Clinical trial NCT02571777
Conditions: Asthma
Keywords: Asthma QVM149 QMF149
Sponsor: Novartis Pharmaceuticals
Start date: 2015-12-08; Completion date: 2019-06-14
Enrollment: 3092 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the trial was to evaluate the efficacy and safety of two different doses of QVM149 (QVM149 150/50/80 μg and QVM149 150/50/160 μg via Concept1) over two respective QMF149 doses (QMF149 150/160 μg and QMF149 150/320) μg via Concept1 in poorly controlled asthmatics as determined by pulmonary function testing and effects on asthma control.

Detailed description:
This study used a 52-week treatment, randomized, double-blind, double-dummy, parallel-group design. A total of 3092 asthma patients were randomized into the 5 treatment groups with a randomization ratio of 1:1:1:1:1 (approximately 617 patients per treatment group): QVM149 150/50/80 μg once daily (o.d.), QVM149 150/50/160 μg o.d., QMF149 150/160 μg o.d. and QMF149 150/320 μg o.d., all delivered via the Concept1 device, and salmeterol/fluticasone 50/500 μg twice daily (b.i.d.) delivered via Accuhaler. The 52 week treatment period was followed by a 30-day Follow-up.

The primary objective of this study was to demonstrate superiority of either QVM149 150/50/80 μg o.d. to QMF149 150/160 μg o.d. or QVM149 150/50/160 μg o.d. to QMF149 150/320 μg o.d in terms of trough Forced Expiratory Volume in One Second (Trough FEV1) (FEV1) at Week 26, all delivered via Concept1.

Arms: arm 1: QVM149 150/50/160 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device arm 2: QVM149 150/50/80 μg (indacaterol acetate/glycopyrronium/mometasone furoate) once daily (o.d.) delivered via Concept1 device arm 3: QMF149 150/320 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device arm 4: QMF149 150/160 μg (indacaterol acetate/mometasone furoate) once daily (o.d.) delivered via Concept1 device arm 5: Salmeterol xinafoate /fluticasone propionate 50/500 μg twice daily (b.i.d.) delivered via Accuhaler®
Interventions: intervention 1: QVM149 150/50/160 intervention 2: QVM149 150/50/80 intervention 3: QMF149 150/320 intervention 4: QMF149 150/160 intervention 5: salmeterol/fluticasone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_001.pdf: 
Global Clinical Development - General Medicine
QVM149B (Indacaterol acetate / Glycopyrronium bromide 
/Mometasone furoate) 
Full Protocol CQVM149B2302 / NCT02571777
A multicenter, randomized, 52-week, double-blind, parallel-
group, active controlled study to compare the efficacy and 
safety of QVM149 with QMF149 in patients with asthma 
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2015-002899-25
Version number:
v06 (Clean)
Development phase:
III
Release date:
18-Dec-2017
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...............................................................................................................10
Amendment 6 ....................................................................................................................11
Summary of amendments issued before this amendment: ................................................13
Protocol summary..............................................................................................................18
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.2
Purpose ..................................................................................................................25
2
Study objectives.................................................................................................................25
2.1
Primary objective...................................................................................................26
2.2
Key Secondary objectives......................................................................................26
2.3
Secondary Objectives ............................................................................................26
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 .......................................................................33
3.5
Purpose and timing of interim analyses/design adaptations..................................34
3.6
Risks and benefits..................................................................................................35
4
Population..........................................................................................................................37
4.1
Inclusion criteria ....................................................................................................38
4.2
Exclusion criteria...................................................................................................39
5
Treatment...........................................................................................................................42
5.1
Protocol requested treatment .................................................................................42
5.1.1
Investigational treatment.......................................................................42
5.1.2
Additional study treatment....................................................................43
5.1.3
Treatment arms......................................................................................43
5.2
Treatment assignment, randomization...................................................................43
5.3
Treatment blinding.................................................................................................44
5.4
Treating the patient................................................................................................44
PPI


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5.4.1
Patient numbering .................................................................................44
5.4.2
Dispensing the investigational treatment ..............................................45
5.4.3
Handling of study treatment..................................................................45
5.4.4
Instructions for prescribing and taking study treatment........................46
5.4.5
Permitted dose adjustments and interruptions of study treatment ........48
5.4.6
Rescue medication ................................................................................48
5.4.7
Concomitant treatment..........................................................................48
5.4.8
Prohibited Treatment.............................................................................48
5.4.9
Discontinuation of study treatment .......................................................51
5.4.10
Withdrawal of consent ..........................................................................53
5.4.11
Lost to follow-up...................................................................................54
5.4.12
Emergency breaking of assigned treatment code..................................54
5.4.13
Study completion and post-study treatment..........................................55
5.4.14
Early study termination.........................................................................55
6
Visit schedule and assessments .........................................................................................55
6.1
Information to be collected on screening failures..................................................64
6.2
Patient demographics/other baseline characteristics .............................................64
6.3
Treatment exposure and compliance .....................................................................65
6.4
Efficacy..................................................................................................................65
6.4.1
Spirometry.............................................................................................65
6.4.2
Health Status (Patient Reported Outcomes)..........................................66
6.4.3
Electronic Diary ....................................................................................67
6.4.4
Worsening of asthma.............................................................................68
6.4.5
Asthma Exacerbation ............................................................................69
6.4.6
Appropriateness of efficacy assessments..............................................71
6.5
Safety.....................................................................................................................71
6.5.1
Physical examination ............................................................................71
6.5.2
Vital signs..............................................................................................72
6.5.3
Height, weight and abdominal circumference ......................................72
6.5.4
Laboratory evaluations..........................................................................72
6.5.5
Electrocardiogram (ECG) .....................................................................73
6.5.6
Serious Asthma outcomes.....................................................................74
6.5.7
Pregnancy and assessments of fertility .................................................74
6.5.8
Appropriateness of safety measurements..............................................74
74
74


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75
7
Safety monitoring..............................................................................................................75
7.1
Adverse events.......................................................................................................75
7.2
Serious adverse events...........................................................................................77
7.2.1
Definition of SAE .................................................................................77
7.2.2
SAE reporting........................................................................................78
7.2.3
Pneumonia Reporting............................................................................78
7.3
Liver safety monitoring .........................................................................................79
7.4
Pregnancy reporting...............................................................................................80
8
Data review and database management.............................................................................80
8.1
Site monitoring ......................................................................................................80
8.2
Data collection.......................................................................................................81
8.3
Database management and quality control............................................................81
8.4
Data Monitoring Committee..................................................................................82
8.5
Adjudication Committee........................................................................................82
8.6
Advisory Board......................................................................................................82
9
Data analysis......................................................................................................................83
9.1
Analysis sets ..........................................................................................................83
9.2
Patient demographics and other baseline characteristics.......................................84
9.3
Treatments .............................................................................................................84
9.4
Analysis of the primary variable(s) and key secondary variables .........................85
9.4.1
Variable(s).............................................................................................85
9.4.2
Statistical model, hypothesis, and method of analysis..........................85
9.4.3
Handling of missing values/censoring/discontinuations.......................86
9.4.4
Multiplicity Adjustment........................................................................86
9.4.5
Key secondary variable.........................................................................87
9.4.6
Supportive analyses...............................................................................87
9.5
Analysis of secondary variables ............................................................................88
9.5.1
Efficacy variables..................................................................................88
9.5.2
Safety variables .....................................................................................92
95
95
95
9.5.6
PK/PD ...................................................................................................95
9.6
Interim Analysis.....................................................................................................95
9.7
Safety Monitoring Analysis...................................................................................95


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9.8
Sample size calculation..........................................................................................96
10 Ethical considerations........................................................................................................96
10.1
Regulatory and ethical compliance........................................................................96
10.2
Informed consent procedures.................................................................................96
10.3
Responsibilities of the investigator and IRB/IEC..................................................97
10.4
Publication of study protocol and results...............................................................97
11 Protocol adherence ............................................................................................................97
11.1
Protocol Amendments ...........................................................................................97
12 References .........................................................................................................................98
13 Appendices ......................................................................................................................100
Appendix 1: Instruction for Use of Concept1 .................................................................100
Appendix 2: Instruction for use of Accuhaler®/Diskus®.................................................105
Appendix 3 Spirometry Guidance...................................................................................109
Appendix 4: ACQ-7 ........................................................................................................112
Appendix 5: AQLQ-S......................................................................................................114
119
Appendix 7: Patient Asthma Control e-Diary .................................................................121
Appendix 8: Liver event definitions and follow-up requirements ..................................122
125
Appendix 10: Low, medium and high Daily Doses of Inhaled Glucocorticosteroids 
for Adults*...........................................................................................................127
List of tables
Table 1-1
Comparison of nominal MF doses in Asmanex Twisthaler, 
QMF149 and QVM149 drug products delivered by Concept1 
(Breezhaler)...........................................................................................25
Table 5-1
Study Treatments ..................................................................................47
Table 5-2
Prohibited asthma-related medications .................................................49
Table 5-3
Prohibited Medications .........................................................................49
Table 5-4
Medications allowed under certain conditions......................................50
Table 5-5
Table of Assessment for Patients who Discontinue Study 
Treatment prematurely..........................................................................52
Table 6-1
Table of Assessment .............................................................................57
Table 6-2
Timed Assessment** ............................................................................63
Table 13-1
Liver Event Definitions.......................................................................122


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Table 13-2
Liver Event Follow Up Requirements ................................................123
List of figures
Figure 3-1
Study design..........................................................................................30
Figure 9-1
Testing Procedure..................................................................................87


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List of abbreviations
ACQ
Asthma Control Questionnaire
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification
ATS/ERS
American Thoracic Society/European Respiratory Society
AQLQ
Asthma Quality of Life Questionnaire
b.i.d.
Twice a day
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CCV
Cardio-/Cerebro-vascular
CFR
US Code of Federal Regulations 
CDS
Core Data Sheet (for marketed drugs) 
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
FPM
Fine particule mass


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FVC
Forced vital capacity
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HV
Healthy volunteer
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
OCS
Oral Corticosteroids
Pbo
Placebo
PEF
Peak expiratory flow
PI
Post inhalation
PPS
Per protocol set
PRO
Patient reported outcome
p.o.
Oral (ly)
RAN
Randomization set
SABA
Short acting beta-2 agonist


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SAE
Serious adverse event
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 6
Amendment rationale
Conduct primary analysis after all patients have completed at least 26 weeks 
treatment (Visit 207):
The primary and key secondary endpoints of CQVM149B2302 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.
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:


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
Add an explanation for primary analysis when all patients have completed 26 weeks of 
treatment as above (Section 3.5, Section 5.3, Section 8.2 and Section 9.6)

Add an additional explanation for the treatment of asthma exacerbation (Section 5.4.8, 
Section 6.4.5)

Add the clarification that the treatment for adverse events (including asthma 
exacerbations) is permitted (Section 5.4.8)

Add the importance of eDiary/PEF data and also reporting asthma events on CRF (Section 
6.4.4)

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 5, 08-Feb-2017); 
however, the text deletion was not done

Add further clarification to ICS/LABA Standard of Care prior to the study. A patient who 
has been treated with FDC (ICS/LABA) plus ICS monotherapy should be avoided because 
his/her ICS treatment would be higher than the ones in the study treatment (Appendix 10)
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.


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Summary of amendments issued before this amendment:
Amendment 5 (08-Feb-2017)
Amendment rationale
1. Modification of inclusion criteria for duration of baseline ICS/LABA requirements from 1 
year to 3 months. This is based on investigator feedback from real world asthma 
populations and intended to address evolving treatment patterns, whereby patient 
medications are more rapidly up-titrated in response to symptoms. This will help identify 
previously ineligible patients who may potentially benefit from treatment with LAMA as 
add-on therapy to existing ICS/LABA treatment.
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.
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:
 
!
Update the required sample size based on the new estimate in terms of drop-out rate at 
Week 26 (Section 4 and Section 9.8)
!
Change the required pre-treatment period of ICS/LABA to 3 months prior to Visit 1 in 
inclusion criteria 4 (Section 4.1)
!
Add the guidance of washout period in inclusion criteria 7 (Section 3.1, Section 4.1)
!
Update the repeat spirometry test including reversibility in inclusion criterion 7, inclusion 
criterion 8, and exclusion criterion 22 (Section 3.1, Section 4.1 and Section 4.2)
!
Change the condition of spacer use for reversibility testing in inclusion 8 and excluding 
spacer use for rescue medication in exclusion criterion 30 (Section 4.1 and Section 4.2)
!
Add a clarification of Myocardial Infarction in exclusion criteria 16 and 19 (Section 4.2)
!
Enhance importance of alert to have appropriate actions taken (Section 6.4.4).
!
Remove ATC code for summarizing concomitant medication(Section 9.3)
!
Align to the analysis plan for the analysis of glucose and potassium value (Section 9.5.2)
!
Update the definition of repeatability in the spirometry guidance (Appendix 3)
!
Add fluticasone furoate in the table of the ICS dose (Appendix 10)
P
P
I


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Amendment 4 (08-Sep-2016)
Amendment rationale
1. Recent approval of tiotropium Respimat® 5 µg o.d. for asthma in September 2014 as well 
as changes to GINA guidelines in 2015 are expected to result in a progressive increase in 
use of tiotropium (LAMA) as add on to ICS/LABA therapy in GINA ≥Step 4 patients. 
This has already been observed, where the uptake in LAMA use has been higher than 
anticipated based on initial expectations at time of protocol development and initial 
feasibility.
To mitigate this issue, in consultation with leading experts in the field of asthma treatment
and based on real-world evidence on asthma treatment, a protocol amendment will be 
implemented to reduce the exclusion period for LAMA use from 12 months to 3 months 
prior to Visit 1. This will broaden the pool of eligible patients and help better reflect 
rapidly evolving medical practice in GINA ≥Step 4 asthma patients. The modified criteria 
will maintain the rigor of the study design including assessment of endpoints in a 
population that may benefit from LAMA in a fixed triple combination, QVM149. A 3 
month timeframe will help ensure there is no carryover effect from recent LAMA use, and 
will NOT require washout at the time of Visit 1. To help ensure continued safety, all 
patients must be free of asthma exacerbations within 6 weeks of Visit 1 or asthma 
worsening within 4 weeks of Visit 1, respectively.
The Protocol Summary, Section 4.2 exclusion criteria and Table 5-2 Prohibited asthma-
related medications were updated accordingly.
2. E-Diary Alert handling during run-in epoch due to asthma worsening (Section 6.4.4). 
Currently, if an asthma worsening alert is observed during the run-in epoch, the patients 
must be discontinued regardless of clinical context and the investigator’s judgment. This
amendment will allow investigator’s discretion in determining the clinical significance of 
asthma worsening e-diary alerts during the run-in epoch and allow the investigator to 
make the most appropriate decision as to whether patients may continue in the study or be 
discontinued. If asthma worsening is confirmed as clinically significant by investigator, 
patients should be discontinued. A combination of e-diary alerts and investigator’s
judgment will help ensure that the most appropriate patients are enrolled in the study, 
while maintaining rigorous monitoring and assessment of patient safety.
The Protocol Summary, Section 4.2 exclusion criteria and Section 6.4.4 Worsening of 
asthma were updated accordingly.
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:

Section 4.1 Inclusion criteria:

Clarify the definition and documentation of asthma exacerbations in the inclusion 
criteria #6.

Align washout period of LABAs and xanthines with Table 5-2 and Table 5-4 in the 
inclusion criteria #07.


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
Clarify that repeat spirometry is permitted in cases where the spirometry did not meet 
percent predicted FEV1 and/or ATS/ERS criteria at Visit 101 in the inclusion criteria 
#07 and the exclusion criteria #22.

Section 4.2 Exclusion criteria:

Clarify that smoking exclusion also pertains to the use of e-cigarettes in the exclusion 
criteria #01.

Change prohibited period of LAMA use from 12 months to 3 months in the exclusion 
criteria #05 (Table 5-2 as well).

Clarify the exclusion criteria #07 and 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 the ECG prior to randomization (Visit 102) in the exclusion criteria #15 and 
#19, although no ECG is scheduled at Visit 102, any clinically significant abnormal 
ECG before Visit 102 (including unscheduled ECG) should lead to exclusion.

Include lactose as an example of hypersensitivity in the exclusion #21 since study 
drug is formulated using lactose blended dry powder.

Specify “severe” narcolepsy and/or insomnia in the exclusion criteria #26.

Exclusion criteria #35

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.

Specify that time between Visit 1 and Visit101 can be adapted according to the required 
wash-out from previous medication as per Table 5-2.

Add IL-5 inhibitor (e.g., mepolizumab) in Table 5-4.

Clarify the conditions in which anti-histamine use is permitted in Table 5-4.

Clarify the timing of urinalysis in Table 6-2.

Align the visit number where pregnancy test is required in Section 6.5.7.

Update of Section 7.2.2 for Serious Adverse Event reporting.

Update the follow-up period “up to 3 months after birth” in case that the female patient is 
pregnant while the patient is on the study treatment in Section 7.4.

Add the maximum duration of device usage in Appendix 1.

As Visit 299 does not have a specific e-CRF 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”.


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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).
Amendment 3 (08-Oct-2015)
Amendment rationale
The purpose of this amendment is to modify the ACQ score inclusion criteria from ACQ ≥2 
to ACQ ≥1.5 based on recent feedback from an external expert advisory board in September 
2015. Initial threshold of ≥2 was defined based on internal modelling and simulation data as 
well as published literature (Barnes 2014). However, expert advisory board members 
suggested that a threshold of 1.5 is more clinically meaningful for this patient population. 
Additionally, there is precedent for this threshold in recent asthma studies (Kerstjens 2015)
The Protocol Summary, Section 3.3 Rationale for dosing, Section 4. Inclusion criteria and
Section 9.4.6 Supportive analysis were updated accordingly.
Changes to the protocol
The described changes in the aforementioned amendment rationale are implemented 
throughout the protocol.
In addition, the following minor clarifications are included in this protocol amendment:

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 value of the best of the three daily PEF efforts over the past 14 days.

Add footnote on Table 6-1 Table of Assessment 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

Add clarification on number of days of hospitalization to number of hospitalization due to 
asthma exacerbation. 
 

Update the analysis method for the duration of asthma exacerbation in Section 9.5.1.6
Asthma exacerbations


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Amendment 2 (31-Aug-2015)
Amendment rationale
The purpose of this administrative Amendment was to replace the Appendix 1 - Instruction 
for use of Concept1 (picture 3 and 5 were missing and a black field was covering the text 
describing Concept1 picture) and the Appendix 5 - AQLQ-S (questions 26-31 of the 
questionnaire were missing and the page was blank and a black field was covering part of the 
question 32) which were incomplete due to a technical issue during protocol publication. 
The opportunity was taken to also clarify that:

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)

at Visit 102 spirometry does not include reversibility test (change in the Table 6-1 Table 
of Assessment)
Amendment 1 (03-Aug-2015)
Amendment rationale
The purpose of this Amendment is to clarify how the data for the ACQ7 instrument will be 
collected.  Questions 1-6 of the ACQ7 will be completed by the patients based on one week 
recall.  Item 7 will be completed by the investigator using the MasterScope spirometer at the 
study site. Derivation of rescue medication from the e-diary (6th item on ACQ7) will not be 
performed. The rationale is that the ACQ7 will be administered to patients in the manner in 
which it has been validated. The update was done on Table 5-5, Table 6-1, Section 6.4.2.1 and
Section 9.5.1.2.
The opportunity was taken to also:

Add the ACQ-7 in Appendix 4 and AQLQ-S questionnaire in Appendix 5

Update the asthma control e-diary questions in order to align to the exacerbations 
definitions in Appendix 7

Specify on Section 6.4.3 and Section 6.4.3.1 from which visit the measurements of rescue 
medication use, PEF, asthma symptoms and study medication compliance start.

Specify in Section 6.3 that the patient will have to enter on the e-diary the timing of study 
drug once a week.

Correct Table 6-1 as the peak flow meter is given on the same time than the e-diary at 
Visit 1 as it is part of the same device 

Make a few edit corrections.


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Protocol summary
Protocol number
CQVM149B2302
Title
A multi-center randomized 52-week treatment, double-blind, parallel group 
controlled study to compare the efficacy and safety of QVM149 with 
QMF149 in patients with asthma
Brief title
Safety and Efficacy study of QVM149 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 QVM149 (QVM149 150/50/80 µg and QVM149 
150/50/160 µg via Concept1) over two respective QMF149 doses (QMF149 
150/160 µg and QMF149 150/320 µg via Concept1 in poorly controlled 
asthmatics as determined by pulmonary function testing and effects on 
asthma control.
Primary Objective(s) 
The primary objective of this study is to demonstrate superiority of either 
QVM149 150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 
150/50/160 µg o.d. to QMF149 150/320 µg o.d. all delivered via Concept1 
in terms of trough FEV1 after 26 weeks of treatment in patients with 
asthma. 
Secondary 
Objectives
The key secondary objective is to demonstrate the superiority of either 
QVM149 150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 
150/50/160 µg o.d. to QMF149 150/320 µg o.d., all delivered via Concept1,
in terms of ACQ-7 after 26 weeks of treatment in patients with asthma.
Study design
52 weeks multi-center, randomized, double-blind, double-dummy, parallel-
group, active controlled study
Population
The study population will consist of approximately 2980 males and females 
with asthma.
Inclusion criteria
1.
Male and female adult patient ≥18 years old and ≤75 years.
2.
Written informed consent must be obtained before any study-related 
assessment is performed. 
3.
Patients with a diagnosis of asthma, (GINA 2015) for a period of at 
least 1 year prior to Visit 1 (Screening).
4.
Patients who have used medium or high dose of ICS/LABA 
combinations (Appendix 10) for asthma for at least 3 months and at 
stable medium or high doses of ICS/LABA 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/LABA. Patients with ACQ-7 score ≥1.5 at
Visit 101 and at Visit 102 (before randomization).

In case that the spirometry is repeated due to a failure of meeting 
criterion 7, ACQ-7 should be repeated as well.
6.
Patients with documented history of at least one asthma exacerbation 
which required medical care from a physician, ER visit (or local 


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equivalent structure) or hospitalization in the 12 months prior to Visit 1,
and required systemic corticosteroid treatment.

Previous asthma exacerbation in this context is based on patient´s
recall of unplanned need for medical care at any primary care
physician, pulmonologist, emergency room or hospital AND
requiring treatment with systemic corticosteroids due to asthma
exacerbation.

Investigator must use appropriate means to ensure the accuracy
of the patient’s exacerbation history (e.g., patient history at Visit 1
documented in source notes, pharmacy records, hospital records,
or chart records are acceptable).
7.
Pre-bronchodilator FEV1 of < 80 % of the predicted normal value for the
patient according to AST/ERS guidelines after withholding
bronchodilators (Table 5-2) at both Visits 101 and 102.

Withholding period of bronchodilators prior to spirometry:

SABA for ≥6 hrs

twice daily LABA (or fixed dose combination (FDC) of
ICS/LABA) for ≥12 hrs

once daily LABA (or FDC of ICS/LABA) for ≥ 24 hrs,

SAMA for ≥8 hrs

short acting xanthines for ≥ 12 hrs

long acting xanthines for ≥ 24 hrs.

A one-time repeat of percent predicated FEV1 (Pre-
bronchodilator) at Visit 101 and/or Visit 102 is allowed. 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 Visit 101.

A one time rescreening is allowed provided the patient returned to
the required treatment as per inclusion criteria 4.
8.
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 then one of the following criteria need to
be met :

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.
If reversibility is not demonstrated at Visit 101 (or after repeated/re-tested
assessment
in 
an
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 or not to use a spacer for the 


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reversibility testing.
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 treated with a LAMA for asthma within 3 months prior Visit 1 
(Screening).

Patients with narrow-angle glaucoma, symptomatic benign prostatic 
hyperplasia (BPH) or bladder-neck obstruction or severe renal 
impairment or urinary retention. BPH patients who are stable on 
treatment can be considered.

Patients who have had a respiratory tract infection or asthma 
worsening as determined by investigator within 4 weeks prior to Visit 1 
(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 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:

QVM149 (indacaterol acetate/ glycopyrronium bromide/MF) 
150/50/80 µg o.d. delivered as powder in capsules via Concept1 

QVM149 (indacaterol acetate/glycopyrronium bromide/MF) 
150/50/160 µg o.d. delivered as powder in capsules via Concept1 
The Comparative treatments are:

QMF149 (indacaterol acetate/MF) 150/160 µg o.d. delivered as powder 
in capsules via Concept1 

QMF149 (indacaterol acetate/MF) 150/320 µg o.d. delivered as powder 
in capsules via Concept1

salmeterol xinafoate/fluticasone propionate 50/500 µg b.i.d. delivered 
as powder via Accuhaler®
In addition the following placebo will be provided to enable the double-
dummy design of the study:

Placebo delivered as powder in capsules via Concept1
Placebo delivered as powder via Accuhaler®
Efficacy assessments

Spirometry

Health Status (PROs)


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
e-Diary

Peak Expiratory Flow

Rescue Medication Use

Asthma Exacerbation
Safety assessments

Medical history and physical examination including oropharyngeal 
examination

Vital signs

Hematology, Blood chemistry, Urinalysis

Evening plasma cortisol 

ECG

Adverse events and serious adverse events

Pregnancy (female patients)

Serious asthma outcomes (asthma-related hospitalizations, intubations 
or deaths)

CCV events and new onset of atrial fibrillation
Data analysis
The primary objective of this study is to demonstrate superiority of either 
QVM149 150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 
150/50/160 µg o.d. to QMF149 150/320 µg o.d. all delivered via Concept1 
in terms of trough FEV1 after 26 weeks of treatment in patients with 
asthma. 
The comparisons of QVM149 150/50/80 µg o.d. vs. QMF149 150/160 µg 
o.d. and QVM149 150/50/160 µg o.d. vs. QMF149 150/320 µg o.d., all 
delivered via Concept1, will be evaluated by testing the following null 
hypothesis (H0) versus the alternative hypothesis (Ha):
H0: QVM149 treatment group is equal to QMF149 treatment group in trough 
FEV1 at Week 26
Ha: QVM149 treatment group is not equal to QMF149 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, 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 estimated adjusted treatment difference (QVM149-QMF149) will be 
displayed along with the associated standard error, 2-sided 95% 
confidence interval (CI), and p-value (2-sided). 
The key secondary objective of this study is to demonstrate superiority of
either QVM149 150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 
150/50/160 µg o.d. to QMF149 150/320 µg o.d. all delivered via Concept1. 
in terms of ACQ-7 after 26 weeks of treatment in patients with asthma.
The key secondary endpoints will be analyzed using the same MMRM 
model (including all available visits) on the FAS as used for the primary 


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analysis but will include baseline ACQ-7 score instead of baseline FEV1.
Multiplicity Adjustment
To control the family-wise type-I error rate at the two-sided 5% significance 
level, a graphic testing procedure based on the generalized Simes test in 
Maurer et al (2011) is used. 
The family for the overall type-I error rate control contains total four 
hypotheses including: two hypotheses for the primary endpoint trough 
FEV1, and two hypotheses for the key secondary endpoint ACQ-7. Denote 
the two hypotheses for the primary endpoint as H1 and H2 for comparing
QVM149 150/50/80 µg o.d. versus QMF149 150/160 µg o.d. and QVM149 
150/50/160 µg o.d. versus QMF149 150/320 µg respectively. Similarly, 
denote the two hypotheses for the key secondary endpoint ACQ-7 as H3 
and H4, for comparing QVM149 150/50/80 µg o.d. versus. QMF149 
150/160 µg o.d. and QVM149 150/50/80 µg o.d. versus. QMF149 
150/320 µg o.d. respectively.
Below is a brief description of the testing procedure based on the 
generalized Simes test in Maurer et al (2011).
Let p1, p2, p3, p4 be the corresponding p-values (2-sided) of the four 
hypotheses of H1, H2, H3, and H4. 
Step 1: Retain all four hypotheses if pi<=0.05 AND the observed treatment 
difference for the corresponding pi is in the wrong direction (i.e. QMF149 is 
performing better than QVM149) for ANY i=1, 2, 3, 4, stop here; otherwise 
go to step2;
Step 2: Reject all four hypotheses if pi<0.05 for ALL i=1, 2, 3, 4 and stop 
here; otherwise go to step 3;
Step 3: If neither step 1 or 2 applies, perform a closed successive weighted 
Bonferroni test as given in Figure 9-1. The initial weights of 0.5 to H1 
(corresponding to 0.025 alpha level, 2-sided) and 0.5 to H2 (corresponding 
to 0.025 alpha level, 2-sided) were assigned. 
Here is a brief summarization of the successive weighted Bonferroni test 
based on Bretz et al (2011): If null H1 is rejected at the initial significance 
level of 0.025, then H3 can be tested at the significance level of 0.025. 
Similarly, if null H2 is rejected at the initial significance level of 0.025, then 
H4 can be tested at the significance level of 0.025. If neither primary null 
hypothesis can be rejected at the initial significance levels, then the testing 
stops and efficacy cannot be claimed for neither of the doses and 
endpoints. Otherwise the graph is sequentially updated with reallocated 
weights after each hypothesis is rejected. 
In addition, if efficacy can be shown for one of the doses on both the 
primary and key secondary endpoint at the initial significance level, the 
associated weight is passed on to the other dose for further testing.
Key words
QVM149, QMF149, asthma


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1
Introduction
1.1
Background 
Asthma is a chronic inflammatory disorder of the airways associated with airways hyper 
responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, 
and coughing, particularly at night or in the early morning. These episodes are usually 
associated with widespread but variable airflow obstruction within the lung that is often 
reversible either spontaneously or with treatment. Airflow limitation occurs as a result of 
obstruction or narrowing of the airways, when exposed to precipitating factors.  Exacerbations 
of asthma are episodic whereas inflammation is chronic (GINA 2015).
Despite existing therapies there is still significant unmet medical needs in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years (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).
Recently, tiotropium (Spiriva® Respimat®) has been approved in EU as an add-on 
maintenance bronchodilator treatment in adult patients (≥18 years) with asthma who are 
currently treated with the maintenance combination of inhaled corticosteroids (≥800µg 
budesonide/day or equivalent) and long-acting beta2-agonists and who experienced one or 
more severe exacerbations in the previous year.
Following tiotropium regulatory approval in asthma, GINA 2015 guideline recommends 
tiotropium as a new add-on option on top of the preferred controller choice for steps 4 and 5 
in patients aged with a history of exacerbations. The preferred controller choice in asthma step 
4 is med/high ICS/LABA and in step 5 add –on treatment e.g. anti-Ig E.
QVM149 is a fixed-dose combination of indacaterol acetate (inhaled LABA with 24 hour 
duration of action), glycopyrronium bromide (inhaled LAMA with 24 hours duration of 
action), and mometasone furoate (MF, ICS) in development for once-daily maintenance 
treatment of asthma GINA step ≥4. All three mono-components, indacaterol maleate, 
glycopyrronium bromide and MF have previously been developed as individual drugs for 
either COPD or asthma. Novartis is developing QVM149 (LABA/ LAMA/ ICS) fixed dose 
combination (FDC) as a lactose-blended inhalation powder to be delivered via Concept1 
(Breezhaler®), a single dose dry powder inhaler (SDDPI) for maintenance treatment for severe 
asthma (GINA 2015 Step ≥4).
In parallel, Novartis is developing QMF149, which is a fixed dose combination of 
mometasone furoate (MF) and indacaterol, in the Concept 1 device.
Data from mono-components: 
QVM149 is being developed in parallel with QMF149 (indacaterol acetate/MF) and existing 
efficacy and safety data for the three mono-components of the QVM149 FDC as well as for 
the two combinations indacaterol/mometasone (QMF149) and glycoppyronium/indacaterol 
(Ultibro®) support investigation in Phase III.


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Indacaterol maleate, delivered via Concept1, a single dose dry powder inhaler (SDDPI) 
(Onbrez® Breezhaler®), is approved in over 110 countries worldwide for the once daily 
maintenance bronchodilator treatment of airflow obstruction in patients with COPD.
Treatment guidelines state that LABAs are most effective when combined with an ICS (GINA 
2015). The Phase III clinical development of indacaterol maleate that included studies in 
patients with asthma (who were receiving background ICS therapy), demonstrated that 
indacaterol maleate was effective and well-tolerated. A study in adolescent and adult patients 
with moderate to severe persistent asthma showed that doses of up to 600 µg o.d. over a 26-
week treatment period (when administered with concomitant ICS therapy) was well-tolerated 
and resulted in effective bronchodilation which was superior to that provided by salmeterol 
(CQAB149B2338).
Studies comparing the indacaterol maleate salt with the acetate salt found that the alternative 
salts were associated with a lower incidence of post-inhalation cough (CQAB149B2102) with 
no impact on efficacy, safety or systemic exposure (CQAB149D2301).
Glycopyrronium bromide (50 μg once daily in a lactose-based formulation) is registered in the 
EU since 2012 as Seebri®
Breezhaler®
(Concept1) for the treatment of COPD. 
Glycopyrronium bromide 50 μg has demonstrated clinically meaningful and statistically 
significant improvements in lung function in COPD patients which is sustained over 24 hours 
and provides significant symptomatic benefits with a favorable safety and tolerability profile.  
The fixed dose combination of indacaterol maleate and glycopyrronium bromide is also 
registered in the EU as Ultibro®, Breezhaler® (QVA149) with the same doses as proposed for 
QVM149. Glycopyrronium bromide has been studied in adults and demonstrated optimal 
bronchodilation from the first dose and efficacy was maintained on once-daily dosing for 
treatment periods of up to a year, with good safety and tolerability. 
MF is marketed in inhalation, nasal, cream, ointment and lotion formulations. The inhalation 
powder formulation which may be administered once or twice daily is marketed as a multi 
dose dry powder inhaler (MDDPI) called Asmanex® Twisthaler ® for the treatment of asthma. 
Asmanex® Twisthaler ® is currently approved in the United States for the treatment of asthma 
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. 
QVM149:
The MF doses in QMF149 program with Concept1 device are comparable to MF 200 µg, 
400 µg and MF 800 µg (400 µg b.i.d.) in Twisthaler® device as demonstrated in study 
(CQMF149E2101, Vaidya S et al, 2012) and after in-vitro fine particle mass adjustment. 
In a 4-week study in patients with persistent asthma (Study CQMF149E2201), MF doses of 
80 μg and 320 μg delivered once daily via Concept1 showed comparable efficacy and 
systemic exposure to MF doses of 200 μg and 800 μg (2 x 400 μg) delivered once daily via 
Twisthaler® confirming the selected doses for MF Concept1 are appropriate for further 
QMF149 Concept1 development.
The nominal doses of MF are 80 µg and 160 µg in the QVM149 FDC to ensure that the fine 
particle mass (FPM, in-vitro aerosol performance) in the lactose blend formulation for the 
triple FDC is similar to the nominal MF doses of 160 µg and 320 µg for QMF149 Concept1 


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program, respectively. In this current study the mid and high doses of MF (see Appendix 10) 
taken forward in QVM149 are 80 µg and 160 µg which are comparable to the MF doses of 
160 µg and 320 µg in the QMF149 products in QMF149B2301.
No adjustments to the doses of indacaterol acetate or glycopyrronium bromide in the FDC 
combinations were required.
Table 1-1
Comparison of nominal MF doses in Asmanex Twisthaler, QMF149 
and QVM149 drug products delivered by Concept1 (Breezhaler)
MF dose 
level
MF in Asmanex delivered by 
Twisthaler
MF in QMF149 delivered by 
Concept1 
MF in QVM149 delivered by 
Concept1 
Mid
400 µg 
160 µg
80 µg
High
800 µg 
320 µg
160 µg
The role of long-acting anticholinergics on top of mid and high dose ICS and LABA (FDC) as 
controller medication (QVM149) is supported based on the asthma clinical trial data with 
tiotropium on top of ICS and LABA/ICS in patients with severe persistent asthma (Kerstjens 
2012).
Given that literature suggests that many asthma patients have poorly controlled disease 
despite currently available controller medications and there is increasing evidence of lung 
function benefit and improved control with triple combination therapy, further investigation of 
QVM149 triple therapy is supported.
Additional information to QVM149 can be found in the QVM149 Investigator’s brochure.
1.2
Purpose 
The purpose of the trial is to evaluate the efficacy and safety of two different doses of 
QVM149 (QVM149 150/50/80 µg and QVM149 150/50/160 µg via Concept1) over two 
respective QMF149 doses (QMF 150/160 µg and QMF 150/320 µg via Concept1 in poorly 
controlled asthmatics as determined by pulmonary function testing and effects on asthma 
control.
2
Study objectives
The primary and key secondary objectives will consider the following 2 comparison groups:

QVM149 150/50/80 µg o.d. compared with QMF149 150/160 µg o.d. both delivered 
via Concept1

QVM149 150/50/160 µg o.d. compared with QMF149 150/320 µg o.d, both delivered 
via Concept1
The secondary objectives will consider the following 4 comparison groups: 

QVM149 150/50/80 µg o.d. compared with QMF149 150/160 µg o.d. both delivered 
via Concept1

QVM149 150/50/160 µg o.d. compared with QMF149 150/320 µg o.d. both delivered 
via Concept1

QVM149 150/50/80 µg o.d. compared with salmeterol xinafoate /fluticasone 
propionate 50/500 µg b.i.d. via Accuhaler®


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
QVM149 150/50/160 µg o.d. compared with salmeterol xinafoate /fluticasone 
propionate 50/500 µg b.i.d. via Accuhaler®
2.1
Primary objective
The primary objective of this study is to demonstrate superiority of either QVM149 
150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 
150/320 µg o.d, all delivered via Concept1 in terms of trough Forced Expiratory Volume in 1 
second (FEV1) after 26 weeks of treatment in patients with asthma.
2.2
Key Secondary objectives
The key secondary objective of this study is to demonstrate superiority of either QVM149 
150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 
150/320 µg o.d. all delivered via Concept1 in terms of asthma control as assessed by the 
Asthma Control Questionnaire (ACQ-7) after 26 weeks of treatment in patients with asthma.
2.3
Secondary Objectives
The secondary objectives will consider the 4 comparison groups explained above and will 
evaluate the following efficacy endpoints:

Trough FEV1 after 52 Weeks treatment

Pre-dose FEV1 and FVC (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) over 52 weeks

Percentage of days with no symptoms, the percentage of days with no awakenings and the 
percentage of mornings with no symptoms on rising over 52 weeks of treatment

Percentage of days without rescue medication usage (salbutamol(albuterol) as recorded by 
e-diary over 26 and 52 weeks of treatment,

Percentage of patients achieving the minimal important difference (MID) ACQ ≥0.5 at 
Week 26 and Week 52

To evaluate the efficacy 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 hospitalization for asthma exacerbation

Time to first asthma exacerbation by exacerbation category

Annual rate of asthma exacerbations excluding measurements in patients requiring 
chronic corticosteroid use after an exacerbation (beyond permitted steroid taper for 
exacerbation) by exacerbation category

Duration in days of asthma exacerbations by exacerbation category

Percentage of patients with at least one asthma exacerbation by exacerbation category


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!
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, as an additional secondary comparison, QVM149 150/50/80 μg o.d. and
QVM149 150/50/160 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
!
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)
and CCV events/atrial fibrillation over 52 weeks of treatment
!
Adverse events, vital signs, ECG and laboratory analysis (haematology, blood
chemistry including glucose and potassium, urinalysis) and treatment discontinuation
due to adverse event over 52 weeks of treatment.
!
Plasma evening cortisol over 52 weeks of treatment
PPI


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3
Investigational plan
3.1
Study design
This study uses a 52 week treatment, randomized, double-blind, double-dummy, parallel-
group design. 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 LABA/ICS for at least 3 months and been on stable mid 
or high dose LABA/ICS for at least 1 month prior to Visit 1. Once patient’s concurrent 
medications comply with the requirements of the study (Table 6-1), patients will enter a Run-
In epoch at Visit 101. At Visit 101 all patients will receive an open-label “medium” dose of 
ICS combined with LABA, salmeterol xinafoate/fluticasone propionate 50/250 μg b.i.d., 
which will be used throughout the Run-In epoch and stopped at Visit 102 (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 medications at the time of 
Visit 1, the time period between Visit 1 and Visit 101 may be shorter than 2 weeks. At Visit 1, 
all patients will be given salbutamol/albuterol to use as rescue medication throughout the 
study and will be given 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 be record PEF. 
PPI


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The Run-In epoch is of 2 weeks 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 once spirometry assessments meet inclusion criteria 
(ATS/ERS quality criteria, FEV1 % predicted normal value, and reversibility) as per 
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) ratio: 

QVM149 150/50/80 µg o.d. delivered via Concept1

QVM149 150/50/160 µg o.d. delivered via Concept1

QMF149 150/160 µg o.d. delivered via Concept1 

QMF149 150/320 µg o.d. delivered via Concept1

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 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 weeks 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 days window. All patients will be required to attend the clinic 
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 Visits 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/asthma exacerbation, safety laboratory exams as needed, concomitant 
medication)
A final telephone contact must be conducted at 30-days after last treatment date (telephone 
Visit 301). Clinic Visit 214 Day 365 (in the morning) is the last dosing day of the treatment 
period. Day 365 the second part of the Visit 214 will take place for trough measurements to be 
made.
The first dose of study medication will be administered at the clinic in the evening (between 
5:00 and 8:00 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. 


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 Evening plasma cortisol will be measured on all patients only at Visits 201, 207 and 214. 
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
2 Open-label salmeterol xinafoate/fluticasone propionate 50/250 µg b.i.d. via Accuhaler®
3.2
Rationale of study design
This study is a pivotal, multi-center, randomized, double-blind, double-dummy, parallel-group, 
phase III study with a 52 week treatment epoch. In order to preserve the integrity of the study, 
a randomized, double-blind study design is used. This design is well-established in respiratory 
clinical trials and 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, GINA step ≥4, whose symptoms are inadequately controlled with mid or
high ICS/LABA doses (GINA, 2015).
The primary objective of the trial is to evaluate the efficacy and safety of two different doses 
of QVM149 (QVM149 150/50/80 µg and QVM149 150/50/160 µg via Concept1) over two
respective QMF149 doses (QMF149 150/160 µg and QMF149 150/320 µg via Concept1) in 
poorly controlled asthmatics as determined by pulmonary function testing, effects on asthma 
Double blind treatment Epoch (52 weeks)
End of Run-in Visit 102
Randomization Visit 201
Screening
Epoch 1
Day -28 to 
Day -14
salmeterol xinafoate /fluticasone propionate 
50/500 µg b.i.d. via Accuhaler®
Day 1 to Day 365
QVM149 150/50/160 µg via 
Concept1 o.d.
Run-in 
Epoch
Open-label
LABA/ICS2
Day -14 to 
Day -1
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QMF149 150/160 µg via Concept1 o.d
QVM149 150/50/80 µg via Concept1 
o.d.
QMF149 150/320 µg via Concept1 o.d
Follow-up
Epoch
30 days
Visit 1
Visit 
101
Visit 301
Rescue medication
Study Completion Visit 214


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control and rescue medication use. In addition secondary endpoints will provide data on 
asthma exacerbations, quality of life, 
 will establish the long term 
safety of the two QVM149 doses in this specific asthma patient population.
The analyses will be performed in a sample size of approximately 2980 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 patients’ safety throughout the study. Details are given in 
Section 8.4
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
QVM149 will be in a similar lactose-based formulation and the same inhalation device as 
QMF149 and selection of the QVM149 combination product doses (150/50/80 µg o.d. and 
150/50/160 µg o.d.) for evaluation in Phase III for asthma is based on the doses of the 
constituent monotherapies which have been approved for either COPD or asthma.
Indacaterol acetate:
Indacaterol maleate at a dose of 150 µg o.d. is marketed for the maintenance treatment of 
COPD. A dose-ranging study of indacaterol maleate in asthmatic patients demonstrated that a 
dose of 150 µg o.d. was safe and effective (Study CQAB149B2357). The acetate salt of 
indacaterol was found to result in a lower incidence of the post-inhalation cough, observed for 
indacaterol maleate, without impact on efficacy or safety CQAB149D2301. The dose of 
indacaterol acetate 150 µg was also confirmed in Study CQMF149E2203 in adult asthma 
patients where indacaterol acetate 150 μg and 75 μg delivered via Concept1 to placebo were 
investigated. Indacaterol acetate 150 µg showed positive trends in terms of trough FEV1, PEF 
and rescue medication use compared with indacaterol acetate 75 μg. In study QMF149A2210, 
QMF149 150/160 µg o.d. showed beneficial effects on asthma exacerbations in terms of the 
time to first exacerbation and the cumulative incidence of serious asthma exacerbations. 
Therefore, a dose of indacaterol acetate 150 µg o.d. has been selected for use in the QVM149 
program. 
For indacaterol, the acetate salt will be used due to lower incidence of post-inhalation cough. 
Data suggests comparable efficacy between the acetate and maleate salts (CQAB149D2301).
Mometasone furoate:
Since available data for the MF component exists in the Twisthaler® device, a 3 step bridging 
approach was conducted to determine MF dose for Concept1 which is comparable to each of 
the registered daily doses of Asmanex® Twisthaler® (mometasone furoate, inhalation powder). 
This is due to difference in device performance characteristics between the Twisthaler® and 
Concept1 
devices. 
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). 


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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. 
In summary, MF doses of 200 µg o.d, 400 µg o.d. and 400 µg b.i.d. delivered by Twisthaler®
are comparable with MF doses of 80 µg o.d, 160 µg o.d. and 320 µg o.d., respectively in 
QMF149 delivered by Concept1. 
For QVM149 program, as a result of a component interaction, an increase in the MF fine 
particle mass (FPM) in the QVM149 combination product compared to the corresponding 
same nominal MF dose in QMF149 (matched to Asmanex® Twisthaler®) was observed. To 
adjust for this, the nominal doses of MF has been reduced to, 80 µg o.d. and 160 µg o.d. to 
ensure that the fine particle mass (FPM, in-vitro aerosol performance) in the lactose blend 
formulation for the triple FDC is comparable to the nominal MF doses of 80 µg o.d., 160 µg 
o.d. and 320 µg o.d. for QMF149 program, respectively. Therefore 400 µg MF via 
Twisthaler® is comparable with 160 µg MF in QMF in Concept 1 and with 80 µg QVM149 
via Concept1; all provide similar fine particle mass and thereby expected to provide similar
lung and systemic exposure, since oral bioavailability of MF is low.
Glycopyrronium bromide:
The dose chosen for glycopyrronium bromide of 44 μg (expressed as dose active moiety 
delivery by the mouthpiece of the inhaler) is the one first approved in the EU on 28- Sep-2012 
for the indication of maintenance bronchodilator treatment to relieve symptoms in adult 
patients with COPD. Outside the EU, the dose of Seebri® Breezhaler® is generally expressed 
as the dose of active moiety in the capsule, i.e. 50 μg.
Although no data exists for glycopyrronium bromide in asthma, extensive data from the Phase 
III development program in COPD supports the efficacy and safety of glycopyrronium 
bromide 50 µg once daily. It has demonstrated clinically meaningful and statistically 
significant improvements in lung function in COPD patients which were sustained over 24 
hours and provided significant symptomatic benefits with a favorable safety and tolerability 
profile. Lung function improvements were comparable to tiotropium 18 µg administered via 
HandiHaler®.
Tiotropium 5ug once daily has recently been approved in Europe for treatment of asthma as 
add on to high dose LABA/ICS in patients with a history of exacerbations. It is recommended 
by GINA guideline (GINA 2015) as an add-on option (on top of the preferred controller 
choice) for Steps 4 and 5 in patients aged ≥18 years with a history of exacerbations.


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It is expected that glycopyrronium bromide 50 µg once-daily will provide similar efficacy in 
an asthma population. 
The two LAMAs, glycopyrronium and tiotropium both demonstrate similar kinetic selectivity 
for M3 over M2 receptors, which is important for their similar long and sustained 
bronchodilator effects (Testi 2014). 
Based on the available data glycopyrronium bromide 50 µg is considered an appropriate dose 
to bring forward into Phase III asthma program as part of triple FDC QVM149 
(LABA/LAMA/ICS).
This current study will compare two doses of QVM149 150/50/80 µg and 150/50/160 µg with 
the respective two doses of QMF149 150/160 µg and QMF149 150/320 µg. The purpose is to 
investigate the additional benefit of glycopyrronium bromide 50 µg on top of mid and high 
ICS/LABA doses (FDCs) in this population of patients whose asthma is inadequately 
controlled with mid/high ICS/LABA (symptomatic patients with an ACQ ≥1.5).
This study is designed to provide efficacy and safety data over a 52 week treatment epoch 
which is considered to be sufficient duration to demonstrate treatment differences of the two 
QVM149 doses, QVM149 150/50/80 µg and QVM149 150/50/160 µg o.d. delivered via 
Concept1 vs the two QMF149 doses, QMF149 150/160 µg as well as QMF149 150/320 µg 
o.d. delivered via Concept1 in terms of lung function, symptom control and other endpoints.
3.4
Rationale for choice of comparator
QMF149 was selected as the comparator in this study in order to demonstrate the additional 
benefit of glycopyrronium bromide on top of QMF149 medium and high dose of MF in 
patients whose asthma is inadequately controlled with mid/high dose ICS/LABA.
Two doses of QMF149 (150/160 µg and 150/320 µg via Concept1) as comparator will be 
used based on previous available data.
The early QMF149 development program in Twisthaler® consisted of two dose-ranging 
studies of indacaterol maleate Twisthaler® (one in asthma and one in COPD) and eight 
clinical studies of FDC QMF149 Twisthaler® to assess the efficacy, safety tolerability and 
pharmacokinetics of multiple doses of indacaterol and QMF149 via Twisthaler®. 
In study CQMF149A2210, 1508 asthmatic patients including 4.4% of adolescents were 
treated. 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 safety study demonstrated that both QMF149 and MF had beneficial effects 
on asthma exacerbations 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, with treatment differences in trough FEV1 between the 
QMF149 and MF treatment groups of 100 to 140 mL in favor of QMF149 throughout the 
study period (Beasley R et al, 2012).


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Salmeterol xinafoate /fluticasone propionate was also selected as a comparator as it is widely 
used standard of care in asthma treatment. Salmeterol xinafoate /fluticasone propionate high 
dose 50/500 µg b.i.d. delivered by DPI (dry-powder inhaler) is marketed as Seretide®
Accuhaler® or Seretide® Diskus® depending on the countries for the treatment of asthma in 
adults and adolescents 12 years and older.
3.5
Purpose and timing of interim analyses/design adaptations
It is planned that the independent data monitoring committee (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.
For Primary Analysis at Week 26
The primary and key secondary endpoints of CQVM149B2302 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.


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3.6
Risks and benefits
The favorable benefit-risk ratio based on QMF149 in asthma and glycopyrronium bromide 
(NVA237) in COPD as well as the so far acquired knowledge about LAMA (tiotropium) on 
top of LABA/ICS in asthma is the rationale to conduct this study with glycopyrronium 
bromide on top of QMF149 as a FDC in asthma.
Dual bronchodilation with ICS controller would be expected to achieve good symptom 
control, minimize airflow obstruction, minimize risk of exacerbations, and hospitalizations in 
this population. Use of multiple, often different devices represents a significant burden for 
asthma patients. Availability of three effective once-daily controller medications in a single 
device may offer advantages in terms of improved adherence and convenience.
Kerstjens et al showed that tiotropium on top of high dose ICS/LABA improved lung function 
and significantly prolonged time to first severe exacerbation (Kertjens 2012). 
The benefit of adding a muscarinic antagonist in the treatment of poorly controlled asthma is 
supported by two replicate studies which compared tiotropium to placebo (Kertjens 2012). 
The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 
226 days), with an overall reduction of 21% in the risk of a severe exacerbation. 
The available asthma clinical trial data suggest that a LAMA may confer bronchodilator 
effects in terms of improved lung function when used in addition to ICS alone or in 
conjunction with LABA/ICS (i.e., “free combination” or “loose” triple therapy) (Fardon 2007, 
Peters 2010, Bateman 2011, Kerstjens 2011, Kerstjens 2012, Guyer 2013). A review 
evaluating the efficacy profile of a LAMA (tiotropium) as add-on therapy to ICS or 
LABA/ICS in patients with uncontrolled moderate to severe persistent asthma concluded that 
the addition of a LAMA resulted in significant improvements in lung function (FEV1 and 
peak expiratory flow) (Befekadu 2014).
Thus, triple therapy could provide an alternative treatment option to theophylline, systemic 
corticosteroids or biologics for GINA Step ≥4 asthma patients inadequately controlled on 
medium- or high-dose LABA/ICS.
There is an extensive evidence of the efficacy and safety of the two dual combinations 
indacaterol acetate/mometasone furoate (QMF149) and indacaterol maleate/glycopyrronium 
bromide (Ultibro®) which is part of the FDC triple QVM149 components. A QMF149 
Twisthaler® program in phase II along with further phase II studies in Concept1 suggest a 
favorable efficacy and safety of the QVM149 compound.
In one large phase II event driven trial with a duration up to 68 weeks in over 1500 asthma 
adults and adolescent patients, QMF149 (indacaterol acetate/mometasone furoate 500/400 μg
delivered by Twisthaler® comparable to indacaterol acetate/mometasone furoate 150/160 μg
delivered by Concept1) a favorable efficacy and safety profile of QMF149 over MF was 
shown (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 
(CQMF149E2203), a device bridging study with MF from Twisthaler® to Concept1 
(CQMF149E2201) and an efficacy and safety study with QMF149 in Concept1 in moderate to 
very severe COPD (CQMF149F2202). The studies showed statistically significant 


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improvements in lung function and symptomatic endpoints including exacerbations and 
confirmed a favorable and robust efficacy and safety profile in phase II.
Glycopyrronium bromide 50 μg is approved for the maintenance bronchodilator treatment to 
relieve symptoms in adult patients with COPD. Evidence for the efficacy and safety of 
glycopyrronium bromide has been extensively provided via studies in 5,489 healthy subjects 
and COPD patients across 22 completed studies. 
Addition of LAMA (tiotropium 5 µg Respimat®) to ICS/LABA is now a recommended 
treatment option in GINA 2015 guideline for step 4 onwards. As glycopyrronium and 
tiotropium (HandiHaler®) demonstrated comparable efficacy and safety in COPD, it is 
reasonable to expect that both drugs would show similar risk/benefit profiles in asthma.
Overall, as concluded from the clinical studies glycopyrronium bromide o.d. was safe and 
well tolerated by the patients and comparable to open label tiotropium. Reporting rates for 
known class effect AEs for anti-cholinergic drugs were low and generally consistent with 
those expected for this class (i.e. constipation, urinary retention, glaucoma, dry mouth). No 
enhanced risk of cardio- or cerebrovascular events relative to placebo was apparent, and the 
death rate in glycopyrronium bromide at all doses was lower than that observed in the placebo 
group.
In summary, as the benefit risk profile of glycopyrronium bromide has shown to be positive in 
COPD patients in which there are more comorbidities than asthma disease, the safety profile 
in asthma population (which is generally younger with less co-morbidities) is expected to also 
be positive.
In this current Phase III pivotal study, two QVM149 doses will be compared to two QMF149 
doses and to salmeterol xinafoate/fluticasone propionate (Seretide®) during 52 weeks of 
treatment period. Participating patients in this study will be randomized to receive either one 
of the two doses of QVM149 or one of the two doses of QMF149 or salmeterol 
xinafoate/fluticasone propionate. The use of other controller medications, i.e. sustained 
release theophylline, leukotriene modifiers and monoclonal antibody (IgE inhibitor, IL-5 
inhibitor) in stable doses will be permitted due to the severity of the disease and as treatment 
guideline (GINA 2015). The expected potential benefit for the patient include an 
improvement in the pulmonary function, a potential translation into better asthma control like 
reductions in symptoms, rescue medication use and lower frequency/ severity of asthma 
exacerbations, and 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. Therefore, investigators may have an early indication of worsening 
symptoms and will be able to monitor the patient closely throughout the study. 


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In line with current medical treatment guidelines, all patients participating in the study will 
receive active “controller” treatment (minimum of ICS/LABA) 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, will any patient be without treatment for asthma.
The risk to the patients in the study is that QVM149 and QMF149 are both under 
development and therefore it is possible that unexpected safety issues may be identified 
(Section 5.4.9) and the risk will be minimized by compliance with the eligibility criteria and 
close clinical monitoring of patients. The risks of side effects from the study medication are 
those known for the individual compounds indacaterol acetate, glycopyrronium bromide and 
MF. Up to now no additional risks have been identified which might occur when the three 
components are administered concurrently or from the same inhaler. Detailed risk-benefit 
information can be obtained from the QVM149 and 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/LAMA/ICS or 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). Patients will receive 
well written instructions as to how to contact the investigator in the event of worsening of 
their asthma symptoms. The investigator should discontinue study treatment for a given 
patient and/or withdraw the patient from the study if, on balance, he/she believes that 
continuation would be detrimental to the patient’s well-being. Patients are also instructed that 
they can withdraw from the study at any time, and for any reason.
In summary, based on available data of components, it is anticipated that QVM149 
150/50/80 µg and QVM149 150/50/160 µg will have a favorable benefit to risk profile in 
patients with asthma. 
4
Population
The study population will consist of approximately 2980 male and female patients with 
asthma.
It is anticipated that approximately 4967 patients will need to be screened in order to 
randomize approximately 2980 patients into the five treatment groups of the study with a 
randomization ratio of 1:1:1:1:1, (i.e. approximately 596 patients in each of the treatment 
groups). It is intended that at least 2680 patients (536 patients per treatment group) will have 
completed 26 weeks of treatment for analysis of primary and key secondary objectives. 
Drop-outs after randomization will not be replaced. This study will enroll multi-nationally and 
patients will be stratified by region to achieve improved homogeneity within each stratum.
 


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4.1
Inclusion criteria
1. Male and female adult patient ≥18 years old and ≤75 years.
2. Written informed consent must be obtained before any study-related assessment is 
performed.
3. Patients with a diagnosis of asthma, (GINA 2015) for a period of at least 1 year prior to 
Visit 1 (Screening).
4. Patients who have used medium or high dose of ICS/LABA combinations (Appendix 10) 
for asthma for at least 3 months and at stable medium or high doses of ICS/LABA 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/LABA. Patients with ACQ-7 score ≥1.5 at Visit 101 and at Visit 102 (before 
randomization).

In case that the spirometry is repeated due to a failure of meeting criterion 7, ACQ-7 
should be repeated as well.
6. Patients with documented history of at least one asthma exacerbation which required 
medical care from a physician, ER visit (or local equivalent structure) or hospitalization in 
the 12 months prior to Visit 1, and required systemic corticosteroid treatment.

Previous asthma exacerbation in this context is based on patient´s recall of unplanned 
need for medical care at any primary care physician, pulmonologist, emergency room 
or hospital, AND treatment with systemic corticosteroids due to asthma exacerbation. 

Investigator must use appropriate means to ensure the accuracy of the patient’s 
exacerbation history (e.g., patient history at Visit 1 documented in source notes, 
pharmacy records, hospital records, or chart records are acceptable).
7. Pre-bronchodilator FEV1 of < 80 % of the predicted normal value for the patient according 
to ATS/ERS guideline after withholding bronchodilators (Table 5-2) at both visits 101 and 
102.

Withholding period of bronchodilators prior to spirometry: 

SABA for ≥6 hrs

Twice daily LABA (or FDC of ICS/LABA) for ≥12 hrs

Once daily LABA (or FDC of ICS/LABA) for ≥24 hrs

SAMA for ≥8 hrs

Short acting xanthines for ≥ 12 hrs

Long acting xanthines for ≥ 24 hrs

Washout period of each drug should be kept as close as possible as above and should 
not be longer. If longer washout period is needed due to scheduling issues, please 
contact Novartis Medical monitor.

A one-time repeat of percentage predicated FEV1 (Pre-bronchodilator) at Visit 101 
and/or Visit 102 is allowed in an ad-hoc visit. Repeat of Visit 101 spirometry should 
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 once spirometry assessment met 
inclusion criteria (ATS/ERS quality criteria, FEV1 % predicted normal value, and 
reversibility) as per equipment.


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
A one-time rescreening is allowed in case the patient fails to meet the criteria at the 
repeat, provided the patient returned to the required treatment as per inclusion criteria 
4
8. 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 then one of the following criteria need to be met:

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.

If reversibility is not demonstrated at Visit 101 (or after repeated assessment in an ad-
hoc visit) and historical evidence of reversibility/bronchoprovocation is not available 
(or was not performed according to the American Thoracic Society/European 
Respiratory Society (ATS/ERS) guidelines patients must be screen failed.

Spacer devices are permitted during reversibility testing only. The Investigator or 
delegate may decide whether or not to use a spacer for the reversibility testing.
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.). This includes nicotine inhalers such as e-cigarettes at time of Visit 1.
2. Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 6 weeks of Visit 1 (Screening). If patients 
experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or 
emergency room visit between Visit 1 and Visit 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 treated with a LAMA for asthma within 3 months prior to Visit 1 (Screening).
6. Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia (BPH) or 
bladder-neck obstruction or severe renal impairment or urinary retention. BPH patients 
who are stable on treatment can be considered.
7. 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.


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8. 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.
9. Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic 
sinusitis) which in the opinion of the investigator may interfere with the study evaluation 
or optimal participation in the study.
10. Patients with a history of chronic lung diseases other than asthma, including (but not 
limited to) chronic obstructive pulmonary disease, sarcoidosis, interstitial lung disease, 
cystic fibrosis, clinically significant bronchiectasis and active tuberculosis.
11. Patients with Type I diabetes or uncontrolled Type II diabetes.
12. Patients who have a clinically significant laboratory abnormality at Visit 101.
13. Use of other investigational drugs within 30 days or 5 half-lives of enrollment, until the 
expected pharmacodynamics effect has returned to baseline, whichever is longer.
14. Patients who, either in the judgment of the investigator or the responsible Novartis 
personnel, have a clinically significant condition such as (but not limited to) unstable 
ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular 
failure arrhythmia, uncontrolled hypertension, cerebrovascular disease, psychiatric disease, 
neurodegenerative diseases, or other neurological disease, uncontrolled hypo- and 
hyperthyroidism and other autoimmune diseases, hypokalemia, hyperadrenergic state, or 
ophthalmologic disorder or patients with a medical condition that might compromise 
patient safety or compliance, interfere with evaluation, or preclude completion of the 
study.
15. Patients with paroxysmal (e.g., intermittent) atrial fibrillation are excluded. Patients with 
persistent atrial fibrillation as defined by continuous atrial fibrillation for at least 6 months 
and controlled with a rate control strategy (i.e., selective beta blockers, calcium channel 
blocker, pacemaker placement, digoxin or ablation therapy) for at least 6 months may be 
considered for inclusion. In such patients, atrial fibrillation must be present at the run-in
visit (Visit 101) with a resting ventricular rate < 100/min.  At Visit 101 the atrial 
fibrillation must be confirmed by central reading.
16. Patients with a history of myocardial infarction (this should be confirmed clinically by the 
investigator) within the previous 12 months.
17. Concomitant use of agents known to prolong the QT interval unless it can be permanently 
discontinued for the duration of study 
18. Patients with a history of long QT syndrome or whose QTc measured at Visit 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).
19. Patients who have a clinically significant ECG abnormality at Visit 101 (Start of Run-In 
epoch) and 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.
20. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.


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21. 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.
22. Patients who have not achieved an acceptable spirometry result at Visit 101 in accordance 
with ATS/ERS criteria for acceptability and repeatability. A one-time repeat spirometry is
allowed in an ad-hoc visit scheduled as close as possible from the first attempt (but not on 
the same day) if the spirometry did not qualify due to ATS/ERS criteria at Visit 101 
and/or Visit 102. If the patient fails the repeat assessment, the patient may be rescreened
once, provided the patient returns to the required treatment as per inclusion criteria 4.
23. Patients receiving any medications in the classes listed in Table 5-3. 
24. 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.
25. 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 conditions have 
been met.
26. Patients with severe narcolepsy and/or insomnia.
27. Patients on Maintenance Immunotherapy (desensitization) for allergies for less than 3 
months prior to Visit 101 or patients on Maintenance Immunotherapy for more than 3 
months prior to Visit 101 but expected to change throughout the course of the study
28. Patients who are serving a custodial sentence, do not have a permanent residence or who 
are detained under local mental health legislation/regulations.
29. Patients who are directly associated with any members of the study team or their family 
members
30. Patients unable to use the Concept1 dry powder inhaler, Accuhaler® or a metered dose 
inhaler. Spacer devices are not permitted for rescue medication.
31. History of alcohol or other substance abuse.
32. 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.
33. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
34. 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.
35. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 30 days after stopping of study treatment.
Only the following highly effective contraception methods will be permitted:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject) if allowed as effective method of contraception by local regulations. Periodic 
abstinence (e.g., calendar, ovulation, symptom-thermal, 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 


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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 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.
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
The Investigational treatments are as follows:

QVM149 (indacaterol acetate/glycopyrronium bromide/MF) 150/50/80 µg o.d. delivered 
as powder in hard capsules via Concept1 

QVM149 (indacaterol acetate/glycopyrronium bromide/MF) 150/50/160 µg o.d. delivered 
as powder in hard capsules via Concept1 
The Comparative treatments are:

QMF149 (indacaterol acetate/MF) 150/160 µg o.d. delivered as powder in  hard capsules 
via Concept1 

QMF149 (indacaterol acetate/MF) 150/320 µg o.d. delivered as powder in hard capsules 
via Concept1

Salmeterol xinafoate/fluticasone propionate 50/500 µg b.i.d. delivered as powder via 
Accuhaler®
In addition the following placebo will be provided to enable the double-dummy design of the 
study:

Placebo delivered as powder in capsules via Concept1

Placebo delivered as powder via Accuhaler®
Under no circumstances is an alternative inhalation device to be used for the 
administration of the investigational or reference therapies during the treatment period.


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5.1.2
Additional study treatment
Starting with Visit 1 (Screening, Day -21) patients will receive short acting beta agonist 
(salbutamol or albuterol) inhaler to use as rescue medication on an “as needed” basis. The 
rescue medication will be provided by the sponsor to the patients for the duration of the study. 
More details regarding rescue medication are in Section 5.4.6
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.
5.1.3
Treatment arms
Patients will be randomized to one of the following five treatment arms in a ratio of 1:1:1:1:1

QVM149 150/50/80 µg o.d. delivered via Concept1, placebo to salmeterol/fluticasone 
50/500 µg b.i.d. (in the morning and  in the evening) delivered via Accuhaler®

QVM149 150/50/160 µg o.d. delivered via Concept1, placebo to salmeterol/fluticasone 
50/500 µg b.i.d. (in the morning and in the evening) delivered via Accuhaler®

QMF149 150/160 µg o.d. delivered via Concept1 (in the evening), 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 (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 QVM149 delivered via Concept1 (in the evening).
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). 
Randomization will be stratified by region.
The randomization scheme for patients will be reviewed and approved by a member of the 
COAR Randomization Group.


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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 QVM149 and 
QMF149 arms of the study to facilitate indacaterol, glycopyrronium bromide (QVM149 
treated patients only) and mometasone furoate bioanalysis. 
 
 
 
Unblinding for primary 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. 
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. 


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If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Epoch Study Disposition 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 follows:
The non-investigational treatment must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 


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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

Salmeterol xinafoate/fluticasone propionate 50/250 µg b.i.d. via Accuhaler® 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 102 (before randomization), all patients will be fully 
trained in the correct use of the Concept1 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 
two inhalational devices to ensure that they are 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 after inhalation of study drug (2 times with approximately 30 
mL water). Water used for mouth rinsing should be spat out and should NOT be swallowed. 
In the evening when sequential inhalations of study drugs from two devices are required, 
mouth rinsing should be done after the last inhalation.
The morning dose (to be taken between 05:00 and 08:00 am) will consist of a single 
inhalation from Accuhaler® device containing either salmeterol/fluticasone or placebo.
The evening dose (to be taken between 05:00 and 08:00 pm) will consist of sequential single 
inhalations from each of the following two devices:


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
One inhalation from the Concept1 device containing either QVM149, QMF149 or placebo 

One inhalation from the Accuhaler® device containing either salmeterol/fluticasone or 
placebo 
Inhalations from the two devices should be taken as close together as possible. Instructions for 
use of the Concept1 and Accuhaler® devices are given in Appendix 1 and Appendix 2, 
respectively.
Table 5-1
Study Treatments
Treatment arm
Morning
Evening
QVM149 
150/50/80 µg
Placebo to 
Salmeterol/ 
fluticasone 
50/500 µg
Accuhaler®
QVM149 150/50/80 µg
Placebo to 
Salmeterol/fluticasone 
50/500 µg
Concept 1 
Accuhaler®
QVM149 
150/50/160 µg
Placebo to 
Salmeterol/ 
fluticasone 
50/500 µg 
Accuhaler®
QVM149 150/50/160 µg
Placebo to 
Salmeterol/fluticasone 
50/500 µg
Concept 1 
Accuhaler®
QMF149 
150/160 µg
Placebo to 
Salmeterol/ 
fluticasone 
50/500 µg
Accuhaler®
QMF149 150/160 µg
Placebo to 
salmeterol/fluticasone 
50/500 µg 
Concept 1 
Accuhaler®
QMF149 
150/320 µg
Placebo to 
Salmeterol/ 
fluticasone 
50/500 µg
Accuhaler®
QMF149 150/320 µg
Placebo to 
Salmeterol/fluticasone 
50/500 µg
Concept 1 
Accuhaler®
Salmeterol/ 
fluticasone 
50/500 µg b.i.d. 
Salmeterol/ 
fluticasone 
50/500 µg
Accuhaler®  
Salmeterol/ fluticasone 
50/500 µg b.i.d. 
Placebo to QVM/QMF
Accuhaler®
Concept 1 
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.


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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 
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 short acting β2-agonist (100 µg 
salbutamol/90 µg albuterol via MDI) which they will be instructed to use throughout the study 
as rescue medication. Nebulized salbutamol is not allowed as rescue medication throughout 
the entire trial. No other rescue treatment is permitted and use of a spacer for rescue 
medication is not allowed at any time throughout the study.
In order to standardize measurements, patients will be instructed to abstain from taking rescue 
medication (salbutamol) within 6 hours of the start of each visit where spirometry is being 
performed unless absolutely necessary. If rescue medication is taken within 6 h prior to 
spirometry assessments, then the visit should be rescheduled to the next day if possible.
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 taken in the previous 12 hours) will be recorded each morning and evening 
throughout the 52 week treatment epoch by the patient in their electronic diary.
The rescue salbutamol/albuterol will be provided to the patients by the study center and 
reimbursed locally by Novartis or supplied to the investigator sites locally by Novartis. 
5.4.7
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 


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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.
Table 5-2
Prohibited asthma-related medications
Class of medication
Minimum washout period prior to Screening (Visit 
1), Run-in (Visit 101) and Randomization (Visit 
201) 1,2,3
Long-acting anticholinergics (LAMA)
Must not be used within 3 months prior to Visit 1.
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 12 hours (24 hours for once 
daily combination) prior to Visit 101.
Fixed combinations of short-acting β2-agonist 
and short-acting anticholinergic
Must not be used within 12 hours prior to Visit 101. 
Salbutamol/albuterol (SABA) provided at Visit 
1 and throughout study as required for rescue 
medication as needed4
Must not be used within 6 hours prior to Visit 101 and 
Randomization (Visit 102)
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 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)
1 Treatment for recorded asthma exacerbation as defined in Section 6.4.5 is allowed ONLY until the asthma 
exacerbation is resolved 
2 This table is not considered all-inclusive. Medications should be assessed for adherence to the indication and 
other inclusion/exclusion criteria.
3These medications are also prohibited if administered for other indications.
4 SABA (salbutamol/albuterol rescue medication) should be withheld for at least 6 hours prior to spirometry 
measurements at clinic visits if possible. Clinic visits may be rescheduled if rescue medication were taken less 
than 6 hours prior to the spirometry assessments
Table 5-3
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
All antipsychotic agents (first, second and third 
generation, inclusive of atypical 
14 days


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Class of medication1
Minimum cessation period prior to Run-in (Visit 
101) 
antipsychotics). Combinations of antipsychotic 
agents with antidepressants are prohibited
Serotonin Noradrenaline Reuptake Inhibitors 
(SNRIs)
14 days
Monoamine-oxidase inhibitors
14 days
Systemic anticholinergics
7 days
Mizolastin or terfenadine (H1 antagonists)
5 days
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
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.
Table 5-4
Medications allowed under certain conditions
Class of medication
Condition
Monoclonal antibody: IgE inhibitors (e.g. 
omalizumab), IL-5 inhibitors (e.g. 
mepolizumab)
Allowed if at stable dose for at least 3 months prior to 
Visit 1
Oral corticosteroids*
Allowed if at stable dose for at least 1 month prior to 
Visit 1 and throughout the study at prednisone 
equivalent dose of 5 mg daily to 10 mg every other 
day
Leukotriene Antagonist and leukotriene 
synthesis inhibitors
Allowed if at stable dose for at least 1 month prior to 
Visit 1 and throughout the study.
Long-acting theophylline (methylxanthine) 
preparations
If stabilized for at least 4 weeks prior to Visit 1 and 
throughout the trial. Not administered within 24h prior 
to study visit.
Short- acting theophylline (methylxanthine)
If stabilized for at least 4 weeks prior to Visit 1 and 
throughout the trial. Not administered within 12h prior 
to study visit.
Mucolytic agents not containing 
bronchodilators
If stabilized for at least 4 weeks prior to Visit 1 and 
throughout the trial.
Systemic mast cell stabilizers e.g 
cromoglycate, nedocromil, ketotifen
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, 
Not administered within 48 hours prior to a study 


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Class of medication
Condition
pneumococcal vaccination or any other 
inactivated vaccine
visit.
Intra-nasal corticosteroids
Stable dose for at least 4 weeks prior to Visit 101
In the case of as needed, 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 as needed, 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.
* The treatment of asthma exacerbations including the initiation of systemic corticosteroids or increase in the 
maintenance dose of OCS 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 longer 7 -10 
days is expected, Novartis Medical Monitor should be contacted and the discontinuation of study treatment should 
be considered.
If patients cannot be safely tapered, oral corticosteroids may be taken chronically after an exacerbation if clinically 
indicated as per Principal Investigator clinical judgement and in accordance with national/local guidelines (and in 
doses not to exceed equivalent of prednisone 5mg daily). Dose should be maintained for at least 3 months before 
tapering.
If indicated for the treatment of an adverse event, including asthma exacerbation, any 
treatment deemed necessary by treating physician for the safety of the patient is allowed from 
the start of the event (asthma exacerbations are defined in Section 6.4.5) until the event is 
resolved. If it is transitioning to chronic treatment, the investigator should 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.
Dosing of biologic therapy (e.g, omalizumab, mepolizumab) should be guided by local 
labelling.
5.4.9
Discontinuation of study treatment 
Patients may voluntarily discontinue study treatment for any reason at any time. In the case 
the patients would want to discontinue the treatment, it is particularly important to ask the 
reason and if they would be willing to remain in the trial to share their safety and vital status 
information 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.
In addition 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.

Patients with > 50% decrease in FEV1 from baseline during the run-in (e.g. Visit 101) or 
treatment epochs (e.g. Visit 201).


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
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 they complete 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. At this study 
treatment discontinuation visit the assessments listed in Table 5-5 should be completed 
and recorded in the e-CRF if the discontinuation takes place at a scheduled or unscheduled 
visit time. 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 those 
discontinuing the study treatment) are adverse events and serious adverse events for up to 
30 days after drug discontinuation and survival status until the end of 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. They should return for the assessments indicated in Table 5-5. If they fail 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 5.4.11.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
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
discontinuation
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


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Assessment
Early Study 
Treatment
Discontinuation 
Visit 
Unscheduled 
Safety Follow-
Up Visit
At time of 
original 
Scheduled  
Clinic Visit 
Early Study
discontinuation
Follow-
up Visit 
301
IRT treatment 
discontinuation call
X
Vital Signs
X
Physical exam
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
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 for the discontinuation.
5.4.10
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. 


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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).
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 


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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 for an individual patient will be when he/she has completed Visit 214 
and as close as possible to SAE follow-up at day 395. Completion of the study will be when 
the last patient completed the study treatment epoch phase. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.4.14
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 will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all 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: Patient reported 
outcome (PRO) questionnaires (i.e. 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). 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 


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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.  As required, 
other assessments can be done after spirometry.


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Table 6-1
Table of Assessment
Visit Number
1
101
102
201
202
2035
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early treat-
ment dis-
continuation
Early 
Study 
Disconti
nuation
3019
Epoch
Scree
n
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
½
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/ 
3656
395
Obtain Informed 
Consent (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
Run-in medication 
X
Pregnancy test 
(serum)1
X
X
X
Pregnancy test (urine) 1
X
X
X


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Visit Number
1
101
102
201
202
2035
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early treat-
ment dis-
continuation
Early 
Study 
Disconti
nuation
3019
Epoch
Scree
n
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
½
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/ 
3656
395
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 (Visit 
101 only), weight, 
abdominal 
circumference (hip and 
waist) 
X
X
X
X
ECG2
X
X
X
X
X
X
X
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


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Visit Number
1
101
102
201
202
2035
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early treat-
ment dis-
continuation
Early 
Study 
Disconti
nuation
3019
Epoch
Scree
n
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
½
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/ 
3656
395
Spirometry Practice
(optional) 
X
Screening spirometry 
and FEV1 reversibility 
test (SABA)10
X
Spirometry2
X
X
X
X
X
X
X
Issue e-Diary 5
X
Issue of Peak Flow 
meter
X
Review and upload e-
Diary recordings5
S
S
S
S
S
S
S
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


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Protocol No. CQVM149B2302
Visit Number
1
101
102
201
202
2035
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early treat-
ment dis-
continuation
Early 
Study 
Disconti
nuation
3019
Epoch
Scree
n
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
½
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/ 
3656
395
Record interruption/
changes 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
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


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Visit Number
1
101
102
201
202
2035
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early treat-
ment dis-
continuation
Early 
Study 
Disconti
nuation
3019
Epoch
Scree
n
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
½
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/ 
3656
395
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
AQLQ-S3
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


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Protocol No. CQVM149B2302
Visit Number
1
101
102
201
202
2035
204
2055
2065
207
2085
2095
210
2115
2125
2135
214
EOT
Early treat-
ment dis-
continuation
Early 
Study 
Disconti
nuation
3019
Epoch
Scree
n
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
½
30
57
86
113
141
183/ 
184 
197
225
254
281
309
337
364/ 
3656
395
Early Study Discontinuation Visit should be used for Premature study withdrawal (please refer to Section 5.4.9) 
*: 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
2 Details of timed assessments are provided in Table 6-2
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. For the ACQ7, question 7 regarding FEV1% predicted should be answered by the investigator based on the spirometry measurement at the 
site using the equipment provided by spirometry vendor.
4 Device training at Visit 1 is for e-diary/peak flow meter. Device training at Visit 102 is for Concept1 and Accuhaler®. The diary is an electronic device. The questionnaires 
and other assessments are based on asthma symptoms
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
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
-25 min
-15 min
X
X
0 min
Evening dosage
2 min
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
2 min
5 min
X
15 min
30 min
X
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
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 timed 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, and only done pre-dose 
6 It is baseline for the evening plasma cortisol
 
**Assessments are to be completed within a 5 min window from Table 6-2 schedule, except for the 2 min sample 
which will be collected as a post-dose sample within a 2 min window.
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)

Sex


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
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 and non-asthma related)

Pre and post-bronchodilator spirometry (screening spirometry and reversibility testing).
6.3
Treatment exposure and compliance
The time of study treatment administration at each in-office dosing visit will be collected on 
the 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 Accuhaler® dose counter. 
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
6.4.1
Spirometry
The following spirometric assessments will be made:


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
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 for QMF149 150/160 µg, QMF149 150/320 µg o.d., QVM149 150/50/80 µg 
and QVM149 150/50/160 µg o.d. delivered via Concept1 is the 24 hr post-dose FEV1 is
calculated 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 3 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 4) will be used to assess improvements in asthma 
symptom control. The ACQ-7 (Juniper 1999; Juniper 2005; 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. The ACQ-7 questionnaire will be 
provided to the site. The ACQ-7 questionnaire consists of five items to assess symptoms and 
activity limitations, one question to assess rescue medication use, and one question to assess 
airway caliber (FEV1% predicted). All seven items are scored on a 7-point Likert scale, with 
0 indicating total control and 6 indicating poor control. The questions are equally weighted 
and the total score is the mean of the seven items. The proportion of patients who achieve an 
improvement of at least 0.5 in ACQ-7 (i.e. decrease of ACQ-7 score of at least 0.5 from 
baseline) at post-baseline visits will also be analyzed.
The first 6 questions of the ACQ-7 should be completed by the patient based on one recall 
over the prior week. The last question should be completed by the investigator at the site 
using data from the equipment provided by spirometry vendor.  The ACQ-7 should be 
completed at the investigators site at Visits 101, 102, 202, 204, 207, 214 and EOT if 
applicable (see footnote 3 of Table 6-1).
6.4.2.2
Asthma Quality of Life Questionnaire (AQLQ-S)
The AQLQ is a 32-item disease specific questionnaire designed to measure functional 
impairments that are most important to patients with asthma (Appendix 5). 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 (Juniper 1992, Juniper 1993). The overall AQLQ score is the mean 
response to all 32 questions. 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).


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AQLQ should be completed at Visits 102, 202, 204, 207, 210 and 214.
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. From Visit 101 they will also record 
clinical symptoms and PEF in the e-diary and from Visit 201 they will record the study 
medication compliance weekly. Daily inhalation of study treatments will also be checked. 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 Patient asthma control e-
Diary questions is provided in Appendix 7.


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6.4.3.1
Peak Expiratory Flow (PEF)
An electronic Peak Flow Meter will be given to each patient at Visit 1 for the measurement of 
morning and evening PEF from Visit 101 until the end of the treatment period.
PEF will be measured at consistent times for a patient, in the morning and evening each day
during the study from Visit 101 to Early Study Discontinuation Visit. The measurements will 
be performed using an ePeak 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 ePEF/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. 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 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 patient diary will also be used to alert the patient and/or investigator 
to possible signs of worsening asthma. The investigator must provide the patient with written 
instructions to contact the investigator if at any time during the trial from the run-in onwards 
one or more of the following criteria of worsening asthma develops:
Asthma Worsening Criteria
1. > 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)
2. > 50% increase in SABA use and >8 puffs per day on 2 out of any 3 consecutive days 
compared to baseline
3. ≥20% decrease in AM or PM PEF from baseline on 2 out of any 3 consecutive days 
compared to baseline
4. < 60% of personal best PEF compared to baseline
5. Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights
6. Urgent unscheduled clinic visit due to asthma related deterioration


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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 average of the best of the 3 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 asthma 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 and to help direct early intervention. Therefore, the 
investigator should do the following when alerts are received:

Reviewing alert trends over time, in particular PEF decreases.

Calling the patient promptly when alerts are received when any one specific alert type (e.g. 
PEF < 60%) is received on consecutive days to further assess the clinical status. This may 
include urgent clinic visits as appropriate and/or immediate treatment.

Implementing prompt treatment as necessary.

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 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 
SCS for at least three consecutive days and/or a need for an ER visit (or local equivalent 
structure), 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
“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 
one. 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 


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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 or 
increase in the maintenance dose of OCS 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 longer than 7-10 days is 
expected, Novartis Medical Monitor should be contacted and the discontinuation of study 
treatment should be considered.
If patients cannot be safely tapered, oral corticosteroids may be taken chronically after an 
exacerbation if clinically indicated as per Principal Investigator clinical judgement and in 
accordance with national/local guidelines (and in doses not to exceed equivalent of prednisone 
5mg daily). Dose should be maintained for at least 3 months before tapering.
At no time may patients self-medicate (other than rescue medication use) for treatment of 
asthma exacerbation or worsening of symptoms.
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 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 
and in case of early study treatment discontinuation visit as described in Table 5-5. An 
oropharyngeal examination will be performed at each clinic visit.


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Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being signed must be 
included in the Relevant Medical History/Current Medical Conditions screen on the patient’s 
eCRF. Significant findings made after informed consent (Visit 1) is given which meet the 
definition of an Adverse Event must be recorded on the Adverse Event screen of the patient’s 
eCRF.
6.5.2
Vital signs 
Systolic and diastolic blood pressure and radial pulse rate (over a 30 sec interval), performed 
in the sitting position, will be recorded at scheduled visits as detailed in Table 6-2. At Visits
101, 102, 201, 202, 204, 207, 210, 214, or EOT if applicable, vital signs should be measured 
directly after the ECG assessments.
6.5.3
Height, weight and abdominal circumference 
Height in centimeters (cm) will be measured at Visit 101. Body weight (to the nearest 0.1 
kilogram [kg] in indoor clothing, but without shoes) and abdominal circumference (hip and 
waist) will be measured at Visits 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 Visits 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.
All patients with laboratory tests containing clinically significant abnormalities should be 
followed regularly until the values return to within the normal ranges or until a valid reason 


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other than drug-related adverse experiences is identified, even after the study medication has 
discontinued.
6.5.4.3
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will be performed 
at Visits 101, 201, 204, 207, 214 and EOT if applicable.
If the urine dipstick is abnormal, the sample will be sent to central laboratory for additional 
testing, including assessment of WBC and RBC sediments.
6.5.4.4
Hepatotoxicity
Any liver event which meets the criteria for “medically significant” event as outlined in 
Table 13-1 of Appendix 8 should follow the standard procedures for SAE reporting as 
described in Section 7.2.
6.5.4.5
Plasma Cortisol
Plasma cortisol will be measured at Visits 201, 207, 214 and EOT (if applicable). The 
sampling point is as shown in 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, 214 or EOT (if applicable), ECGs will be measured at -
35min pre-dose (evening dose) and post dose 30 min/ 1 hours, at Visit 204 ECG will be 
measured pre-dose only as indicated in Table 6-2. At Visit 210, the ECG will be done pre-
dose. All electrocardiograms should include 12 standard leads. An ECG tracing will be taken 
for those patients who prematurely discontinue from the study.
For each ECG performed, original trace should be printed. Each ECG will be sent 
electronically for central review directly from the ECG machine. One print-out will be 
generated and kept at the investigator site as source documentation and will be dated and 
signed. The 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 


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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.
New cases (not present during screening / run-in epochs) of atrial fibrillation reported from 
the ECG measurements (or reported as an AE during the course of the study) will be 
adjudicated. Additional information regarding the Atrial Fibrillation / Atrial Flutter may be 
requested to be sent to the Adjudication Committee. All cases of atrial fibrillation, regardless 
of seriousness, will be reviewed by the Adjudication Committee.
6.5.6
Serious Asthma outcomes
Asthma-related hospitalizations, asthma-related intubations and asthma-related deaths over 
the 52 week treatment epoch will be recorded and will all be reviewed by the Adjudication 
Committee. Hospitalization is defined as an inpatient stay or a ≥24 hour stay in an 
observation area in an emergency department or other equivalent facility.
6.5.7
Pregnancy and assessments of fertility 
A urine or serum 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 pregnancy test at Visits 1, 101, 102, 207 
(Week 26), and 214, EOT Visit (if applicable) 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, 


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
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

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.


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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 

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.


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All AEs (serious and non-serious) are captured on the e-CRF, SAEs also require 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 alter) 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 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 reoccurrence, 
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 


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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
Please refer to Table 13-1 in Appendix 8 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 8 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 in Appendix 8.
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.


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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 to 3 months after the birth, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications.
Pregnancy 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 study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization.   
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.


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


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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 of 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 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 
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 [FDA, 
2006] and CHMP guidelines [CHMP, 2006] on DMC’s. 
8.5
Adjudication Committee 
An independent adjudication committee will be established to assess serious asthma outcomes 
(asthma-related hospitalizations, intubations and deaths), serious cardiovascular and 
cerebrovascular (CCV) events, new onset of atrial fibrillation and flutter as well as all deaths. 
All serious CCV events occurring from the time of 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 to provide guidance regarding the conduct of this 
study. 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:


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
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.
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.


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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 and AQLQ
will be summarized by treatment group.
Continuous variables will be summarized using descriptive statistics (mean, median, standard 
deviation, minimum, and maximum) and categorical variables will be summarized in terms of 
the number and percentage of patients in each category.
Baseline is defined as the last measurement before first dose of study drug.
No statistical analyses will be provided for baseline comparability among the treatment 
groups.
9.3
Treatments 
Study drug administration and concomitant medication data will be listed and summarized 
using Safety set. 
The duration of exposure and the number of patients randomized who completed the study
and who discontinued from study medication will be summarized.
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 administration, the recorded pre-specified drug 
subcategories (including types of combination) and preferred term. Concomitant medications 
not related to asthma will be summarized by route of administration and preferred term. 
SABA usage (number of puffs) during the screening epoch will be summarized. 
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.


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9.4
Analysis of the primary variable(s) and key secondary variables
9.4.1
Variable(s)
The primary objective of this study is to demonstrate superiority of either QVM149 
150/50/80 µg o.d. to QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 
150/320 µg o.d, all delivered via Concept1, in terms of trough FEV1 after 26 weeks of 
treatment in patients with asthma.
The key secondary objective of this study is to demonstrate superiority of either QVM149 
150/50/80 µg o.d. to QMF149 150/160 µg o.d.or QVM149 150/50/160 µg o.d. to QMF149 
150/320 µg o.d., all delivered via Concept1, in terms of ACQ-7 after 26 weeks treatment in 
patients with asthma.
9.4.2
Statistical model, hypothesis, and method of analysis
The comparisons of QVM149 150/50/80 µg o.d. versus QMF149 150/160 µg o.d. and 
QVM149 150/50/160 µg o.d. versus QMF149 150/320 µg o.d., all delivered via Concept1,
will be evaluated by testing the following null hypothesis (H0) versus the alternative 
hypothesis (Ha):
H0: QVM149 treatment group is equal to QMF149 treatment group in trough FEV1 at Week 
26
Ha: QVM149 treatment group is not equal to QMF149 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, 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 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 (QVM149-QMF149) 
will be displayed along with the associated standard error, 2-sided 95% confidence interval
(CI), and p-value (2-sided).


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9.4.3
Handling of missing values/censoring/discontinuations
If any of the 23 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 
hours 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 graphic 
testing procedure based on the generalized Simes test in Maurer et al (2011) is used. The 
family for the overall type-I error rate control contains total 4 hypotheses including: two 
hypotheses for the primary endpoint trough FEV1 and two hypotheses for the key secondary 
endpoint ACQ-7. Denote the two hypotheses for the primary endpoint as H1 and H2 for 
comparing QVM149 150/50/80 µg o.d. versus QMF149 150/160 µg o.d. and QVM149 
150/50/160 µg o.d. versus QMF149 150/320 µg o.d. respectively. Similarly, denote the two 
hypotheses for the key secondary endpoint ACQ-7 as H3 and H4 for comparing QVM149 
150/50/80 µg o.d. versus QMF149 150/160 µg o.d. and QVM149 150/50/160 µg o.d. versus 
QMF149 150/320 µg o.d. respectively. 
Below is a brief description of the testing procedure based on the generalized Simes test in 
Maurer et al (2011).
Let p1, p2, p3, p4 be the corresponding p-values (2-sided) of the four hypotheses of H1, H2, H3, 
and H4. 
Step 1: Retain all four hypotheses if pi<=0.05 AND the observed treatment difference for the 
corresponding pi is in the wrong direction (i.e. QMF149 is performing better than QVM) for 
ANY i=1, 2, 3, 4, stop here; otherwise go to step 2;
Step 2: Reject all four hypotheses if pi<0.05 for ALL i=1, 2, 3, 4 and stop here; otherwise go 
to step 3;
Step 3: If neither step 1 or 2 applies, perform a closed successive weighted Bonferroni test as 
given in Figure 9-1. The initial weights of 0.5 to H1 (corresponding to 0.025 alpha level, 2-
sided) and 0.5 to H2 (corresponding to 0.025 alpha level, 2-sided) were assigned. Here is a 
brief summarization of the successive weighted Bonferroni test based on Bretz et al (2011): If 
null H1 is rejected at the initial significance level of 0.025, then H3 can be tested at the 
significance level of 0.025. Similarly, if null H2 is rejected at the initial significance level of 
0.025, then H4 can be tested at the significance level of 0.025. If neither primary null 


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hypothesis can be rejected at the initial significance levels, then the testing stops and efficacy 
cannot be claimed for neither of the doses and endpoints. Otherwise the graph is sequentially 
updated with reallocated weights after each hypothesis is rejected. In addition, if efficacy can 
be shown for one of the doses on both the primary and key secondary endpoints at the initial 
significance level, the associated weight is passed on to the other dose for further testing.
Figure 9-1
Testing Procedure
Note: Full details of the testing procedure will be described in a reporting analysis plan before unblinding of the treatment 
code and database lock.
For each of the four hypotheses, the corresponding testing statistics (estimated least square 
mean difference) follows normal distribution. Hence for any two out of the four hypotheses, 
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 Mauer et al (2011).
Other than the 4 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.
9.4.6
Supportive analyses 
As supportive analyses, 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.


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For ACQ-7, the same MMRM model used for key secondary endpoint will also be performed 
on the FAS excluding measurements in patients requiring chronic corticosteroid use after an 
exacerbation (beyond permitted steroid taper for exacerbation of approximately 7-10 days).
The following exploratory subgroup analyses for trough FEV1 using MMRM will be 
performed (using the appropriate interaction term in the model and additional covariate as a 
fixed effect if necessary) for the FAS population to explore the treatment effect in:

Race (Caucasian, Black, Asian, Other)

Sex (male, female)

History of asthma exacerbation in the 12 months prior to screening (1, 2, 3, ≥4)

Patients’ prior therapies before Run-in period (e.g. mid and high dose ICS/LABA)

FEV1 response according to % predicted FEV1 range at baseline (<40%, 40% -<60% and 
60%-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 each dose of QVM149 o.d vs. salmeterol xinafoate /fluticasone propionate 
50/500 µg b.i.d. will be performed using the same model for the comparison of QVM149 
versus QMF149 at the corresponding doses 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 (except for patients who were on stable corticosteroids), 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-square 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.


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To estimate the add-on effect of glycopyrronium over QMF149, the average of following 
treatment contrasts will be computed:
QVM149 (150/50/80 µg) vs. QMF149 (150/160 µg)
QVM149 (150/50/160 µg) vs.QMF149 (150/320 µg)
QVM149 and QMF149 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.
9.5.1.2
ACQ at Weeks 4, 12, and 52
The ACQ measures asthma symptom control and consists of 7 items: 5 on symptom 
assessment, 1 on rescue bronchodilator use and 1 on airway caliber (FEV1 % predicted). 
Patient recall is 1 week. All 7 questions of the ACQ 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 the scores on all questions.
ACQ-7 at post-baseline visits will be analyzed using the same MMRM model as specified for 
the primary analysis (including all available visits) except that baseline FEV1 will be replaced 
with baseline ACQ-7.
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, region, visit, and treatment-by-visit interaction as 
fixed effects with baseline ACQ-7 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.
The estimated adjusted odds ratios will be displayed along with the associated 95% (two-
sided) confidence intervals and p-values.
To estimate the add-on effect of glycopyrronium over QMF149, the average of following 
treatment contrasts will be computed:
QVM149 (150/50/80 µg) vs. QMF149 (150/160 µg)
QVM149 (150/50/160 µg) vs.QMF149 (150/320 µg) The details of this analysis will be 
provided in the SAP.
All the analyses described above will be repeated for ACQ-5.


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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, region as fixed effect factors with center nested within region as a random effect, 
and baseline rescue medication use, FEV1 prior to inhalation and FEV1 within 15 to 30 min 
post inhalation of salbutamol/albuterol (components of SABA reversibility) as covariates. No 
imputation will be done for missing data.
The adjusted mean (LS mean) treatment 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 ‘rescue 
medication free days’ 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 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 mean 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.


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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 
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

The annual rate of asthma exacerbation excluding measurements in patients requiring
corticosteroid use after an exacerbation (beyond permitted steroid taper for 
exacerbation) 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 region. 
The model will include treatment and history of asthma exacerbation in the 12 months prior to 
screening (the number of asthma exacerbations in the 12 months prior to screening) 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 QVM149 over QMF149 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 the generalized linear model 
assuming the negative binomial distribution including treatment, region and history of asthma 
exacerbation in the 12 months prior to screening (the number of asthma exacerbations in the 


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12 months prior to screening) 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 region and history of asthma 
exacerbation in the 12 months prior to screening (1, 2, ≥3).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 glycopyrronium over QMF149 in terms of exacerbations, the 
average of following treatment contrasts will be computed:
QVM149 (150/50/80 µg) vs. QMF149 (150/160 µg)
QVM149 (150/50/160 µg) vs.QMF149 (150/320 µg)
All inferential analyses mentioned above for exacerbation will be repeated to explore the 
overall efficacy of QVM149 compared with QMF149, QVM149 and QMF149 doses will be 
pooled using appropriate contrasts within the analyses models. 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.


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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. 
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. 


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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.
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 (the number of asthma exacerbations 
in the 12 months prior to screening) 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.


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The analyses on AQLQ will be based on the FAS for all post-baseline visits.
9.5.6
PK/PD
Not applicable
9.6
Interim Analysis
The primary and key secondary endpoints of CQVM149B2302 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).
9.7
Safety Monitoring Analysis 
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 


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analysis. Since the purpose of the DMC is not based on efficacy for stopping rule, there will 
be no alpha spent for the safety monitoring analysis. All analyses will be considered 
exploratory.
9.8
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 90mL between QVM149 vs. QMF149 at 
the corresponding doses, assuming standard deviation of 380mL based on studies 
QMF149A2210, QMF149E2201 and QMF149E2203, and Kerstjens (2012);
2. To achieve at least 80% power (with multiplicity adjustment) for key secondary 
endpoint ACQ-7 with a treatment difference of 0.15 between QVM149 vs. QMF149 
at the corresponding doses, assuming standard deviation of 0.80 based on studies 
QMF149A2210, QMF149E2201 and QMF149E2203 and Kerstjens (2012);
If 10% dropout rate is assumed, then calculation shows that the sample size of 2980 patients 
(i.e 596/arm) will provide 97% power for item 1 and 82% power for item 2, with multiplicity 
adjustment as given in Figure 9-1. 
The sample size and power calculations are performed in R 3.1.2 with package gMCP.
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 


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the investigator must be agreed to by Novartis before submission to the IRB/ IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/ IEC approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
10.3
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution 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 


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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 for safety monitoring should be followed.
12
References 
References are available upon request:
Barnes PJ et al (2014) The Asthma Control Questionnaire as a clinical trial endpoint: past 
experience and recommendations for future use. 
Bateman ED et al (2004) Can guideline-defined asthma control be achieved?  The Gaining 
optimal Asthma ControL Study. Am J Respir Crit Care Med;170:836-844.
Bateman ED et al (2011) Tiotropium is noninferior to salmeterol in maintaining improved 
lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol 2011; 128:315-
22.
Beakes DE (1997) The use of anticholinergics in asthma. J Asthma 34 (5): 357-368).
Beasley R, Lanier B, Varkonyi I et al (2012). Safety of once-daily QMF149 in patients with 
persistent asthma. Eur Respir J; 40 (Suppl 56): P371.
Beasley R, Lanier B, Mark Z et al (2012a). Long-term efficacy of QMF149 in persistent 
asthma. Eur Respir J; 40 (Suppl 56): P31
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
Befekadu E,  Onofrei C, Colice GL (2014) . Tiotropium in asthma, a systemic review.  JAA ; 
7: 11-21.
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, Posch M, Glimm E, Klinglmueller F, Maurer W, and Rohmeyer K (2011). Graphical 
approaches for multiple comparison procedures using weighted Bonferroni, Simes, or 
parametric tests. Biometrical Journal; 53: 894-913.
European Medicines Agency (2013). Note for guidance on clinical investigation of medicinal 
products for treatment of asthma. CHMP/EWP/2922/01-rev.1. 27 June 2013.
Fardon T et al (2007) A proof of concept study to evaluate stepping down the dose of 
fluticasone in combination with salmeterol and tiotropium in severe persistent asthma. 
Respiratory Medicine; 101: 1218-1228.
Global Initiative for Asthma (GINA) 2015 Global Strategy for Asthma Management and 
Prevention (available on GINA website) Updated 2017 (available upon request)


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Guyer AC, Long AA (2013) Long-acting anticholinergics in the treatment of asthma. Allergy Clin 
Immunol; 13:392-398
Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE (1993) Measuring quality of life in asthma. Am 
Rev Respir Dis. Apr; 147(4):832-8
Juniper EF et al (1994) Determining a minimal important change in a disease-specific quality 
of life questionnaire. J Clin Epidemiol; 47: 81-87.
Juniper EF et al (1999) Development and validation of the questionnaire to measure asthma 
control. Eur Resp J; 14: 902-907.
Juniper EF, Svensson K, Mork AC et al. Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. Respir Med 2005; 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.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics 1997; 53(3):983-97.
Kerstjens HAM et al (2011) Tiotropium improves lung function in patients with severe 
uncontrolled asthma: A randomized controlled trial. J Allergy Clin Immunol; 128:308-314.
Kerstjens HAM et al (2012). Tiotropium in Asthma Poorly Controlled with Standard 
Combination Therapy. N Engl J Med; 367: 1198-1207
Kerstjens HAM et al (2015) Tiotropium or salmeterol as add-on therapy to inhaled 
corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, 
placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir 
Med.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
Maurer W, Glimm, and Bretz F (2011). Multiple and repeated testing of primary, coprimary, 
and secondary hypotheses. Statistics in Biopharmaceutical Research; 3; 336-352.
Peters SP et al (2010) Tiotropium bromide as step-up therapy for adults with uncontrolled 
asthma. N Engl J Med; 363(18): 1715-1726.
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.
Rohmeyer K, Klinglmueller F, and Bornkamp B (2012). Package ‘gMCP’ graph based
multiple comparison procedures: http://cran.r-project.org/web/packages/gMCP/gMCP.pdf.
Testi 2014, White Paper, Long Acting Muscarinic Agent (LAMA). A new Frontier for COPD 
and Asthma Treatment. Available on www.cromsource.com
Vaidya S, Khindri S, Robertson J et al (2012) Pharmacokinetics (PK) of single doses of 
mometasone furoate (MF) delivered via the Breezhaler® (BH) and Twisthaler® devices in 
healthy subjects. Eur Respir J; 40 (Suppl 56): P382. 


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13
Appendices
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: Instruction for use of 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


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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).
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


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


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Acceptability
An acceptable maneuver has the following characteristics: 

No hesitation or false start;

A rapid start;

No cough, especially during the first second of the maneuver;

No glottic closure or obstruction by tongue or dentures

No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended and no volume change for at least 1 second), or the subject cannot continue 
to exhale further. Overall acceptability will be determined by expert over-read by 
spirometry vendor.
Repeatability
The 2 largest FEV1 values from 3 acceptable maneuvers should not vary by more than 
0.150 L.
Recording of data
The 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. 
References
1 Miller MR et al, Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161.
2 Quanjer PH et al. ERS Global Lung Function Initiative. Multi ethnic reference values for 
spirometry for the 3-95 year age range: the global lung function 2012 equations. Report of the 


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Global Lung Function Initiative (GLI). ERS Task Force to establish improved Lung Function 
Reference Values.
3Kubota, Kobayashi, Quanjer PH, et al. Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values. Clinical Pulmonary Functions Committee of the Japanese Respiratory Society.   
Respiratory Investigations 2014, 242-250.   


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Appendix 4: ACQ-7


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Appendix 5: AQLQ-S


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Appendix 7: Patient Asthma Control e-Diary
The following information will be captured:
In the MORNING
In the EVENING
Peak expiratory flow rate
How did you sleep last night?
Did you have asthma symptoms upon 
awakening in the morning?
Number of puffs of rescue medication 
during the past 12 hours
Peak expiratory flow
Did your respiratory symptoms stop you 
from performing your usual daily activities?  
How severe was your shortness of breath 
today?
How was your wheeze during the past 12 
hours?
How was your cough during the past 12 
hours?
Did you have Chest tightness during the past 
12 hours?
Number of puffs of rescue medication 
during the past 12 hours


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Appendix 8: 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, 
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit


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Criteria
Event type
Actions required
Follow-up monitoring
establish causality
≤ 2 x ULN
(patient is 
asymptomatic)
N/A
Repeat LFT at next visit
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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Amended Clinical Trial Protocol V06 Clean
Protocol No. CQVM149B2302


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Amended Clinical Trial Protocol V06 Clean
Protocol No. CQVM149B2302


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Amended Clinical Trial Protocol V06 Clean
Protocol No. CQVM149B2302
Appendix 10: Low, medium and high Daily Doses of Inhaled 
Glucocorticosteroids for Adults*
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 Furoate
NA
100
200
Mometasone furoate
110-220
>220-440
≥ 440
Triamcinolone 
acetonide
> 1000 – 2000
> 2000
*GINA 2015, Summary of Product Characteristics of Relvar Ellipta for Fluticasone Furoate 
** Beclomethasone dipropionate CFC is included for comparison with older literature.
CFC: chlorofluorocarbon propellant; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant.
Patients treated with ICS mono-therapy in addition to combination of ICS/LABA are not eligible for the 
study

SAP_000.pdf: 
Clinical Development
QVM149B (Indacaterol acetate / Glycopyrronium bromide /
Mometasone furoate)
CQVM149B2302 / NCT02571777
A multicenter, randomized, 52-week, double-blind, parallel-
group, active controlled study to compare the efficacy and 
safety of QVM149 with QMF149 in patients with asthma
RAP Module 3 – Detailed Statistical Methodology
Author:
, CRO Trial Statistician
Document type:
RAP Documentation
Document status:
Amendment 2
Release date:
28-Sep-2018
Number of pages:
47
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 6 (released 18-Dec-2017). 
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.
Sample size has been updated in Section 2.10 based on new 
drop-out rate.
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 2.6.2.2.
Modified the handling of missing items in the AQLQ overall and 
domain scores in Section 2.6.2.7.
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. regimen salmeterol/fluticasone 50/500 μg 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 2.6.2.2 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 analysis in 
Section 3.1.
 
Added the analysis of add-on effect of glycopyrronium to 
QMF149 treatment for trough FEV1 in Section 2.6.2.1, ACQ in 
Section 2.6.2.2, and asthma exacerbations in Section 2.6.2.6.


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Version
Date
Changes
Re-organized Section 2.6.2.6 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
28-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 
two sites which were 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.
Adjusted categories for adjudicated CCV events in Section 
2.7.2.
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.......................................................................................................7
2.1.2
Key secondary objective............................................................................................8
2.1.3
Secondary objectives..................................................................................................8
9
2.1.5
Changes in the conduct of the study or planned analyses........................................10
2.2
Analysis sets .................................................................................................................10
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..............................................................11
2.4
Study medication ..........................................................................................................12
2.4.1
Duration of exposure................................................................................................12
2.4.2
Compliance ..............................................................................................................12
2.5
Prior and concomitant medication................................................................................13
2.6
Efficacy evaluation .......................................................................................................13
2.6.1
Analysis of the primary and key secondary variables..............................................13
2.6.1.1
Variables..............................................................................................................13
2.6.1.1.1
Primary variable trough FEV1 ........................................................................13
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 .......................................................................................16
2.6.1.4
Supportive analyses for the primary objective....................................................16
2.6.2
Analysis of secondary variables...............................................................................17
2.6.2.1
Spirometry data other than the primary endpoint................................................18
2.6.2.2
ACQ at Weeks 4, 12 and 52................................................................................18
2.6.2.3
Peak Expiratory Flow Rate (PEF).......................................................................19
2.6.2.4
Rescue medication...............................................................................................19
2.6.2.5
Asthma symptom based on e-Diary ....................................................................20
2.6.2.6
Asthma exacerbations .........................................................................................21
2.6.2.7
Quality of life as assessed by Asthma Quality of Life Questionnaire 
(AQLQ) ...............................................................................................................22
2.7
Safety evaluation...........................................................................................................23
2.7.1
Serious asthma outcomes.........................................................................................23


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2.7.2
Adverse events .........................................................................................................23
2.7.3
Laboratory data ........................................................................................................26
2.7.4
Vital signs ................................................................................................................28
2.7.5
Electrocardiogram (ECG) ........................................................................................28
29
29
29
2.9
Interim analysis.............................................................................................................30
2.9.1
Data Safety Monitoring Board (DMC)....................................................................30
2.9.2
Primary analysis after all patients have completed at least 26 weeks treatment......30
2.10
Sample size calculation.................................................................................................31
3
Analyses to be reported outside of CSR............................................................................31
3.1
Subgroup analyses ........................................................................................................31
32
32
33
33
Clinical Study Report -  Appendix 16.1.9  Documentation of statistical methods...................34
16.1.9.1
Introduction .........................................................................................................34
16.1.9.2
Major protocol deviations and other exclusion criteria.......................................34
16.1.9.3
Assessment windows, baseline and post-baseline definitions, missing data 
handling...............................................................................................................36
16.1.9.3.1
Data pooling and assessment windows ...............................................................36
16.1.9.3.2
Baseline measurements .......................................................................................36
16.1.9.3.3
Post-baseline measurements................................................................................38
16.1.9.4
Laboratory parameters – direction of interest and definition of clinically 
notable values......................................................................................................39
16.1.9.5
Vital signs and ECG – definition of clinically notable values ............................41
16.1.9.6
Statistical methodology and assumptions ...........................................................42
16.1.9.7
Multiplicity adjustment .......................................................................................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 6 (released 18-Dec-2017). 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.


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1
Introduction
This document contains details of the statistical methods that will be used in the phase III 
clinical trial CQVM149B2302. This study is designed to evaluate the efficacy and safety of two 
different doses of QVM149 (QVM149 150/50/80 μg and QVM149 150/50/160 μg via 
Concept1) over two respective QMF149 doses (QMF149 150/160 µg and QMF149 150/320 µg 
via Concept1) 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 after at least 26 weeks of treatment (Visit 207) or prematurely withdrawn 
from the study. 

Full CSR: To support analyses once all patients have completed 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 of primary, key and other secondary, 
 objectives will be 
performed for specific countries (e.g. Japan). These analyses will be identified in the tables, 
figures, and listings shell document.
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 two sites in order to evaluate 
whether the data from these sites have an impact on overall results:
1271 (India), 1760 (Switzerland).
2
Detailed statistical methodology
2.1
Study objectives
Section 2 of the study protocol lists the following primary, key secondary, other secondary 
 
 objectives.
2.1.1
Primary objective
The primary objective of the study is to demonstrate superiority of either QVM149 150/50/80 
µg o.d. to QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 150/320 µg 


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o.d., all delivered via Concept1, in terms of trough FEV1 after 26 weeks of treatment in patients 
with asthma.
2.1.2
Key secondary objective
The key secondary objective is to demonstrate the superiority of either QVM149 150/50/80 µg 
o.d. to QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 150/320 µg o.d., 
all delivered via Concept1, in terms of asthma control as assessed by the Asthma Control 
Questionnaire (ACQ-7) after 26 weeks of treatment in patients with asthma.
2.1.3
Secondary objectives
Secondary objectives are to compare:
1) QVM149 150/50/80 µg o.d. to QMF149 150/160 µg o.d. both delivered via Concept1, 
2) QVM149 150/50/160 µg o.d. to QMF149 150/320 µg o.d. both delivered via Concept1,
3) QVM149 150/50/80 µg o.d. delivered via Concept1 to salmeterol xinafoate/fluticasone 
propionate 50/500 µg b.i.d. via Accuhaler®,
4) QVM149 150/50/160 µg o.d. delivered via Concept1 to salmeterol xinafoate/fluticasone 
propionate 50/500 µg b.i.d. via Accuhaler®,
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 Weeks 4, 12 and 52

Percentage of patients achieving the minimal important difference (MID) in ACQ-7 of ≥ 
0.5 at Week 26 and Week 52

Percentage of days with no symptoms, the percentage of nights with no night-time 
awakenings, and the percentage of mornings with no symptoms on rising over 52 weeks of 
treatment, as recorded by e-diary

Percentage of days without rescue medication usage (salbutamol/albuterol) as recorded by 
e-diary 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 excluding measurements in patients requiring 
chronic corticosteroid use after an exacerbation (beyond permitted steroid taper for 
exacerbation) by exacerbation category


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-
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 comparisons, QVM149 150/50/80 µg o.d. and 
QVM149 150/50/160 µg o.d. delivered via Concept1 will be compared with salmeterol 
xinafoate /fluticasone propionate 50/500 µg via Accuhaler® (comparisons 3) and 4)) for 
the primary and key secondary endpoints:
-
Trough FEV1 measured after 26 weeks of treatment
-
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 adjudicated serious asthma 
outcomes (i.e. asthma-related hospitalization, asthma-related intubation, or asthma-
related death),adjudicated cardiovascular and cerebrovascular (CCV) events, and 
adjudicated atrial fibrillation/flutter over 52 weeks of treatment
-
Adverse events, vital signs, ECG and laboratory analysis (hematology, blood 
chemistry including glucose and potassium, urinalysis) over 52 weeks of treatment
-
Plasma evening cortisol over 52 weeks of treatment


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2.1.5
Changes in the conduct of the study or planned analyses
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. regimen salmeterol/fluticasone 50/500 μg. This is considered clinically justified based 
on the 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 


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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. 
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.


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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 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 medical care into 1, 2, 3, ≥ 4

pre-bronchodilator FEV1 into < 40 %, 40 - < 60%, 60% - < 80% of predicted FEV1

ACQ-7 into 1.5- < 2, 2 – < 2.5, ≥ 2.5 (< 1.5 will be added in case of protocol 
deviations)

prior asthma treatment into medium and high dose ICS/LABA
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 three administrations, i.e., the Accuhaler both 


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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 
group 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.
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 QVM149 150/50/80 µg o.d. to 
QMF149 150/160 µg o.d. or QVM149 150/50/160 µg o.d. to QMF149 150/320 µg o.d. in terms 
of trough FEV1 after 26 weeks of treatment. The key secondary objective is to demonstrate the 
same 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 (except for patients who were on stable systemic corticosteroids as 


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background therapy), or within 6 hours of rescue medication use, 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. regimen salmeterol/fluticasone 50/500 μg), 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 
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 


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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
The two comparisons of QVM149 150/50/80 µg o.d. versus QMF149 150/160 µg o.d. and 
QVM149 150/50/160 µg o.d. versus QMF149 150/320 µg o.d. will be evaluated by testing the 
following null hypotheses (H0) versus the alternative hypotheses (Ha) for both the primary 
variable trough FEV1 after 26 weeks of treatment and key secondary variable ACQ-7 after 26 
weeks of treatment:
H01: QVM149 150/50/80 µg is equal to QMF149 150/160 µg 
versus
Ha1: QVM149 150/50/80 µg is not equal to QMF149 150/160 µg
and
H02: QVM149 150/50/160 µg is equal to QMF149 150/320 µg 
versus
Ha2: QVM149 150/50/160 µg is not equal to QMF149 150/320 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, region (Eastern 
Europe, Western Europe, India, Japan, Asia (other than India and Japan), 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. 


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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 
(QVM149 – QMF149) will be displayed along with the associated standard error (SE), 2-sided 
95% confidence interval (CI), and p-value (2-sided).
In addition, to estimate the add-on effect of glycopyrronium to QMF149, the average of
QVM149 doses (150/50/80 μg and 150/50/160 μg) vs. the average of QMF149 doses (150/160 
μg and 150/320 μg) will be computed in terms of FEV1. QVM149 and QMF149 doses will be 
pooled using appropriate contrasts within the MMRM specified above.
The key secondary variable, 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.
2.6.1.3
Multiplicity adjustment
To control the family-wise type-I error rate at the two-sided 5% significance level, a testing 
procedure based on the generalized Simes test as described in Maurer et al (2011) will be used. 
The family for the overall type-I error rate control contains four hypotheses: two hypotheses for 
the primary endpoint trough FEV1 (H1 and H2 for comparing QVM149 150/50/80 μg vs. 
QMF149 150/160 μg and QVM149 150/50/160 μg vs. QMF149 150/320 μg) and two 
hypotheses for the key secondary endpoint ACQ-7 (H3 and H4 for the same treatment 
comparisons as H1 and H2). 
A description of the testing procedure is provided in Appendix 16.1.9.
Other than the 4 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 
salmeterol/fluticasone 50/500 μg b.i.d. regimen) will be excluded.


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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 of 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 QVM149 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 
QVM149 arms are then adjusted by a delta value. A detailed description of the analysis steps is 
provided in Appendix 16.1.9.
The following exploratory subgroup analyses for trough FEV1 at Week 26 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:

Race (Caucasian, Asian, Black and other)

Sex (male, female)

History of asthma exacerbation in the 12 months prior to screening (1, 2, 3, ≥ 4)

Patients’ prior therapies before run-in period (mid and high dose ICS/LABA; see 
Appendix 10 of the study protocol for the definition of ICS dose levels)

Pre-bronchodilator FEV1 in % of predicted FEV1 at run-in visit 101 (< 40%, 40% - < 60%, 
60% - < 80%)

ACQ-7 at baseline (1.5 - < 2, 2 - < 2.5, ≥ 2.5)
The subgroup analyses for patient's prior therapies before run-in period (mid and high dose 
ICS/LABA) will also be performed for endpoints ACQ-7 and AQLQ at Week 26.
For ACQ-7, the same MMRM used for key secondary endpoint will also be performed on the 
FAS excluding measurements in patients requiring chronic corticosteroid use after an 
exacerbation (beyond permitted steroid taper for exacerbation of approximately 7-10 days). 
That means, if an asthma exacerbation requires either an initiation of systemic corticosteroids 
or an increase in the maintenance dose of oral corticosteroids (OCS) which is extended to more 
than 10 days, then all ACQ-7 measurements during that period from start to stop date will be 
excluded.
2.6.2
Analysis of secondary variables
In addition to the two primary treatment comparisons QVM149 150/50/80 μg vs. QMF149 
150/160 μg and QVM149 150/50/160 μg vs. QMF149 150/320 μg, each dose of QVM149 will 
be compared vs. salmeterol xinafoate /fluticasone propionate 50/500 µg b.i.d. for all secondary 
variables (and for the primary and key secondary variables too).
The estimation of the add-on effect of glycopyrronium to QMF149 (i.e., the average of 
QVM149 150/50/80 μg and QVM149 150/50/160 μg vs. the average of QMF149 150/160 μg 
and QMF149 150/320 μg) will be done for trough FEV1, ACQ (mean change and responder 
analysis), and asthma exacerbations.


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2.6.2.1
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 (except for patients who were 
on stable systemic corticosteroids as background therapy), 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.
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.
2.6.2.2
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.


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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.
As already mentioned above, subgroup analyses for patient's prior therapies before run-in period 
(mid and high dose ICS/LABA) will be performed for ACQ-7 at Week 26 (using the appropriate 
interaction term in the model and additional covariate as a fixed effect).
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 
not Question 1 ('On the average, during the past week, how often were you woken by your 
asthma during the night?').
2.6.2.3
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 and 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.
2.6.2.4
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.


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The mean daily number of puffs of rescue medication use will be calculated for each patient 
over the first 26 weeks, 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.
2.6.2.5
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 rising, 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 rising 
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. 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.


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2.6.2.6
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 will be 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.
As already mentioned above, the add-on effect of glycopyrronium to QMF149 (i.e., the average 
of QVM149 150/50/80 μg and QVM149 150/50/160 μg vs. the average of QMF149 150/160 
μg and QMF149 150/320 μg) will also be estimated for asthma exacerbations.
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 
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 and region as fixed-effect 
factors, and history of asthma exacerbation in the 12 months prior to screening (i.e., the number 
of asthma exacerbations in the 12 months prior to screening), 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.
An additional analysis of the annual rate of asthma exacerbations will be done by excluding
events/days in patients requiring corticosteroid use after an exacerbation (beyond permitted 
steroid taper for exacerbation). If an asthma exacerbation requires either an initiation of 
systemic corticosteroids or an increase in the maintenance dose of OCS extended to more than 
10 days treatment, all data from start to stop date of that systemic corticosteroid use will be 
excluded.
Time to first asthma exacerbation, by exacerbation category
Time-to-event variables will be analyzed using a Cox regression model stratified by region. The 
model will include treatment as fixed-effect factor, and history of asthma exacerbation in the 
12 months prior to screening (i.e., the number of asthma exacerbations in the 12 months prior 
to screening), 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


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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 region and history of asthma 
exacerbation in the 12 months prior to screening (1, 2, ≥ 3).
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.
2.6.2.7
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.


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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 Day 1 assessment constitutes the baseline value. The post-baseline 
visits are scheduled for Weeks 4, 12, 26, 36, and 52.
As mentioned above, subgroup analyses for patient's prior therapies before run-in period (mid 
and high dose ICS/LABA) will be performed for AQLQ at Week 26 (using the appropriate 
interaction term in the model and additional covariate as a fixed effect).
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.
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


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
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

adjudicated serious cardiovascular and cerebrovascular (CCV) events

adjudicated new onset of atrial fibrillation/ flutter

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 
of frequency in the QVM149 150/50(160 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 QVM149 150/50/160 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). 
Serious CCV events will be adjudicated as Major Adverse Cardiovascular Event (MACE) or 
non-MACE. The MACE events will be categorized into: Coronary revascularization (CABG or 
PCI), heart failure requiring hospitalization, non-fatal unstable angina, , non-fatal myocardial 
infarction, and non-fatal stroke. Non-MACE events will not be categorized.
Atrial fibrillation and atrial flutter will be adjudicated according to their onset into: new onset, 
recurrent/persistent, or unknown.
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.


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AEs and SAEs of special interest and adjudicated serious CCV events will also be analyzed for 
the following selected subgroups: 
-
Sex (male, female)
-
Pre-bronchodilator FEV1 in % of predicted FEV1 at run-in visit 101 (< 40%, 40% - < 
60%, 60% - < 80%)
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)
-
adjudicated serious CCV event (composite endpoint, MACE, non-MACE – if there are 
more than 10% of patients with events)
-
new onset of adjudicated atrial fibrillation/flutter (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.
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.


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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 
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 (all 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. All analyses will be considered exploratory. 
2.9.2
Primary analysis after all patients have completed at least 26 weeks 
treatment
The primary and key secondary endpoints of CQVM149B2302 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 


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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:

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 90 mL between QVM149 vs. QMF149 at the
corresponding doses, assuming standard deviation of 380 mL based on internal studies
QMF149A2210, QMF149E2201, QMF149E2203 and Kerstjens (2012);
2.
To achieve at least 80% power (with multiplicity adjustment) for key secondary endpoint 
ACQ-7 with a treatment difference of 0.15 between QVM149 vs. QMF149 at the
corresponding 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 that the sample size of 2980 patients 
(i.e., 596 per arm) will provide 97% power for item 1 and 82% power for item 2, with 
multiplicity adjustment.
The sample size calculation was performed in R 3.1.2 with package gMCP (Rohmeyer, 2012).
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

Philippines

Thailand

Vietnam


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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

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 < 18 years or > 75 years or missing

INCL03: No current diagnosis of persistent Asthma of at least 12 months prior to V1

INCL04.A5: Patients are not treated with medium or high doses of ICS/LABA
combination for at least 3 months and/or not at stable dose 30 days prior to Visit 1

INCL05: ACQ-7 score < 1.5 at V101 and/or V102

INCL05.01: Patient used invalidated ACQ due to translation issue at Visit 101 and/or 
Visit 102

INCL06: Patients without at least one documented asthma exacerbation in the 12 months 
prior to Visit 1 that required physician care/ER/hospitalization and systemic corticosteroid

INCL07: Pre-bronchodilator FEV1 at V101 and/or V102 ≥80% of predicted normal at 
Visit 101

INCL07.01: Patient has not achieved assessments according to ATS/ERS criteria

INCL08: Patient has not achieved an acceptable spirometry result and does not have 
historical reversibility or bronchoprovocation

INCL08.01: Patient without Historical reversibility OR bronchoprovocation according to 
ATS/ERS as per source documentation

INCL 08.02: Increase in FEV1 < 12% or < 200 mL of pre-bronchodilator value in the 
reversibility test without historical data

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: Patient who use smoking nicotine inhalers (e.g., e-cigarette) at Visit 1

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.A4: Patients treated with a LAMA for asthma within 3 months prior Visit 1

EXCL07: Asthma exacerbation within 4 weeks prior to V1

EXCL07.01: Respiratory tract infection or asthma worsening between screening and run-
in Visit 102

EXCL07.02: Respiratory tract infection within 4 weeks prior to V1


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
EXCL08: Visual clinical significant oropharyngeal candidiasis between Visit 101 and 
Visit 102

EXCL09: Chronic condition affecting upper respiratory tract 

EXCL10: Patient has a history of chronic lung diseases other than asthma

EXCL13: Other investigational drugs used within 5 half lives or until return of baseline 
pharmacodynamics effect whichever is longer

EXCL27: Patient is not on maintenance immunotherapy for allergies for at least 3 months 
prior to V101

EXCL30: Unable to use the dry powder inhaler device at V101 and/or V201

EXCL31: Patient has history of alcohol or other substance abuse 

OTH15: Patient received incorrect dose of run-in medication (Visit 101 to Visit 102)

COMD07: Use of parenteral corticosteroids less than 4 weeks prior to Visit 101 not in 
stable dose (OCS)

COMD08: Intra-muscular corticosteroid less than 3 months prior to Visit 101

COMD09: Use of biologic less than 3 months prior to Visit 101 not in stable dose

COMD10: Xanthine's use less than 30 days prior to Visit 101 not in stable dose

COMD11: Leukotriene antagonists and leukotriene synthesis inhibitors taken less than 30 
days prior to Visit 101 not in a stable dose

COMD12: ICS and LABA, not discontinued before required washout period to Visit 101 
and/or Visit 102

COMD13: Last LABA wash out more than 4 days before 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

COMD06: Use of SABA other than rescue medication, not discontinued at Visit 1

COMD01: Banned asthma related Concomitant medication

WITH01: More than 5 exacerbation and still on treatment
Exclusions from full analysis set and per-protocol set:

OTH05: Patient randomized more than one trial

OTH18: Patient randomized more than once in this trial
Exclusions from full analysis set, per-protocol set, safety set, 
:

OTH02: Patient was randomized but no study drug was taken
Exclusions from randomized set, full analysis set, per-protocol set, 
:

Patient who received study medication without randomization


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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, or within 7 days of systemic corticosteroid use (except for patients who were on stable 
systemic corticosteroids as background therapy), or within 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-7 score, 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.


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Baseline PEF will be calculated separately for morning and evening values.
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. 


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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 
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 (except for patients who were on stable systemic corticosteroids as 
background therapy) 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 salmeterol xinafoate/fluticasone propionate 50/500 μg b.i.d. 
regimen) 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 and15 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 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 


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date and time values are assigned to pre or post-dose assessment based on the actual date/time. 
However, values with missing date/time are assigned to their respective scheduled visit date 
and time given the visit number and time point are non-missing. If a measurement scheduled as 
pre-dose is actually performed post-dose, or vice versa, the data will not be used for by time 
point assessments but will be included in the summaries of the notable values and extreme 
values.
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
Eosinophils
High
Lymphocytes
Low and high
Monocytes
High
Neutrophils
Low and high
Platelets
Low and high
B. Chemistry
Albumin
Low
Alkaline Phosphatase
High
ALT/SGPT
High
AST/SGOT
High
Bilirubin Total
High
Blood Urea Nitrogen (BUN) 
High
Creatinine
High
Glucose
Low and high 
Gamma GT
High
Potassium
Low and high
Magnesium
Low and high
Uric acid
High
Plasma cortisol
Low and high
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined. 


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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 + 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 QVM149 (150/50/80 & 150/50/160 µg) and QMF149 (150/160 & 
150/320 µg) will be derived by weighting treatment groups equally.
 


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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 QVM149 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 QVM149 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 QVM149 vs. QMF149 comparison on the 
primary endpoint to be no longer statistically significant. Different delta values are possible for 
QVM149 150/50/80 µg o.d. versus QMF149 150/160 µg o.d. and QVM149 150/50/160 µg o.d. 
versus QMF149 150/320 µg o.d. 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 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 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 QVM149 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, 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 QVM149 
treatment effect is still statistically significantly superior to QMF149), 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 score (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 region, baseline 
ACQ value, FEV1 prior to inhalation and 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, 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 QVM149 (150/50/80 & 150/50/160 µg) and QMF149 (150/160 & 
150/320 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 + 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: λQVM(t) / λControl(t) = 1, where λ(t) is the hazard function for the failure 
time of patients treated with QVM and the control group, respectively. The Cox regression 


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model will be stratified by region and will include terms for treatment, history of asthma 
exacerbation in the 12 months prior to screening (i.e., the number of asthma exacerbations in 
the 12 months prior to screening), 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 QVM149 (150/50/80 & 150/50/160 µg) and QMF149 (150/160 & 
150/320 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, region, history of asthma exacerbation in the 12 months prior to screening 
(i.e., the number of asthma exacerbations in the 12 months prior to screening), 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 QVM149 (150/50/80 & 150/50/160 µg) and QMF149 (150/160 & 
150/320 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 region and history of asthma exacerbation in the 12 months prior to screening 
(1, 2, ≥ 3).
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.
16.1.9.7
Multiplicity adjustment
To control the family-wise type-I error rate at the two-sided 5% significance level, a testing 
procedure based on the generalized Simes test as described in Maurer et al (2011) will be used. 
The family for the overall type-I error rate control contains four hypotheses: two hypotheses for 
the primary endpoint trough FEV1 and two hypotheses for the key secondary endpoint ACQ-7. 
Denote the two hypotheses for the primary endpoint as H1 and H2 for comparing QVM149 


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150/50/80 μg vs. QMF149 150/160 μg and QVM149 150/50/160 μg vs. QMF149 150/320 μg 
respectively. Similarly, denote the two hypotheses for the key secondary endpoint ACQ-7 as 
H3 and H4, for comparing QVM149 150/50/80 μg vs. QMF149 150/160 μg and QVM149 
150/50/160 μg vs. QMF149 150/320 μg respectively. 
Below is a brief description of the testing procedure based on the generalized Simes test in 
Maurer et al (2011).
Let p1, p2, p3, p4 be the corresponding p-values (2-sided) of the four hypotheses of H1, H2, 
H3, and H4.
Step 1: Retain all four hypotheses 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, 3, 4, stop here; otherwise go to Step 2.
Step 2: Reject all four hypotheses if pi < 0.05 for ALL i=1, 2, 3, 4 and stop here; otherwise go 
to Step 3.
Step 3: If neither Step 1 or 2 applies, perform a closed successive weighted Bonferroni test as 
given in Figure 9-1. The initial weights of 0.5 to H1 (corresponding to 0.025 alpha level, 2-
sided) and 0.5 to H2 (corresponding to 0.025 alpha level, 2-sided) were assigned. Here is a brief 
summarization of the successive weighted Bonferroni test based on Bretz et al (2011): If H1 is 
rejected at the initial significance level of 0.025, then H3 can be tested at the significance level 
of 0.025. Similarly, if H2 is rejected at the initial significance level of 0.025, then H4 can be 
tested at the significance level of 0.025. If neither primary null hypothesis can be rejected at the 
initial significance levels, then the testing stops and efficacy cannot be claimed for neither of 
the doses and endpoints. Otherwise the graph is sequentially updated with reallocated weights 
after each hypothesis is rejected. In addition, if efficacy can be shown for one of the doses on 
both the primary and key secondary endpoints at the initial significance level, the associated 
weight is passed on to the other dose for further testing.
Figure 9-1
Testing Procedure
For each of the four hypotheses, the corresponding testing statistics (estimated least square 
mean difference) follows normal distribution. Hence for any two out of the four hypotheses, 
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 Maurer et al (2011).


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References
Maurer W, Glimm, and Bretz F (2011). Multiple and repeated testing of primary, coprimary, 
and secondary hypotheses. Statistics in Biopharmaceutical Research; 3; 336-352.
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.