summary, over 1,700 subjects have been exposed to QMF149 in 8 completed studies in 
healthy volunteers or asthma patients. These clinical studies used either indacaterol maleate or 
QMF149 FDC (indacaterol maleate /MF) delivered by Twisthaler® at doses up to 500/800 μg 
(comparable with 150/320 μg in Concept1) once daily. Studies using the Twisthaler® device 
include component interaction (CQMF149A2102 and CQMF149A2206) in healthy volunteers, 
ethnic sensitivity (CQMF149A2101) in Japanese and Caucasian healthy volunteers, 
mechanistic disposition (CQMF149A2212) in healthy volunteers, 24 hour lung function 


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profiling (CQMF149A2202) in asthma patients, and efficacy, safety and tolerability 
(CQMF149A2203, CQMF149A2204 and CQMF149A2201) in asthma patients.
In addition to Twisthaler® data, there is clinical data for QMF149 delivered by Concept1 from 
the ethnic sensitivity study CQMF149E1101 and from component interaction study 
CQMF149E2102. PK, safety and tolerability of multiple, once daily doses of QMF149 
150/80 μg (fixed-dose combination of 150 μg indacaterol acetate, 80 μg MF) and 150/320 μg 
orally inhaled via Concept1 were evaluated in 48 healthy Japanese and Caucasian male subjects 
in Study CQMF149E1101. Results showed an increase (23-30%) in exposure for indacaterol 
and MF in Japanese subjects that is not thought to be clinically relevant and is not expected to 
raise any safety concerns.
Study CQMF149E2102 in which 64 healthy volunteers were exposed to repeated doses of 
QMF149 (indacaterol acetate/MF) 150/320 µg showed similar systemic exposure was noted for 
the free vs. mono comparison for both analytes, indicating a lack of PK interaction.
The efficacy and safety available data for QMF149 and its monocomponents supports progress 
to Phase III to evaluate further the efficacy and safety in asthma.
1.2
Purpose 
The purpose of the trial is to evaluate efficacy and long term safety of two different doses of 
QMF149 (QMF149 150/160 µg and QMF149 150/320 µg via Concept1) over two respective 
MF doses (MF 400 µg and MF 800 µg via Twisthaler® (total daily dose)) in poorly controlled 
asthmatic patients as determined by pulmonary function testing and effects on asthma control.
2
Study objectives
2.1
Primary objective
The primary objective is to demonstrate the superiority of either QMF149 150/160 µg delivered 
via Concept1 o.d. (in the evening) to MF 400 µg o.d (in the evening) delivered via Twisthaler® 
or QMF149 150/320 µg delivered via Concept1 o.d. (in the evening) to MF 800 µg delivered 
via Twisthaler® (delivered as 400 µg b.i.d.) in terms of trough FEV1 after 26 weeks of treatment 
in patients with asthma.
2.2
Key Secondary objective
The key secondary objective is to demonstrate the superiority of QMF149 (150/160 and 
150/320 µg combined) to mometasone furoate doses (MF, 400 µg and 800 µg combined) in 
terms of ACQ-7 after 26 weeks of treatment in patients with asthma.
2.3
Secondary Objectives
The secondary objectives will consider the following 2 comparison groups: 

QMF149 150/160 µg o.d. delivered via Concept1 compared to MF 400 µg o.d. delivered 
via Twisthaler® 

QMF149 150/320 µg o.d. delivered via Concept1 compared with MF 400 µg b.i.d. 
delivered via Twisthaler®


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The secondary objectives will evaluate the efficacy in terms of:

Trough FEV1 at Week 52

Pre-dose FEV1 (defined as the mean of -45 min and -15min FEV1 values pre-evening 
dose) at Week 4 and Week 12

FEV1, Forced Vital Capacity (FVC) and Forced Expiratory Flow between 25% and 75% 
of FVC (FEF25-75) over 52 weeks

Morning and Evening Peak Expiratory Flow Rate (PEF) over 26 and 52 weeks of 
treatment

Asthma control as assessed by the Asthma Control Questionnaire (ACQ-7) at Week 4, 
Week 12 and Week 52

Percentage of patients achieving the minimal important difference (MID) ACQ ≥0.5 at 
Week 26 and Week 52

Daily e-Diary recordings of the percentage of asthma symptoms free days , no day-time 
symptoms, the percentage of nights with no night-time awakenings and the percentage of 
mornings with no symptoms on awakening over 52 weeks of treatment 

e-Diary recordings of rescue salbutamol/albuterol usage (mean daily, nighttime and 
daytime use) over 26 and 52 weeks of treatment 

To evaluate the efficacy of in terms of asthma exacerbation-related parameters described 
here further during 52 weeks of treatment. The analysis will be performed by exacerbation 
category wherever specified. The exacerbation categories are: mild, moderate, severe and 
moderate or severe:

Time to first asthma exacerbation  by exacerbation category

Time to first hospitalization for asthma exacerbation

Annual rate of asthma exacerbations by exacerbation category

Duration in days of asthma exacerbations by exacerbation category

Percentage of patients with at least one asthma exacerbation by exacerbation category

Time in days to permanent discontinuation of study medication due to asthma
exacerbations

Percentage of patients who  permanently discontinued study medication due to asthma 
exacerbations

Total amounts of systemic corticosteroids (in doses) used to treat asthma 
exacerbations.

% of rescue medication free days over 26 and 52 weeks of treatment

Quality of life as assessed by Asthma Quality of Life Questionnaire (AQLQ) over 52 
weeks
Furthermore, an additional secondary comparison, QMF149 150/320 µg o.d. delivered via 
Concept1 will be compared with salmeterol xinafoate /fluticasone propionate 50/500 µg via 
Accuhaler® for all the listed secondary endpoints above as well as the following ones:

Trough FEV1 measured after 26 weeks of treatment*
*Trough FEV1 will be tested for non-inferiority versus salmeterol/fluticasone 50/500 µg. 
If non-inferiority criteria are met, this will be tested for superiority.


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
Asthma control as assessed by the Asthma Control Questionnaire (ACQ-7) after 26 
weeks treatment 
The following safety and tolerability endpoints will be evaluated for all treatment comparison
groups:

Cumulative incidence of the composite endpoint of serious asthma outcomes (i.e. asthma-
related hospitalization, asthma-related intubation, or asthma-related death) over 52 weeks 
of treatment 

Adverse events, vital signs, ECG and laboratory analysis (haematology, blood chemistry 
including glucose and potassium, urinalysis, evening plasma cortisol) over 52 weeks of 
treatment


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3
Investigational Plan
3.1
Study design
This study uses a 52 week treatment, randomized, double-blind, triple-dummy, parallel-group 
design. The primary endpoint will be evaluated over 26 weeks. 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 medications are replaced with permitted asthma medications for use 
throughout the study.
All patients must have used inhaled medium or high dose corticosteroids and/or low dose 
LABA/ICS for at least 3 months and on a stable dose for at least 1 month prior to Visit 1. Once 
patients concurrent medications comply with the requirements of the study (Section 5.4.7 and 
Section 5.4.8) patients will enter a Run-In epoch at Visit 101. At this point, the patients must 
also have an ACQ ≥1.5 at Visit 101. At 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 low dose 
equivalent as per Appendix 11) which will be used throughout the Run-In epoch and 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 wash-out of prior asthma 
medication according to the protocol. Depending on prior asthma medication the time between 
Visit 1 and Visit 101 may be shorter than 2 weeks. (i.e.If the patient was on ICS only, the Visit 
1 and Visit 101 may be scheduled the same day).
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 in the Run-In epoch (Visit 101), 
patients will record PEF. The Run-In epoch is 2 weeks in duration and will be used to assess 
eligibility of the patients to enter the treatment epoch and to collect baseline values for some 
variables.
Run-in medication should be dispensed only when spirometry assessment meet the inclusion 
criteria (FEV1 predicted normal values, ATS/ERS criteria and reversibility) as per spirometry 
equipment. 
At Visit 102 patients whose eligibility is confirmed will be randomized to one of the five 
treatment groups with an equal (1:1:1:1:1) randomization ratio:


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
QMF149 150/160 µg delivered via Concept1 o.d.

QMF149 150/320 µg delivered via Concept1 o.d.

MF 400 µg o.d. delivered via Twisthaler®

MF 800 µg (as 400 µg b.i.d.) delivered via Twisthaler®

Salmeterol xinafoate /fluticasone propionate 50/500 µg b.i.d. delivered via Accuhaler®
Visits 102 and 201 take place sequentially on the same date. The assessments at Visit 102 should 
be performed prior to administration of the first dose of study medication. Randomized patients 
will enter the 52 week treatment epoch during which they will be required to inhale study 
medication via Concept1 once daily in the evening (between 5:00 and 8:00 pm) and twice daily 
via Twisthaler® or Accuhaler® once in the morning (between 5:00 and 8:00 am) and once in the 
evening 12 hours after the morning dose (between 5:00 and 8:00 pm).
Patients will be followed at regular intervals throughout the 52 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, 12, 26, 36 and 52 weeks. All clinic visits should occur as 
scheduled on the Table 6-1. For Visit 214 (Week 52), in case of logistical issues, the visit is 
allowed to take place within a 4 day window. All 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 26 and 52 weeks of treatment (Clinic Visit (CV) 207 and 214). Telephone reviews 
of patients’ status will be conducted after 8, 16, 20, 28, 32, 40, 44 and 48 weeks of treatment. 
Telephone contacts 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 52
weeks).
The first dose of study medication will be administered at the clinic in the evening (between 
05:00 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. Patients will also be reminded to take the morning dose of study medication on the 
morning of the Clinic Visit appointment at home. 
 
Evening plasma cortisol will be measured on all patients only at Visit 201, 207 and 214.


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Figure 3-1
Study design
1 Please refer to Table 5-2 for details of adjustments to concomitant asthma medication and 
appropriate washout times prior to spirometry testing. For run-in medication, Fluticasone propionate 
100 µg b.i.d. should be delivered via Accuhaler®. In case it is not available in a particular country, 
125 µg b.i.d by MDI inhaler will be accepted. If fluticasone 125 µg b.i.d by MDI inhaler is not available 
in a particular country, an equivalent low dose fluticasone may be used (Appendix 11).
3.2
Rationale of study design
This study is a pivotal, multi-center, randomized, double-blind, triple-dummy, parallel-group, 
phase III study with a 52 week treatment epoch which is required to assess the safety and 
efficacy of QMF149 in asthma. The primary endpoint will be evaluated over 26 weeks. This is 
considered an adequate duration 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.
In order to preserve the integrity of the study, a randomized, double-blind study design is used. 
This design enables the study treatments to be given for an appropriate and practical length of 
time to assess the efficacy and safety of the treatments. The study design does not include a 
placebo control, as this would not be considered ethical in this population of asthmatic patients
with GINA step 3 (GINA, 2015).
Double blind treatment Epoch (52 weeks)
End of run-in Visit 102
Randomization Visit 201
Screening
Epoch 
Day -28 to 
Day -14
salmeterol xinafoate /fluticasone propionate j
50/500 µg b.i.d. via Accuhaler®
Day 1 to Day 365
QMF149 150/320 µg o.d via Concept1 
Run-in 
Epoch 1
Day -14 to 
Day -1
MF 400 µg o.d via Twisthaler®
QMF149 150/160 µg o.d via Concept1 
MF 400 µg b.i.d. via Twisthaler®
Follow-up
Epoch
30 days
Visit 1
Visit 
101
Visit 301
Low dose ICS
eg. Fluticasone 
propionate
100 µg b.i.d.
Rescue Medication available
Study Completion 
Visit 214


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The primary objective of the trial is to evaluate the efficacy and long term safety of two different 
doses of QMF149 (QMF149 150/160 µg o.d. and QMF149 150/320 µg o.d. via Concept1) over 
two respective MF doses (MF 400 µg and MF 800 µg via Twisthaler® total daily dose) in poorly 
controlled (i.e. not optimally controlled) asthmatics as determined by pulmonary function 
testing, effects on asthma control and rescue medication use. In addition secondary endpoints 
will provide data on asthma exacerbations, quality of life, 
and will establish the long term safety of the studied QMF149 doses in this specific asthma 
patient population. Furthermore the study will compare QMF 150/320 µg with an active 
comparator (salmeterol/fluticasone via Accuhaler®) as a secondary endpoint. This will provide 
a perspective on how QMF149 compares with a widely used treatment for asthma.
The analyses will be performed in a sample size of approximately 2000 patients to ensure the 
adequacy and reliability of the data.
An independent semi-blinded Data Monitoring Committee is planned to evaluate the safety data 
during the trial to ensure patient safety throughout the study.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
The dose regimens of QMF149 selected in this study (150/160 µg o.d. and 150/320 µg o.d.
delivered via Concept1) are based on the findings of previous studies identifying effective and 
safe doses of the individual components of the FDC, indacaterol and MF. 
Indacaterol maleate at a dose of 150 µg o.d. is approved in various countries for the maintenance 
treatment of COPD. A dose-ranging study CQAB149B2357 of indacaterol maleate in asthmatic 
patients demonstrated that a dose of 150 µg o.d. was safe and effective and furthermore, a 26 
week study in asthmatic patients showed that indacaterol maleate at doses of 300 µg and 600 µg 
o.d. were also well-tolerated in this population (Study CQAB149B2338). 
A 12-week study (CQMF149E2203) investigated indacaterol acetate 75 μg and 150 μg
delivered via Concept1 in adult patients with persistent asthma. The study demonstrated 
superiority of indacaterol acetate 75 μg and 150 μg over placebo in most of the efficacy 
endpoints and showed positive trends in favor of indacaterol acetate 150 μg regarding 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. 
In summary, the totality of Phase II data support the selection of indacaterol acetate 150 µg o.d. 
as the most appropriate dose to move forward in Phase III for the development of QMF149. 
MF at a dose of 400 µg b.i.d. administered via a multi-dose dry powder inhaler (MDDPI) is 
approved as Asmanex® Twisthaler®
for the treatment of asthma. A single-dose, 
pharmacokinetic study (QMF149E2101, Vaidya S et al, 2012) conducted in healthy volunteers 
compared systemic exposure to MF following oral inhalation from the registered Twisthaler® 
inhaler and the Concept1 inhaler and found that the mean dose of MF in the Concept1 that 
provided comparable systemic exposure to 400 µg delivered via Twisthaler® was 160 µg (after 
in vitro fine particle mass adjustment). Based on dose proportional changes in MF systemic 
exposure following administration via both devices, 800 µg MF delivered via Twisthaler® was 
expected to be comparable to 320 µg delivered via Concept1. In a 4-week Phase II study in 
patients with persistent asthma (Study CQMF149E2201), MF doses of 80 μg and 320 μg 


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delivered once daily via Concept1 showed comparable efficacy in trough FEV1 and slightly 
lower systemic exposure compared to MF doses of 200 μg and 800 μg (2 x 400 μg), respectively
delivered once daily via Twisthaler® confirming the selected doses for MF Concept1 are 
appropriate for further QMF149 Concept1 development.
This study QVM149B2301 will compare two doses of QMF149 (indacaterol acetate 150 µg/ 
MF 160 µg and indacaterol acetate 150 µg /MF 320 µg) via Concept1 with the respective two 
doses of MF 400 µg and MF 800 µg (administered as 400 µg b.i.d.) delivered via Twisthaler®. 
The purpose is to investigate whether the QMF149 doses in Concept1 provide additional 
benefits over the respective MF doses in Twisthaler® in asthma patients whose asthma is 
inadequately controlled (symptomatic patients with an ACQ-7≥1.5) and who are qualified for 
treatment with LABA/ICS (GINA 2015, Step 3).
This study is designed to provide efficacy and safety data over a 52 weeks treatment epoch 
which is considered to be sufficient duration to demonstrate treatment differences of the two 
QMF149 doses, QMF149 150/160 µg and QMF149 150/320 µg o.d. delivered via Concept1, 
vs the two respective MF doses, MF 400 µg o.d. and MF 800 µg (administered as 400 µg b.i.d.) 
delivered via Twisthaler® in terms of lung function, symptom control and other endpoints.
However, the primary endpoint, trough FEV1 will be assessed at 26 weeks, which is an 
appropriate timepoint based on known pharmacodynamics of the monocomponents and is 
consistent with endpoints used in pivotal studies of other fixed dose combinations in asthma.
3.4
Rationale for choice of comparator
The MF inhalation powder formulation is marketed as a MDDPI called Asmanex® Twisthaler®
for the treatment of asthma. Asmanex® Twisthaler® is currently approved in the United States 
for the treatment of asthma in adults and children ≥4 years of age and is approved in over 55
countries world-wide for the treatment of asthma in adults and adolescents ≥12 years of age. 
In addition, MF in combination with formoterol fumarate as Dulera® has been approved in the 
United States and as Zenhale® in Canada as a maintenance treatment for asthma in adults and 
children who are at least 12 years old.
MF was selected as a marketed comparator for QMF149 in this study in order to demonstrate 
the additional benefit of a LABA (indacaterol acetate 150 µg) on top of a medium and high 
dose ICS (see Appendix 11) in patients whose asthma is inadequately controlled with ICS alone 
or combination. 
The two approved daily doses of MF (400 µg o.d. and 400 µg b.i.d.) delivered via Twisthaler®) 
are comparable to MF 160 µg o.d. and to MF 320 µg o.d. delivered via Concept1.
Salmeterol xinafoate/fluticasone propionate 50/500 µg b.i.d. is marketed as a DPI (dry-powder 
inhaler) (Seretide® Accuhaler® or Seretide® Diskus® depending on the countries) for the 
treatment of asthma in adults and adolescents 12 years and older. Salmeterol xinafoate 
/fluticasone propionate was also selected as a marketed comparator in the secondary endpoints 
as it is widely used in asthma treatment.
3.5
Purpose and timing of interim analyses/design adaptations
It is planned that the independent DMC will review semi-blinded (i.e., treatment group named 
as A, B, C, D, or E) safety data.


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The details of the information flow, confidentiality and specific analyses required for the safety 
monitoring analysis will be documented in the DMC Charter. 
 
 
 
For Primary Analysis at Week 26The primary and key secondary endpoints of 
CQVM149B2301 study are trough FEV1 and ACQ-7 after 26 weeks of treatment, respectively 
while the entire study treatment period is 52 weeks. Novartis has decided to perform primary 
analysis once all patients have completed 26 weeks of treatment (Visit 207) or prematurely 
withdrawn from the study which will be used for internal decision making prior to study 
completion. The study will continue as planned in a blinded manner for full 52 weeks period 
(plus 30 days of safety follow-up).
In terms of reporting, two separate CSRs will be written:

CSR I: To support analyses once all patients have completed the assessments after 26 
weeks of treatment (Visit 207) or prematurely withdrawn from the study. This will consist 
of primary and key secondary objectives as well as other pre-specified objectives up to 
and including Week 26. The CSR will be based on variable duration of exposure with 
minimum of 26 weeks (Visit 207) and maximum of 52 weeks (Visit 214)

CSR II: To support analysis once all patients have completed 52 weeks of treatment (Visit 
214) plus follow up (Visit 301) or prematurely withdrawn from the study. CSR II will 
consist of primary and secondary objectives analyzed in CSR I and all other objectives 
evaluated after 26 weeks and up to 52 weeks (plus follow up).
Since the primary analysis (CSR I) will be performed prior to all patients completing the study, 
a dedicated unblinded team will be involved in CSR I related activities. In order to maintain the 
integrity of the study data, a separate blinded team will continue the study until its completion. 
The details outlining this process including appropriate firewalls will be maintained in a 
separate charter.
3.6
Risks and benefits 
LABA/ICS FDCs are frequently used as controller medications and are foundation therapy in 
GINA step≥3 (GINA 2015).
QMF149 (indacaterol 150 µg as a FDC with MF 160 µg or 320 µg) is a new once daily 
LABA/ICS FDC whose phase II development was recently completed.
There is an extensive evidence of the efficacy and safety of the mono components indacaterol 
and MF in asthma and COPD (indacaterol). There is in addition supportive efficacy and safety 
information from the early QMF149 development in the Twisthaler® device (see section 1.1 
Background and QMF149 Investigator Brochure). To further investigate the overall risk and 
benefit evaluation of QMF149 FDC delivered by Concept1, two different MF doses in 
combination with indacaterol acetate (QMF149) are selected for further evaluation in Phase III. 


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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 
old), 
QMF149 
(indacaterol/mometasone 500/400 µg delivered by Twisthaler comparable to indacaterol 
150/160 µg delivered by Concept1) showed a favorable efficacy and safety profile over MF 
(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 (QMF149 E2203), 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 (QMF149 F2202). 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 summary, the QMF149 Twisthaler® program in phase II along with further phase II studies 
with QMF149 delivered by the Concept 1 inhaler suggest a favorable efficacy and safety profile 
of the compound.
In the current Phase III, one year pivotal trial (QVM149B2301), two QMF149 doses are 
compared to the respective MF doses and to salmeterol/fluticasone propionate (Seretide®). In 
this large study with a double-blind, triple-dummy, active controlled design, the patients must 
be symptomatic (defined by ACQ-7 mean score ≥1.5) despite medical care according to the 
current GINA guideline as of year 2015. The patients need to have moderate to severe persistent 
asthma with a ≥50% FEV1 < 80% of predicted normal (at Visit 1) under ongoing asthma 
medication. All patients will continue with either one of two different doses of QMF149 or one 
of two different doses of MF or one dose of Seretide®. Throughout the trial all patients will 
have free access to rescue medication (i.e. short acting beta 2-agonist), thus limiting the risk for 
patients with a significant asthmatic adverse events. 
The potential benefit for the patient includes an improvement in the pulmonary function testing 
and a potential translation into better asthma control like reductions in symptoms and rescue 
medication use, an improved quality of life. A thorough medical evaluation of the patients’ 
disease and close clinical monitoring for the duration of the study will provide additional benefit 
to the patient care.
Frequent and regular contacts will occur in terms of clinic visits and telephone contacts to each 
patient throughout the 52-week treatment epoch.  In addition, safety monitoring (e.g. symptom 
collection and rescue medication use via electronic diary), assessment of compliance with the 
study medication regimen, and PEF (daily) measurements at regular intervals throughout the 
study will help assess status of the patient’s asthma symptom control. Diary data will be 
transmitted electronically from the device to the investigator daily. Therefore, investigators 
may have an early indication of worsening symptoms and will be able to monitor the patient 
closely throughout the study.
In line with current medical treatment guidelines, all patients participating in the study will 
receive active “controller” treatment for their asthma throughout the 52-week treatment period. 
In addition, providing the patients with rescue medication for use as needed to treat any 
breakthrough constriction throughout study mitigates these risks. At no time during the study 
will any patient be without treatment for asthma.


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The risk to the patients in participating in the study is that QMF149 is under development and 
therefore it is possible that unexpected safety issues may be identified in patients randomized 
to treatment with QMF149 (Section 5.4.9) and will be minimized by compliance with the 
eligibility criteria and close clinical monitoring. The risks of side effects from the study 
medication are those known for the individual compounds indacaterol and MF, and no 
additional risks have been identified that might occur when the two components are 
administered concurrently or from the same inhaler. Further information can be obtained from 
the QMF149 Investigator’s Brochure.
There are concerns that LABA treatment used alone in asthma might cause severe asthma 
exacerbations. To address this safety concern all patients are treated with a FDC of LABA/ICS
in this study so LABA alone will not be allowed.
Guidance to manage potential worsening of asthma symptoms will be provided to investigators 
consistent with guideline recommendations (GINA 2015), as well as to patients via written 
instructions to contact the investigator in the event of worsening asthma symptoms.
The investigator should discontinue study treatment for a given patient and/or withdraw the
patient from the study if, he/she believes that continuation would be detrimental to the patient’s 
well-being. Patients are also instructed that they can withdraw from the study at any time, and 
for any reason.
In summary, based on the available data of QMF149 and the efficacy and safety data of the 
marketed monotherapy components, it is anticipated that QMF149 150/160 µg and QMF149 
150/320 µg will have a favorable benefit to risk profile in patients with asthma.
4
Population
The study population will consist of approximately 2000 males and females (approximately 5%
of adolescents) with asthma.
It is anticipated that approximately 4000 patients will need to be screened in order to randomize 
approximately 2000 patients into the five treatment groups of the study with a randomization 
ratio of 1:1:1:1:1, (i.e. approximately 400 patients in each of the treatment groups). It is intended 
that at least 1800 patients (360 patients per treatment group) will have completed 26 weeks of 
treatment for primary and key secondary objectives.
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 17 years or ≥18) (Section 
4.1, Inclusion Criteria 1) and non-prognostic factor region to achieve improved homogeneity 
within each stratum.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Male and female adult and adolescent patients aged ≥12 years old (or ≥18 years old 
depending upon regulatory and/or IRB/IEC/REB approval and/or country participation) 
and ≤75 years


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2. Written informed consent must be obtained before any study-related assessment is 
performed. Patients below the legal age of consent are required to have the Informed 
Consent Form signed by the patient’s parent / guardian; adolescents are required to sign an 
assent form
3. Patients with a documented diagnosis of asthma for a period of at least 1 year prior to 
Visit 1 (Screening)
4. Patients who have used medium or high dose ICS (please refer to Appendix 11 for 
guidance) or low dose of LABA/ICS combination for asthma for at least 3 months and at 
stable doses for at least 1 month prior to Visit 1
5. Patients must be symptomatic at screening despite treatment with mid or high stable doses 
of ICS and/or combinations of ICS (low dose) with long-acting beta adrenergic agent.
Patients must have ACQ-7 score ≥1.5 at Visit 101 and at Visit 102 (prior to double-blind 
treatment) and qualify for treatment with medium or high dose LABA/ICS 

In case that the spirometry is repeated due to a failure of meeting criteria 6, ACQ-7 
should be repeated as well.
6. Pre-bronchodilator FEV1 ≥50 % and < 85 % of the predicted normal value for the   
patient according to ATS/ERS criteria after withholding bronchodilators (see Table 5-2) at 
both Visit 101 and 102

Withholding period of bronchodilators prior to spirometry:

SABA for ≥6 hours

FDC or free combinations of ICS*/LABA for ≥48 hours

SAMA for ≥8 hours

xanthines ≥7 days
Washout period of each drug should be kept as close as possible as above and should not be 
longer. If wash-out period is considered to be longer, please contact your Novartis Medical 
Monitor
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 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.
A one-time rescreening is allowed in case the patients fail to meet the criteria at the repeat, 
provided the patients return to their previous treatment until rescreened.
* in case of combination LABA/ICS, ICS should be continued.
7. Patients who demonstrate an increase in FEV1 of 12% and 200 mL within 15 to 30 
minutes after administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at 
Visit 101

All patients must perform a reversibility test at Visit 101
If reversibility is not demonstrated at Visit 101:

Reversibility should be repeated once


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
Patients may be permitted to enter the study with historical evidence of reversibility
that was performed according to ATS/ERS guidelines within 2 years prior to Visit 1.

Alternatively, patients may be permitted to enter the study with a historical positive
bronchoprovocation 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/bronchoprovocation is not available (or was not 
performed according to ATS/ERS guidelines) patients must be screen failed.
Spacer devices are permitted during reversibility testing only. The Investigator or delegate may 
decide whether to use spacer or not for the reversibility testing.
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 within the 6 month period 
prior to Visit 1, or who have a smoking history of greater than 10 pack years (Note:1 
pack is equivalent to 20 cigarettes. 10 pack years = 1 pack /day x 10 yrs., or ½ 
pack/day x 20 yrs.) or use of nicotine inhalers such as e-cigarettes at the time of Visit 
1.
2. Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization (> 24 hours) or emergency room visit (≤24 hours) 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
3. Patients who have ever required intubation for a severe asthma attack/exacerbation
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 investigator within 4 weeks prior to Visit 1 (Screening) or between 
Visit 1 and Visit 102. Patients may be re-screened 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 re screened once 
their candidiasis has been treated and has resolved.
7. Patients with any chronic conditions affecting the upper respiratory tract (eg. chronic 
sinusitis) which in the opinion of the investigator may interfere with the study 
evaluation or optimal participation in the study.
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.


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10. Patients who have a clinically significant laboratory abnormality at Visit 101.
11. Use of other investigational drugs within 5 half-lives of enrollment, or until the 
expected pharmacodynamic effect has returned to baseline, whichever is longer.
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 (this should be confirmed clinically 
by the investigator) within the previous 12 months.
14. Concomitant use of agents known to prolong the 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 (these patients should not be rescreened).
16. Patients who have a clinically significant ECG abnormality at Visit 101 (Start of 
Run- In epoch) and at any time between Visit 101 and Visit 102 (including 
unscheduled ECG).  ECG evidence of myocardial infarction at Visit 101 (via central 
reader) should be clinically assessed by the 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.
18. Patients with a history of hypersensitivity to lactose, any of the study drugs or to 
similar drugs within the class including untoward reactions to sympathomimetic 
amines or inhaled medication or any component thereof
19. Patients who have not achieved an acceptable spirometry results at Visit 101 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 scheduled as close as possible from the first attempt (but not on the 
same day) if the spirometry did not qualify due to ATS/ERS criteria at Visit 101 
and/or Visit 102. If the patients fail the repeat assessment, the patients may be 
rescreened once, provided the patients return to their treatment prior until rescreened
20. Patients receiving any medications in the classes listed in Table 5-3
21. Patients receiving any asthma-related medications in the classes specified in Table 5-
2 unless they undergo the required washout period prior to Visit 101 and Visit 201 
and follow the adjustment to treatment program.
22. Patients receiving medications in the classes listed in Table 5-4 should be excluded 
unless the medication has been stabilized for the specified period and the stated 
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23. Patients with severe narcolepsy and/or insomnia.
24. Patients on Maintenance Immunotherapy (desensitization) for allergies or 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.
25. Patients who are serving a custodial sentence, do not have a permanent residence or 
who are detained under local mental health legislation/regulations.
26. Patients who are directly associated with any members of the study team or their 
family members.
27. Patients unable to use the Concept1 dry powder inhaler, Twisthaler®, Accuhaler® or 
a metered dose inhaler. Spacer devices are not permitted for rescue medication.
28. History of alcohol or other substance abuse.
29. Patients with a known history of non-compliance to medication or who were unable 
or unwilling to complete a patient diary or who are unable or unwilling to use 
Electronic Peak Flow with e-diary device.
30. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night 
shift workers).
31. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test.
32. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing of study treatment and for 30 days after stopping of study treatment
Only the following highly effective contraception methods are permitted:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject) if allowed as effective method of contraception according to local 
regulations. 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 subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
       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 


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profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment is she 
considered not of child-bearing potential.
33. LAMA use within 3 months prior to visit 101
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The Investigational treatments are as follows:

QMF149 (indacaterol acetate/MF) 150/160 µg o.d. (in the evening) delivered as powder in 
hard capsules via Concept1 inhaler

QMF149 (indacaterol acetate/MF) 150/320 µg o.d. (in the evening) delivered as powder in 
hard capsules via Concept1 inhaler
The Comparative treatments are:

MF 400 µg o.d. (in the evening) delivered as powder via Twisthaler®

MF 800 µg total daily dose (equivalent to 400 µg b.i.d. (in the morning and in the 
evening)) delivered as powder via Twisthaler®

Salmeterol/fluticasone 50/500 µg b.i.d. (in the morning and in the evening) delivered as 
powder via Accuhaler®
In addition the following placebo will be provided to enable the triple-dummy design of the 
study:

Placebo, delivered as powder via Twisthaler® (in the morning and in the evening or in the 
morning only)

Placebo delivered as powder in capsules via Concept1 inhaler (in the evening)

Placebo delivered as powder via Accuhaler® (in the morning and in the evening)
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 study treatment
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 
5.4.6 for more details regarding rescue medication.
Salbutamol (100 µg) or albuterol (90 µg) will either be supplied to the investigator sites locally 
by Novartis or provided by the study center and reimbursed by Novartis.
During the run-in, low dose fluticasone propionate 100 µg b.i.d. (or , if not available in a specific 
country, 125 µg b.i.d. MDI or fluticasone low dose equivalent as outlined in Section 3.1) will 


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either be supplied to the investigator sites locally by Novartis or provided by the study center 
and reimbursed by Novartis.
5.1.3
Treatment arms
Patients will be assigned to one of the following five treatment arms in a ratio of 1:1:1:1:1

QMF149 150/160 µg o.d. delivered via Concept1 inhaler (in the evening), placebo to 
MF 400 µg o.d. delivered via a first Twisthaler®(in the evening), placebo to MF 
400 µg o.d. delivered via a second Twisthaler® (in the morning), placebo to 
salmeterol/fluticasone 50/500 µg b.i.d. (in the morning and in the evening) delivered 
via Accuhaler®

QMF149 150/320 µg o.d. delivered via Concept1 inhaler (in the evening), placebo to 
MF 400 µg o.d. delivered via a first Twisthaler®(in the evening), placebo to MF 
400 µg o.d. delivered via a second Twisthaler® (in the morning), placebo to 
salmeterol/fluticasone 50/500 µg b.i.d. (in the morning and in the evening) delivered 
via Accuhaler®

MF 400 µg o.d. delivered via a first Twisthaler® (in the evening), placebo to QMF149 
delivered via Concept1 inhaler (in the evening), placebo to MF 400 µg o.d. delivered 
via a second Twisthaler® (in the morning), placebo to salmeterol/fluticasone 50/500 µg 
b.i.d. (in the morning and in the evening) delivered via Accuhaler®

MF 400 µg b.i.d. delivered via Twisthaler® (400 µg o.d. from one Twisthaler® in the 
morning, and 400 µg o.d. from another Twisthaler® in the evening), placebo to 
QMF149 delivered via Concept1 inhaler (in the evening), placebo to 
salmeterol/fluticasone 50/500 µg b.i.d. (in the morning and in the evening) delivered 
via Accuhaler®.

Salmeterol/fluticasone 50/500 µg b.i.d. (in the morning and in the evening) delivered 
via Accuhaler®, placebo to QMF149 delivered via Concept1 inhaler (in the evening), 
placebo to MF 400 µg o.d. delivered via a first Twisthaler® (in the evening), placebo to 
MF 400 µg o.d. delivered via a second Twisthaler® (in the morning)
5.2
Treatment assignment, 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 investigational treatment 
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). 


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Randomization will be stratified by factors of age (12 to 17 years or ≥18) (Section 4.1, Inclusion 
Criteria 2) and region. 
The randomization scheme for patients will be reviewed and approved by a member of the IQS
Randomization Group.
5.3
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 else 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, schedule of administration, appearance, taste, and odor.
The bioanalyst will be unblinded to enable identification of samples from the QMF149 and MF 
Twisthaler® arms of the study to facilitate indacaterol/MF bioanalysis.
 
 
 
Unblinding for 26 week analysis
At the time of primary analysis once all patients have completed the assessments after 26 weeks 
of treatment (Visit 207), limited pre-specified members will be unblinded. The study will 
continue under the management of a separate blinded team who will be responsible for study 
conduct after the primary analysis (at 26 week) until the end of study. In order to maintain the 
integrity of the study data, separate blinded team members will not have access to any of the 
unblinded data. The detailed procedures will be described in a separate charter. The remainder 
of members including clinical study team, investigators, and patients will be kept blinded until 
final database lock.
During the study, the individual patient unblinding can occur in the case of patient emergencies, 
request from the Data Monitoring Committee if needed for the safety interim analysis (Section 
8.4) or as an outcome of their evaluation and at the conclusion of the study (see Section 5.4.12).
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.
5.4
Treating the patient 
5.4.1
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
patient, the Subject Number will not be reused. 


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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 
CRF book with a matching Subject Number from the EDC system to enter data. 
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening Epoch 
Study Disposition CRF.
5.4.2
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance.
The investigational treatment 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 investigational treatment 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. 
5.4.3
Handling of study treatment 
5.4.3.1
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all investigational 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 
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 investigational 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 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits or remotely and at the completion of the trial. 
Patients will be asked to return all unused investigational treatment and packaging at the end of 
the study or at the time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.4.3.2
Handling of other study treatment 
The following non-investigational treatment has to be monitored as follow:


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The non-investigational treatment must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designees have access. Clinical supplies are to be dispensed only in accordance 
with the protocol.
The investigator must maintain an accurate record of the shipment and dispensing of the non-
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits or remotely and at the completion of the trial. 
Patients will be asked to return all unused non- investigational treatment and packaging at the 
end of the run-in for the run-in medication and at the end of the study or at the time of 
discontinuation of investigational treatment for the rescue medication. 
These medications are:

Salbutamol (100 µg) or albuterol (90 µg) used as rescue medication from Visit 1 to Visit 
214

Fluticasone propionate (100 µg b.i.d. or acceptable dose equivalent as outlined in Section 
3.1) used as run-in medication from Visit 101 to Visit 102 
Details are described in the CRF completion guidelines.
5.4.4
Instructions for prescribing and taking study treatment 
The investigator should 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 should 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 dosages prescribed and dispensed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF (e-CRF).
At Visit 1 all patients will be instructed how to use a MDI to administer rescue 
salbutamol/albuterol correctly. At Visit 101 patients will be trained to the use of the peak flow 
meter and e-diary and at Visit 102 all patients will be fully trained in the correct use of the 
Concept1, Twisthaler®, and Accuhaler® 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 that he/she is using each device correctly. Additional device training should be provided 
if required.
Patients will be instructed to take both morning and evening doses of study medication at 
approximately the same time of day (both in the morning and evening). Patients will be 
instructed to rinse their mouth 2 times with approximately 30 mL of water after the last 
inhalation of the study drug which is in the evening after sequential inhalations of study drugs 
from three devices and in the morning after sequential inhalations of study drugs from two 
devices. Water used for mouth rinsing should be spat out and should NOT be swallowed. 
The morning dose (to be taken between 05:00 and 08:00 am) will consist of a single inhalation
from the morning Twisthaler® device (label colored in yellow) containing either MF or placebo 


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and a single inhalation from Accuhaler® device containing either salmeterol/fluticasone or 
placebo.
The evening dose (to be taken between 05:00 pm and 08:00 pm) will consist of sequential 
single inhalations from each of the following three devices:
-
One inhalation from the Concept1 device containing either QMF149 or placebo 
-
One inhalation from the evening Twisthaler® device (label colored in blue) containing 
either MF or placebo 
-
One inhalation from the Accuhaler® device containing either salmeterol/fluticasone or 
placebo 
Inhalations from the two devices (in the morning) and three devices (in the evening) should be 
taken as close together as possible. Instructions for use of the Concept1 inhaler, Accuhaler®and 
Twisthaler® devices are given in Appendix 1, Appendix 2 and Appendix 3, respectively.
Table 5-1
Study Treatments
Treatment arm
Morning
Evening
QMF149 
150/160 µg
o.d.
Pbo to MF 400 µg
Pbo to salmeterol/ 
fluticasone 50/500 µg
Twisthaler *
Accuhaler
QMF149 150/160 µg
Pbo to MF 400 µg
Pbo to 
salmeterol/fluticasone 
50/500 µg
Concept 1 
Twisthaler *
Accuhaler
QMF149 
150/320 µg
o.d.
Pbo to MF 400 µg
Pbo to salmeterol/ 
fluticasone 50/500 µg
Twisthaler *
Accuhaler
QMF149 150/320 µg
Pbo to MF 400 µg
Pbo to 
salmeterol/fluticasone 
50/500 µg
Concept 1 
Twisthaler*
Accuhaler
MF 400 µg o.d.
Pbo to MF 400 µg
Pbo to salmeterol/ 
fluticasone 50/500 µg
Twisthaler *
Accuhaler
MF 400 µg
Pbo to QMF149
Pbo to 
salmeterol/fluticasone 
50/500 µg
Twisthaler*
Concept 1 
Accuhaler
MF 400 µg
b.i.d. 
MF 400 µg 
Pbo to salmeterol/ 
fluticasone 50/500 µg
Twisthaler *
Accuhaler
MF 400 µg 
Pbo to QMF149
Pbo to 
salmeterol/fluticasone 
50/500 µg
Twisthaler*
Concept 1 
Accuhaler
Salmeterol/ 
fluticasone
50/500 µg b.i.d. 
Salmeterol/ fluticasone 
50/500 µg
Pbo to MF 400 µg
Accuhaler
Twisthaler *
Salmeterol/fluticasone 
50/500 µg
Pbo to QMF149
Pbo to MF 400 µg
Accuhaler
Concept 1 
Twisthaler*


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* In order to keep the blind, 2 Twisthaler devices will be given to the patient. One to be used in the morning (yellow label), one to 
be used in the evening (blue label). Each of them will have either active or placebo (Pbo) treatment, depending on the arm the 
patient is randomized into. 
The study treatment can be taken without regard to sleep, meals, and other activities. On days 
of scheduled clinic visits, patients should take their evening dose of study treatment at the study 
center. Therefore patients will be instructed not to take their evening dose of study medication 
when he/she returns home.
The duration of active treatment is 52 weeks, with the last dose of study treatment occurring in 
the morning of Day 365 (Visit 214).
All kits of investigational treatment assigned by the IRT will be recorded in the IRT. All used 
and unused study medication/packaging must be returned by the patient at each study visit 
and/or at the time of discontinuation.
The investigator should 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 should be instructed to contact the investigator 
if he/she is unable for any reason to take the study treatment as prescribed.
If any faults are identified with either the device and/or the blisters, these should be returned to 
Novartis Drug Supply Management with the completed Device Return Form. The forms will 
be supplied to each investigator site by the Field Monitor.
5.4.5
Permitted dose adjustments and interruptions of study treatment 
The Investigational treatment 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 Administration Record CRF (e-CRF).
In case of blind broken, the study medication is to be permanently discontinued.
5.4.6
Rescue medication 
At Visit 1, all patients will be provided with a SABA (100 µg salbutamol or 90 µg 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 e-CRF, 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 e-CRF. From Visit 1, daily use of rescue medication (number of puffs 


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taken in the previous 12 hours) will be recorded each morning and evening throughout the 52 
week treatment epoch by the patient in his/her 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. 
5.4.7
Concomitant treatment 
The investigator should 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.
5.4.8
Prohibited Treatment 
Prohibited medications, as listed in Table 5-2, must not be taken during the study (unless for 
the treatment of asthma exacerbations). The specified minimum washout periods prior to the 
Run-In epoch (Visit 101) and/or randomization (Visit 201) are described in Table 5-2. The 
classes of medication listed in Table 5-3 are not permitted to be taken during the study. The 
medications in Table 5-4 are only permitted under the circumstances given. Each concomitant 
drug must be individually assessed against all exclusion criteria and the tables below to see if it 
is allowed. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
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 5-2
Prohibited asthma-related medications
Class of medication
Minimum washout period prior to screening visit 
(visit  1) Run-in (Visit 101) and Randomization 
(Visit 201) 1,2, 3,
Short acting anticholinergics (SAMA)
Must not be used within 8 hours prior to Visit 101. 
Fixed combinations of β2-agonists and inhaled 
corticosteroids
Must not be used within 48 hours prior to Visit 101. 
Patients can 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 µg b.i.d. (or equivalent 
dose) from Visit 101 to Visit 102 (Figure 3-1). All 
other ICS must not be used at Visit 101.
Fixed combinations of short-acting β2-agonist 
and short-acting anticholinergic
Must not be used within 8 hours prior to Visit 101.  
Leukotriene Antagonist and leukotriene 
synthesis inhibitors
Must not be used within 7 days prior to Run-In (Visit 
101)
Long-acting β2-agonists (LABAs) 
LABAs b.i.d. not be used within 48 hours prior to Visit 
101. Indacaterol (LABA o.d.) 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. 


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Class of medication
Minimum washout period prior to screening visit 
(visit  1) Run-in (Visit 101) and Randomization 
(Visit 201) 1,2, 3,
Salbutamol/albuterol (SABA) provided at Visit 
1 and throughout study as required for rescue 
medication prn
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 not be used 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 not be used within 4 weeks prior to Run-In 
(Visit 101)
Intra-muscular depot corticosteroids
Must not be used within 3 months prior to Run-In 
(Visit 101)
Monoclonal antibody: IgE inhibitors (e.g., 
omalizumab), IL-5 inhibitors (e.g., 
mepolizumab)
Must not be used within 4 months prior to Run-In 
(Visit 101)
Xanthines
Must not be used within 7 days prior to Run-In (Visit 
101)
Systemic mast cell stabilizers e.g 
cromoglycate, nedocromil, ketotifen
Must not be used within 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 6.4.5 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.
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
Patients using LAMA within 3 months prior to Visit 101 are not allowed in the trial as per exclusion 33 
Table 5-3
Prohibited Medications
Class of medication1
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 (Please note that 
tetracyclics which are similar in class with 
regards to drug interaction are also to be 
excluded)
14 days


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Class of medication1
Minimum cessation period prior to Run-in (Visit 
101) 
Other investigational drugs 
30 days or 5 half-lives, whichever is longer
Noradrenaline reuptake inhibitors
7 days
Live attenuated vaccine
30 days
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria. The wash-out of these prohibited medications is not to be encouraged.
Treatment for AEs including asthma events are permitted if required. However if it is transitioning to chronic 
treatment, the investigator should contact Novartis Medical Monitor.  
Table 5-4
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 prn, provided 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 prn, provided an established pattern of 
use has been documented.
Topical corticosteroids for the treatment of 
eczema
In recommended doses and dosage regimens
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 adverse event including asthma exacerbation, any treatment
deemed necessary for the safety of the patient is allowed from the start of the event (defined as 
per protocol Section 6.4.5 for asthma exacerbation) until the event is resolved. If it is required 
as chronic treatment, the investigator should contact/discuss with Novartis Medical Monitor.
Patients may NOT self-medicate (other than administration of rescue medication) or adjust 
therapy without permission/guidance from treating physician.
5.4.9
Discontinuation of study treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. In the case that 
the patients would want to discontinue the treatment, it is particularly important to ask if they 
would be willing to remain in the trial and share his/her safety and vital status information until 
the scheduled final visit in order to ensure the scientific integrity of the trial.
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.


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Study treatment must be discontinued under the following circumstances:

Patients who experience 5 or more asthma exacerbations during the treatment epoch that 
required treatment with systemic corticosteroids.

Adolescent patients (12 to 17 years old) who experience one asthma exacerbation 
requiring hospitalization

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/AE that requires prolonged use of prohibited 
treatment as per Section 5.4.8 or if patient exhibits a behavior of non-compliance 
regarding prohibited medications.
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 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 e-CRF page. 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 will be discontinued from the trial.
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
He/she should return for the assessments indicated in Table 5-5. If he/she fails to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact them as specified in Section 5.4.9
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 


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Table 5-5
Table of Assessment for Patients who Discontinue Study Treatment 
prematurely
Assessment
Early Study 
Treatment
Discontinuation 
Visit 
Unscheduled 
Safety Follow-
Up Visit
At time of 
original 
Scheduled  
Clinic Visit 
Early Study
discontinuatio
n
Follow-
up Visit 
301
Clinic/Telephone
C
T
T
T
T
Week
Disc. Date
Disc.date+4 
weeks
56
Day 
Disc. Date
Disc.date+30 
days
395
IRT treatment 
discontinuation call
X
Vital Signs
X
Physical exam
X
Record Height 
(Adolescent only)
X
Oropharyngeal 
examination
S
Pregnancy test (serum)
X
Collect study medication
X
Concomitant medication
X
Record 
interruption/changes in 
Drug Administration to 
assess compliance
X
Download/review e Diary
S
Review rescue 
medication use
S
Review AEs 
X
X
Review SAEs
X
X
X
X
X
Review asthma 
exacerbations
X
X
X
X
X
Review surgery and 
procedures
X
X
X
X
X
Safety Lab assessments 
(haematology, clinical 
chemistry, urinalysis)
X
Spirometry1
X
ECG
X
ACQ-7 2
X
Evening Plasma cortisol 
X
Survival Status
X
X
X
X
Record Healthcare visit 
for asthma worsening
X
Record end of treatment 
epoch disposition page
X


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1 Details of timed assessments are provided in Table 6-2
2 All PROs assessed at Clinic should be completed before any other assessment. When a scheduled visit is 
planned on 2 consecutive days the PROs are to be completed on the first day of the discontinuation
5.4.10
Withdrawal of 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, 
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 
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 treatment
discontinuation visit (see section relating to Discontinuation of Study Treatment above), 
and enter on the e-CRF as Early Study Discontinuation Visit provided the patient gives 
consent for these assessments. 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. Publically available survival information should be obtained until the safety 
follow-up visit (Visit 301) unless the patient requests this should not be used.

The investigator must also notify the IRT (IVRS/IWRS) of the premature discontinuation 
of study treatment.

Patients who prematurely discontinue study treatment and withdraw from the study will not 
be replaced.
5.4.11
Lost to follow-up 
For patients who are lost to follow-up (i.e. those patients whose status is unclear because he/she 
fails to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by making appropriate efforts to re-establish contact with patient and 
attempts to contact the patient should be documented in the source documents, e.g. dates of 
telephone calls / emails, registered letters, etc.  If contact has not been re-established, all efforts 
should still be made to locate the patient and obtain information regarding concomitant 
medications, serious adverse events, and survival status at the end of the 52 weeks intended 
treatment epoch (Visit 214). This information should also be obtained at the safety follow-up 
visit (Visit 301).


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5.4.12
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 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 Global Trial Lead (GTL) 
that the code has been broken.
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT code break in case of emergency. The investigator will inform the patient how to 
contact his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide protocol number, study treatment name (if available, patient number, and instructions 
for contacting the local Novartis Country Pharma Organization CPO (or any entity to which it 
has delegated responsibility for emergency code breaks) to the patient in case an emergency 
treatment code break is required at a time when the investigator and backup are unavailable.
Study drug must be discontinued after emergency unblinding. Study drug must also be 
discontinued for any patient whose treatment code has been inadvertently broken. 
5.4.13
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 SAE follow-up at day 395. 
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. 
QMF149 has not been approved by the US Food and Drug Administration (FDA) for the 
treatment of asthma. 
In the US, QMF149 will not be available to patients once they complete the study. There are 
currently no plans to make this medication commercially available in the US. However, there 
are several alternative treatments in the same medication class (LABA/ICS) as QMF149 that 
are widely available in the US for treatment of asthma
Upon completion of the study (including pre-mature discontinuation), the investigator should 
evaluate patient’s condition to assess the best treatment option for the patient. Should 
combination LABA/ICS be clinically indicated, the investigator should consider treatment with 
one of these alternative LABA/ICS combinations.
5.4.14
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator 


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will be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
The study will consist of a screening epoch, a run-in epoch, a 52 week blinded treatment epoch 
and a follow-up epoch of 30 days after the last treatment.
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
day or as close as possible to that date. A visit window of 4 days is allowed for Visit 214 as 
described in Section 3.1. All data obtained for these assessments must be supported in the 
patients’ source documentation.
The following assessments are scheduled to be performed in order as follows: PROs (AQLQ, 
, ACQ,), ECG, pulse rate, blood pressure, blood sample/urine samples, followed 
by spirometry in a manner that the spirometry measurements occur at the scheduled time point 
(See Table 6-2 for Timed Assessments). A minimum 3 min rest period from the beginning of 
ECG assessments to the start of spirometry manoeuvres must be observed at all times.  
Whenever ECG is to be taken after a succession of spirometry measurements as described in
Table 6-2, a minimum 10 min rest period from the end of spirometry maneuvers and the 
beginning of ECG assessments must be observed.
Whenever other assessments are scheduled at the same time-point, spirometry must take 
precedence such that it occurs at the scheduled time point or as near as possible.  If necessary 
other assessments (excluding PROs) can be done after spirometry.


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Table 6-1
Table of assessment
Visit Number
1
101
102
201
202
203
5
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early 
treatment 
discontinu
ation
Early 
study 
discont
inuatio
n
3019
Epoch
Screen
Run-In
Treatment
PSW
Follow-
up
Clinic (C) 
/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
T
C
T
T
T
C
C
T
T
Week – Start of 
Week
-4 to
-2*
- 2
0
0
4
8
12
16
20
26
28 
32 
36
40
44
48
52
56
Day Number
-28 to -
14*
-14
1
1/2
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/
3656
395
Obtain Informed 
Consent and/or 
assent (including 
for sub-group)
X
Current 
medication 
review/
adjustment
X
Inclusion/
exclusion criteria
X
X
X
Randomization 
via IRT
S
Medical History, 
Demography 
X
History of Asthma 
exacerbation
X
Smoking history 
and status
X


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Visit Number
1
101
102
201
202
203
5
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early 
treatment 
discontinu
ation
Early 
study 
discont
inuatio
n
3019
Epoch
Screen
Run-In
Treatment
PSW
Follow-
up
Clinic (C) 
/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
T
C
T
T
T
C
C
T
T
Week – Start of 
Week
-4 to
-2*
- 2
0
0
4
8
12
16
20
26
28 
32 
36
40
44
48
52
56
Day Number
-28 to -
14*
-14
1
1/2
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/
3656
395
Run-in medication 
X
Pregnancy test 
(serum)1
X
X
X
Pregnancy test 
(urine) 1
X
X
X
Urine analysis 
(dipstick)
S
S
S
S
S
S
Device training4
S
S
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination 
S
S
S
S
Oropharyngeal 
examination
S
S
S
S
S
S
S
S
S
Record height 
(adult patients to 
record it ONLY at 
Visit 101) and
weight
X
X
X
X
ECG2
X
X
X
X
X
X
X


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Visit Number
1
101
102
201
202
203
5
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early 
treatment 
discontinu
ation
Early 
study 
discont
inuatio
n
3019
Epoch
Screen
Run-In
Treatment
PSW
Follow-
up
Clinic (C) 
/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
T
C
T
T
T
C
C
T
T
Week – Start of 
Week
-4 to
-2*
- 2
0
0
4
8
12
16
20
26
28 
32 
36
40
44
48
52
56
Day Number
-28 to -
14*
-14
1
1/2
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/
3656
395
Vital signs2
X
X
X
X
X
X
X
X
X
Issue rescue 
medication as 
necessary 
S
S
S
S
S
S
S
Review rescue 
medication use
X
X
X
X
X
X
X
X
X
Spirometry 
Practice
(optional) 
X
Screening 
spirometry 
X
FEV1 reversibility 
test (SABA)10
X
Spirometry2
X
X
X
X
X
X
Issue e-Diary5
X
Issue Peak Flow 
meter
X
Review and 
upload e-Diary 
recordings5
S
S
S
S
S
S
S


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Visit Number
1
101
102
201
202
203
5
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early 
treatment 
discontinu
ation
Early 
study 
discont
inuatio
n
3019
Epoch
Screen
Run-In
Treatment
PSW
Follow-
up
Clinic (C) 
/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
T
C
T
T
T
C
C
T
T
Week – Start of 
Week
-4 to
-2*
- 2
0
0
4
8
12
16
20
26
28 
32 
36
40
44
48
52
56
Day Number
-28 to -
14*
-14
1
1/2
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/
3656
395
Administer study 
drug at visit
X
X
X
X
X
X
Dispense study 
medication via 
IRT
X
X
X
X
X
Call IRT for visit 
confirmation
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Collect unused 
study medication
S
S
S
S
S
S
Record 
interruption/chang
es in Drug 
Administration to 
assess 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE recordings 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Surgery 
and Procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Disposition 
(Screening)
X


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Visit Number
1
101
102
201
202
203
5
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early 
treatment 
discontinu
ation
Early 
study 
discont
inuatio
n
3019
Epoch
Screen
Run-In
Treatment
PSW
Follow-
up
Clinic (C) 
/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
T
C
T
T
T
C
C
T
T
Week – Start of 
Week
-4 to
-2*
- 2
0
0
4
8
12
16
20
26
28 
32 
36
40
44
48
52
56
Day Number
-28 to -
14*
-14
1
1/2
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/
3656
395
Study disposition 
(Run-In)
X
X
Study disposition 
End of Treatment
epoch (end of 
study)
X
X
Study disposition 
(Follow-Up)
X
Survival Status
X
X
Review asthma 
exacerbations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Lab 
assessments 
(haematology, 
clinical chemistry, 
urinalysis, 
 
)
X
X
X
X
X
X
Evening plasma 
cortisol  2
X
X
X
X
ACQ-73
X
X
X
X
X
X
X


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Visit Number
1
101
102
201
202
203
5
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early 
treatment 
discontinu
ation
Early 
study 
discont
inuatio
n
3019
Epoch
Screen
Run-In
Treatment
PSW
Follow-
up
Clinic (C) 
/Telephone (T)
C
C
C
C
C
T
C
T
T
C
T
T
C
T
T
T
C
C
T
T
Week – Start of 
Week
-4 to
-2*
- 2
0
0
4
8
12
16
20
26
28 
32 
36
40
44
48
52
56
Day Number
-28 to -
14*
-14
1
1/2
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/
3656
395
AQLQ-S+123
X
X
X
X
X
X
Telephone patient 
1 day in advance 
of visit
S
S
S
S
S
S
Record 
healthcare visits 
for asthma 
worsening
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit early study discontinuation should be used for Premature study withdrawal (please refer to Section 5.4.10 and Section 5.4.11)
*: Time between Visit 1 and 101 can be adapted according to the required wash-out from previous medication listed in Table 5-2
S These assessments are source documentation only and will not be entered into the e-CRF
X assessment to be reported in the clinical database
1 For females of child-bearing potential only unless surgically sterile. Additional pregnancy testing might be performed if requested by local requirements
3 All PROs assessed at Clinic should be completed before any other assessment. When a scheduled visit is planned on 2 consecutive days the PROs are to be completed 
on the first day. 
4 Device training at Visit 1 is for e-diary/peak flow meter. Device training at Visit 102 is for Concept1, Twisthaler®  and Accuhaler®. The diary is an electronic device and the 
questionnaires and other assessments are based on asthma symptoms


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5 Site to call patient at specified timepoints in between clinic visits to check if patient asthma symptoms have worsened, any treatment required and e-diary completed 
accordingly. In case of an asthma exacerbation, the patient should be encouraged by the site to contact it 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. 
6 The last dose of study medication will be taken on day 365 in the morning (Visit 214) 
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 If reversibility fails on the first attempt as well as on the repeat, historical reversibility or bronchoprovocation would be acceptable as specified in Section 4.1


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Table 6-2
Timed Assessment**
Visit 
(Day)
Timepoint1
Spirometry 
(FEV1, 
FVC)4
Hematology
Chemistry 
Urinalysis 5
Plasma 
cortisol
ECG3
Vital 
sign2
Visit 201
(Day 1)
-45 min
X
- 35 min
X
-25 min
X
-20 min
X5
X6
-15 min
X
0 min
Evening dosage
5 min
X
15 min
X
20 min
X
30 min
X
X
1 h
X
X
X
Visit 201
(Day 2)
23h15 min
X
23h45 min
X
0 min
Evening dosage
Visit 202
(Day 30)
-45 min
X
- 30 min
-25 min
-15 min
X
X
0 min
Evening dosage
5 min 
X
15 min
30 min
X
1 h
X
Visit 204
(Day 86)
-45 min
X
- 35 min
X
-25 min
-15 min
X
X5
X
0 min
Evening dosage
5 min
X
15 min
30 min
X
55 min
1 h
X
Visit 207
(Day 
183)
-45 min
X
- 35 min
X
-25 min
X
- 20 min
X5
X
-15 min
X
0 min
Evening dosage


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Visit 
(Day)
Timepoint1
Spirometry 
(FEV1, 
FVC)4
Hematology
Chemistry 
Urinalysis 5
Plasma 
cortisol
ECG3
Vital 
sign2
5 min
X
30 min
X
X
1h
X
X
Visit 207 
(Day 
184)
23hr15 min
X
23h45 min
X
Visit 214
(Day 
364 )
-45 min
X
- 35 min
X
-25 min
X
- 20 min
X5
X
-15 min
X
0 min
Evening dosage
5 min
X
20 min
X
30 min
X
X
1h
X
X
X
Visit 214
(Day 
365)
23h15 min
X
23h45 min
X
X
X
1 Study drug time doses. All study medication doses to be administered in the clinic. Time relates to the dose 
given from first device at visit unless otherwise specified
2 Systolic and diastolic blood pressure and heart rate (radial pulse)
3 A minimum 3 min rest period from the beginning of ECG assessments to the start of spirometry manoeuvres 
must be observed at all times.
4 A minimum 10 min rest period from the end of spirometry maneuvers and the beginning of ECG assessments 
must be observed at all times. At all timepoints ECG should always be done first. 
5 Urine analysis is to be done only if the urine dipstick is abnormal
6 It is baseline for the evening plasma cortisol
**Assessments are to be completed within a ± 5 mn window from Table 6-2 schedule
6.1
Information to be collected on screening failures 
All patients who have signed informed consent but not entered into the run-in epoch will have 
the study completion page for the screening and/or run-in epoch, demographics, baseline 
characteristics, inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse 
events that are not SAEs will be followed by the investigator and collected only in the source 
data.
6.2
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 

Year of birth

Age (calculated)


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
Sex

Race and ethnicity

Patients initials (where allowed by local legislation)

Height and Weight

BMI (calculated)

Baseline physical examination (not databased other than in the context of relevant 
medical history)

Vital signs

ECG

Date of diagnosis of asthma

Relevant medical history/ current medical condition present before signing the informed 
consent

Smoking history and status

Health status

Prior concomitant medication (Both asthma related an 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 
e-CRF as well as any dosing interruptions. For assessments where spirometry is performed, the 
time of dosing is to be taken from the spirometer. While at home, the time of study treatment 
administration will be recorded by the patient in the e-Diary once a week. The data from the e-
Diary will be reviewed at each visit.
Study treatment compliance should be assessed by the investigator and/or center personnel at 
all visits. 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, 204, 207, 210 and 214 (or at Early Treatment Discontinuation/end of treatment Visit (EOT) 
or Study Withdrawal visit if applicable). Study treatment compliance will be assessed from the 
capsule count from previously dispensed blister strips for the Concept1® and the recording of 
the dose counter number of remaining doses in Twisthaler® and Accuhaler®.
6.4
Efficacy
The following assessments of efficacy will be performed:

Spirometry

Health Status (PROs)

e-Diary

Peak Expiratory Flow

Rescue Medication Use

Asthma Exacerbations


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6.4.1
Spirometry
The following spirometric 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, 207, 214 and EOT (if 
applicable) as indicated in Table 6-2.
Trough FEV1 is defined as the mean of the two FEV1, values measured at 23 hr 15 min and 23 
hr 45 min after the evening dose taken at the site.
Pre-dose FEV1 is defined as the mean of the two FEV1 values measures 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
Health Status (Patient Reported Outcomes)
6.4.2.1
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 1999; Juniper 2005 and Juniper 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 ACQ-7 should be completed by the patient (first 6 questions) and investigator (for the last 
ACQ question – airway caliber FEV1% predicted based on the equipment provided by 
spirometry vendor at the investigators site at Visits 101, 102, 202, 204, 207, 214 and EOT if 
applicable.
6.4.2.2
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 
1992, Juniper 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 1994).
AQLQ should be completed at Visits 102, 202, 204, 207, 210 and 214.


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6.4.3
Electronic Diary
At Visit 1, all patients will be provided with an electronic diary (referred to as an e-Diary) to 
record rescue medication (salbutamol/albuterol) use and clinical symptoms, and from Visit 101 
on, the PEF and compliance with the study treatment. The patients will be instructed to routinely 
complete the e-Diary twice daily – at the same time each morning and again approximately 12 
hours later in the evening.  The e-Diary is to be reviewed at each clinic visit until study 
completion. Sites and patients will receive appropriate training and guidance on the use of the 
e-Diary device. A list of the asthma control e-Diary questions is provided in Appendix 8.


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6.4.3.1
Peak Expiratory Flow (PEF)
An electronic Peak Flow Meter part of the e-diary device will be provided to each patient at 
Visit 1 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 214. The measurements will be performed using an e-Peak 
Flow Meter provided to the patients at Visit 1. PEF will be measured twice a day; in the evening 
just prior to taking study medication and again 12 hours later and as soon as possible after 
waking in the morning. Patients should be encouraged to perform morning and evening PEF
measurements BEFORE the use of any rescue medication. At each timepoint, 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.
6.4.3.2
Rescue Medication Usage
The use of rescue salbutamol/albuterol should be recorded by patients in their e-Diary twice 
each day in the morning and evening prior to taking study medication from Visit 1 until Visit 
214. 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.
6.4.3.3
Investigational Medication Usage
In order to ensure compliance and safety follow-up, the patients will be requested to record 
once per week in the e-diary whether he/she missed any dosage in the morning or in the evening, 
and from which inhalation device from visit 201 to visit 214.
6.4.4
Worsening of asthma
Investigators and patients will be instructed how to deal with worsening of asthma symptoms. 
The data captured in the e-Diary 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 
develops:
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

Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights


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
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 
past 14 days.
If any of the above criteria (including the alert from e-diary) are met while a patient is in the 
run-in or treatment epoch, the investigator should assess the patient condition. If this occurs 
during run-in epoch, and it is considered a clinically significant worsening in the investigator’s 
opinion, the patient should be treated as appropriate and discontinued prior to randomization. 
Once the condition is resolved, if eligibility criteria are met, the patient may be reconsidered 
for rescreening.
The alerts which are trigged by above criteria are in place to detect early onset of asthma 
worsening at any time during the study to help direct early intervention. Therefore the 
investigator should do the following when alerts are received:

Reviewing alert trends over time, in particular PEF decreases 

Call the patient promptly when any one specific alert type (e.g. PEF<60%) is received on 
consecutive days to further assess the clinical status. This may include urgent clinic visits 
as appropriate and/or immediate treatment.

Implementing prompt treatment as necessary

Reporting all type of events in the Asthma Exacerbation Episode CRF.
If patients believe their symptoms are worsening and/or receive alerts as outlined above, the 
patient should also notify the investigator and be evaluated by the investigator and treated as 
clinically appropriate. 
Should there be any compliance issue on study drug or e-diary completion potentially putting 
the patient’s safety at risk, please consider temporary or permanent discontinuation of study 
drug
Patients may also be withdrawn for any other 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.
6.4.5
Asthma Exacerbation
All type of asthma exacerbations meeting below criteria must be recorded in the Asthma 
Exacerbation Episode CRF (Asthma worsening as defined above should also be reported).
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 
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, 
hospitalization due to asthma or death due to asthma.

Start date and end date:


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
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 CRF.
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
- Night time 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 SCSs 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


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“Start and end dates” of each reported event in the CRF 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. If systemic corticosteroids 
are required, a patient may return to the study after successfully completing a taper of 
approximately 7-10 days. If patients require significantly longer treatment periods or chronic 
administration, they must be discontinued from treatment.
6.4.6
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

Adverse events including asthma exacerbations and serious adverse events

Pregnancy (female patients). Additional pregnancy testing might be performed if 
requested by local requirements.

Serious asthma outcomes (asthma-related hospitalizations, intubations or deaths)
ECG and Laboratory assessments will be centralized.
6.5.1
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed at Visits 101, 207, 214 or 
EOT (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 
e-CRF. Significant findings made after informed consent (Visit 1) is given which meet the 
definition of an Adverse Event must be recorded on the Adverse Event screen of the patient’s 
e-CRF.


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6.5.2
Vital signs 
Systolic and diastolic blood pressure and radial pulse rate (over a 30 sec interval), performed in 
the sitting position, will be recorded at each scheduled clinic visits as detailed in Table 6-2. (At 
visit 101, 102, 201, 202, 204, 207, 210, 214, or EOT (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 and will be measured 
only in adolescents at visit 207, 214 or EOT if applicable. Body weight (to the nearest 0.1 
kilogram [kg] in indoor clothing, but without shoes) will be measured at Visit 101, 207, 214 or
EOT (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, 
) will 
be performed at Visit 101, 201, 204, 207, 214 and EOT 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, AST (SGOT), ALT (SGPT), bilirubin, creatinine, γ-GT, 
glucose, potassium, magnesium, BUN and uric acid will be measured.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal range, 
total bilirubin should be differentiated into the direct and indirect reacting bilirubin.
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will be performed 
at Visit 101, 201, 204, 207 and 214.
If the urine dipstick is abnormal, the sample will be sent to central laboratory for additional 
testing, including assessment of WBC and RBC sediments.


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6.5.4.4
Hepatotoxicity
Any liver event which meets the criteria for “medically significant” event as outlined in Table 
13-1 of Appendix 9 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, 207 and 214 and EOT if applicable. 
The sampling time point is shown in Table 6-1 and Table 6-2.
6.5.5
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
When the ECG recording time coincides with vital signs, spirometry, and blood draws, the ECG 
must be performed first, followed by vital signs and 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 102/201, 207, and 214, ECGs will be measured at -35min pre-dose (evening dose) 
and post dose 30 min/ 1 hour. At Visit 204 ECG will be measured pre-dose only as indicated in
Table 6-2. At Visit 210, the ECG will be done -35min pre-dose only. All electrocardiograms 
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 traces and 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 subject'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 investigational treatment.
If a patient experiences a clinically significant change in cardiac rhythm or other clinically 
significant cardiovascular abnormality, the investigator should consider withdrawing the patient 
from the study.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions/AE CRF/e-CRF page as appropriate.


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6.5.6
Serious Asthma outcomes
Asthma-related hospitalizations, asthma-related intubations or asthma-related deaths over the 
52-week treatment epoch will be recorded and will all be reviewed by the Adjudication 
Committee. Hospitalization is defined as an inpatient stay or a ≥ 24 hour stay in an observation 
area in an emergency department or other equivalent facility.
6.5.7
Pregnancy and assessments of fertility 
A plasma and urine pregnancy test will be performed in pre-menopausal women who are not 
surgically sterile (tests provided by the Central Laboratory) per Assessment Schedule Table 6-
1. If the urine pregnancy test at Visit 1, Visit 102 and Visit 207 is positive a plasma testing is 
to be done to confirm the pregnancy. A positive plasma pregnancy test at Visit 1, Visit 101, 
Visit 102,Visit 207 (Week 26) ,Visit 214 or EOT or at any time during the study requires the 
patient to be discontinued from the study treatment. Refer to Section 5.4.9 and Section 7.4 for 
more details. Additional pregnancy testing might be performed if requested by local 
requirements.
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 subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results 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 adverse events.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information.

The severity grade mild: usually transient in nature and generally not interfering with 
normal activities

Moderate: sufficiently discomforting to interfere with normal activities

Severe: prevents normal activities


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
Its relationship to the study drug (s) (suspected/not suspected)

Study treatment (no/yes), or

Investigational treatment (no/yes), or

The other study treatment (non-investigational) (no/yes) or both or indistinguishable, 

Its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.

Whether it constitutes a serious adverse event (SAE - See section 7.2 for definition of 
SAE)

Action taken regarding the study treatment 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: 

No action taken (i.e. further observation only) 

Study treatment dosage adjusted/temporarily interrupted 

Study treatment  permanently discontinued due to this adverse event 

Concomitant medication given 

Non-drug therapy given 

Patient hospitalized/patient’s hospitalization prolonged 

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event 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) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
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 adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

is fatal or life-threatening 


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
results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, 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 (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline).
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 e-CRF. SAEs are also required for
individual reporting to 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 learning of its occurrence. Any SAEs experienced after the 30 
days period should only be reported to Novartis safety if the investigator suspects a causal 
relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 


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different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form, all applicable sections of the form must be 
completed in order to provide a clinically thorough report. The investigator must assess the 
relationship of each SAE to each specific component of study treatment, complete the SAE 
Report Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signature are to be found in 
the investigator folder provided to each site.
Follow- up information is submitted as instructed in the investigator folder. Each reoccurence, 
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 treatment code 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 investigational treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same investigational treatment that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
7.2.3
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 by either X-ray or radiologist reading report of 
the X-ray (to be kept in the source documents). If not confirmed by X-ray, it should be reported 
as lower respiratory tract infection.
7.3
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion of 
the standard base liver CRF pages


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Please refer to Table 13-1 in Appendix 9 for complete definitions of liver laboratory triggers 
and liver events
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 9 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 in Appendix 9.
For the liver laboratory trigger:

Repeating the 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 CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up for 3 months after the birth 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 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 CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of patient records, the accuracy of entries on the 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 CRA organization. Additionally, a 
central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
Prior to the final database lock, CSR I (Section 3.5) will be prepared. The database for this CSR 
will consist of:

All data in all patients up to 26 weeks (Visit 207)

Data for the subset of patients who have completed 52 weeks treatment plus follow up 
(Visit 214 and 301) or prematurely withdrawn from the study.


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
Data up to last available visit for patients who have already completed 26 weeks (Visit 
207) but have not yet completed 52 week treatment plus follow up (Visit 214/301)
8.3
Database management and quality control 
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will make 
the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
ECG readings will be processed centrally and the results will be sent electronically to Novartis.
Spirometry readings will be processed centrally and the results will be sent electronically to 
Novartis
Diary data will be entered into an electronic diary by the patient. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis.
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).
8.4
Data Monitoring Committee 
An independent, external data safety monitoring committee (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. 
A charter for the independent DMC will be developed in a separate document. The DMC is the 
autonomous data and safety advisory group for Novartis. The purpose of the charter is to define: 
1. The membership of the DMC 
2. Responsibilities of the DMC and Novartis 
3. Responsibilities of independent biostatistician and programmer 


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4. The relationship of the 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 DMC’s. 
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 will include:

Data interpretation 

Publications

Presentations
9
Data analysis 
There will be two separate CSRs prepared for this study.

CSR I: To support analyses once all patients have completed the assessments after 26 
weeks of treatment (Visit 207) or prematurely withdrawn from the study. This will consist 
of :

Primary and key secondary objectives as well as other secondary objectives up to and 
including Week 26.
 

CSR II: To support analysis once all patients have completed 52 weeks of treatment (Visit 
214) plus follow up (Visit 301) or prematurely withdrawn from the study. CSR II will 
consist of:

Primary and secondary objectives analyzed in CSR I

All other objectives evaluated after 26 weeks up to 52 weeks (plus follow up), which 
will be updated from CSR I.


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9.1
Analysis sets 
The following analysis sets are defined for data analysis.
The randomized (RAN) set will consist of all patients who were assigned a randomization 
number, regardless of whether or not they actually received study medication.
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 un-blinding 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 assign 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, abdominal circumference (hip and waist), body mass 
index (BMI), relevant medical history, screening spirometry parameters: (FEV1, FVC,
FEV1/FVC and FEF25-75), FEV1 reversibility, % 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, 
pulse rate), QTc using Fridericia’s correction and baseline ACQ-7, 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.


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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.
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 route of administrations, the recorded pre-specified drug 
subcategories (including type of combinations) and preferred term. Concomitant medications 
not related to asthma will be summarized by route of administration and preferred term. 
SABA usage (number of puffs) during the screening epoch will be summarized. 
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(s) and key secondary variables
9.4.1
Variable(s)
The primary objective is to demonstrate the superiority of either QMF149 150/160 µg delivered 
via Concept1 o.d. (in the evening) to MF 400 µg delivered via Twisthaler® or QMF149 
150/320 µg delivered via Concept1 o.d. (in the evening) to MF 800 µg delivered via 
Twisthaler® (delivered as 400 µg b.i.d.) in terms of trough FEV1 after 26 weeks of treatment in 
patients with asthma.
The key secondary objective is to demonstrate the superiority of QMF149 (150/160 and 
150/320 µg combined) to mometasone furoate doses (MF, 400 µg and 800 µg combined) in 
terms of ACQ-7 after 26 weeks of treatment in patients with asthma.
9.4.2
Statistical model, hypothesis, and method of analysis
The comparisons of QMF149 150/160 µg versus MF 400 µg and QMF149 150/320 µg versus
MF 800 µg 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 26
Ha: QMF149 treatment group is not equal to MF treatment group in trough FEV1 at Week 26
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, 
184, and 365), 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 


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modeled using the 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 primary analysis, if the model does not converge, data only up to week 26 (i.e. Days 2 
and 184) will be used (with unstructured covariance matrix). If still the model fails to converge, 
compound symmetry covariance matrix will be used. For the final analysis, if the model does 
not converge with unstructured covariance matrix, the compound symmetry covariance matrix
will be used in the mixed model. 
Restricted maximum likelihood method will be used. Each 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 factor corresponding to 
Day 184.
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).
9.4.3
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 are collected 
within 7 days of systemic corticosteroid use, 6 h of rescue medication, or actual measurement 
times are outside the 22 - 25 hour post-evening dose time window (or 10-13 hour post-morning 
dose time window) then the individual FEV1 value will be set to missing.
If one of the two values is missing (or set to missing) then the remaining non-missing value will 
be taken as trough FEV1. If both values are missing, or if the patient withdrew from the study, 
regardless of the reason for discontinuation, then trough FEV1 will be regarded as missing in 
which case the missing value(s) of the patient at the particular visit(s) would not directly 
contribute to the primary analysis.
The MMRM model 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 
imputation.
9.4.4
Multiplicity Adjustment
To control the family-wise type-I error rate at the two-sided 5% significance level, a multiple
testing procedure based on the trimmed Simes test in Brannath et al (2009) is used. The family 
for the overall type-I error rate control contains three hypotheses including two hypotheses for 
the primary endpoint trough FEV1 and one hypothesis for the key secondary endpoint ACQ-7. 
Denote the two hypotheses for the primary endpoint as H1 and H2 for comparing QMF149 
150/160 µg vs. MF 400 µg and QMF149 150/320 µg vs. MF 800 µg respectively. Similarly, 
denote the hypothesis as H3 for the key secondary endpoint ACQ-7, for comparing QMF149 
vs. MF.
Below is a brief description of the testing procedure based on the trimmed Simes test in 
Brannath et al (2009).
Let p1, p2, p3 be the corresponding p-values (2-sided) of the three hypotheses of H1, H2, and
H3. 


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Step 1: Retain both H1 and H2 if pi ≤0.05 AND the observed treatment difference for the 
corresponding pi is in the wrong direction (i.e. MF is performing better than QMF) for ANY i
= 1, 2, stop here; otherwise go to Step 2;
Step 2: Reject H1 and H2 if pi < 0.05 for BOTH i = 1, 2 and go to Step 3; otherwise go to Step 
4;
Step 3: Reject H3 if p3 < 0.05 and stop;
Step 4: If neither Step 1 nor Step 2 applies, perform the Bonferroni test to H1 and H2. Thus 
reject H1 if p1 < 0.025 or reject H2 if p2 < 0.025 and stop.
For each of the three hypotheses, the corresponding testing statistic (estimated least squares
mean difference) follows normal distribution. Hence for H1 and H2, their corresponding testing 
statistics follow jointly a bivariate normal distribution. Therefore this testing procedure controls 
the overall type–I error rate at the 2-sided 0.05 level in the strong sense regardless if the bivariate 
normal distributions have positive or negative correlations as shown in Brannath et al (2009).
Other than the three analyses mentioned above for the primary and the key secondary endpoint, 
all other analyses will be performed at the nominal 2-sided 0.05 level (2-sided) without 
multiplicity adjustment.
9.4.5
Key secondary variable
The key secondary variable is ACQ-7 after 26 weeks of treatment. 
It will be analyzed using the same MMRM model (including all available visits) on the FAS as 
used for the primary analysis but will include baseline ACQ-7 score instead of baseline FEV1.
To demonstrate the superiority of QMF149 (150/160 and 150/320 combined) to mometasone 
furoate (MF 400 µg and 800 µg combined), the average of following treatment contrasts will 
be computed:
QMF149 (150/160 µg) vs. MF 400 µg
QMF149 (150/320 µg) vs. MF 800 µg
Least squares means (95% CI) will be presented graphically to assess the interaction between 
indacaterol and dose levels of MF.
9.4.6
Supportive analyses 
As supportive analysis, the same MMRM model used in the primary analysis will be also 
performed on the PPS to assess the treatment effect in protocol adherers. The same primary 
MMRM model 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 window (or 10-13 hour post-morning dose window) will not be 
included.The following 
 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 17 years, ≥18 years)

Race (Caucasian, Black, Asian, Other)


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
Sex (male, female)

History of asthma exacerbation in the 12 months prior to screening (Yes, No)

Patients’ prior therapies before Run-in period (e.g. medium dose ICS, high dose ICS and 
low dose ICS/LABA)

FEV1 response according to % predicted FEV1 range at baseline (50% to < 60%, 60% to 
< 80% and <50% or > 80%)

ACQ-7 Baseline (1.5- < 2,  2< 2.5, ≥2.5)
9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
The comparison of QMF149 150/320 µg o.d vs. salmeterol xinafoate /fluticasone propionate 
50/500 µg b.i.d. (Seretide®) will be performed using the same model for the comparison of 
QMF149 vs. MF as specified below for the corresponding endpoint unless otherwise specified.
9.5.1.1
Spirometry
All spirometric efficacy variables will be analyzed for the FAS, unless otherwise specified.
Spirometry measurements contributing to the trough FEV1, if collected within 7 days of 
systemic corticosteroid use, and/or 6 hours of rescue use, and/or 3 months of single depot 
corticosteroid injection, will be set to missing and not be imputed, unless specified otherwise.
Spirometry data by visit
Trough FEV1 at Day 2 and at post-baseline visits will be analyzed using the same MMRM 
model 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 corresponding to the respective visit. 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 FEV1, post-dose FEV1 (5 mins, 30 mins, 1 hr),
FVC and FEF25-75.
Change from baseline in the spirometry values will be also analyzed using the same MMRM 
model.
To estimate the add-on effect of indacaterol (QAB149) to existing MF treatment (in terms of 
trough FEV1), the average difference between QMF and MF will be computed across two dose 
levels. This difference is interpreted as an average effect of adding indacaterol to MF, under the 
assumption that indacaterol effect is not altered by dose of MF. To compute the difference, the 
QMF149 and MF doses will be pooled using appropriate contrasts within the MMRM model, 
as specified for the primary analysis. The details of this analysis will be provided in the SAP.
Comparison of QMF149 150/320 µg vs salmeterol xinafoate /fluticasone 
propionate 50/500 µg b.i.d. in term of trough FEV1 at Week 26


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The comparison of QMF149 150/320 µg o.d. vs active control (salmeterol xinafoate 
/fluticasone propionate 50/500 µg b.i.d.) will be performed using the same model as specified 
for the primary endpoint. The result will be interpreted based on the 95% confidence interval 
(CI) of the treatment difference of QMF149 – active control. The lower bound of the 95% CI is 
the difference that can be ruled out. For example, if the lower bound of the 95% CI is larger 
than the non-inferiority margin -90 mL (i.e. the entire 95% CI is to the right of -90 mL), 
QMF149 150/320 µg can be considered non-inferior to active control, and if the lower bound 
of the 95% CI is greater than 0, then QMF149 150/320 µg can be considered superior to active 
control with regard to trough FEV1 at Week 26. Note that the comparison versus active control 
is not part of the confirmatory testing strategy.
The estimation of the non-inferiority margin of -90 mL is provided in Appendix 12.
9.5.1.2
ACQ at Weeks 4, 12 and 52
The ACQ-7 measures asthma symptom control and consists of 7 items: 5 on symptom 
assessment, 1 on rescue bronchodilator use and 1 on airway calibre (FEV1 % predicted). 
Patient recall is 1 week. All 7 questions of the ACQ-7 are equally weighted. Items 1-5 are 
scored along a 7-point response scale, where 0 = totally controlled and 6 = severely 
uncontrolled. The 7th item will be scored by the investigator based on the FEV1 % predicted 
from the equipment provided by spirometry vendor at the site. The total score is calculated as 
the mean of all questions.
ACQ-7 at post-baseline visits will be analyzed using the same MMRM model as specified for 
the primary analysis except that baseline FEV1 will be replaced with baseline ACQ-7 and all 
post-baseline visits corresponding to ACQ-7 will be included.
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 the
logistic regression model via the generalized estimating equations (GEE). The model will 
include terms for treatment, age (12 to 17 or ≥18 years), region, visit, and treatment-by-visit 
interaction as fixed effects with 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 ratios will be displayed along with the associated 95% (two-sided) 
confidence intervals and p-values.
To explore the potential interaction effect, the individual treatment contrasts will be presented.
All the analyses described above will be repeated for ACQ-5.
9.5.1.3
Rescue medication
The number of puffs of the rescue medication use in the previous 12-hour is recorded twice 
(morning/evening) by the patient in the e-Diary. The mean daily number of puffs of rescue 
medication use over the first 26 weeks and over the whole 52 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 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 


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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 differences along with the corresponding two-sided 
95% confidence intervals and corresponding p-values will be presented. This analysis will be
performed for morning (nighttime) and evening (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 approximate 4 weekly intervals and analyzed using a similar MMRM model 
as specified for the primary analysis with the baseline FEV1 value replaced with the appropriate
baseline rescue medication use.
9.5.1.4
Peak Expiratory Flow Rate (PEF)
All the patients are instructed to record PEF twice daily using a mini Peak Flow Meter device, 
once in the morning (before taking the morning dose) and once approximately 12 h later in the 
evening (before taking the evening dose), from screening and throughout the study.
The morning/evening PEF (liters/min) will be averaged over the first 26 weeks and over the 
whole 52 weeks. E-diary data recorded during the screening period will be used to calculate the 
baseline value.
Mean morning/evening PEF will be summarized by treatment. Between-treatment differences 
of the change from baseline in mean morning/evening PEF will be performed using the same 
models 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 treatment differences.
In addition, the mean morning/evening PEF will be summarized by approximate 4 weekly 
intervals and analysed using a similar MMRM model as specified for the primary analysis with
baseline FEV1 value replaced with the appropriate baseline PEF.
9.5.1.5
Asthma symptom based on e-Diary
The percentage of days with no day-time symptoms will be calculated for each patient over the 
52 weeks of treatment period and will be analyzed by the same ANCOVA model used for the
analysis of % of rescue medication free days with the appropriate baseline as a covariate.
The same ANCOVA model as specified above except using the appropriate baseline as a 
covariate will be used to analyze the percentage of days with no night-time awakenings over 52
weeks of treatment, the mean total daily symptom scores averaged over 26 and 52 weeks of 
treatment and the percentage of mornings with no symptoms on rising over 52 weeks of 
treatment.
In addition, the percentage of days with no night-time awakenings, the mean total daily 
symptom scores and the percentage of mornings with no symptoms on rising will be 


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summarized by approximate 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.
9.5.1.6
Asthma Exacerbations
The following asthma exacerbation-related parameters over the 52 weeks will be summarized 
by treatment (asthma exacerbation is defined in Section 6.4.5). 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, and severe.  

Time to first asthma exacerbation by exacerbation category

Time to first hospitalization for asthma exacerbation

The annual rate of asthma exacerbations by exacerbation category 

Duration of asthma exacerbations in days by exacerbation category

The percentage of patients with at least one asthma exacerbation by exacerbation 
category

Time to permanent study drug discontinuation due to asthma exacerbation

The percentage of patients who permanently discontinued study drug due to asthma 
exacerbation

Total amounts (in doses) of systemic corticosteroids used to treat asthma 
exacerbations
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 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 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 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.
The duration of asthma exacerbation is defined as the sum of the duration of days recorded as 
an exacerbation for all exacerbations recorded per patient. This will be analyzed for treatment 
group differences using the Van Elteren test stratified for age (12 to 17, or ≥18), region and 
history of asthma exacerbation in the 12 months prior to screening (Yes, No).
The proportion of patients with at least one asthma exacerbation will be analyzed using logistic 
regression. The model will include terms for treatment, age (12 to 17 or ≥18), region and history 
of asthma exacerbation in the 12 months prior to screening (Yes, No), as fixed effects with 
center nested within region as a random effect, and FEV1 prior to inhalation and FEV1 15 to 30


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min post inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates. 
The estimated adjusted odds ratios will be displayed along with the associated 95% (two-sided) 
confidence intervals and p-values.
The percentage of patients who permanently discontinued study drug due to asthma 
exacerbation will be analyzed using the same model as for the proportion of patients with at 
least one asthma exacerbation.
Total amount (in prednisone-equivalent doses) of systemic corticosteroid used to treat asthma
exacerbation during the 52 week treatment period will be summarized descriptively (i.e., n, 
mean, standard deviation, median, first and third quartile, minimum and maximum) by 
treatment group.
To estimate the add-on effect of indacaterol (QAB149) to existing MF treatment (in terms of 
exacerbations), the average difference between QMF and MF will be computed for all 
inferential analyses mentioned above. This difference is interpreted as an average of adding 
indacaterol to MF, under the assumption that indacaterol effect is not altered by dose of MF. 
To compute the difference, the QMF149 and MF doses will be pooled using appropriate 
contrasts within the specified analyses. The details of these analyses will be provided in the 
SAP.
9.5.2
Safety variables 
All safety endpoints will be summarized for the safety set.
Adverse events
All study emergent adverse events including asthma exacerbations will be summarized and 
listed. Adverse events starting on or after the time of the first inhalation of study drug will be 
classified as a treatment emergent adverse event. Any adverse events that started during the 
study before the time of the first inhalation of study drug will be classified as a prior adverse 
event. 
The following treatment emergent adverse event summaries will be produced, overall by system 
organ class and preferred term, overall by system organ class, preferred term and maximum 
severity, suspected drug-related adverse events by system organ class and preferred term, 
serious adverse events by system organ class and preferred term, and adverse events leading to 
permanent discontinuation of study-drug by system organ class and preferred term.
The number and exposure-adjusted event rate of patients with the most frequent AEs will be 
summarized by treatment. 
Electrocardiogram (ECG) and vital signs
Data from the electrocardiogram will be summarized by treatment and visit.
Vital signs (blood pressure and radial pulse rate) data will be summarized by treatment and visit.
The maximum (QTc, systolic blood pressure, pulse rate and heart rate) or minimum (diastolic 
blood pressure) post first dosing (i.e. post baseline) value will also be summarized. Changes 
from baseline will also be summarized by treatment. 


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Weight will be summarized by visit and treatment group. Changes from baseline will also be 
summarized by treatment. The baseline measurement will be the measurement at Visit 101.
All data will be included in the analysis regardless of rescue medication usage.
The number (%) of patients with pulse rate of < 40 and > 90 bpm; systolic blood pressure of 
< 90 and > 140mmHg; diastolic blood pressure of < 50 and > 90 mmHg will be summarized 
by treatment group.
Notable values for vital signs and change from baseline will be summarized. A notable value is 
defined as follows:
Systolic blood pressure
“Low” criterion: < 75 mmHg, or ≤90 mmHg and decrease from baseline ≥20 mmHg
“High” criterion: > 200 mmHg, or ≥180 mmHg and increase from baseline ≥20 mmHg
Diastolic blood pressure
“Low” criterion: < 40 mmHg, or ≤50 mmHg and decrease from baseline ≥15 mmHg
“High” criterion: > 115 mmHg, or ≥105 mmHg and increase from baseline ≥15 mmHg
Pulse rate
”Low” criterion: < 40 bpm, or ≤50 bpm and decrease from baseline ≥15 bpm
“High” criterion: > 130 bpm, or ≥120 bpm and increase from baseline ≥15 bpm
Notable QTc values and changes from baseline will be summarized. A notable value is defined 
as a QTc interval of greater than 450 ms (male), 460 ms (female) and 500 ms (both) at baseline 
and the number of newly occurring or worsening notable QTc values for post baseline time 
points. The categories used for the change from baseline in QTc are less than 30 ms, 30 to 60 
ms and greater than 60 ms.
QTc will be calculated from the QT interval and RR (in seconds) 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.
Laboratory data
All laboratory data will be listed with abnormal values flagged. The laboratory values and the 
change from baseline for continuous laboratory parameters will be summarized at each visit. A 
frequency table of results for categorical laboratory parameters will be produced by visit. Shift 
tables relative to the normal reference ranges will be used to summarize the change from 
baseline to post-baseline by visit for each laboratory parameter.
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.


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Unscheduled primary and secondary care visits due to asthma worsening
The number of unscheduled primary and secondary care visits per patient per year will be 
analyzed for the FAS using the same generalized linear model assuming negative binomial 
distribution as specified for the number of asthma exacerbations except excluding history of 
asthma exacerbation in the 12 months prior to screening (Yes, No) from the model.
Absenteeism from work due to asthma worsening
The number of days off (absenteeism) from work due to asthma worsening will be described 
descriptively by treatment on the FAS. The number and percentage of patients absent from work 
due to asthma worsening will be summarized by treatment on the FAS.
9.5.2.2
Asthma Quality of Life Questionnaire (AQLQ) at Post-baseline Visits
AQLQ (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.
For the overall score and each respective domain score, treatment group comparisons will be 
performed using the same MMRM model as specified for the primary analysis with baseline 
AQLQ as covariate.
The proportion of patients who achieve an improvement of at least 0.5 in the change from 
baseline in AQLQ (i.e. increase of AQLQ score of at least 0.5 from baseline) at post-baseline 
visits will be analyzed using the same logistic regression model via GEE specified for the ACQ-
7 analysis except that baseline AQLQ will be used instead of the baseline ACQ-7.
The analyses on AQLQ will be based on the FAS for all post-baseline visits.


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9.6
Interim Analysis
The primary and key secondary endpoints of CQVM149B2301 study are trough FEV1 and 
ACQ-7 after 26 weeks of treatment, respectively while the entire study treatment period is 52 
weeks. Novartis has decided to perform primary analysis once all patients have completed 26 
weeks of treatment (Visit 207) or prematurely withdrawn from the study which will be used for 
internal decision making prior to study completion. The study will continue as planned in a 
blinded manner for full 52 weeks period (plus 30 days of safety follow-up).
Since the analysis of primary and key secondary objectives will be performed only for CSR I, 
this interim analysis will not require any adjustment to the overall type I error rate. 
9.7
Safety Monitoring Analyses
No interim analysis for efficacy is planned. It is planned that the independent DMC will review 
semi-blinded (i.e., treatment group named as A, B, C, D, or E) 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. 
9.8
Sample size calculation
The sample size calculation takes into account the following consideration:


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
To achieve at least 90% power (with multiplicity adjustment) for primary endpoint 
trough FEV1 with a treatment difference of 100 mL between QMF149 vs. MF at the 
corresponding doses, assuming standard deviation of 380 mL based on internal studies 
QMF149A2210, QMF149E2201, QMF149E2203 and literature data;

To achieve at least 80% power (with multiplicity adjustment) for key secondary 
endpoint ACQ-7 with a treatment difference of 0.15 between QMF149 vs. MF based on 
pooled doses, assuming standard deviation of 0.80 based on studies QMF149A2210, 
QMF149E2201, QMF149E2203 and Kerstjens (2012).
If 10 % dropout rate is assumed, then calculation shows the sample size of 2000 patients (i.e 
400/arm) will provide 94% power for item 1 and 85% power for item 2, with multiplicity 
adjustment as given in Section 9.4.4. 
The sample size calculation is performed in R 3.2.3. 
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.
10.2
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the patient. 
In cases where the patient’s representative gives consent, the patient 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. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential 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.


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10.3
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. 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 
Novartis assures that 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.
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 should an 
investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs.
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. 
All significant protocol deviations will be recorded and reported in the CSR.
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 should be followed.


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12
References 
References are available upon request
Annex IV, ICH-E2D Guideline. Available from www.ich.org
Barnes PJ et al (2014). The asthma control questionnaire as a clinical trial endpoint: past 
experience and recommendations for future use. European Journal of Allergy and Clinical 
Immunology; 69 (9): 119-1140
Beasley R et al (2015). Effect of once-daily indacaterol maleate/mometasone furoate on
exacerbation risk in adolescent and adult asthma: a double-blind randomised controlled trial; 
BMJ Open 5(2):e006131. doi: 10.1136/bmjopen-2014-006131
Beasley Ret al (2012). Safety of once-daily QMF149 in patients with persistent asthma. Eur 
Respir J; 40 (Suppl 56): 371.
Beasley R, et al (2012a). Long-term efficacy of QMF149 in persistent asthma. Eur Respir J; 
40 (Suppl 56): 31
Brannath, W., Bretz, F., Maurer, W., & Sarkar, S. (2009). Trimmed weighted Simes' test for 
two one-sided hypotheses with arbitrarily correlated test statistics. Biometrical Journal, 51(6), 
885-898.
Bretz F, Maurer W, Brannath W, and Posch M (2009). A graphical approach to sequentially 
rejective multiple test procedures. Statistics in Medicine; 28: 586-604.
Bretz F et al (2011). Graphical approaches for multiple comparison procedures using 
weighted Bonferroni, Simes, or parametric tests. Biometrical Journal; 53: 894-913.
EuroQol Group (1990). EuroQol-A new facility for the measurement of health-related quality 
of life. Health Policy. 16: 199-208.
European Medicines Agency (2013). Note for guidance on clinical investigation of medicinal 
products for treatment of asthma. CHMP/EWP/2922/01-rev.1. 
FDA (1999). Guidance for Industry: Population Pharmacokinetics. U.S. Department of Health
and Human Services, Food and Drug Administration, Center for Drug Evaluation and
Research (CDER), Center for Biologics Evaluation and Research (CBER), February 1999, CP
1.
Global Initiative for Asthma (GINA) (2015). Global Strategy for Asthma Management and 
Prevention. Available from http://ginasthma.org
Juniper EF et al (1999) Development and validation of the questionnaire to measure asthma 
control. Eur Resp J; 14: 902-907.
Juniper EFet 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: 616-62.
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 (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. 


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Juniper EF, et al (1993). Measuring quality of life in asthma. Am Rev Respir Dis; 147: 832-
838. 
Kenward MG, Roger JH (1997). Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics ;53(3):983-97.
Kerstjens HAM et al (2012). Tiotropium in asthma poorly controlled with standard 
combination therapy. N Engl J Med; 367:1198-207.
Kerstjens et al (2015). Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for 
patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, 
parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015 May;3(5):367-
76.
Masoli M et al (2004). The Global Burden of Asthma Report, Global Initiative for Asthma 
(GINA). Available from www.ginasthma.org
Quanjer PH, et al. (1993), Lung volumes and forced ventilatory flows. Report Working Party 
Standardization of Lung Function Tests, European Community for Steel and Coal. Official 
Statement of the European Respiratory Society. Eur Respir J; 6 suppl. 16: 5-40.
Relvar Summary of Product Characteristic. Available from: 
http://hcp.gsk.co.uk/products/relvar/prescribing/indications.html
 
Rohmeyer K, Klinglmueller F,  Bornkamp B (2012). Package ‘gMCP’ graph based multiple 
comparison procedures. Available from http://cran.r-
project.org/web/packages/gMCP/gMCP.pdf.
Vaidya S, et al (2012). Pharmacokinetics (PK) of single doses of mometasone furoate (MF) 
delivered via the Breezhaler® (BH) and Twisthaler® devices in healthy subjects. Eur Respir 
J; 40 (Suppl 56): P382.


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Appendices
Appendix 1: Instruction for Use of Concept1
Instructions for using inhaler and capsules.
Do not swallow capsules.
Follow the instructions below for using your inhaler. You will take the study drug contained 
within the capsules by inhalation using the inhaler. If you have any questions, please ask the 
doctor or nurse at the study center.
Your inhaler and capsules
The study drug package consists of both the inhaler and one or more blister-packaged 
capsules.

Capsules are supplied in blisters.

Inhaler consists of a cap, mouthpiece and a base.
Your inhaler is designed to deliver the medicine contained within the capsules.
Do not use the study medication capsules with any other capsule inhaler, and do not use the 
inhaler to take any other capsule medicine.


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


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


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


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


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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
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 for about 10 seconds or as long as you 
comfortable can.


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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
Figure 5-Closed inhaler
IT IS IMPORTANT TO REPEAT STEPS 1AND 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 your 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 
American Thoracic Society (ATS)/European Respiratory Society (ERS) Standardization of 
Spirometry1. Spirometers must have the capacity to print FVC tracings.  All spirometry values 
should be reported at BTPS by the method established by the manufacturer.
Calibration
The spirometer should be calibrated every morning before any spirometric measurements for 
the study are performed. Calibration reports should be printed and stored as source data at the 
site. 
Preparing the test subject
On study days when spirometry will be performed, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages  for 4 hours prior to spirometry

Alcohol for 4 hours prior to spirometry

Strenuous activity for 12 hours prior to spirometry 

Smoking within at least 1 hour of testing

Exposure to environmental smoke, dust or areas with strong odors 
Every effort should be made to assure consistent testing conditions throughout the study.  A 
seated position with nose clips is recommended to reduce risks related to dizziness or syncope.  
When possible, spirometry should be conducted by the same technician using the same 
spirometer.  To minimize the effects of diurnal variation on lung function, spirometry visits 
should start at approximately the same time of day at each visit.
Performing Spirometry
The subject’s age, height and gender will be entered into the spirometer.  It is important that the 
height is measured accurately at the study site. Spirometry, an effort-dependent test, requires 
careful instruction and cooperation of the subject.  The technician should ensure a good seal 
around the mouthpiece, and confirm that the subject’s posture is correct. The subject should be 
instructed to perform a maximal inspiration, followed by maximum forced expiration until no 
more air can be exhaled or for at least 6 seconds. Expiration must be rapid with exertion of 
maximal effort. The results of spirometry should meet the ATS/ERS criteria for acceptability
and repeatability. Acceptability criteria should be applied before repeatability is determined.  
Number of trials
A minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed.  If a 
subject is unable to perform a single acceptable maneuver after 8 attempts, testing may be 
discontinued. 
Acceptability
An acceptable maneuver has the following characteristics: 

No hesitation or false start;


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
A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures

No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, and no volume change for at least 1 second) or the subject cannot continue 
to exhale further. Overall acceptability will be determined by expert over-read by 
spirometry vendor

Repeatability
The 2 largest FEV1 values from 3 acceptable maneuvers should not vary by more than 0.150 L.
Recording of data
The 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 µg 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)
Subjects 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
References
1 Miller MR et al, Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.


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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 8: Patient Asthma Control e-Diary
For illustrative purposes only:  
The following information will be captured:
In the MORNING
In the EVENING
Peak expiratory flow rate
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 9: Liver event definitions and follow-up requirements
Table 13-1
Liver Event Definitions
Definition/ threshold
Adverse event of special 
interest
Laboratory values
ALT or AST > 3 x ULN
ALP > 2 x ULN
TBL > 1.5 x ULN
Medically significant event 
(SAE)
Laboratory values
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction])
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction])
TBL > 3 x ULN
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and TBL 
> 2 x ULN [mainly conjugated fraction] without notable increase in 
ALP to > 2 x ULN)
Adverse events
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT
* 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


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Table 13-2
Liver Event Follow Up Requirements
Criteria
Event type
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize, if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
ALT or AST
> 8 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 5 to ≤ 8 x ULN
Medically
significant
Repeat LFT within 48 hours
If elevation persists for more 
than 2 weeks, discontinue the 
study drug
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 x ULN
accompanied by 
symptomsb
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
> 3 to ≤5 x ULN 
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Investigator & Novartis
Repeat LFT once or twice in the 
week
If elevation persists, establish 
causality
Investigator discretion
Monitor LFT within 1 to 4
weeks or at next visit
≤3 x ULN 
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
ALP (isolated)
> 5 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, report to 
Novartis as an SAE
Establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
> 2 to ≤5 x ULN 
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Investigator & Novartis
Repeat LFT once or twice in the 
weekIf elevation persists, 
establish causality
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
≤2 x ULN
N/A
Repeat LFT at next visit


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Criteria
Event type
Actions required
Follow-up monitoring
(patient is 
asymptomatic)
TBL (isolated)
> 3 x ULN
Medically 
significant
Repeat LFT within 48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin,
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤3 x ULN
(patient is 
asymptomatic)
AESI
Central laboratory to report to 
Novartis
Repeat LFT once or twice in the 
weekIf elevation persists, 
establish causality
investigator discretion
Monitor LFT within 1 to 4
weeks or at next visit
≤1.5 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
Preferred terms
Jaundice
Medically 
significant
Discontinue the study drug 
immediately
Hospitalize the patient
Report to Novartis as an SAE
Establish causality
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion)
“Drug-related 
hepatic 
disorders - severe 
events only” SMQ 
AE
Medically 
significant
Discontinue the study drug 
hospitalization if clinically 
appropriate
Report to Novartis as an SAE
Establish causality
Investigator discretion
a
Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN
b
General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia
c
Resolution is defined as an outcome of one of the following: return to baseline values, stable 
values at three subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a 
maximum of 6 months, liver transplantation, and death.


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Appendix 11: ICS Dose level
Table 13-3
Low, medium and high Daily Doses of Inhaled Glucocorticosteroids 
for Adults and adolescents (12 years and older)* (GINA 2015)
Drug
Total Daily Dose (µg/day)
Low
Medium
High
Beclomethasone dipropionate –
CFC*
200-500
> 500 -– 1000
> 1000 
Beclomethasone dipropionate –
HFA
100-200
> 200 -– 400
> 400
Budesonide- DPI
200-400
> 400 – 800
> 800 
Ciclesonide – HFA
80-160
> 160 – 320
> 320 
Fluticasone propionate – DPI
100-250
> 250 – 500
> 500 
Fluticasone propionate – HFA
100-250
> 250 – 500
> 500
Fluticasone Furuoate**
NA
100
200
Mometasone furoate
110-220
> 220-440
≥440
Triamcinolone acetonide
400-1000
> 1000 -– 2000
> 2000
DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant.
* Beclomethasone dipropionate CHF is included for comparison with older literature.
** As per SmPC


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Appendix 12: Estimation of non-inferiority margin of comparing QMF149 
versus active control (salmeterol xinafoate /fluticasone propionate)
The non-inferiority margin of QMF149 vs active control (salmeterol xinafoate /fluticasone 
propionate) is based on the results from Kavuru et al (2000), Nathan et al (2006), and Relvar®
Ellipta’s asthma studies HZA106827 and HZA113091 (GSK Breo Ellipta Advisory Committee 
briefing document, March 2015) on the treatment effect of the three different doses of active 
control over placebo. Table 13-4 summarizes the key inclusion criteria for these studies, the 
adjusted mean for each treatment of active control and placebo, standard error (SE) of the mean, 
treatment difference, and its 95% CI. In addition the table summarizes the meta-analysis based 
on the pooled estimates from these studies. 
From Table 13-4, the historical evidence of drug effect of active control over placebo (from the 
meta-analysis) is 354 mL with its 95% CI from 281 mL to 426 mL. Hence based on the lower 
limit of the pooled estimate, 281 mL, by demonstrating the NI with the chosen NI margin of -90 mL, 
the treatment effect of QMF149 would be at least 191 mL over (putative) placebo with 95% 
confidence level, which represents 68% preservation of the treatment effect of active control over 
placebo. 
Table 13-4
Historical evidence of sensitivity of drug effect of active control fixed-
dose combination (FDC) for trough FEV1 in patients with persistent 
asthma
Study
(Duration)
Key Inclusion Criteria
Treatment
(n)
Mean 
(L)*
(SE)
Difference vs. 
placebo
(95% CI)
Nathan et. al. 
(12 weeks) 

≥12 years old with asthma 
requiring pharmacotherapy for at 
least 6 month before the study 

Use of ICS therapy for ≥3 
months before the study and at a 
consistent dose for the previous 
month 

40% < FEV1 < 85% 

≥15% increase in FEV1 from pre 
to post SABA 
FDC 42/220
μg
BID
(n = 92) 
0.41 
(0.04) 
0.53 
(0.405, 0.655) 
Placebo 
(n = 87) 
-0.12 
(0.05) 
Kavura et. al. 
(12 weeks) 

≥12 years old with asthma 
requiring pharmacotherapy for at 
least 6 month before the study 

Use of ICS therapy for ≥3 
months before the study and at a 
consistent dose for the previous 
month 

40% < FEV1 < 85% 

≥15% increase in FEV1 from pre 
to post SABA 
FDC 50/100
μg BID
(n = 87) 
0.51 
(0.05) 
0.50 
(0.319, 0.681) 
Placebo 
(n = 77) 
0.01 
(0.07) 
Relvar 
Asthma 
Program 2015
See Table 13-5
FDC 
50/250 μg
BID 
(n=389)
0.191**
(0.089, 0.293)


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(Briefing 
Book)
Placebo 
(n=193)
Meta-
Analysis***
FDC
(n = 576)
0.354
(0.281, 0.426)
Placebo
(n = 357)
* Change from baseline in pre-dose FEV1 at week 12. 
** Treatment effect is estimated based on combining studies HZA106827 and HZA113091 from 
Relvar® asthma program (briefing book) as summarized in Table 13-5.
*** Meta-analysis is based on pooling of the results from Nathan et al (2006), Kavuru et al (2000), and 
Relvar’s asthma program from studies HZA106827 and HZA113091 and using the inverse variance 
weighting method. 
Table 13-5
Summary of studies HZA106827 and HZA113091 for trough FEV1 from 
Relvar® asthma program 
Study 
(Duration)
Key Inclusion Criteria
Treatment 
(n) 
Mean (L) 
(SE) 
Treatment 
Difference 
(95% CI) 
Relvar 
Asthma 
Program 
Study 
HZA106827 
(12 weeks)

Outpatients at least 12 years of 
age

Male and female; female 
subjects of childbearing 
potential must be willing to use 
birth control

Pre-bronchodilator FEV1 of 40-
90% predicted normal

Reversibility FEV1 of at least 
12% and 200 mL

Current asthma therapy 
includes inhaled corticosteroid 
use for at least 12 weeks prior 
to first visit
FF/VI 
100/25 μg
(n=200)
0.368 
(0.0304)
0.172
(0.087, 0.258)
Placebo 
(n=193)
0.196 
(0.0310)
Relvar 
Asthma 
Program 
Study 
HZA113091 
(24 weeks)

Clinical diagnosis of asthma

Reversibility of at least 12% and 
at least 200 mL within 10-40 
minutes following 2-4 
inhalations of albuterol

FEV1 of 40-85% predicted 
normal

Currently using inhaled 
corticosteroid therapy
FF/VI 
100/25 μg
(n=397)
0.281 
(0.0191)
-0.019 
(-0.073, 0.034)
FP/SAL 
250/50 μg
BID
(n=389)
0.300 
(0.0193)
Reference:
Kavuru MD et al (2000) Salmeterol and fluticasone propionate combined in a new powder 
inhalation device for the treatment of asthma: A randomized, double-blind, placebo-controlled 
trial. J Allergy Clin Immunol (2000); 105: 1108-16.
Nathan et al (2006) Efficacy and tolerability of fluticasone propionate/salmeterol administered 
twice daily via Hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients 


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Clinical Trial Protocol v05 clean version
QVM149B2301
with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study. 
Clinical Therapeutics (2006); 28: 73-85.

SAP_001.pdf: 
Clinical Development 
QVM149B (QMF149: Indacaterol acetate/Mometasone furoate) 
CQVM149B2301 / NCT02554786
A multi-center, randomized, 52 week treatment, double-
blind, triple-dummy, parallel-group study to assess the 
efficacy and safety of QMF149 compared with mometasone 
furoate in patients with asthma 
RAP Module 3 – Detailed Statistical Methodology 
Author: 
, CRO Trial Statistician 
Document type: 
RAP Documentation 
Document status: 
Amendment 2  
Release date: 
27-Sep-2018
Number of pages: 
49 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
Final 2.0 
25-Nov-2015 
 
Amendment 1 
30-May-2018 
The amendment is largely based on the changes made in the 
Clinical Trial Protocol Amendment 5 (released 17-Jan-2018). 
More details about the rationale of the major changes are given in 
the section "Amendment 1". In summary, the following changes 
are implemented: 
• The primary analysis will be conducted after all patients have 
completed the Week 26 assessments or discontinued from the 
study; changes are made in multiple sections with details given 
in Section 2.9. 
• Modified key secondary objective in Section 2.1.2 and updated 
analysis accordingly in Section 2.6.1. 
• Updated testing strategy for multiplicity due to the change in 
key secondary objective. 
• Sample size has been updated in Section 2.10. 
• Added the estimand statements in Section 2.1. 
• Modified the handling of missing items when calculating the 
ACQ-7 score and clarified the handling of missing ACQ-7 score 
for ACQ-responder analysis in Section 2.6.1.1.2. 
• Added ACQ-5 in Section 2.6.2.3. 
• Modified the handling of missing items in the AQLQ overall and 
domain scores in Section 2.6.2.8. 
• Added exposure-adjusted analyses of adverse events in 
Section 2.7.2. 
• Changed the analysis plan for glucose and potassium data. 
• Removed the logistic regression analysis for percentage of 
patients with at least one asthma exacerbation by exacerbation 
category and patients who permanently discontinued study 
medication due to asthma exacerbations in Section 2.6.2.7. 
• Extended the post-morning dose time window restriction in 
handling of spirometry measurements from 10-13 hours to 8-13 
hours for b.i.d. regimens in Section 2.6.1.1. 
• Modified the multiple imputation method in tipping point 
analysis from monotone method to fully conditional 
specification method in Section 2.6.1.4 and Section 16.1.9.6. 
• Combined the imputation steps into one step for the ACQ 
responder analysis in Section 2.6.2.3 and Section 16.1.9.6. 
• Removed SAS code from SAP  in Section 16.1.9.6 and 
included them in TFLs. 
• Removed the definitions of AEs of special interest from Section 
2.7.2. 
• Updated criteria for Hy’s law as per current guideline. 
• Added Section 3 for specifying analyses that will be reported 
outside of CSR. 
• Added Japanese and Chinese patients in subgroup analyses in 
Section 3.1. 


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Version 
Date 
Changes 
 
 
• Added the analysis of add-on effect of indacaterol to existing 
MF treatment for trough FEV1 in Section 2.6.2.2 and asthma 
exacerbations in Section 2.6.2.7. 
• Re-organized Section 2.6.2.7 to place the detailed analysis 
under each parameter of interest. 
• Added the AE summary based on incidence rates per 100 
patient-years in Section 2.7.2. 
• Deleted several safety endpoints for time to event analyses in 
Section 2.7.2. 
• Added major protocol deviations list in Section 16.1.9.2. 
• Some other minor changes. 
• Added notable criterion for Magnesium. 
Amendment 2 
27-Sep-2018 
• Updated action plan if model fails to converge in Section 
2.6.1.2 and 16.1.9.6. 
• Added non-parametric test exploration in case of non-
convergence or highly skewed data in Section 2.6.2.4 and 
2.6.2.5. 
• Outlined the sensitivity analyses to be done with and without a 
site which was identified to have lack of quality issues in 
Section 1. 
• Correction, removed "The responder analysis will use the same 
imputed datasets as that of ACQ-7", as for ACQ-5 same 
analyses is done as for ACQ-7 but not same imputed dataset 
as multiple imputation is for each score separately in Section 
2.6.2.3. 
• Correction of PD-ID in Section 16.1.9.2. 
• Changed notable criteria for Magnesium to SI unit for 
consistency in Section 16.1.9.5. 
• Added the details of least squares mean computation in 
Section 16.1.9.6. 
• Added additional analyses on potassium excluding all flagged 
data in Section 2.7.3. 
• Added the definition of implausible value for FEV1 in Section 
2.6 and 16.1.9.3. 
 


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Table of contents 
Amendment 1 ............................................................................................................................. 6 
1 
Introduction ......................................................................................................................... 7 
2 
Detailed statistical methodology ......................................................................................... 7 
2.1 
Study objectives .............................................................................................................. 7 
2.1.1 
Primary objective ....................................................................................................... 8 
2.1.2 
Key secondary objective ............................................................................................ 8 
2.1.3 
Secondary objectives.................................................................................................. 9 
 
 10 
2.1.5 
Changes in the conduct of the study or planned analyses ........................................ 10 
2.2 
Analysis sets ................................................................................................................. 11 
2.3 
Patient disposition, background and demographic characteristics ............................... 11 
2.3.1 
Patient disposition and protocol deviations ............................................................. 11 
2.3.2 
Demographics and baseline characteristics .............................................................. 12 
2.4 
Study medication .......................................................................................................... 13 
2.4.1 
Duration of exposure ................................................................................................ 13 
2.4.2 
Compliance .............................................................................................................. 13 
2.5 
Prior and concomitant medication ................................................................................ 13 
2.6 
Efficacy evaluation ....................................................................................................... 14 
2.6.1 
Analysis of the primary and key secondary variables .............................................. 14 
2.6.1.1 
Variables .............................................................................................................. 14 
2.6.1.1.1 
Primary variable trough FEV1 ........................................................................ 14 
2.6.1.1.2 
Key secondary variable ACQ-7 score ............................................................ 14 
2.6.1.2 
Statistical model, hypothesis, and method of analysis ........................................ 15 
2.6.1.3 
Multiplicity adjustment ....................................................................................... 17 
2.6.1.4 
Supportive analyses for the primary objective .................................................... 18 
2.6.2 
Analysis of secondary variables ............................................................................... 19 
2.6.2.1 
Comparison of QMF149 150/320 μg vs salmeterol xinafoate/fluticasone 
propionate 50/500 μg b.i.d. in term of trough FEV1 at Week 26 ........................ 19 
2.6.2.2 
Spirometry data other than the primary endpoint ................................................ 19 
2.6.2.3 
ACQ at Weeks 4, 12 and 52 ................................................................................ 20 
2.6.2.4 
Peak Expiratory Flow Rate (PEF) ....................................................................... 21 
2.6.2.5 
Asthma symptom based on e-Diary .................................................................... 21 
2.6.2.6 
Rescue medication ............................................................................................... 22 
2.6.2.7 
Asthma exacerbations ......................................................................................... 22 
2.6.2.8 
Quality of life as assessed by Asthma Quality of Life Questionnaire 
(AQLQ) ............................................................................................................... 24 


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2.7 
Safety evaluation........................................................................................................... 25 
2.7.1 
Serious asthma outcomes ......................................................................................... 25 
2.7.2 
Adverse events ......................................................................................................... 25 
2.7.3 
Laboratory data ........................................................................................................ 27 
2.7.4 
Vital signs ................................................................................................................ 30 
2.7.5 
Electrocardiogram (ECG) ........................................................................................ 30 
 
 31 
 
 31 
 
 31 
2.9 
Interim analysis ............................................................................................................. 32 
2.9.1 
Data Safety Monitoring Board (DMC) .................................................................... 32 
2.9.2 
Primary analysis after all patients have completed at least 26 weeks treatment ...... 32 
2.10 
Sample size calculation ................................................................................................. 33 
3 
Analyses to be reported outside of CSR ............................................................................ 33 
3.1 
Subgroup analyses ........................................................................................................ 33 
 
 34 
 
 34 
 
 35 
 
 35 
Clinical Study Report -  Appendix 16.1.9  Documentation of statistical methods................... 37 
16.1.9.1 
Introduction ......................................................................................................... 37 
16.1.9.2 
Major protocol deviations and other exclusion criteria ....................................... 37 
16.1.9.3 
Assessment windows, baseline and post-baseline definitions, missing data 
handling ............................................................................................................... 39 
16.1.9.3.1 
Data pooling and assessment windows ............................................................... 39 
16.1.9.3.2 
Baseline measurements ....................................................................................... 39 
16.1.9.3.3 
Post-baseline measurements ................................................................................ 41 
16.1.9.4 
Laboratory parameters – direction of interest and definition of clinically 
notable values ...................................................................................................... 42 
16.1.9.5 
Vital signs and ECG – definition of clinically notable values ............................ 44 
16.1.9.6 
Statistical methodology and assumptions ........................................................... 45 
 
 
 


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Amendment 1 
This amendment of the statistical analysis plan (SAP) is largely based on the changes made in 
the Clinical Trial Protocol Amendment 5 (released 17-Jan-2018). The rationale of the major 
changes in protocol is provided in the following. 
Amendment Rationale 
Conduct primary analysis after all patients have completed at least 26 weeks treatment: 
An interim database freeze will be conducted to perform the primary analysis. The database for 
primary analysis will contain all data up to the Data Lock Point (DLP), which is defined as the 
date when all patients complete Week 26 (V207) assessments or withdraw from the study. For 
patients who are ongoing at the time of interim database freeze, the database will include all 
data available until the last completed visit. 
Primary analysis includes primary and key secondary endpoints as well as other pre-specified 
endpoints at Week 26. 
 
Safety data will also be summarized. 
In terms of reporting, two separate clinical study reports (CSRs) will be written. CSR 1 will 
base on the interim database freeze and CSR 2 on the final database lock. A dedicated unblinded 
team will be involved in CSR 1 related activities. In order to maintain the integrity of the study 
data, a separate blinded team will continue the study until its completion. 
Modification of analysis of key secondary endpoint, ACQ-7: 
The key secondary objective has been modified to demonstrate the superiority of add-on 
indacaterol (QAB149) 150 µg by demonstrating superiority of QMF (150/160 and 150/320 µg 
combined) to mometasone furoate doses (MF, 400 µg and 800 µg combined) in terms of Asthma 
Control Questionnaire (ACQ-7) after 26 weeks of treatment. The add-on effect of indacaterol 
will be tested only if the individual treatment comparisons are significant for the primary 
endpoint (i.e., there is evidence of efficacy of both doses of QMF over respective MF doses in 
terms of lung function).  
Sample size is re-calculated based on updated analysis and multiplicity adjustment. As a result, 
a more modest sample size is needed to establish efficacy while providing sufficient safety 
exposure for QMF149. Assuming 10% dropout, the calculation shows that the sample size of 
2000 patients (i.e., 400/arm) will provide 94% power for primary endpoint trough FEV1 and 
85% power for key secondary endpoint ACQ-7. 


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1 
Introduction 
This document contains details of the statistical methods that will be used in the phase III 
clinical trial CQVM149B2301. This study is designed to evaluate the efficacy and long term 
safety of two different doses of QMF149 (QMF149 150/160 μg and QMF149 150/320 μg via 
Concept1) over two respective mometasone furoate (MF) doses (i.e., total daily doses of MF 
400 μg and MF 800 μg via Twisthaler®) in poorly controlled asthmatic patients as determined 
by pulmonary function testing and effects on asthma control. 
Data will be analyzed according to Section 9 of the study protocol. The primary analysis will 
be conducted using all data up to the Data Lock Point (DLP), which is defined as the date when 
all patients have completed the assessments after at least 26 weeks of treatment (Visit 207) or 
prematurely withdrawn from the study. In particular for efficacy analysis, each patient’s data 
until the last available study visit (scheduled or unscheduled) prior to the DLP will be included. 
For safety analysis, data up the DLP will be included too. This will include all planned analyses 
presented in this SAP.  
Two separate CSRs will be published: 
• Primary Analysis CSR: To support analyses once all patients have completed the 
assessments at least 26 weeks of treatment (Visit 207) or prematurely withdrawn from the 
study. 
• Full CSR: To support analyses once all patients have completed the assessments after 52 
weeks of treatment (Visit 214) plus follow-up (Visit 301) or prematurely withdrawn from 
the study. 
This SAP is valid for analyses of both CSRs. 
Important information is given in the following sections and details are provided, as applicable, 
in Appendix 16.1.9. 
Subgroup analyses will be performed for adolescent patients (12 - 17 years old) and for specific 
countries (e.g., China, Japan). These analyses will be identified in the tables, figures, and 
listings shell document. 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. This is different than the country-specific subgroup 
analyses where only the patients of the respective country will be included. 
In consideration of the lack of quality control applied by the PI on study source data, a 
sensitivity analysis will be performed by assessing for primary, key secondary endpoints and 
AEs/SAEs both with and without patient data from the following site in order to evaluate 
whether the data from this site have an impact on overall results: 
. 
2 
Detailed statistical methodology 
2.1 
Study objectives 
Section 2 of the study protocol lists the following primary, key secondary, other secondary 
 
 objectives. 


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2.1.1 
Primary objective 
The primary objective is to demonstrate the superiority of either QMF149 150/160 μg delivered 
via Concept1 o.d. (in the evening) to MF 400 μg o.d (in the evening) delivered via Twisthaler® 
or QMF149 150/320 μg delivered via Concept1 o.d. (in the evening) to MF 800 μg delivered 
via Twisthaler® (delivered as 400 μg b.i.d.) in terms of trough FEV1 after 26 weeks of treatment 
in patients with asthma. 
The primary estimand can be described by defining the following components: 
• Population: adolescent (12-17 years old) and adult asthmatic patients (≥18 years old) 
receiving medium or high dose inhaled corticosteroids (ICS) or low dose ICS/long acting 
beta-2 agonist (LABA) combination 
• Variable: trough FEV1 after 26 weeks of treatment 
• Summary measures: mean differences between treatment groups for each MF dose level 
(QMF149 150/160 µg vs MF 400 µg; QMF149 150/320 µg vs MF 800 µg). 
• Intervention effect of interest: add-on effect of indacaterol evaluated at each MF dose 
level, based on randomized treatments, if all patients had remained on randomized 
treatment for 26 weeks, with the following post-randomization events accounted for by 
assessing: 
o Intake of non-study drugs with effect on FEV1: the effect outside of period of 
worsening disease that necessitates non-study medication 
o Discontinuation of study treatment prior to week 26: hypothetical on-treatment week 
26 FEV1 value 
o Week 26 FEV1 measurements taken outside of the 22-25 hour post-evening (or 8-
13 hour post morning for b.i.d. regimens) dose time window: hypothetical on-
treatment week 26 FEV1 value 
2.1.2 
Key secondary objective 
The key secondary objective is to demonstrate the superiority of QMF149 (150/160 µg and 
150/320 µg combined) to MF (400 and 800 µg combined) in terms of Asthma Control 
Questionnaire (ACQ-7) after 26 weeks of treatment in patients with asthma. 
The key secondary estimand can be described by defining the following components: 
• Population: adolescent and adult asthmatic patients receiving medium or high dose ICS 
or low dose ICS/LABA combination 
• Variable: ACQ-7 after 26 weeks of treatment 
• Summary measure: mean treatment difference between QMF149 and MF (i.e. average of 
differences between [QMF149 150/160 µg vs MF 400 µg] and [QMF149 150/320 µg vs 
MF 800 µg]). 
• Intervention effect of interest: add-on effect of indacaterol on MF irrespective of the 
dose level of MF, based on randomized treatments, if all patients had remained on 
randomized treatment for 26 weeks, with the following post-randomization event 
accounted for by assessing: 


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o Discontinuation of study treatment prior to week 26: hypothetical on-treatment week 
26 ACQ-7 value 
2.1.3 
Secondary objectives 
Secondary objectives are to compare a) QMF149 150/160 μg o.d. delivered via Concept1 
compared to MF 400 μg o.d. delivered via Twisthaler® and b) QMF149 150/320 μg o.d. 
delivered via Concept1 compared with MF 400 μg b.i.d. delivered via Twisthaler® in terms of: 
• Trough FEV1 at Week 52 
• Pre-dose FEV1 (defined as the mean of -45 min and -15min FEV1 values pre-evening 
dose) at Week 4 and Week 12 
• FEV1, Forced Vital Capacity (FVC) and Forced Expiratory Flow between 25% and 
75% of FVC (FEF25-75) over 52 weeks 
• Morning and Evening Peak Expiratory Flow Rate (PEF) over 26 and 52 weeks of 
treatment 
• Asthma control as assessed by the ACQ-7 at Week 4, Week 12 and Week 52 
• Percentage of patients achieving the minimal important difference (MID) ACQ ≥ 0.5 
at Week 26 and Week 52 
• Daily e-Diary recordings of the percentage of asthma symptom-free days , no daytime 
symptoms, the percentage of nights with no nighttime awakenings and the percentage 
of mornings with no symptoms on awakening over 52 weeks of treatment 
• e-Diary recordings of rescue salbutamol/albuterol usage (mean daily, nighttime and 
daytime use) over 26 and 52 weeks of treatment 
• % of rescue medication-free days over 26 and 52 weeks of treatment 
• To evaluate the efficacy of in terms of asthma exacerbation-related parameters 
described here during 52 weeks of treatment. The analysis will be performed by 
exacerbation category wherever specified. The exacerbation categories are: mild, 
moderate, severe and moderate or severe: 
- Time to first asthma exacerbation by exacerbation category 
- Time to first hospitalization for asthma exacerbation 
- Annual rate of asthma exacerbations by exacerbation category 
- Duration in days of asthma exacerbations by exacerbation category 
- Percentage of patients with at least one asthma exacerbation by exacerbation 
category 
- Time to permanent discontinuation of study medication due to asthma exacerbations 
- Percentage of patients who permanently discontinued study medication due to 
asthma exacerbations 
- Total amounts of systemic corticosteroids (in doses) used to treat asthma 
exacerbations 
• Quality of life as assessed by Asthma Quality of Life Questionnaire (AQLQ) over 52 
weeks 
Furthermore, as additional secondary objectives, QMF149 150/320 μg o.d. delivered via 
Concept1 will be compared with salmeterol xinafoate /fluticasone propionate 50/500 μg via 
Accuhaler® for all the listed secondary endpoints above as well as the following ones: 


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• Trough FEV1 measured after 26 weeks of treatment  
Trough FEV1 will be tested for non-inferiority versus salmeterol/fluticasone 50/500 
μg. If non-inferiority criteria are met, this will be tested for superiority. 
• Asthma control as assessed by the ACQ-7 after 26 weeks treatment. 
The following safety and tolerability endpoints will be evaluated for all treatment comparison 
groups: 
• Cumulative incidence of the composite endpoint of serious asthma outcomes (i.e. 
asthma-related hospitalization, asthma-related intubation, or asthma-related death) 
over 52 weeks of treatment 
• Adverse events, vital signs, ECG and laboratory analysis (hematology, blood 
chemistry including glucose and potassium, urinalysis, evening plasma cortisol) over 
52 weeks of treatment 
2.1.5 
Changes in the conduct of the study or planned analyses 
The logistic regression analysis for the percentage of patients with at least one asthma 
exacerbation by exacerbation category has been removed because of the existence of time to 
event analysis, which is a more valid approach as it takes into account the event, censoring, and 


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event/censoring times. The percentages will be presented in the time to event tables. Similarly, 
the logistic regression for the percentage of patients who permanently discontinued study 
medication due to asthma exacerbations has been removed. 
The restriction on trough FEV1 measurement (at Visit 201, 207, and 214) time that it has to fall 
into 10-13 hours post-morning dose time window has been extended to 8-13 hours and only for 
b.i.d. regimens. This is considered clinically justified based on Seretide® dosing interval and 
expected duration of the bronchodilator effect. The original 10-13 hours post-morning dose 
time window is considered conservative based on Seretide® dosing regimen from the evidence 
in available literature showing that the bronchodilator effect starts to decrease after 8 hours 
(Pearlman et al. 1992). 
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 medication. 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 medication. 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. Major protocol deviations will be defined in the validation analysis plan 
prior to database lock and the un-blinding of the study. The list of major protocol deviations 
is available in Appendix 16.1.9. 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 medication 
including non-randomized patients who received study drug 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. 
 
 
 
 
2.3 
Patient disposition, background and demographic 
characteristics 
2.3.1 
Patient disposition and protocol deviations 
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 of that phase.  


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The number of patients who completed the 52-week study treatment and who discontinued 
prematurely will be shown including the reasons for discontinuation of study treatment. In the 
Primary Analysis CSR, the number of patients who are ongoing at the time of interim database 
freeze will be presented. Time to premature treatment discontinuation will be displayed 
graphically for each treatment group using a Kaplan-Meier curve for the safety set. The date of 
premature treatment discontinuation is defined as the date of last dose of study medication. 
Patients who completed the study treatment will be censored at the date of last dose of study 
medication. In the interim analysis, patients who are ongoing at the time of interim database 
freeze will be censored at the Data Lock Point (DLP), which is defined as the date when all 
patients have completed at least Week 26 assessments or prematurely withdrawn from the study. 
Number of patients with protocol deviations will be tabulated by category (e.g., selection 
criteria not met, prohibited concomitant medication, key procedures not performed as per 
protocol) and deviation.  
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 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized by treatment group using the 
RAN set. Summaries will include age, gender, race, ethnicity, height, weight, body mass index 
(BMI), relevant medical history, pre- and post-bronchodilator screening spirometry parameters: 
(FEV1 in L and % of predicted FEV1, FVC, FEV1/FVC and FEF25-75), FEV1 reversibility (in L 
and %), duration of asthma, history of asthma exacerbations, prior asthma treatment, and 
smoking history. 
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. 
Baseline is defined as the last available measurement before first dose of study drug. 
No statistical analyses will be provided for baseline comparability among the treatment groups.  
In addition, the following categorizations 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 50 - < 60%, 60% - < 85% of predicted FEV1 
• ACQ-7 into < 1.5, 1.5- < 2, 2 – < 2.5, ≥ 2.5 (< 1.5 will be added in case of protocol 
deviations) 
• prior asthma treatment into ICS medium dose, ICS high dose, ICS/LABA low dose, 
ICS/LABA other than low dose 


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Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most actual version at the time of database lock. 
History/conditions will be summarized for the 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 
Study medication 
2.4.1 
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 (ignoring the duration when study 
treatment may have been interrupted). 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 drug for each 1 - 29 days, 30 – 86 days, 87 – 183 
days, 184 – 254 days, 255 – 365 days, and > 365 days.  
In the interim analysis, patients who are ongoing at the time of interim database freeze will be 
considered as exposed until the DLP. 
2.4.2 
Compliance 
Compliance will be calculated by counting the days where study drug was administered "As 
per protocol" according to the records on the Dosage Administration Record (DAR) Summary 
eCRF. The percentage of days divided by the days of exposure will be analyzed. To be counted 
as a day of compliance with study treatment, all five administrations, i.e., the Twisthaler and 
Accuhaler both in the morning and evening and the Concept 1 inhaler in the evening, have to 
be taken as per protocol. Compliance will be calculated by study treatment. 
Compliance will be categorized into < 80 % and 80 % - 100 % and summarized by treatment 
for the safety set. 
2.5 
Prior and concomitant medication 
Each medication, either an asthma or non-asthma medication, will have the start and end dates 
recorded on the eCRF. Separate tables will be provided for medications which were started and 
stopped prior to the first dose of study drug and medications which were taken concomitantly 
to the study drug (regardless of whether continued or started after the first dose of study drug).  
Asthma medications will be summarized by the route of administration, the recorded pre-
specified drug subcategories (including types of combination) and the coded preferred terms. 
The summary will be repeated by showing ingredients instead of preferred terms.  
Non-asthma medications will be summarized by route of administration and preferred term. 
Surgical and medical procedures (non-drug therapies) will be coded using MedDRA and 
presentations will be done by MedDRA primary system organ class and preferred term, 
separately for prior procedures and those after start of study drug. 


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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. 
2.6 
Efficacy evaluation 
All efficacy analyses will be performed on the FAS and selected analyses will be repeated on 
the PPS. Measurements made after patients discontinue randomized treatment (off-treatment 
measures) will not be used for any efficacy evaluation. 
2.6.1 
Analysis of the primary and key secondary variables 
The primary objective is to demonstrate the superiority of either QMF149 150/160 μg to MF 
400 μg or QMF149 150/320 μg to MF 800 μg in terms of trough FEV1 after 26 weeks of 
treatment. The key secondary objective is to demonstrate the superiority of QMF149 (150/160 
µg and 150/320 µg combined) to MF (400 and 800 µg combined) in terms of ACQ-7 after 26 
weeks of treatment. 
2.6.1.1 
Variables 
2.6.1.1.1 Primary variable trough FEV1 
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, Day 184 (Week 
26, the primary endpoint) and Day 365.  
If any of the 23 hr 15 min and 23 hr 45 min values contributing to the trough FEV1 are collected 
within 3 months of a single depot corticosteroid injection, or within 7 days of systemic 
corticosteroid use, or within 6 hours of rescue medication, or if actual measurement times are 
outside of the 22 - 25 hour post-evening dose time window for o.d. regimens (or 8 – 13 hour 
post-morning dose time window for b.i.d. regimens), 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, then trough FEV1 will be missing. 
2.6.1.1.2 Key secondary variable ACQ-7 score 
The ACQ-7 measures asthma symptom control and consists of 7 items: 5 on symptom 
assessment, 1 on rescue bronchodilator use, and 1 on airway calibre (FEV1 % predicted). Patient 
recall is considered 1 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 = poorly 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 the 
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), that missing 


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response will be imputed as per the method given in the following paragraph and then the ACQ 
score will be calculated. 
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 
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 baseline, missing item at Day 1 will be imputed by using Day -14 data or data from any 
unscheduled run-in visit, whichever is later. 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. 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.  
ACQ-7 measurements are scheduled for Days -14, 1, 30, 86, 183, and 364. 
2.6.1.2 
Statistical model, hypothesis, and method of analysis 
Primary variable 
The primary objective to demonstrate superiority of either QMF149 150/160 μg to MF 400 μg 
or QMF149 150/320 μg to MF 800 μg in terms of trough FEV1 after 26 weeks of treatment will 
be evaluated by testing the following null hypotheses (H0) versus the alternative hypotheses 
(Ha): 
H01: QMF149 150/160 µg is equal to MF 400 µg 
versus 
Ha1: QMF149 150/160 µg is not equal to MF 400 µg 
and 


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H02: QMF149 150/320 µg is equal to MF 800 µg 
versus 
Ha2: QMF149 150/320 µg is not equal to MF 800 µg 
The primary variable, trough FEV1 at Week 26, will be analyzed using a mixed model for 
repeated measures (MMRM) on the FAS. The model will contain treatment, age group (12 to 
17, or ≥ 18 years), region (Eastern Europe, Western Europe, India, Japan, other Asia, rest of 
world), visit (Days 2, 184, and 365), 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 (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).  
For the primary analysis, if the model does not converge, data only up to week 26 (i.e., Days 2 
and 184) will be used (with unstructured covariance matrix). If still the model fails to converge, 
compound symmetry covariance matrix will be used. If model still does not converge, the 
random effects of center will be removed. For the final analysis, if the model does not converge 
with unstructured covariance matrix, the compound symmetry covariance matrix will be used 
in the mixed model. If still the model does not converge, the random effects of center will be 
removed. For both analyses, if the model converges after removing the random center effects, 
the original model without random center effects will be re-assessed. If the final model for the 
primary analysis converges without Week 52 data, only summary statistics will be provided for 
Week 52 data analysis. Restricted maximum likelihood method will be used.  
The MMRM is based on the missing at random (MAR) assumption where missingness is 
independent of the unobserved data provided that relevant observed data are accounted for in 
the statistical model. 
Baseline FEV1 is defined as the mean of the 45 min and 15 min pre-evening dose FEV1 
measurements at Day 1 (V201). If one of the two measurements is missing, the non-missing 
measurement will be taken as the baseline FEV1. If both are missing, the pre-bronchodilator 
reversibility measurement (at V101 or repeated V101) will be used as baseline FEV1. 
Each 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 factor corresponding to Day 184. The estimated adjusted treatment difference 
(QMF149 – MF) will be displayed along with the associated standard error (SE), 2-sided 95% 
confidence interval (CI), and p-value (2-sided). 
Key secondary variable 
The key secondary objective to demonstrate superiority of QMF149 (150/160 µg and 150/320 
µg combined) to MF (400 and 800 µg combined) in terms of ACQ-7 after 26 weeks of treatment 
will be evaluated by testing the following null hypothesis (H0) versus the alternative hypothesis 
(Ha): 
H03: QMF149 (150/160 & 150/320 µg combined) is equal to MF (400 & 800 µg combined) 


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versus 
Ha3: QMF149 (150/160 & 150/320 µg combined) is not equal to MF (400 & 800 µg 
combined) 
ACQ-7 after 26 weeks of treatment will be analyzed using the same MMRM (including all 
scheduled visits with ACQ-7 data) on the FAS as used for the primary analysis but will include 
baseline ACQ-7 score instead of baseline FEV1. 
To demonstrate the add-on effect of indacaterol over MF for combined doses, the average of 
following treatment contrasts will be computed: 
QMF149 (150/160 µg) vs. MF 400 µg 
QMF149 (150/320 µg) vs. MF 800 µg 
Least squares means (95% CI) will be presented graphically to assess the interaction between 
QAB and dose levels of MF. 
The doses-combined between-treatment comparison as well as each individual 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 factor corresponding to Day 184. The estimated adjusted treatment difference 
(QMF149 – MF) will be displayed along with the associated standard error (SE), 2-sided 95% 
confidence interval (CI), and p-value (2-sided). 
2.6.1.3 
Multiplicity adjustment 
To control the family-wise type-I error rate at the two-sided 5% significance level, a multiple 
testing procedure based on the trimmed Simes test as described in Brannath et al (2009) will be 
used. The family for the overall type-I error rate control contains three hypotheses: two 
hypotheses for the primary endpoint trough FEV1 and one hypothesis for the key secondary 
endpoint ACQ-7. Denote the two hypotheses for the primary endpoint as H1 and H2 for 
comparing QMF149 150/160 μg vs. MF 400 μg and QMF149 150/320 μg vs. MF 800 μg 
respectively. Similarly, denote the hypothesis as H3 for the key secondary endpoint ACQ-7, for 
comparing QMF149 vs. MF combined doses.  
Below is a brief description of the testing procedure based on the trimmed Simes test in 
Brannath et al (2009). 
Let p1, p2, p3 be the corresponding p-values (2-sided) of the three hypotheses of H1, H2, and 
H3. 
Step 1: Retain both H1 and H2 if pi ≤ 0.05 AND the observed treatment difference for the 
corresponding pi is in the wrong direction (i.e. MF is performing better than QMF) for ANY i 
= 1, 2, stop here; otherwise go to Step 2. 
Step 2: Reject H1 and H2 if pi < 0.05 for BOTH i=1, 2 and go to Step 3; otherwise go to Step 
4. 
Step 3: Reject H3 if p3 < 0.05 and stop; 
Step 4: If neither Step 1 nor 2 applies, perform the Bonferroni test to H1 and H2. Thus reject 
H1 if p1 < 0.025 or reject H2 if p2 < 0.025 and stop. 


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For each of the three hypotheses, the corresponding testing statistics (estimated least square 
mean difference) follows normal distribution. Hence for H1 and H2, their corresponding testing 
statistics follow jointly bivariate normal distribution. Therefore this testing procedure controls 
the overall type I error rate at the 2-sided 0.05 level in the strong sense regardless if the bivariate 
normal distributions have positive or negative correlations as shown in Brannath et al (2009). 
Other than the 3 treatment comparisons mentioned above for the primary and the key secondary 
endpoint, all other analyses will be performed at the nominal 2-sided 0.05 level (2-sided) 
without multiplicity adjustment. 
2.6.1.4 
Supportive analyses for the primary objective 
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 single depot corticosteroid injection, other systemic corticosteroid use, 
or rescue medication use. However, measures taken outside of the 22 – 25 hour post-evening 
dose window for o.d. regimens (or 8 - 13 hour post-morning dose window for b.i.d. regimens) 
will be excluded. 
As a further 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. 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 Week 26 values using the multiple imputation (MI) method 
based on the missing at random (MAR) assumption. The imputed Week 26 values for the 
QMF149 arms are then adjusted by a delta value. A detailed description of the analysis steps is 
provided in Appendix 16.1.9. 
The following 
 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 to explore the treatment effect in: 
• Age group (12 to 17 years, ≥ 18 years) 
• Race (Caucasian, Asian, Black and other) 
• Sex (male, female) 
• History of asthma exacerbation in the 12 months prior to screening (Yes, No ) 
• Patients’ prior therapies before run-in period (medium dose of ICS, high dose of ICS, and 
low dose ICS/LABA; see Appendix 11 of the study protocol for the definition of ICS dose 
levels) 
• Pre-bronchodilator FEV1 in % of predicted FEV1 at run-in visit 101 (50% to < 60%, 60% 
to < 85%) 
• ACQ-7 at baseline (1.5 - < 2, 2 - < 2.5, ≥ 2.5) 


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2.6.2 
Analysis of secondary variables 
Three treatment comparisons will be performed on all secondary variables: 1) QMF149 150/160 
μg vs. MF 400 μg, 2) QMF149 150/320 vs MF 800 μg, 3) QMF149 150/320 μg vs. salmeterol 
xinafoate /fluticasone propionate 50/500 μg b.i.d.. The third comparison will be done on the 
key secondary variable too and on the primary variable as described below. 
2.6.2.1 
Comparison of QMF149 150/320 μg vs salmeterol xinafoate/fluticasone 
propionate 50/500 μg b.i.d. in term of trough FEV1 at Week 26 
QMF149 150/320 μg will be compared to active control (salmeterol xinafoate /fluticasone 
propionate 50/500 μg b.i.d.) for non-inferiority and – if non-inferiority is shown – for 
superiority on the primary endpoint. The same MMRM as specified above will be applied. The 
margin for non-inferiority is defined as 90 mL (see Appendix 12 of the study protocol for the 
estimation of non-inferiority margin). The result will be interpreted based on the two-sided 95% 
confidence interval (CI) of the treatment difference QMF149 – active control. The lower bound 
of the 95% CI is the difference that can be ruled out, i.e., if the lower bound of the 95% CI is 
larger than the non-inferiority margin of -90 mL, then QMF149 150/320 μg can be considered 
non-inferior to active control, and if the lower bound of the 95% CI is greater than 0, then 
QMF149 150/320 μg can be considered superior to active control with regard to trough FEV1 
at Week 26. Note that the comparison versus active control is not part of the confirmatory 
testing strategy. 
2.6.2.2 
Spirometry data other than the primary endpoint 
Trough FEV1 at Day 2 and at Day 365 will be analyzed using the same MMRM as specified for 
the primary analysis 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 corresponding to the respective visit. Adjusted mean (LS 
mean) will be displayed for each treatment group (for both the absolute FEV1 value and the 
change from baseline value) along with the estimated treatment differences and the 95% 
confidence intervals and the two-sided p-values by visit. 
In addition to trough FEV1, pre-dose trough FEV1 is defined as the average of the two FEV1 
measurements taken 45 min and 15 min pre-evening dose. Measurements will be done at Days 
30, 86, 183, and 364. As for all spirometry data, measurements taken within 6 hours of rescue 
medication use or within 7 days of systemic corticosteroid use or within 3 months of a single 
depot corticosteroid injection will be set to missing. However, the post-evening dose time 
window of 22 – 25 hours or the post-morning dose time window of 8 – 13 hours cannot be 
applied here since the dosing data of the previous day or the morning of the day of pre-dose 
measurements will not be recorded. The same MMRM as for trough FEV1 will be applied, 
however, with other visits included. 
Post-dose FEV1 measurements (5 min, 15 min, 30 min, 1 hr) will be analyzed separately by 
visit using the same MMRM as for trough FEV1 with post-dose time point as repeat variable 
(i.e., in the MMRM, visit will be replaced by time point). 
Pre- and post-dose FVC and FEF25-75 will be analyzed similar to FEV1. 


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To estimate the add-on effect of indacaterol to existing MF treatment (in terms of trough FEV1), 
the average difference between QMF149 and MF will be computed across two dose levels. This 
difference is interpreted as an average effect of adding indacaterol to MF, under the assumption 
that indacaterol effect is not altered by dose of MF. To compute the difference, the QMF149 
and MF doses will be pooled by averaging the following contrasts within the MMRM model, 
as specified for the primary analysis: 
• QMF149 (150/160 µg) vs. MF 400 µg 
• QMF149 (150/320 µg) vs. MF 800 µg. 
For all spirometry measurements, we exclude the implausible values. Specifically, 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. 
2.6.2.3 
ACQ at Weeks 4, 12 and 52 
ACQ-7 at Weeks 4, 12 and 52 will be analyzed using the same MMRM as specified for the key 
secondary endpoint ACQ-7 at Week 26. Change from baseline in the ACQ-7 will be also 
analyzed using the same MMRM model. 
In addition, the proportion of patients who achieve an improvement of at least 0.5 in ACQ-7 
(i.e., a decrease of ACQ-7 score of at least 0.5 from baseline) at Week 4, 12, 26, and 52 visits 
will be analyzed using a logistic regression model. First, missing continuous ACQ-7 values will 
be imputed using a MI method under MAR assumption. Then continuous ACQ values will be 
converted into binomial responses and generalized estimating equation (GEE) method will be 
used to analyze the imputed datasets and then the results from GEE method will be combined 
for the inference. The model will include the same terms as used for the analysis of ACQ-7 but 
no random effect for center nested within region. The estimated adjusted odds ratios will be 
displayed along with the associated 95% (two-sided) confidence intervals and p-values. 
In addition to the contrast of QMF149 average vs. MF average, the individual treatment 
contrasts of QMF149 (150/160 µg) vs. MF 400 µg and QMF149 (150/320 µg) vs. MF 800 µg 
will be presented. 
Additionally, the number (%) of patients will be summarized by visit with the following 
categories: Response (decrease from baseline of ≥ 0.5 units in ACQ-7), no change (-0.5 < 
change from baseline in ACQ-7 < 0.5), worsening (increase from baseline of ≥ 0.5 units in 
ACQ-7). Net response is expressed as the number of patients with response – the number of 
patients with worsening.  
All the analyses described above will be repeated for ACQ-5, including the responder analysis 
with the same threshold of 0.5.. 
The ACQ-5 consists of five items on symptom assessment, which is a subset of ACQ-7. All 5 
questions of the ACQ-5 are equally weighted. The total score is calculated as the mean of all 
five questions, which is calculated as the sum of scores divided by the number of questions that 
were answered, as long as there were at least 4 questions answered and the missing question is 


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not Question 1 ('On the average, during the past week, how often were you woken by your 
asthma during the night?'). 
2.6.2.4 
Peak Expiratory Flow Rate (PEF) 
All the patients are instructed to record PEF twice daily using a mini Peak Flow Meter device, 
once in the morning (before taking the morning dose) and once approximately 12 h later in the 
evening (before taking the evening dose), from screening and throughout the study. 
PEF (liters/min) will be analyzed separately for morning and evening values. The baseline 
values are defined as the average from all non-missing records taken over the last 14 days of 
the run-in period between run-in Visit 101 and up to one day before first dose of study drug. 
Mean values will be calculated over the first 26 weeks and over the whole 52 weeks of double-
blind treatment. 
Separate ANCOVA will be performed to investigate treatment differences in the change from 
baseline in mean morning/evening PEF during the first 26 weeks and during the whole 52 weeks 
of double-blind treatment. The ANCOVA 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 
morning/evening PEF, FEV1 prior to inhalation and FEV1 within 15 to 30 min post inhalation 
of salbutamol/albuterol (components of SABA reversibility) as covariates. LS means and 
associated 95% confidence intervals will be presented for treatments and treatment differences. 
In addition, the mean morning/evening PEF will be summarized by 4 weekly (28 days) intervals 
and analyzed using a similar MMRM as specified for the primary analysis with baseline FEV1 
value replaced with the appropriate baseline PEF. 
2.6.2.5 
Asthma symptom based on e-Diary 
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  
The baseline values are defined as the average from all non-missing records taken over the last 
14 days of the run-in period between run-in Visit 101 and up to one day before first dose of 


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study drug. Daily scores will be averaged for each patient over Weeks 1-26, the complete 52 
weeks double-blind period, and over 4 weekly intervals (from Weeks 1-4 up to Weeks 49-52). 
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 terms of 
percentages. The percentages will be calculated as 100 * total number of days without 
symptoms (daytime, night-time, morning, etc.) / total number of days in the interval (i.e. 28 
days for 4 week interval). The same intervals as used for average scores will be used for 
analyzing 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 baseline PEF 
value replaced with the appropriate baseline percentage. 
2.6.2.6 
Rescue medication 
The number of puffs of rescue medication during the past 12 hours is recorded twice 
(morning/evening) by the patient in the e-Diary. The baseline values are defined as the average 
from all non-missing records taken over the last 14 days of the run-in period between run-in 
Visit 101 and up to one day before first dose of study drug. 
The mean daily number of puffs of rescue medication use will be calculated for each patient 
over the first 26 weeks, over the whole 52 weeks of double-blind treatment, and over 4 weekly 
intervals as described for other data of the e-Diary. This will be done separately for morning 
(night-time), evening (daytime), and daily (night-time plus daytime) rescue medication use. 
Similar ANCOVA and MMRM as used for the analysis of PEF with baseline PEF value 
replaced with the appropriate baseline mean number of puffs.  
The percentage of ‘rescue medication free days’ (defined as any day where the patient did not 
use any puffs of rescue medication during daytime and night-time) will be summarized by 
treatment and analyzed in the same way as described for the number of puffs of rescue 
medication use with baseline mean number of puffs replaced with the baseline percentage of 
rescue medication free days as a covariate. In case of non-convergence or evidence of highly 
skewed data, non-parametric tests such as Wilcoxon Rank Sum Test will be explored. 
2.6.2.7 
Asthma exacerbations 
All analyses will base on data as reported on the "Asthma Exacerbation Episodes" eCRF. 
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. 
The following asthma exacerbation-related parameters will be summarized considering the 
whole 52 weeks of double-blind treatment. The analysis will be performed by exacerbation 


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category wherever specified. The exacerbation categories are: All (mild, moderate, severe), the 
combination of moderate or severe, and severe. 
The annual rate of asthma exacerbations, by exacerbation category 
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, ≥ 18 years), 
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 15 to 30 min post inhalation of 
salbutamol/albuterol (components of SABA reversibility) as covariates. The log exposure in 
years will be used as an offset variable in the model (see Section 2.4.1 for the definition of 
exposure). The estimated rate ratio along with two-sided 95% interval and corresponding p-
value will be provided. 
Time to first asthma exacerbation, by exacerbation category 
Time-to-event variables will be analyzed using a Cox regression model stratified by age (12 to 
17, ≥ 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 15 to 30 min post inhalation of salbutamol/albuterol (components of SABA 
reversibility) as covariates. For treatment comparisons the estimated adjusted hazard ratio 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 an event will be considered as censored at the earliest 
date of (last treatment + 1, death, last visit). In the interim analysis, patients without an event 
who are ongoing at the time of interim database freeze will be censored at the DLP. For patients 
having an event, the start date of the exacerbation will be considered to calculate the time to 
event (i.e., the number of days from start of treatment up to the event start date).  
Time to first hospitalization for asthma exacerbation (only for severe 
exacerbations possible) 
The analysis is similar to time to first asthma exacerbation. 
Time to permanent discontinuation of study drug due to asthma exacerbation 
The analysis is similar to time to first asthma exacerbation. 
Duration of asthma exacerbations in days, by exacerbation category 
The duration of asthma exacerbations is defined as the sum of days per patient over all 
exacerbations and the respective lengths (from start to end date). This will be analyzed for 
treatment group differences using the van Elteren test stratified for age (12 to 17, or ≥ 18), 
region and history of asthma exacerbation in the 12 months prior to screening (Yes, No). 


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Total amounts (in doses) of oral corticosteroids used to treat asthma 
exacerbations 
Total amount (in prednisone-equivalent mg doses) of oral corticosteroid used to treat asthma 
exacerbations during the 52 week treatment period will be summarized descriptively by 
treatment group. 
To estimate the add-on effect of indacaterol (QAB149) to exisiting MF treatment (in terms of 
exacerbations), the average difference between QMF149 and MF will be computed for all 
inferential analyses mentioned above. This difference is interpreted as an average of adding 
indacaterol to MF, under the assumption that indacaterol effect is not altered by dose of MF. 
To compute the difference, the QMF149 and MF doses will be pooled by averaging the 
following contrasts within the specified analyses: 
• QMF149 (150/160 µg) vs. MF 400 µg 
• QMF149 (150/320 µg) vs. MF 800 µg. 
2.6.2.8 
Quality of life as assessed by Asthma Quality of Life Questionnaire 
(AQLQ)  
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, treatment group comparisons will be 
performed using the same MMRM model as specified for the primary analysis with baseline 
AQLQ as covariate. The post-baseline visits are scheduled for Weeks 4, 12, 26, 36, and 52. 
The proportion of patients who achieve an improvement in the AQLQ (i.e., an increase in the 
AQLQ overall score of ≥ 0.5 from baseline) at post-baseline visits will be analyzed using the 
same logistic regression model via GEE as specified for the ACQ-7 analysis except that baseline 
AQLQ will be used instead of the baseline ACQ-7. 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. 


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2.7 
Safety evaluation 
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 2.9 Interim analysis. 
2.7.1 
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. If a sufficient number of events (≥ 10% of patients) occurs, the 
composite endpoint and its components will be also analyzed for the time to event and the 
annual rate of events; similar inferential analyses as described for asthma exacerbations will be 
performed. 
2.7.2 
Adverse events 
All adverse events (AEs) 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 drug but not later than 7 days (30 days in the case of a serious adverse 
event, SAE) after the last administration. 
The number, percentage, and exposure-adjusted rate of patients who reported treatment-
emergent adverse events will be summarized by primary system organ class, preferred term, 
and treatment for 
• all adverse events 
• all adverse events by maximum severity 
• adverse events suspected to be related to study drug 
• all adverse events with time at onset ≤ 26 weeks 
• adverse events leading to permanent study drug discontinuation 
• all adverse events by standardized MedDRA query (SMQ) level, and by SMQ level and 
preferred term 
• serious adverse events 
• serious adverse events suspected to be related to drug 
• serious adverse events leading to permanent study drug discontinuation 
• fatal adverse events 
• adverse events of special interest (by risk and preferred term) 
• serious adverse events of special interest (by risk and preferred term) 
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 


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of frequency in the QMF149 150/320 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. 
In addition, the most frequent adverse events will be presented by preferred term in descending 
order of frequency in the QMF149 150/320 µg treatment group.  
To control for possible differences in exposure between the treatment groups, AEs will also be 
presented with incidence rates per 100 patient-years, for first onset of event where the exposure 
is only counted up to the time of the first event. The incidence rate per 100 patient years will be 
calculated as 100*(the total number of patients with the event of interest divided by the total 
number of exposure in patient-years). In the denominator, patients with the event of interest 
will be counted up to the time of the first event while patients without the event of interest will 
be counted with their full exposure (see Section 2.4.1 for the definition of exposure). Total 
patient years will be computed as sum of days of exposure over all patients divided by 365.25).  
The Compound Case Retrieval Strategy 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 and SAEs of special interest will be presented by risk and 
preferred term and will also be analyzed for the following selected subgroups:  
- 
Age group (12 to 17 years, ≥ 18 years) 
- 
Sex (male, female) 
- 
Pre-bronchodilator FEV1 in % of predicted FEV1 at run-in visit 101 (50% to < 60%, 
60% to < 85%) 
All 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 dose and the last dose + 30 days, 
then those deaths will be included in summary tables. The adjudicated primary cause of death 
will be summarized with pre-defined categories (cardiovascular, respiratory, cancer, other, 
intermediate causes) and subcategory.  
In addition, time to event analyses will be done for the following endpoints: 
- 
adverse event by the 5 most frequent preferred terms, 
- 
serious adverse event (if there are more than 10% of patients with at least one SAE) 
- 
adverse event of special interest by risk category (if there are more than 10% of 
patients with events in the respective risk category) 
- 
adjudicated serious asthma outcome (composite endpoint and by single component – if 
there are more than 10% of patients with events) 
The adverse event onset date will be considered as the date of event. Patients who did not 
experience the event of interest will be taken as censored. For those patients who either 
completed or discontinued study treatment, the censoring time will be the minimum of (the last 
treatment day + 30 days, day of death, day of follow-up day Visit 301). For patients who are 
ongoing at the time of interim database freeze, the DLP date will be used for censoring. 


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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 
3% 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. 
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. 
2.7.3 
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.  
Laboratory data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
The following analyses will be performed by treatment: 
• absolute values and change from baseline summarized for continuous laboratory 
parameters by visit and time point 
• frequency table of results for categorical laboratory parameters by visit and time point 
• shift tables relative to the normal reference ranges summarizing the change from baseline 
to most extreme post-baseline value for each continuous laboratory parameter 
• shift tables from baseline to the worst post-baseline value for categorical laboratory 
parameters 
• the number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (see Appendix 16.1.9 for definition of 
notable values) summarized by laboratory parameter, scheduled post-baseline visit and 
time point and additionally at any time on treatment considering all post-baseline data 
from scheduled, unscheduled and premature discontinuation visits 
The by-visit/time point summaries will include the worst case post-baseline values (determined 
from all post-baseline data even if from unscheduled and premature discontinuation visits, if 
not measured more than 7 days after last dose). To determine the worst case, the direction of 
interest (maximum and/or minimum value) is tabulated for hematology and biochemistry 


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parameters in Appendix 16.1.9. 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.  
The maximum change from baseline will be summarized for liver parameters (ALT, AST, 
alkaline phosphatase, total bilirubin).  
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 following criteria: 


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Notable liver function test values 
Criterion   
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin > 1 x ULN 
Total bilirubin > 1.5 x ULN 
Total bilirubin > 2 x ULN 
Total bilirubin > 3 x ULN 
ALP > 1.5 x ULN 
ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law) 
ALT or AST > 3 x ULN and (nausea or vomiting or fatigue or general malaise or abdominal pain or (rash and 
eosinophilia))* 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
*  Based on the signs/symptoms information as recorded on the liver events eCRF, not the adverse events eCRF. 
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur at the same time (i.e., within the same sample). A 
case where all criteria are met at a post-baseline time point will be considered as newly 
occurring if the criteria are not met at baseline and will be considered as worsening if the criteria 
are met at baseline and at least one component is worsening from baseline irrespective of 
whether the other(s) are better. 
Listings of patients with clinically notable LFT values will be provided. 
During the trial, there has been an unexpected high reporting rate of elevated potassium by 
Central Lab, which was investigated and in the end considered clinically irrelevant and no risk 


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to patient safety. Central Lab was notified to flag all the elevated potassium data. As additional 
analyses, potassium data without flagged values will be summarized. 
2.7.4 
Vital signs 
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), pulse 
rate (measured at Visit 101, 102, 201, 202, 204, 207, 210, 214, EOT – early treatment 
discontinuation), and body weight (measured at Visit 101, 207, 214, EOT – early treatment 
discontinuation).  
Vital signs data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
The following analyses will be performed by treatment: 
• absolute values and change from baseline summarized by parameter, 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 Appendix 16.1.9 for definition of notable values) summarized by 
parameter, scheduled post-baseline visit and time point and additionally at any time on 
treatment considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits 
The by-visit/time point summaries will include the maximum and minimum post-baseline SBP, 
DBP, and pulse rate values (even if from post-baseline unscheduled and premature 
discontinuation visits, if not measured more than 7 days after last dose). 
The same approach as for notable laboratory values will be used to define a newly occurring 
notable vital sign value and a worsening notable vital sign value. 
A listing of all patients with notable vital sign values and changes will be provided. 
2.7.5 
Electrocardiogram (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. 
ECG data measured more than 7 days after last inhalation of study drug are regarded as post-
treatment data and will not be summarized, only listed. All data will be included in the analyses 
regardless of rescue medication use. 
The following analyses will be performed by treatment: 
• absolute values and change from baseline summarized by parameter, visit and time point 
• the number and percentage of patients with newly occurring or worsening notable QTcF 
values (see Appendix 16.1.9 for definition of notable values) summarized by scheduled 


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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.  


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2.9 
Interim analysis 
2.9.1 
Data Safety Monitoring Board (DMC) 
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. 
It is planned that the independent DMC will review semi-blinded (i.e., treatment group named 
as A, B, C, D, or E) 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. 
  
2.9.2 
Primary analysis after all patients have completed at least 26 weeks 
treatment 
The primary and key secondary endpoints of CQVM149B2301 study are the trough FEV1 and 
ACQ-7 after 26 weeks of treatment, respectively while the entire study treatment period is 52 
weeks. In order to support a marketing authorization filing once all patients have completed 26 
weeks of treatment (V207) or prematurely withdrawn from the study, an interim database freeze 
will be conducted to perform the Primary Analysis.  
The database for Primary Analysis will contain data up to 26 weeks for all patients and data up 
to 52 weeks for patients who have completed the study. For patients who are ongoing at the 
time of interim database freeze, the database will include data available until last completed 
visit.  
Primary analysis includes primary and key secondary endpoints as well as other pre-specified 
endpoints at Week 26. 
 
At the time of interim database freeze for Primary Analysis, a limited number of pre-specified 
Sponsor members will be unblinded to the study data to work on study and submission related 
activities which require knowledge of these data. 
The study will continue under the management of a separate blinded team who will be 
responsible for study conduct from the time of the 26 week interim database freeze until end of 
study. In order to maintain the integrity of the study data, the blinded team members will not 
have access to any of the unblinded data or results. In addition, all patients and investigators 
will remain blinded. 
Two separate CSRs will be published: 


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• Primary Analysis CSR: To support analyses once all patients have completed the 
assessments after 26 weeks of treatment (Visit 207) or prematurely withdrawn from the 
study. This will include analysis of primary and key secondary as well other pre-
specified endpoints which are evaluable at this time. 
• Full CSR: To support analysis once all patients have completed the assessments after 
52 weeks of treatment (Visit 214) plus follow up (Visit 301) or prematurely withdrawn 
from the study. 
Since the analysis of primary and key secondary objectives will be performed only for the 
Primary Analysis CSR, the interim analysis will not require any adjustment to the overall type 
I error rate. 
2.10 
Sample size calculation 
The sample size calculation takes into account the following consideration: 
1. To achieve at least 90% power (with multiplicity adjustment) for primary endpoint trough 
FEV1 with a treatment difference of 100 mL between QMF149 vs. MF at the corresponding 
doses, assuming standard deviation of 380 mL based on internal studies QMF149A2210, 
QMF149E2201, QMF149E2203 and literature data; 
2. To achieve at least 80% power (with multiplicity adjustment) for key secondary endpoint 
ACQ-7 with a treatment difference of 0.15 between QMF149 vs. MF based on pooled doses, 
assuming standard deviation of 0.80 based on studies QMF149A2210, QMF149E2201, 
QMF149E2203 and Kerstjens (2012). 
If 10% dropout rate is assumed, then calculation shows the sample size of 2000 patients (i.e., 
400 per arm) will provide 94% power for item 1 and 85% power for item 2, with multiplicity 
adjustment. 
The sample size calculation was performed in R 3.2.3. 
3 
Analyses to be reported outside of CSR 
3.1 
Subgroup analyses 
Subgroup analyses for Japanese, Chinese, and Asian patients will be performed for the FAS to 
explore the treatment effect in respective sub populations. 
Asian subgroup contains patients from the following countries: 
• China 
• Japan 
• Rep of Korea 
The following endpoints will be summarized and/or analyzed for all three sub populations using 
similar methods as described in previous sections, if not marked with special symbol. 
• Patient disposition 
• Protocol deviations 


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• 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 * 
• Rescue medication* 
• Asthma exacerbations* 
• Asthma Quality of Life Questionnaire (AQLQ-S+12)* 
 
  
• Exposure 
• Concomitant asthma medications 
• Laboratory data 
• Vital signs 
• ECG 
• Adverse events 
*: only needed for Japanese subgroup analyses 
The specific outputs for each sub population under each endpoint will be specified in the TFLs. 


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Clinical Study Report -  
Appendix 16.1.9 Documentation of statistical methods 
16.1.9.1 
Introduction 
This appendix gives details about statistical methods in addition to the report text. All analyses 
will be performed by using SAS Version 9.4.  
16.1.9.2 
Major protocol deviations and other exclusion criteria 
The following protocol deviations will be considered as major and will lead to exclusion of 
patients from analysis sets:  
Exclusions from per-protocol set: 
• INCL01: Age < 12 years or > 75 years or missing 
• INCL03: No current diagnosis of persistent Asthma of at least 12 months prior to V1 
• INCL04.A4: Patient not  treated with  medium/high dose ICS or LOW dose  ICS/LABA 
combination for at least 3 months and/or not at stable dose 30 days prior to Visit 1 
• INCL05: ACQ score < 1.5 at V101 and/or V102 
• INCL05.01: ACQ INVALID ASSESSMENT; Patient used invalidated ACQ7 at Visit 101 
and/or Visit 102. 
• INCL06.A4: Pre- Bronchodilator FEV1 at V101 and V102 < 50% or >= 85% of predicted 
normal at visit 101 
• INCL06.01: Patient has not achieved assessments according to ATS/ERS criteria 
• INCL07: Patient has not achieved an acceptable spirometry result and does not have 
historical reversibility or bronchoprovocation 
• INCL07.01: Patient has not achieved an acceptable spirometry result and does not have 
Historical reversibility or bronchoprovocation according to ATS/ERS as per source 
documentation  
• EXCL01: Patient has a smoking history of > 10 pack years or missing  
• EXCL01.01: Patient smoked or inhaled tobacco within the 6 month period prior to V1 
• EXCL01.02: Patients smoking nicotine inhaler at inclusion. 
• EXCL02: Asthma attack/exacerbation requiring SCS or hospitalization or ER visits within 
6 weeks prior to V1 
• EXCL03: History of severe asthma exacerbation requiring intubation prior to visit 1 
• EXCL05: Asthma exacerbation within 4 weeks prior to V1 
• EXCL05.01: Respiratory Tract Infection or asthma worsening between screening and run-
in 102 visits 
• EXCL05.02: Respiratory Tract Infection within 4 weeks prior to V1 
• EXCL06: Visual clinical significant oropharyngeal candidiasis between visit 1 and visit 
102 
• EXCL07: Chronic condition affecting upper respiratory tract 
• EXCL08: Patient has a history of chronic lung diseases other than asthma 


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• EXCL11:Investigational drugs used within 5 half lives or until the return of baseline 
pharmacodynamic effect whichever is longer 
• EXCL24: Patient is not on maintenance immunotherapy for allergies for at least 3 months 
prior to V101  
• EXCL27: Unable to use dry powder inhaler device at V101 and/or V201 
• EXCL28: Patient has history of alcohol or other substance abuse  
• EXCL33.A4: Use of LAMA within 3 months prior to Visit 101 
• OTH08: Patient not having correct run in medication (i.e. 100mcg accuhaler or 125 mcg 
via MDI inhaler) or dose equivalentCOMD07: Use of parenteral or oral corticosteroids 
less than 4 weeks prior to visit 101  
• COMD08: Intra muscular corticosteroid less than 3 months prior to Visit 101 
• COMD09: Use of Ige inhibitor less than 4 months prior to visit 101 
• COMD10: Xanthine's use less than 7 days prior to visit 101 
• COMD12: Last LABA washout more than 4 days prior to visit 101 or last ICS wash out 
more than 7 days before visit 101 
• OTH06: Compliance failure of the patient influencing the safety and efficacy data as per 
investigator judgement 
• OTH04: Patient receiving investigational drug other than study drug during the course of 
the study 
• COMD05: Leukotriene antagonists and leukotriene synthesis inhibitors taken less than 7 
days prior to visit 101 
• COMD06: Use of SABA other than rescue medication, not discontinued at Visit 1 
• COMD11: LABA taken less than 48h before Visit 101 
• COMD01: Banned asthma related Concomitant medication 
• WITH01: More than 5 exacerbation and still on treatment 
• WITH02: Adolescent patient experience one severe exacerbation requiring hospitalization 
(ER>24) and is still on treatment 
 
 
 
Exclusions from full analysis set and per-protocol set: 
• OTH05: Patient Randomized more than one Trial. 
• OTH14: Patient randomized more than once into this trial 
Exclusions from full analysis set, per-protocol set, safety set, 
: 
• OTH02: Patient randomized but did not receive study drug  
Exclusions from randomized set, full analysis set, per-protocol set,
 
• Patient received study drug but was not randomized 


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16.1.9.3 
Assessment windows, baseline and post-baseline definitions, 
missing data handling 
16.1.9.3.1 
Data pooling and assessment windows 
Data from unplanned or unscheduled visits or the early treatment/study discontinuation visits 
will be listed. For patients who do not complete the study, 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. 
16.1.9.3.2 
Baseline measurements 
In general, baseline is defined as the last measurement before the first dose of study drug at Day 
1.  
1) For all FEV1, FVC, and FEF25-75 endpoints, the baseline value is defined as the average of 
the values taken at -45 and -15 min prior to first dose of study drug at the evening of Day 1. 
Checks will be performed to ensure both values were indeed taken prior to the first dose of 
study drug. 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, and/or within 7 days of systemic corticosteroid use, and/or 3 months of single depot 
corticosteroid injection, will be set to missing. 
For all baseline spirometry measurements, we exclude the implausible values. Specifically, if a 
patient has implausible FEV1 value (defined as > 7 L) at baseline assessment, all spirometry 
measurements related to that assessment will be excluded. 
2) For the ACQ scores, the baseline value is defined as the score obtained at Day 1 (V102). If 
the value is missing, the last measurements from run-in visit 101 or unscheduled run-in visits 
will be used.  
3) For patient diary data (PEF, symptoms, and rescue medication use), the baseline values 
are defined as the average from all non-missing records taken in the run-in period over 14 days 
from Visit 101 up to one day before first dose of study drug (i.e., from Day -14 to Day -1 
inclusively). Missing diary data will not be imputed. 
Baseline PEF will be calculated separately for morning and evening values. 


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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, 
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'. The average of the 5 scores is defined as the daytime symptom score. The 
baseline scores will be derived by averaging over the days of the run-in period with non-missing 
data, separately for each score, the night-time, morning, and daytime symptom score.  
The baseline total daily symptom score will be obtained in the first step by adding the night-
time 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. 
Rescue medication use will be analyzed separately for the number of puffs during daytime, 
night-time, and over the complete 24 hours. Baseline is defined as the average number of puffs 
per day in the run-in period. 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 respective baseline value will 
be set to missing. 
4) Laboratory data include hematology, biochemistry, urinalysis, and plasma cortisol. 
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 drug 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 
drug will be used for baseline. Otherwise, the baseline laboratory data will be set to missing.  
5) Vital signs include pulse rate and systolic and diastolic blood pressures. Baseline vital signs 
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 drug 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 drug will be used for 
baseline.  
6) Baseline height and weight are defined as the measurements taken at the run-in Visit 101. 
Missing baseline will not be imputed.  
7) Baseline ECG is defined as ECG measured 35 minutes prior to the first dose of study drug 
on Day 1. Checks will be performed to ensure the ECG was indeed assessed prior to the first 


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dose of study drug. 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 
drug will be used. Otherwise, the ECG baseline will be set to missing without imputation.  
16.1.9.3.3 
Post-baseline measurements 
Post-baseline measurements are defined as those assessments after the first dose of study drug. 
FEV1, FVC and FEF25-75 measurements taken within 6 hours of rescue use or within 7 days of 
systemic corticosteroid use or within 3 months of single depot corticosteroid injection will be 
set to missing. The trough value is defined as the average of the two measurements taken 23 hr 
15 min and 23 hr 45 min post-evening dose. If the actual measurement times will be outside of 
the 22 - 25 hour post-evening dose time window for o.d. regimens (or outside the 8 - 13 hour 
post-morning dose time window for b.i.d. regimens), then the individual 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 the trough value. If both values are missing, then the trough value will be 
missing. In a similar way pre-dose trough is defined as the average of the two measurements 
taken 45 min and 15 min pre-evening dose. Pre-dose measurements will be set to missing when 
they are actually taken post-dose. However, the post-evening dose time window of 22 – 25 
hours or the post-morning dose time window of 8 – 13 hours for b.i.d. regimens can not be 
applied here since the dosing data of the previous day or the morning of the day of pre-dose 
measurements 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.  
Post-dose spirometry measurements (i.e., at 5, 15, 30, 60 min) which were actually taken pre-
dose will be set to missing and not used for by time point assessments. 
For all post-baseline spirometry measurements, we exclude the implausible values. Specifically, 
if a patient has implausible FEV1 value (defined as > 7 L) at an assessment, all spirometry 
measurements related to that assessment will be excluded. 
For diary data (PEF, symptom scores and rescue medication use), 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), for Weeks 1 – 26 (defined 
up to Visit 207, Day 183), and for Weeks 1 – 52 (defined as the whole treatment period up to 
Visit 214, Day 365). 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 – 26 and 1 – 52, summary values will only be calculated if a patient 
has at least 30% of their diary days and at least 20 diary days with evaluable data for that 
variable in the period of interest. 
For safety data, post-baseline measurements comprise recordings up to the last dose of study 
drug + 7 days for laboratory, ECG, vital signs, non-serious AE and up to the last dose of study 
drug + 30 days for SAEs and death. ECG, vital signs and laboratory values which have complete 
date and time values are assigned to pre or post-dose assessment based on the actual date/time. 
However, values with missing date/time are assigned to their respective scheduled visit date 
and time given the visit number and time point are non-missing. If a measurement scheduled as 


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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. 
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. 
16.1.9.4 
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. 


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Direction of interest for worst case value for laboratory parameters 
Laboratory Parameter 
Direction of interest for worst case value 
A. Hematology 
Hemoglobin 
Low 
Hematocrit 
Low 
Erythrocytes 
Low 
Leukocytes 
Low and high 
Basophils 
High 
 
 
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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Clinical notable criteria for selected laboratory tests 
Laboratory parameter (unit) 
Lower bound of clinically notable 
range 
Upper bound of clinically notable 
range 
Hematology 
 
 
Hematocrit (v/v)) 
     Male 
     Female 
 
0.37 
0.32 
 
- 
- 
Hemoglobin (g/L) 
    Male 
    Female 
 
115 
95 
 
- 
- 
Platelets (x10E9/L) 
75  
700 
Leukocytes (x109/L) 
2.8 
16.0 
Chemistry 
 
 
Albumin (g/L) 
25 
- 
Alkaline Phosphatase (U/L) 
- 
3 x ULN 
ALT/SGPT (U/L) 
- 
3 x ULN 
AST/SGOT (U/L) 
- 
3 x ULN 
Bilirubin Total (µmol/L) 
- 
34.2 
BUN (mmol/L) 
- 
9.99 
Creatinine (µmol/L) 
- 
176.8 
Glucose (mmol/L) 
2.78 
9.99 
Gamma GT (U/L) 
- 
3 x ULN 
Potassium (mmol/L) 
3 
6 
Magnesium (mmol/L) 
0.51 
1.07 
v = volume, ULN = upper limit of normal  
16.1.9.5 
Vital signs and ECG – definition of clinically notable values 
The following table shows the clinical notable criteria for vital signs. 
Clinical notable criteria for vital signs 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of clinically 
notable range 
Notable value considering newly occurring or worsening cases 
Systolic blood pressure (mmHg) 
< 75 
> 200 
Diastolic blood pressure (mmHg) 
< 40 
 
> 115 
Pulse rate (bpm) 
< 40 
> 130 
Notable change from baseline 
Systolic blood pressure (mmHg) 
≤ 90 and decrease from 
baseline by ≥ 20  
≥ 180 and increase from 
baseline by ≥ 20 
Diastolic blood pressure (mmHg) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 105 and increase from 
baseline by ≥ 15 
Pulse rate (bpm) 
≤ 50 and decrease from 
baseline by ≥ 15 
≥ 120 and increase from 
baseline by ≥ 15 
The following table shows the clinical notable criteria for QTcF. 


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Clinical notable criteria for QTcF (Fridericia's formula) 
ECG parameter (unit) 
Clinically notable range 
Notable value considering newly occurring or worsening cases 
QTc (ms) 
> 450 (male) 
QTc (ms) 
> 460 (female)  
QTc (ms) 
> 500  
Notable change from baseline 
QTc 
30 – 60 
QTc 
> 60 
Combination of QTc above a threshold and QTc increase from baseline above a threshold 
QTc (ms) 
> 500 ms and increase from baseline > 60 ms 
16.1.9.6 
Statistical methodology and assumptions 
In this section, the least squares mean (LSM) is estimated by the expected response for an 
“average” patient (with covariates set as weighted average of the covariates value in the 
population) based on the model (using OM option in PROC MIXED in SAS). 
• 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 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 primary analysis, if the model does not converge, data only up to Week 26 (i.e., Days 2 
and 184) will be used (with unstructured covariance matrix). If still the model fails to converge, 
compound symmetry covariance matrix will be used. If the model still does not converge, the 
random effects of center will be removed. For the final analysis, if the model does not converge 
with unstructured covariance matrix, the compound symmetry covariance structure will be used. 
If still the model does not converge, the random effect of center will be removed. For both 
analyses, if the model converges after removing the random center effects, the original model 
without random center effects will be re-assessed. If the final model for the primary analysis 
converges without Week 52 data, only summary statistics will be provided for Week 52 data 
analysis. 
Results will be presented with LSM and standard error (SE) for treatment effects and LSM, SE, 
associated two-sided 95% confidence interval, and two-sided p-value for all relevant treatment 
contrasts. 
The combined effects of QMF149 (150/160 & 150/320 µg) and MF (400 & 800 µg) will be 
derived by weighting treatment groups equally. 
In the analysis of eosinophil blood count, the covariates FEV1 prior to inhalation and FEV1 15 
to 30 min post inhalation will not be included in the MMRM. 


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• Tipping point analysis for trough FEV1 at Week 26 
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 26. 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 first impute the missing 
Week 26 values using the multiple imputation (MI) method based on the MAR assumption. The 
imputed Week 26 values for the QMF149 arms are then adjusted by a delta value. 
The endpoint is assumed to have a normal distribution at Day 2, Week 26 and Week 52. 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. Different delta values are possible for QMF149 
150/160 μg vs. MF 400 μg and QMF149 150/320 vs MF 800 μg. 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. 
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 26 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 26 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 two QMF149 treatment 
arms only, make the imputed value at Week 26 worse by a value of delta (i.e., subtract 
delta from the imputed value at Week 26). 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 model with treatment, age group, geographic region, 
baseline FEV1, FEV1 prior to inhalation, and FEV1 15 to 30 min post inhalation as 
predictors of trough FEV1 at Week 26. 
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 1 until the tipping 
point is found (when p > 0.05). 
• Logistic regression analysis 


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The proportions of patients who achieve a clinically relevant improvement in ACQ-7 (i.e., 
decrease of ACQ-7 score of at least 0.5 from baseline) at the scheduled post-baseline visits will 
be analyzed using logistic regression. The following steps will be performed for imputation of 
missing ACQ-7 data and following logistic regression analysis: 
1. First, missing ACQ-7 values (continuous) at Visit 202, 204, 207, and 214 will be 
imputed sequentially using the MI method under MAR assumption. Missing values will 
be imputed separately for each treatment group using a model with age group (12 to 17, 
or ≥ 18 years), region, baseline ACQ value, FEV1 prior to inhalation, FEV1 within 15 to 
30 min post inhalation of salbutamol/albuterol, and previous post-baseline ACQ-7 
values as predictors for 100 times.  
2. Continuous ACQ values will be converted into binomial responses (1 = an improvement 
of at least 0.5, 0 = no such improvement) and generalized estimating equation (GEE) 
method will be used to analyze the dataset (by imputed dataset). The GEE model will 
include terms for treatment, age group (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. 
Combining results from 100 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 combined effects of QMF149 (150/160 & 150/320 µg) and MF (400 & 800 µg) will be 
derived by weighting treatment groups equally. 
The proportions of patients who achieve a clinically relevant improvement in AQLQ (i.e., 
decrease of AQLQ score of at least 0.5 from baseline) at the scheduled post-baseline visits (Visit 
202, 204, 207, 210, and 214) will be analyzed using the same procedures as mentioned above 
for ACQ-7, except that baseline ACQ-7 is replaced by baseline AQLQ in all steps.  
• Linear Mixed Model Analysis of Covariance (ANCOVA) 
The following linear mixed ANCOVA model will be used for diary data summarized over 26 
or 52 weeks: 
Dependent variable = intercept + treatment + age group + region + baseline value + FEV1 
prior to inhalation + FEV1 15 to 30 min post inhalation + random effect of center nested 
within region + error. 
Results will be presented with LSM and SE for treatment effects and LSM, SE, associated 
two-sided 95% confidence interval, and two-sided p-value for all relevant treatment contrasts. 
• Cox regression analysis 
A Cox proportional hazards regression model 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 Cox regression 


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model will be stratified by age group (12 – 17, ≥ 18 years) and will include terms for treatment, 
region, history of asthma exacerbation in the 12 months prior to screening (Yes, No), FEV1 
prior to inhalation and FEV1 within 15 to 30 min post inhalation of salbutamol/albuterol 
(components of SABA reversibility). 
Results will be presented with adjusted hazard ratios for treatment group comparisons and 
associated 95% confidence intervals and two-sided p-values. P-values 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). 
The combined effects of QMF149 (150/160 & 150/320 µg) and MF (400 & 800 µg) will be 
derived by weighting treatment groups equally. 
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 model will include 
terms for treatment, age (12 – 17, ≥ 18 years), region, history of asthma exacerbation in the 12 
months prior to screening (Yes, No), FEV1 prior to inhalation and FEV1 within 15 to 30 min 
post inhalation of salbutamol/albuterol (components of SABA reversibility).  
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.  
Treatment group ratios of exacerbation rates will be presented together with 95% confidence 
intervals and two-sided p-values. 
The combined effects of QMF149 (150/160 & 150/320 µg) and MF (400 & 800 µg) will be 
derived by weighting treatment groups equally. 
• Van Elteren test 
The duration of asthma exacerbations (= the sum of days with an exacerbation, summarized by 
exacerbation category) will be analyzed for treatment group differences using the van Elteren 
test stratified for age (12 to 17, or ≥ 18), region and history of asthma exacerbation in the 12 
months prior to screening (Yes, No). 
Modified ridit scores (scores=modridit) represent the expected values of the order statistics of 
the uniform distribution on (0,1). Modified ridit scores are derived from rank scores. The 
‘Row Mean Scores Differ’ statistic gives the relevant p-value of the test. To obtain p-values 
for pairwise treatment comparisons, the code above will be applied separately on datasets 
which include only the two treatments to be compared. 
References 
Brannath, W., Bretz, F., Maurer, W., & Sarkar, S. (2009). Trimmed weighted Simes' test for 
two one-sided hypotheses with arbitrarily correlated test statistics. Biometrical Journal, 51(6), 
885-898. 


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Ratitch, B., O’Kelly, M., and Tosiello, R. (2013). Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models. Pharmaceutical Statistics, 12, 
337-347. 
Pearlman, D., Chervinsky, P., LaForce C., et al. (1992). A comparison of salmeterol with 
albuterol in the treatment of mild-to-moderate asthma. The New England Journal of Medicine, 
327(20), 1420-1425.