Clinical trial NCT03063086
Conditions: Asthma
Sponsor: Novartis Pharmaceuticals
Start date: 2017-01-21; Completion date: 2018-08-02
Enrollment: 116 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess peak FEV1 of two doses of QVM149 compared to a fixed-dose combination of salmeterol/fluticasone (50/500μg b.i.d.) and to characterize the respective 24 hour bronchodilator effect profiles in patients with asthma. Data from this study will complement lung function data obtained in the pivotal QVM149 phase 3 program by assessing the bronchodilatory effect of QVM149 at multiple time-points over an entire dosing interval of 24 hours.

Detailed description:

Arms: arm 1: A-B-C arm 2: A-C-B arm 3: B-C-A arm 4: B-A-C arm 5: C-A-B arm 6: C-B-A
Interventions: intervention 1: QVM149 150/50/80 μg o.d. intervention 2: QVM149 150/50/160 μg o.d. intervention 3: salmeterol/fluticasone FDC 50/500 μg b.i.d.
Intervention descriptions: intervention 1: A intervention 2: B intervention 3: C

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
QVM149
Clinical Trial Protocol CQVM149B2208
A randomized, double-blind, double-dummy, active-
controlled, 3-period complete cross-over study to assess 
the bronchodilator effect and safety of two doses of 
QVM149 compared to a fixed dose combination of 
salmeterol/fluticasone in patients with asthma
Document type:
Amended Protocol Version
EUDRACT number:
2016-005164-34
Version number:
v01 (Clean)
Clinical Trial Phase:
II
Release date:
12-Jan-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report 

Submit SAE report to Novartis Drug Safety and Epidemiology (DS&E) within 
24 hours after awareness of the SAE 

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations
Manual. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of figures......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol synopsis...............................................................................................................14
1 Introduction.......................................................................................................................19
1.1
Background............................................................................................................19
1.3
Clinical data...........................................................................................................22
1.3.1
Human safety and tolerability data.......................................................22
1.3.2
Human pharmacokinetic data................................................................23
1.3.3
Human pharmacodynamic data.............................................................23
1.4
Study purpose........................................................................................................24
2 Study objectives and endpoints.........................................................................................24
2.1
Primary objective(s)...............................................................................................24
2.2
Secondary objective(s)...........................................................................................24
3 Investigational plan...........................................................................................................26
3.1
Study design...........................................................................................................26
3.2
Rationale for study design.....................................................................................27
3.3 
Rationale for dose/regimen, route of administration and duration of treatment....28
3.4
Rationale for choice of comparator.......................................................................31
3.6
Risks and benefits..................................................................................................31
3.6.1
Blood sample volumes..........................................................................34
4 Population..........................................................................................................................34
4.1
Inclusion criteria....................................................................................................34
4.2
Exclusion criteria...................................................................................................35
5 Restrictions for Study Subjects.........................................................................................39
5.1
Contraception requirements...................................................................................
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5.2
Prohibited treatment...............................................................................................39
5.3
Dietary restrictions and smoking...........................................................................41
5.4
Other restrictions ...................................................................................................41
6
Treatment...........................................................................................................................41
6.1
Study treatment......................................................................................................41
6.1.1
Investigational and control drugs..........................................................41
6.1.2
Additional study treatment....................................................................42
6.2
Treatment Arms.....................................................................................................42
6.3
Treatment assignment and randomization.............................................................42
6.4
Treatment blinding.................................................................................................43
6.5
Treating the subject................................................................................................44
6.6
Permitted dose adjustments and interruptions of study treatment.........................45
6.7
Emergency breaking of assigned treatment code ..................................................45
6.8
Treatment exposure and compliance .....................................................................46
6.9
Recommended treatment of adverse events ..........................................................46
6.10
Rescue medication.................................................................................................46
6.11
Concomitant treatment...........................................................................................47
7
Study Completion and Discontinuation.............................................................................47
7.1
Study completion and post-study treatment ..........................................................47
7.2
Discontinuation of study treatment........................................................................48
7.3
Withdrawal of informed consent ...........................................................................50
7.4
Lost to follow-up ...................................................................................................50
7.5
Study stopping rules ..............................................................................................50
7.6
Early study termination by the sponsor .................................................................50
8
Procedures and assessments ..............................................................................................51
8.1
Assessment schedule .............................................................................................51
8.2
Informed consent procedures.................................................................................56
8.3
Subject screening...................................................................................................56
8.4
Subject demographics/other baseline characteristics.............................................57
8.4.1
Alcohol test, Drug screen, Urine cotinine.............................................57
8.4.2
Reversibility..........................................................................................57
8.5
Efficacy / Pharmacodynamics ...............................................................................57
8.5.1
Spirometry.............................................................................................57
8.5.2
Peak expiratory flow .............................................................................59
8.6
Safety.....................................................................................................................59
8.6.1
Physical examination ............................................................................59


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8.6.2
Vital signs..............................................................................................60
8.6.3
Height and weight.................................................................................60
8.6.4
Laboratory evaluations..........................................................................60
8.6.5
Electrocardiogram (ECG).....................................................................60
8.6.6
Pregnancy and assessments of fertility.................................................61
8.7
Pharmacokinetics...................................................................................................61
8.8
Other assessments..................................................................................................61
8.8.1
Patient diary..........................................................................................61
8.8.2
Device training......................................................................................62
9 Safety monitoring..............................................................................................................63
9.1
Adverse events.......................................................................................................63
9.2
Serious adverse event reporting.............................................................................64
9.2.1
Definition of SAE.................................................................................64
9.2.2
SAE reporting........................................................................................65
9.3
Liver safety monitoring.........................................................................................66
9.4
Medication errors including misuse/abuse............................................................67
9.5
Pregnancy reporting...............................................................................................68
9.6
Prospective suicidality assessment........................................................................68
9.7
Early phase safety monitoring...............................................................................68
10 Data review and database management.............................................................................69
10.1 Site monitoring......................................................................................................69
10.2 Data collection.......................................................................................................69
10.3 Database management and quality control............................................................70
10.4 Data Monitoring Committee..................................................................................71
10.5 Adjudication Committee........................................................................................71
11 Data analysis......................................................................................................................71
11.1 Analysis sets..........................................................................................................71
11.2 Subject demographics and other baseline characteristics......................................71
11.3 Treatments.............................................................................................................71
11.4 Analysis of the primary variable(s).......................................................................71
11.4.1
Variable(s).............................................................................................71
11.4.2
Statistical model, hypothesis, and method of analysis..........................72
11.4.3
Handling of missing values/censoring/discontinuations.......................72
11.4.4
Sensitivityanalyses...............................................................................
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11.5 Analysis of secondary variable(s)..........................................................................72
11.5.1
Efficacy / Pharmacodynamics...............................................................72
11.5.2
Safety.....................................................................................................73
11.5.3
Other assessments.................................................................................73
11.7 Sample size calculation..........................................................................................74
11.8 Power for analysis of key secondary variables......................................................75
12 Ethical considerations........................................................................................................76
12.1 Regulatory and ethical compliance........................................................................76
12.2 Responsibilities of the investigator and IRB/IEC..................................................76
12.3 Publication of study protocol and results...............................................................76
13 Protocol adherence............................................................................................................76
13.1 Protocol Amendments...........................................................................................77
14 References.........................................................................................................................78
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................79
16 Appendix 2: Instruction for Use of Concept1...................................................................81
17 Appendix 3: How to Use salmeterol xinafoate/ fluticasone propionate and its inhaler....86
List of tables
Table 3-1
Comparison of the comparable nominal MF component doses 
between Asmanex Twisthaler, QMF149 and QVM149.......................30
Table 5-1
Withholding period of bronchodilators prior to any spirometry 
assessment during the trial....................................................................39
Table 5-2
Prohibited asthma medication during treatment period........................39
Table 5-3
Prohibited treatment, cessation periods.................................................40
Table 5-4
Medication allowed under certain conditions if taken as follows.........40
Table 6-1
Overview of study medication..............................................................41
Table 6-2
Definition of treatment sequences.........................................................42
Table 6-3
Blinding and unblinding plan................................................................44
Table 8-1
Assessment Schedule............................................................................51
Table 8-2
Spirometry –Assessments....................................................................55
Table 9-1
Summary of reporting requirements for medication errors...................68
Table 15-1 
Liver Event Definitions.........................................................................79
Table 15-2
Actions required for Liver Events.........................................................79
Table 15-3
Exclusion of underlying liver disease...................................................
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List of figures
Figure 3-1
Study design..........................................................................................27


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AV
atrioventricular
b.i.d.
twice a day
BA
Bioanalytical
BMI
Body Mass Index
BP
blood pressure
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CO2
carbon dioxide
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report/Record Form (paper or electronic)
CSR
clinical study report
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
FDA
Food and Drug Administration
FDC
fixed-dose combination
FEF25-75%
Forced Expiratory Flow (25-75%)
FEV1
Forced Expiratory Volume in 1 second
FPM
fine particle mass
FVC
forced vital capacity
GCP
Good Clinical Practice
h
Hour
HbA1C
hemoglobin a1c


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HBsAG
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
i.v.
Intravenous
IB
Investigator's Brochure
IBD
International birthdate
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
inhaled corticosteroid
IEC
Independent Ethics Committee
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
kg
Kilogram
LABA
Long-acting β2 agonist
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
MDDPI
Multi-dose dry powder inhaler
mg
milligram(s)
ml
milliliter(s)
o.d.
once a day
OTC
over-the-counter
p.o.
Oral
PD
pharmacodynamic(s)
PEF
peak expiratory flow
PI
post-inhalation
PK
pharmacokinetic(s)
pMDI
pressurized metered-dose inhaler


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RBC
red blood cell(s)
REB
Research Ethics Board
SABA
Short-acting β2 agonist
SAE
serious adverse event
SD
standard deviation
SDDPI
single-dose dry powder inhaler
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
γ-GT
gamma-glutamyl transferase
μg
Microgram


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Baseline
Period after screening and  prior to the first dose of Treatment 
period 1
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a 
placebo) which is used as a comparator to the investigational 
drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject 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
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, 
treatment, follow-up), which applies across all arms of a study.
Investigational drug
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3  and 
Directive 2001/20/EC  and is synonymous with “investigational 
new drug” or “test substance”
Medication pack number
A unique identifier on the label of each drug package in studies 
that dispense study treatment using an IRT system
Non-investigational 
medicinal Product (NIMP)
Products which are not the object of investigation (e.g. any 
background therapy administered to each of the clinical trial 
subjects, regardless of randomization group, rescue medication, 
active drug run-ins etc.)
Part
A single component of a study which contains different 
objectives 
or 
populations 
within 
that 
single 
study. 
Common parts within a study are: a single dose part and a 
multiple dose part, or a part in patients with established disease 
and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest
Screen Failure
A subject who is screened but is not treated or randomized
Subject
A trial participant (can be a healthy volunteer or a patient)


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Subject number
A unique number assigned to each subject upon signing the 
informed consent. This number is the definitive, unique 
identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample 
labels, etc.
Randomization number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment
Study treatment
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment 
prior to the defined study treatment completion date
Variable
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a 
subject does not want to participate in the study any longer, and 
does not want any further visits or assessments, and does not 
want any further study related contact, and does not allow 
analysis of already obtained biologic material


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Protocol synopsis
Protocol number
CQVM149B2208
Title
A randomized, double-blind, double-dummy, active-controlled, 3-period 
complete cross-over study to assess the bronchodilator effect and safety of 
two doses of QVM149 compared to a fixed dose combination of 
salmeterol/fluticasone in patients with asthma
Brief title
Assess the bronchodilator effect and safety of QVM149 compared to 
salmeterol/fluticasone in patients with asthma
Sponsor and 
Clinical Trial Phase
Novartis 
Phase II
Intervention type
Drug
Study type
Interventional
Purpose and 
rationale
To assess peak FEV1 of two doses QVM149 compared to a fixed-dose 
combination of salmeterol/fluticasone (50/500μg b.i.d.) and to characterize 
the respective 24 hour bronchodilator effect profiles in patients with asthma. 
Data from this study will complement lung function data obtained in the 
pivotal QVM149 phase 3 program by assessing the bronchodilatory effect of 
QVM149 at multiple time-points over an entire dosing interval of 24 hours.
Primary Objective(s)
To demonstrate superiority in peak bronchodilator effect of QVM149 at a 
dose of 150/50/160 μg o.d. and 150/50/80 μg o.d. compared to a FDC of 
salmeterol/fluticasone at a dose of 50/500 μg b.i.d. after 3 weeks of treatment 
in patients with asthma
Secondary 
Objectives
To evaluate the bronchodilator effect of each dose of QVM149 compared to 
salmeterol/fluticasone FDC after 3 weeks of treatment.
To evaluate the bronchodilator effect of each dose of QVM149 compared to 
salmeterol/ fluticasone FDC by measuring standardized FEV1 AUCs after 
3 weeks of treatment respective period.
To evaluate post-dose trough bronchodilator effect of each dose of QVM149 
compared to salmeterol/fluticasone FDC after 3 weeks of treatment in the 
respective treatment period.
To evaluate safety and tolerability of each dose of QVM149 and salmeterol/ 
fluticasone FDC when administered for 3 weeks.
Study design
This 
is 
a 
confirmatory, 
randomized, 
double-blind, 
double-dummy, 
active-controlled, 3-period complete cross-over study. During the 2-week 
screening period, patients will be required to abstain from using any asthma 
medication before screening lung function assessments in line with cessation 
periods. Patients are allowed to use their previous asthma medication 
between screening spirometry and randomization but need to stop at 
randomization when study drug administration commences.
Short-acting beta-2-agonist bronchodilators will be provided to each patient to 
be used as rescue medication throughout the trial. Rescue medication use 
will be recorded in the patient diary.
The 2-week screening period may be divided into more than one visit for 
operational reasons with the informed consent being obtained prior to any 
study related activities.


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Eligible subjects may be re-screened once if they are not included in the 
study within the allowed 2 week screening period.  Subjects may also be 
re-screened at the discretion of the Investigator, and following discussion with 
the Medical Monitor and/or Sponsor, if the reason for screen failure was 
considered temporary in nature.  All screening data must be obtained within 
2 weeks prior to administration of study medication, as stipulated above.  
Subjects who are re-screened will re-consented and will be allocated a new 
screening number.
At the end of the screening period, patients will be randomized to one of 
6 possible treatment sequences), each consisting of 3 double-blind, 
double-dummy treatment periods of 21 days (cross-over design). 
There is no washout period between treatments periods since drug effects 
from the previous period are not expected to be present after 3 weeks with 
current treatment in each period.
Each treatment sequence will have approximately 19 subjects.
Procedures in treatment periods two and three are identical to the procedures 
of treatment period one. At the end of the last treatment period, subjects will 
then undergo Study Completion evaluations and will be discharged from the 
study site. 
Safety assessments will include physical examinations, ECGs, vital signs,
standard clinical laboratory evaluations (hematology, blood chemistry and 
urinalysis), adverse event and serious adverse event monitoring.
Population
Male and female patients aged between 18 and 75 years with asthma and
who have been treated with ICS and LABA for at least 12 months prior to 
screening


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Key Inclusion 
criteria

Male and female adult patients ≥ 18 years old and ≤ 75 years.

Patients with a documented physician diagnosis of asthma for a period of 
at least 12 months prior to Visit 1 (Screening).

Patients who have used ICS and  LABA combinations for asthma for at 
least 3 months and at a stable medium or high dose of ICS for at least 1 
month prior to Visit 1 (Screening).

Pre-bronchodilator FEV1 of < 80 % of the predicted normal value at 
screening Visit 1 (spirometry will not be repeated at baseline prior to 
randomization).

Patients who demonstrate an increase in FEV1 of  ≥ 12 % and 200 mL 
after administration of 400 µg salbutamol/360 µg albuterol (or equivalent 
do se) at Visit 1 (Screening). All patients must perform a reversibility test 
at Visit 1 (Screening). If reversibility is not demonstrated at Visit 1 
(Screening), then, reversibility testing may be repeated once during the 
screening period.

If reversibility is not demonstrated at Visit 1 (retesting allowed once), 
patients must be screen failed. Spacer devices are not permitted during 
reversibility testing.
Key Exclusion 
criteria

Patients who have smoked or inhaled tobacco products within the 
6 month period prior to Visit 1

Patients who have had an asthma attack/exacerbation requiring systemic 
steroids or hospitalization or emergency room visit within 6 weeks of Visit 1

Patients with narrow-angle glaucoma, symptomatic benign prostatic 
hyperplasia (BPH) or bladder-neck obstruction or severe renal 
impairment or urinary retention

Patients who have had a respiratory tract infection or asthma worsening 
within 4 weeks prior to Visit 1

Patients with any chronic conditions affecting the upper respiratory tract

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 Type I diabetes or uncontrolled Type II diabetes 
(HbA1c >9% at screening).

Patients who have a clinically significant ECG abnormality at Visit 1

Patients with a history of hypersensitivity or intolerance to any of the 
study drugs (including excipients)

Patients with narcolepsy and/or insomnia.

Patients on Maintenance Immunotherapy (desensitization) for allergies 
for less than 3 months prior to Visit 2 or patients on Maintenance 
Immunotherapy for more than 3 months prior to Visit 2 but expected to 
change throughout the course of the study.

Pregnant or nursing (lactating) women

Women of child-bearing potential must use Highly effective contraception 
methods

Patients who have discontinued LAMA therapy in the past for any safety, 
tolerability or perceived lack of efficacy reason.

History of paradoxical bronchospasm in response to inhaled medicines.

Patients with a history of clinically relevant bronchoconstriction upon 
repeated forced expiratory maneuvers.

Patient with a serum potassium level below the laboratory limit of normal 
at screening.


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Study treatment
QVM149 150/50/160 μg o.d. (indacaterol acetate 150 μg/ glycopyrronium 
bromide 50 μg/ MF 160 μg once daily)
QVM149 150/50/80 μg o.d. (150 μg/ 50 μg/ 80 μg once daily)
salmeterol/fluticasone FDC 50/500 μg b.i.d.
Key safety 
assessments

Physical examination

Vital signs

Laboratory evaluations; hematology, blood chemistry and urinalysis

Electrocardiogram (ECG)
Other assessments

Patient diary to record; Rescue medication use, Study treatment 
administration: am and pm and PEF measurements: am and pm

Device training for the e-diary/peak flow meter device used to collect 
information on rescue medication use and to store PEF meter 
measurements. Subject will also be trained with inhalation devices using 
respective training kits.
Data analysis
The primary objective is to demonstrate superiority in peak bronchodilator 
effect of QVM149 at a dose of 150/50/160 μg o.d. and 150/50/80 μg o.d. 
compared to a FDC of salmeterol/fluticasone at a dose of 50/500 μg b.i.d. 
after 3 weeks of treatment in patients with asthma.
The primary endpoint is the peak FEV1 (mL) defined as the highest 
bronchodilatory effect on FEV1 during a period of 5 min to 4 h after the last 
dose of the preceding 3-week treatment period.
The following hypothesis will be tested for each of QVM149 doses versus 
salmeterol/fluticasone separately:
H0: There is no difference in terms of the peak FEV1 after 21 days of 
treatment between:
the QVM149 high dose and salmeterol/fluticasone 
OR 
the QVM149mid dose and salmeterol/fluticasone 
H1: There is a difference in terms of the peak FEV
1after 21 days of treatment 
between:
the QVM149high dose and salmeterol/fluticasone 
AND 
the QVM149mid dose and salmeterol/fluticasone 
Each test will be conducted at a one-sided 2.5% level.
The primary variable will be analyzed using a linear mixed model. The model 
will include period, treatment, and sequence as fixed effect factors and 
patient as a random effect. Restricted maximum likelihood method will be 
used. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. 
No adjustment for multiplicity is planned because both tests are required to 
be positive.
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The pairwise treatment differences of each QVM149 dose versus 
salmeterol/fluticasone along with the corresponding 2-sided 95% confidence 
intervals will be presented.
Key words
Asthma


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1
Introduction
1.1
Background
Asthma is a chronic inflammatory disorder of the airways associated with airway 
hyperresponsiveness 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 bronchial airflow obstruction 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 (GINA2016).
Despite existing therapies there is still significant unmet medical need in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years (DALYs) are lost annually due to 
asthma, representing 1% of the total global burden. Annual worldwide deaths have been 
estimated at 250,000 (Beasley 2004).
Recently, tiotropium (long-acting muscarinic antagonist; LAMA) has been approved in
the 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 
(ICS;
≥
800μg
budesonide/day
or
equivalent)
and
long-acting
beta2-agonists (LABA), and who experienced one or more severe exacerbations in the
previous year. This is reflected in the GINA 2016 guideline by recommending tiotropium as
an add-on option in patients requiring asthma therapy step 4 and 5 according to the GINA 
treatment algorithm.
There is mounting evidence that in patients who are poorly controlled on mid and high dose 
ICS/LABA a triple combination of LABA, LAMA and ICS can provide additional benefit
in terms of lung function, symptom control and a reduction in exacerbations.
QVM149 is a fixed-dose combination of indacaterol acetate (LABA), glycopyrronium 
bromide (LAMA), and mometasone furoate (MF; ICS) in development for once-daily 
maintenance treatment of asthma GINA step ≥4. QVM149 is formulated as lactose-
blended inhalation powder delivered via the Concept1 inhalation device (Breezhaler®), a
single dose dry powder inhaler (SDDPI). The three mono-components of QVM149,
indacaterol acetate, glycopyrronium bromide and MF have previously been developed as 
individual drugs or dual combinations (indacaterol acetate/MF called QMF149; indacaterol 
maleate/glycopyrronium bromide called QVA149) for treatment of either COPD or asthma 
as detailed below, thereby supporting the efficacy and safety of individual components and 
the selection of doses for their combination in QVM149.


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Indacaterol
Indacaterol maleate delivered via Concept1 (Onbrez
® Breezhaler®) is approved in over 
110countries worldwide at doses of 150 μg to 300 μg once daily for the  maintenance 
bronchodilator treatment of airflow obstruction in patients with COPD.
The clinical development program of indacaterol maleate included studies in patients with 
asthma on background ICS therapy as recommended by GINA 2016 treatment guidelines and 
demonstrated that indacaterol maleate was effective and well-tolerated. A study in adolescent 
and adult patients with moderate to severe persistent asthma receiving concomitant ICS 
therapy showed that indacaterol maleate at dosesof up to 600 μg o.d. over a 26-week 
treatment period was well-tolerated and resulted in effective bronchodilation superior to that 
provided by salmeterol (CQAB149B2338).
Studies comparing the indacaterol maleate salt with the acetate salt found that the acetate salt 
was associated with a lower incidence of post-inhalation cough 
 with no 
impact on efficacy, safety or systemic exposure (CQAB149D2301).Indacaterol acetate 
bronchodilator effects, control of asthma symptomsand safety of indacaterol acetate (150μg 
or 75 μg o.d.; on top of MF background medication) were furthersubstantiated in study 
QMF149E2203 in patients with asthma. Therefore, the acetate saltis being used in the 
QVM149 FDC.
Glycopyrronium bromide
Glycopyrronium bromide (50 μg once daily in a lactose-based formulation delivered via 
Concept1) is registered in the EU since 2012 as Seebri® Breezhaler® for the treatment of 
COPD. 
Glycopyrronium bromide 50 μg has demonstrated clinically meaningful and statistically 
significant improvementsin lung function in COPDpatients which is sustained over 24 hours 
and provides significant symptomatic benefits with a favorable safety and tolerabilityprofile. 
The fixed dose combination of indacaterol maleate and glycopyrronium bromide(QVA149)is 
alsoregisteredintheEUasUltibro
® Breezhaler
® withthedelivered dosesasproposedfor
QVM149. Glycopyrronium bromide has been studied in adults and demonstrated optimal 
bronchodilationfromthefirstdose;efficacywas maintained with once-daily dosingfor 
treatment periods of up to a year with good safety and tolerability.
Mometasone furoate (MF)
MF is marketed in inhalation, nasal, cream, ointment and lotion formulations. Theinhalation 
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. The recommended daily 
doses of Asmanex®Twisthaler
®
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range from 200 μg to 800 μg.


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LABA/ICS dual combination QMF149
QMF149 combines two of the components of QVM149 in a fixed-dose combination of 
indacaterol acetate and MF. This dual combination is also currently being developed for the 
once daily maintenance treatment of asthma. As in QVM149 (please see below) a dose 
adjustment for the MF component neededto be made: primarily to account for differences in 
inhalation device performance the nominal dose of MF in Concept1 needed to be adjusted to 
matchthe MF dose delivered by the Twisthaler® device. 
 
 
In a 4-week study in patients with persistent asthma 
(StudyCQMF149E2201), 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 
(2x400 μg) delivered once daily via Twisthaler®confirming appropriate dose adjustment of 
the MF component for QMF.
QVM149
DuetoQVM149formulationrequirementswhenaddingtheLAMAtoLABA/ICS (QMF149) 
thedose ofMF(ICS component)inQVM149needed tobe adjusted (Table 3-1): the nominal 
doses of MF in QVM149 are 80 μg and 160 μg to ensure that the fine particle mass 
inthelactoseblendformulationforQVM149 is
similar to the nominalMFdoses of 160 μg and 320 μgused forQMF149(Section 3.3).
No adjustmentstothe dosesofindacaterolorglycopyrroniumintheFDC QVM149 
combination are required.Additional detail is provided inSection 3.3
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discussing the dose 
rationaleofthisstudy.
The most relevant data for the present study are summarized in the sections below. 
Fordetailed information, please refer to the Investigator
's Brochure.
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1.3
Clinical data
1.3.1
Human safety and tolerability data
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To date no results fromclinical studies being performed with QVM149 are available,
however the currently available data for the monotherapy and dual combination products are 
considered adequateto supportinvestigationof QVM149 ina comprehensive drug 
development program including phase 1 to phase 3 studies. 
ItisexpectedthatthesafetyprofileofQVM149iscomparabletothatofitscomponents
since thesystemicexposuretoindacaterol,glycopyrroniumand MF followinginhalationof 
QVM149isexpectedtobe comparabletothesystemicexposurefollowinginhalationofthe 
individual monocomponents or available dual combinations.Therisksofsideeffectsfromthe 
study medicationarethoseknownforLABAs,LAMAsandICS.Reportingratesofadverse 
drugreactionshave beenlowacrosstheclinicalstudieswiththemonocomponentsas wellas 
the dual combinations.
For indacaterol,thecharacteristicadverseeffectsof inhaledβ2-adrenergicagonistscan occur 
asaresult ofactivationofsystemicβ-adrenergicreceptors.Themost common adverse effects 
include skeletalmuscle tremorandcramps, insomnia,tachycardia,decreasesinserum 
potassium and increases in plasmaglucose.
Forglycopyrronium, adverseexperiencestypicallyassociatedwith muscarinic antagonists 
suchasdrymouth,gastro-intestinal disturbances and urinary retention/difficulty voiding 
urinewere reported atlow rates. The frequency of cardiovascular related adverse experiences 
was generally low, however ahigher rateof atrial fibrillationwas observed with
glycopyrronium thanwith placebo.The COPD populationinvestigatedinthiscontext,
however,hadahigh prevalence of CVcomorbidity
.
For MF, thecharacteristicadverse effects ofICScan occur. The most prominent of these 
includeoral candidiasisfollowinglocaldeposition of thesteroidintheoropharynx.
Systemiceffectscan alsooccur. These mayinclude Cushing
's syndrome, Cushingoid
features,adrenal suppression,growthretardation in childrenandadolescents, decrease in 
bone mineral density, cataracts,glaucoma, andyetmore rarely, a range of psychological or 
behavioraleffects.
Uptonownoadditionalriskshavebeenidentifiedincompletedandongoingclinicalstudies 
with themonocomponentsand theFDCswhichmight occur when thethreecomponents are 
administered concurrentlyor from the same inhaler.


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Detailed information on the safety and tolerability profile of QVM149 can be obtained
from the QVM149 Investigator’s Brochure.
1.3.2
Human pharmacokinetic data
No clinical pharmacokinetic trials have been conducted with QVM149 to date.
The clinical pharmacokinetics program for QVM149 is based upon the clinical programs and 
post-marketing data for individual active drugs as well as the clinical programs for the dual 
combinations QVA149 (indacaterol maleate and glycopyrronium bromide) and QMF149 
(indacaterol acetate and mometasone furoate). Details on the pharmacokinetic data for the 
monotherapy and dual combinations can be found in the IB.
1.3.3
Human pharmacodynamic data
In QVM149 dual bronchodilation (LABA and LAMA) plus controller (ICS) are combined in 
one medication. This is expected to provide good symptom control, minimize airflow 
obstruction, minimize risk of exacerbations, and hospitalizations in a population of severe
asthma patients. Use of multiple, often different devices represents a significant burden for
these patients. Availability of three effective once- daily controller medications in a single
device may offer advantages in terms of improved adherence and convenience.
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:
(Kerstjens et al 2012) showed that tiotropium on top of high dose ICS/LABA improved
lung function and led to a significantly prolonged time to first severe exacerbation 
(Kerstjens et al 2012).
The
available
asthma
clinical
trial
data
suggest
that
a
LAMA
may
confer
broncho-dilator 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 et al 2007, Peters et al 2010, Bateman et al 2011, Kerstjens et al 2011, 
Kerstjens et al 2012, Guyer and Long 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 et al 2014).
Thus, triple therapy can 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.
No human pharmacodynamic trials have been conducted with QVM149 to date.
Details on the pharmacodynamic data of the monotherapy and dual combinations can be 
found in the QVM149 IB.


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1.4
Study purpose
The purpose of this study is to assess peak FEV1 of two doses of QVM149 compared to a
fixed-dose combination of salmeterol/fluticasone (50/500μg b.i.d.) and to characterize the 
respective 24 hour bronchodilator effect profiles in patients with asthma. Data from this
study will complement lung function data obtained in the pivotal QVM149 phase 3 program
by assessing the bronchodilatory effect of QVM149 at multiple time-points over an entire
dosing interval of 24 hours.
2
Study objectives and endpoints
2.1
Primary objective(s)
Objective
Endpoint

To demonstrate superiority in peak 
bronchodilator effect of QVM149 at a 
dose of 150/50/160 μg o.d. and 
150/50/80 μg o.d. compared to a FDC of 
salmeterol/fluticasone at a dose of 
50/500 μg b.i.d. after 3 weeks of 
treatment in patients with asthma

Peak FEV1 (mL) defined as the highest 
bronchodilatory effect on FEV1 during a 
period of 5 min to 4 h after the last 
evening dose of each treatment period.
2.2
Secondary objective(s)
Objective
Endpoint

To evaluate the bronchodilator effect of 
each dose of QVM149 compared to 
salmeterol/fluticasone FDC after 3 weeks 
of treatment.

FEV1, Forced Vital Capacity (FVC), and 
FEV1/FVC ratio at the following 
timepoints in relation to evening dose :
- 45 min, -15 min, 5 min, 15 min, 30 min, 
1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h
55 min, 14 h, 18 h, 21 h, 23 h 15 min,
23 h 45 min.

To evaluate the bronchodilator effect of 
each dose of QVM149 compared to 
salmeterol/ fluticasone FDC by measuring 
standardized FEV1 AUCs after 3 weeks of 
treatment respective period.

FEV1AUC 5 min - 1 h (Day 21) 
FEV1AUC 5 min - 4 h (Day 21)

FEV1AUC 5 min (Day 21) - 23 h 45 min
(Day 22)

To evaluate post-dose trough 
bronchodilator effect of each dose of 
QVM149 compared to 
salmeterol/fluticasone FDC after 3 weeks 
of treatment in the respective treatment 
period.

Trough FEV1 (mL; mean of FEV1 at
23 h 15 min and 23 h 45 min post-dose)


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Objective
Endpoint
To evaluate safetyand tolerabilityof 
each dose of QVM149 and salmeterol/ 
fluticasone FDCwhen administered for 
3 weeks.
Hematology
Blood chemistry
Urine analysis
Vital signs
ECG
Adverse events 
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3
Investigational plan
3.1
Study design
This is a confirmatory, randomized, double-blind, double-dummy, active-controlled, 3-period 
complete cross-over study. During the 2-week screening period, patients will be required to 
abstain from using any asthma medication before screening lung function assessments in line 
with cessation periods detailed in. Section 5.2 Patients are allowed to use their previous 
asthma medication between screening spirometry and randomization but need to stop at 
randomization when study drug administration commences.
Short-acting beta-2-agonist bronchodilators will be provided to each patient to be used as 
rescue medication throughout the trial as detailed in Section 5.2. Rescue medication use will 
be recorded in the patient diary.
The 2-week screening period may be divided into more than one visit for operational reasons 
with the informed consent being obtained prior to any study related activities.
Eligible subjects may be re-screened once if they are not included in the study within the 
allowed 2 week screening period.  Subjects may also be re-screened at the discretion of the 
Investigator, and following discussion with the Medical Monitor and/or Sponsor, if the reason 
for screen failure was considered temporary in nature.  All screening data must be obtained 
within 2 weeks prior to administration of study medication, as stipulated above.  Subjects who 
are re-screened will re-consented and will be allocated a new screening number.
At the end of the screening period, patients will be randomized to one of 6 possible treatment 
sequences (Figure 3-1), each consisting of 3 double-blind, double-dummy treatment periods 
of 21 days (cross-over design). Details of study drug administration procedures are provided 
in Section 6.
There is no washout period between treatment periods since drug effects from the previous 
period are not expected to be present after 3 weeks with current treatment in each period.
The treatments are:
1. QVM149 150/50/160 μg o.d. (indacaterol acetate 150 μg/ glycopyrronium bromide 50 μg/ 
MF 160 μg once daily)
2. QVM149 150/50/80 μg o.d. (150 μg/ 50 μg/ 80 μg once daily)
3. salmeterol/fluticasone FDC 50/500 μg b.i.d.
Each treatment sequence will have approximately 19 subjects.
Procedures in treatment periods two and three are identical to the procedures of treatment 
period one. At the end of the last treatment period, subjects will then undergo 
Study Completion evaluations and will be discharged from the study site. 
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry and urinalysis), adverse event and
serious adverse event monitoring.


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The study design is shown in Figure 3-1.
Figure 3-1
Study design
3.2
Rationale for study design
This short-term treatment cross-over design is chosen to characterize the bronchodilator 
effects of two doses of once daily QVM149 (indacaterol/glycopyrronium/MF 150/50/160 µg and 
150/50/80 µg) compared to the FDC salmeterol /fluticasone 50/500 µg b.i.d. in asthma patients.
A 2-week screening period will allow for sufficient flexibility for patients and at the site to 
schedule all required assessments to ensure patient selection based on the inclusion and 
exclusion criteria. Screening procedures may be performed over more than one day.
The entire treatment epoch consists of 3 successive treatment periods of 21 days each
(up to 25 days if required for operational reasons). Patients will receive successively the
3 study treatments, one treatment per period plus placebo that matches the comparator in a 
double-dummy fashion to enable adequate blinding (e.g. QVM149 medium dose plus
placebo to the salmeterol/fluticasone FDC).The crossover design (rather than a parallel group 
design) was chosen because within patient variability is expected to be less than between 
subject variability for the assessed parameters. This allows for greater precision to be 
achieved whilst exposing a smaller number of patients to study treatment and assessments. 
The three treatment periods will not be separated by a washout -period and lung function 
assessments will be conducted at the end of each 21-day treatment period only. During each 
21-day treatment period the bronchodilatory effects of the study drug administered during this 


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period will replace the effect of the preceding period's study drug. The effect of indacaterol on 
FEV1, which has a longer duration of action than salmeterol, is expected to last for 
approximately 48 hours after the last dose based on data from study CQAB149B2223. 
Based on 24-hour spirometry data, the half-life of the bronchodilatory effect of 
glycopyrronium is estimated to be ≤80 hours. Therefore the bronchodilatory effect is expected 
to be washed -out at the very latest 17 days after the last dose.
The direct succession of treatment periods also allows for minimizing the risk of patients' 
health deteriorating over the course of the trial since patients will continuously be either on 
LABA/ICS (standard of care) or LABA/ICS plus LAMA.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
Dose/regimen
The components of QVM149 at the daily doses investigated in this trial are approved for 
COPD or asthma. QVM149 will be delivered via the Concept 1 inhalation device, called 
Breezhaler® for approved products. QVM149 is formulated in a similar lactose-based 
formulation as in Onbrez Breezhaler® and Seebri Breezhaler® which are approved for use in 
COPD. In this formulation mometasone furoate is integrated as the third component. 
MF delivered with the Twisthaler® inhalation device is approved for asthma at matching 
doses. The two QVM149 doses (differing in MF content) also reflect the doses investigated in 
Phase 3 pivotal trials.
For indacaterol, the acetate salt will be used due to a lower incidence of post -inhalation 
cough compared to the marketed maleate salt. Data suggest comparable efficacy between the 
acetate and maleate salts (study CQAB149D2301).
Details for each component of QVM149 are given below:
Indacaterol acetate
Indacaterol maleate at a dose of 150 µg o.d. is marketed for the maintenance treatment of 
COPD.  In  a  dose  ranging  study  with  indacaterol  maleate  in  asthma  patients 
(Study CQVA149A2210) which investigated single doses of indacaterol of 150 µg, 75 µg, 
and 37.5 µg o.d. with serial spirometry over 24 hours a clear dose-response profile was 
established for FEV1 over the entire dosing interval of 1 day with no discernible differences 
in the safety and tolerability profile between the doses. Another dose-ranging study of 
indacaterol maleate in asthmatic patients also demonstrated that a dose of 150 µg o.d. was 
safe and effective following 14 days of treatment (Study CQAB149B2357). In study 
CQAB149D2301, the acetate salt of indacaterol was found to result in a lower incidence of 
the post-inhalation cough compared to indacaterol maleate, without impact on efficacy or 
safety. Thus the acetate salt of indacaterol is selected to be the LABA component of the 
QVM149 FDC (see also Section 1.1. 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 and placebo were investigated following 12 weeks 
of treatment. Indacaterol acetate 150 µg showed positive trends in terms of PEF and rescue 


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medication use compared with indacaterol acetate 75 μg and significantly improved lung 
function compared to placebo. 
Glycopyrronium bromide
Glycopyrronium bromide (NVA237: 50 μg once daily in a lactose-based formulation) has 
been registered in the EU since 2012 as Seebri®Breezhaler®for the treatment of COPD. 
Although no data exists for glycopyrronium bromide in asthma, extensive data from the 
PhaseIII  development  program  in  COPD  supports  the  efficacy  and  safety  of  
glycopyrroniumbromide 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
®.
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). In phase 2 and phase 3 studies in COPD patients 
glycopyrronium bromide 50 µg o.d. and tiotropium (HandiHaler 
®) 18 µg o.d. show similar 
bronchodilator effects (Studies CNVA237A2205 and CNVA237A2303). It is therefore 
expected that glycopyrronium bromide 50 µg once daily will provide similar efficacy in an 
asthma population as tiotropium Respimat®5 μg once daily (recently approved in Europe for 
treatment of asthma and considered comparableto tiotropium18 µg administered via 
HandiHaler®).
Based on the available data glycopyrronium bromide 50 µg is considered an appropriate dose 
for further development in asthma as part of triple FDC QVM149 (LABA/LAMA/ICS) used 
in this study.
Mometasone furoate
Mometasone furoate (MF) is approved for the treatment of asthma in doses of up to 800 μg 
per day as Asmanex® Twisthaler® in many countries of the EU, Japan, the US, Canada, and 
other countries world-wide. Since available data for the MF component exists in the 
Twisthaler® device, a 3 step bridging approachwas conducted to determine the MF dose 
(tobe delivered with the Concept 1 inhalation device) which is comparable to each of the 
registered daily doses of Asmanex®Twisthaler®(MF, inhalation powder). This was necessary 
due to differences indevice performance characteristics between the Twisthaler® and 
Concept1 devices.
 Step 1 and 2, 
 
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
®
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.
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For Step 3, two of the MF doses in Twisthaler® and Concept1 were 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 (2x400 μg) delivered once daily via Twisthaler®
confirming the selected doses for MF Concept 1 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 Concept 1.
For QVM149, as a result of a component interaction in the pharmaceutical formulation, 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
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 Concept 1 (Table 3-1); all provide similar fine particle mass and thereby are expected to 
provide similar lung and systemic exposure, since oral bioavailability of MF is low.
Table 3-1
Comparison of the comparable nominal MF component doses 
between Asmanex Twisthaler, QMF149 and QVM149
MF dose level
Asmanex Twisthaler
MF in QMF149
MF in QVM149
Low
200 µg
80 µg
N/A
Mid
400 µg
160 µg
80 µg
High
800 µg
320 µg
160 µg
Duration of treatment
The treatment duration of 21 days per treatment period was chosen for this study to allow for 
plateauing of the ICS effects on lung function as assessed by spirometry. The time-course of 
bronchodilatory action of ICS in asthma was investigated in study CQMF149E2201 which 
compared mometasone at two different doses in two different inhalers (Concept 1 and 
Twisthaler®) over 28 days. Most of the benefit on FEV1 was achieved after one week of 
treatment  with  incremental  additional  benefits  observed  after  two  and  three  weeks  of 
treatment. No consistent additional benefit was observed thereafter suggesting that ICS effect 
on FEV1 plateaued after two to three weeks of treatment. 


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Bronchodilatory effects of the long-acting bronchodilators (LABAs and LAMA) used in this 
study within the fixed-dose combinations elicit a maximal or near maximal effect shortly after 
initiation of treatment. Indacaterol maleate achieves pharmacodynamicsteady state within 
14days (Studies CQAB149B2357 and 
. In a 12 week lung function study 
(study CQMF149E2203) with indacaterol acetate in asthma patients this has been confirmed: 
a near maximal FEV1 effect was seen on Day 2 of treatment already. In addition, based on the 
comparability  of  the  two  salts  from  the  7 -day  PD  and  systemic  exposure  data  from 
Study CQAB149D2301, the acetate salt of indacaterol is not expected to differ from that of an 
identical nominal dose of indacaterol maleatein terms of time to full bronchodilatory effect.
Based on data from COPD patients and the comparability of bronchodilatory mechanism of 
LAMAs in COPD and asthma it is expected that glycopyrronium reaches its maximum 
bronchodilator effect within the first few days of dosing.
Clinically meaningful improvements in spirometric measurements were observed after one 
week of treatment with glycopyrronium in study CNVA237A2205.  Similarly, in study 
CNVA237A2208, which investigated lung function over 28 days, FEV1 was improved on all 
assessment days compared to placebo (Day 1, Day 14, Day 28; no assessments on Day7). 
The totality of data in COPD patients suggests that no substantial further increase in lung 
function is observed after 7 days of treatment.
3.4
Rationale for choice of comparator
Salmeterol xinafoate/fluticasone propionate was selected as the active comparator in this 
study as it is widely used standard of care in asthma treatment. 
Salmeterolxinafoate/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 
region/country for the treatment of asthma in adults and adolescents 12 years and older.  
Lungfunction improvements of QVM149 compared to this current standard of care will 
provide valuable insight into the additional patient benefit provided by QVM149.
3.6
Risks and benefits
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The risks to which subjectsparticipating in this study will be exposed may be divided into 
those associated with the conduct of the study itself, and those associated with the 
investigational treatment (QVM149) and the active comparator (FDC of 
salmeterol/fluticasone).
Subjectswill be required to perform repetitive lung function measurements during the study, 
and these can lead to cough, shortness of breath, dizziness, or exhaustion. Sincepatients only 
carry out full forced maneuvers during clinic visits (not at home), these will be performed 
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under medical supervision to ensure availability of immediate aid if required. Considering the 
3 week treatment duration per period, the number of assessments is small and these are part of 
the regular medical assessments of this patient population. Other procedural risks are related 
to blood sampling for safety laboratory. Puncturing of the veins can cause discomfort, pain, 
hematoma, or in rare cases lead to an infection.
In light of their underlying asthma disease and the inclusion requirement in this study, 
subjects have been exposed to LABA/ICS combinations before entering the trial. The safety 
and tolerability profile of indacaterol, the LABA component in QVM149 and of MF, the ICS 
component of QVM149 is comparable to that of other medications of the same classes. 
This also holds true for the FDC of salmeterol/fluticasone which is the active comparator used 
in this study.
The third component of QVM149, 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 approximately 6,028 healthy subjects and COPD patients across 
34 completed studies. Addition of LAMA (tiotropium 5 µg Respimat®) to ICS/LABA is now 
a recommended treatment option in GINA 2016
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. The benefit risk profile of glycopyrronium bromide has been shown to be 
positive in COPD patients. Overall there is less comorbidity in asthma patient populations; 
therefore the safety profile in an asthma population is also expected to be positive.
With any inhaled drug allergic reaction to the drug or to formulation excipients cannot be fully 
ruled out. Also, reflex bronchoconstriction can occur as an unspecific intolerance reaction to 
inhaled drugs. Subjects are under clinical observation at the site when inhaling the drugs for 
the first time so that the emergence of allergic or other intolerance reactions can be detected. 
When indacaterol is inhaled subjects may react with short-lasting cough immediately after 
inhalation; this post-inhalational cough was not associated with other symptoms or bronchial 
obstruction in previous studies.
The characteristic adverse effects, contraindications, warnings and interactions with other 
medications of the components of QVM149 are provided in Section 1.3.1 and in more detail 
in 
the 
QVM149 
investigator 
brochure
as 
well 
as 
SmPCs 
for 
indacaterol 
(Onbrez® Breezhaler®), 
mometasone 
(Asmanex®
Twisthaler®) 
and 
glycopyrronium 
(Seebri® Breezhaler®) as well as Seretide® SmPC (the FDC active comparator used in this 
study). Subjects participating in this trial may experience these adverse effects. 
In addition, there is extensive evidence of the efficacy and safety of the two dual 
combinations 
indacaterol 
acetate/mometasone 
furoate 
(QMF149) 
and 
indacaterol 
maleate/glycopyrronium bromide (QVA149, marketed as Ultibro® Breezhaler®) which are 
part of the FDC triple QVM149. Up to now no additional risks have been identified in 
completed and ongoing clinical studies with the FDCs which might occur when two or three 
of the components are administered concurrently or from the same inhaler.


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The expected potential benefit for the patient in the current study may include an 
improvement in pulmonary function and a potential translation into better asthma control such 
as reductions in symptoms and rescue medication use during the treatment periods. 
A thorough medical evaluation of the patient’s disease and close clinical monitoring for the 
duration of the study may provide additional patient benefit.
Frequent and regular contacts between patients and study staff will occur in terms of clinic 
visits throughout the treatment periods. In addition, safety monitoring (e.g. collection of 
symptoms and rescue medication use via an electronic diary), assessment of compliance with 
study medication regimen, and twice daily PEF measurements throughout the study will help 
assess a patient’s health status. Therefore, investigators may have an early indication of 
worsening symptoms and will be able to monitor the patient closely throughout the study.
QVM149 and QMF149 are both under development and therefore it is possible that 
unexpected safety issues may be identified. Risks will be minimized by compliance with the 
eligibility criteria and close clinical monitoring of patients. 
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.
This treatment regimen is in-line with the treatment that the patients received before entering 
the study since only patients who were on LABA/ICS before screening will be enrolled.
In addition, providing the patients with rescue medication for use as needed to treat any 
bronchoconstriction throughout study mitigates patient risks. At no time, will any patient be 
without treatment for asthma.
Guidance to manage potential worsening of asthma symptoms will be provided to 
investigators consistent with guideline recommendations (GINA 2016). 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.
Women of child bearing potential should be informed that taking the investigational drug 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 highly effective contraception
requirement for the duration of the study (see Section 4.2). If there is any question that the 
subject will not reliably comply, they should not be entered in the study.
Since glucocorticosteroids are teratogenic in rodents and rabbits only women of child bearing 
potential (WOCBP) who agree to use highly effective methods of contraception 
(see Section 4.2) will be permitted to participate in the study.
There may be unknown risks of QVM149 which may be serious.
In conclusion, the risk-benefit assessment for this study suggests that the subjects are not 
exposed to any undue risk, that adequate safety measures are in place to protect study 
participants, and that the study according to this protocol is conducted in accordance with 
ethical and regulatory requirements.


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3.6.1
Blood sample volumes
A maximum of approximately110 mL of blood is planned to be collected over a period of 
78 days, from each subject as part of the study. Additional samples for monitoring of any 
safety findings would be in addition to this. This is not considered to be a risk for this 
population.
Timings of blood sample collection are outlined in the Assessment Schedule, Section 8.1.
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage and shipment information.
See Section 8.9 regarding the potential use of residual samples. 
4
Population
The study population will consist of male and female patients aged between 18 and 75 years 
with asthma and who have been treated with ICS and LABA for at least 12 months prior to 
screening.
A total of approximately 114 patients will be enrolled and randomized with the intention that 
at least 95 patients complete the study.
The investigator must ensure that all patients being for the study meet the following eligibility
criteria. No additional criteria should be applied by the investigator, in order that the study
population is representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at 
screening and prior to randomization. A relevant record (e.g. checklist) must be stored
with the source documentation at the study site.
Replacement subjects may be enrolled to replace subjects who discontinue the study for 
reasons other than safety. Patients dropped out may be replaced if the drop-out rate reaches 
10 %.
Deviation from any entry criterion excludes a patient from enrollment into the study.
4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria as 
assessed at Screening and Baseline:
1. Written informed consent must be obtained before any study assessment is performed.
2. Male and female adult patients ≥18 years old and ≤ 75 years at Baseline.
3. Patients with a documented physician diagnosis of asthma for a period of at least
12 months prior to Screening.
4. Patients who have used ICS and LABA combinations for asthma for at least 3 months
and at a stable medium or high dose of ICS for at least 1 month prior to Screening.


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5. Pre-bronchodilator FEV1 of < 80 % of the predicted normal value for the patient 
(afterwithholding bronchodilators)at Screening(spirometrywill not be repeated at 
baseline prior to randomization).
Withholding periods of bronchodilators prior to spirometryare given in Table 5-1
(also applicable for inclusion criterion 6)
Re-testing is allowed onceduring screening period. Re-assessment of percentage 
predicted FEV1 should be done in an ad-hoc visit to be scheduled on adate that 
would provide sufficient time to receive confirmation from the spirometrydata central 
reviewer of the validityof the assessment before randomization.
6. Patients who demonstrate an increase in FEV1 of ≥ 12 % and ≥ 200 mL after 
administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at Screening. 
All patientsmustperformareversibilitytestatScreening.Ifreversibilityisnot 
demonstratedatScreening,then,reversibilitytestingmayberepeatedonce during 
the screening period.
IfreversibilityisnotdemonstratedatScreening(retestingallowedonce),patientsmust
be screen failed. Spacer devices are not permitted during reversibilitytesting.
7. At screening, and first baseline, vital signs (systolic and diastolic blood pressure and pulse 
rate) will be assessed in the sitting position and again (when required) in the standing 
position as outlined in the SOM.
Note:Hypertensive patients must have been on stable antihypertensive therapy for at 
least 4 weeks prior to screening to be included in the trial.
If vital signs are outside these ranges, the Investigator should obtain two additional 
readings,so that a total of up to three consecutive assessments are made, following the 
procedure in the SOM.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are noteligible for inclusion in this study. 
Corporate Confidential Information
1. Current smokers and patients who have smoked or inhaled tobacco products within the 
6month 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.).
2. Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 6 weeks of Screeningor during screening 
period. If patients experience an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit during screening period, they may be re-screened 
6 weeks after recovery (on investigator
's judgment) from the exacerbation.
3. Patients who have ever required intubation for a severe asthma attack/exacerbation.
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4. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks 
prior to Screening or during screening period. Patients may be re-screened 4 weeks after 
recovery from their respiratory tract infection or asthma worsening.
5. Patients with evidence upon visual inspection (laboratory culture is not required) of 
clinically significant (in the opinion of investigator) oropharyngeal candidiasis 
Screening or at Baseline (prior to randomization), with or without treatment. Patients may
be re-screened once their candidiasis has been treated and has resolved.
6. 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.
7. 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.
8. Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c > 9% at screening).
9. Patient with a serum potassium level below the laboratory limit of normal at screening.
10. Patients who have a clinically significant laboratory abnormality at Visit 1 in the opinion 
of the investigator (Screening visit, one re-test is allowed before the randomization).
11. Use of other investigational drugs within 30 days or 5 half-lives of screening in this study, 
until the expected pharmacodynamics effect has returned to baseline, whichever is longer.
12. Patients who, in the judgment of the investigator, have a clinically significant condition 
such as (but not limited to) unstable ischemic heart disease, New York Heart Association 
(NYHA) Class III/IV left ventricular failure, arrhythmia, uncontrolled hypertension, 
cerebrovascular disease, psychiatric disease, neurodegenerative diseases, or other 
neurological disease, uncontrolled hypo- and hyperthyroidism and other autoimmune 
diseases, hypokalemia, hyperadrenergic state, or ophthalmologic disorder or patients with 
a medical condition that might compromise patient safety or compliance, interfere with 
evaluation, or preclude completion of the study
13. Patients with 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 
screening (Visit 1) and prior to randomization visits with a resting ventricular rate
<100/min.
14. Concomitant use of an agent known to prolong the QT interval unless it can be 
discontinued for the duration of study.
15. Patients with a history of myocardial infarction within the previous 12 months.
16. Patients with a history of long QT syndrome or whose QTc measured at Visit 1 
(Fridericia method) is prolonged (> 450 msec for males and > 460 msec for females), 
these patients should not be rescreened.
17. Patients who have a clinically significant ECG abnormality at Baseline e.g. second or third 
degree AV block, or ventricular arrhythmias.


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18. 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.
19. Patients with a history of hypersensitivity or intolerance to any of the study drugs 
(including excipients) or to similar drugs within the class including untoward reactions to 
sympathomimetic amines or inhaled medication or any component thereof.
20. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption.
21. 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.
22. Patients receiving any asthma-related medications in the classes specified in Table 5-1
unless they undergo the required washout period prior to Screening and follow the 
adjustment to treatment program.
23. Patients receiving any prohibited medications in the classes listed in Table 5-2 and Table 5-3.
24. 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.
25. Patients on Maintenance Immunotherapy (desensitization) for allergies for less than 
3 months prior to Baseline or patients on Maintenance Immunotherapy for more than
3 months prior to Baseline but expected to change throughout the course of the study.
26. Patients who are serving a custodial sentence do not have a permanent residence or who 
are detained under local mental health legislation/regulations.
27. Subjects incapable of understanding the nature, significance and implications of the 
clinical trial and therefore incapable of giving consent personally
28. Patients who are directly associated with any members of the study team or their family 
members
29. Patients unable to use the Concept1 dry powder inhaler or a metered dose inhaler.
30. History of alcohol or other substance abuse during 5 years prior to enrolment.
31. Patients with a known history of non-compliance to medication or who were unable or 
unwilling to complete a patient diary or who are unable or unwilling to use Electronic 
Peak Flow with e-diary device.
32. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
33. Patients with narcolepsy and/or insomnia.
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 
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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 of study treatment and up to 30 days after completion of study medication.
Highly effective contraception methods include:

Total abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.

Male partner sterilization (at least 6 months prior to screening). For female study
patients, the vasectomised male partner should be sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should be stable on the same contraceptive 
medication for a minimum of 3 months before taking study treatment.
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 (i.e., age appropriate history of vasomotor symptoms) or have had surgical
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal
ligation at least six weeks ago. In the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential.
A pregnancy test will be done on all female patients regardless of reported reproductive
status at specified time points throughout the study.
If requested by local authorities, additional and more frequent pregnancy testing might be 
performed.
36. Patients who have discontinued LAMA therapy in the past for any safety, tolerability or 
perceived lack of efficacy reason.
37. History of paradoxical bronchospasm in response to inhaled medicines.
38. Patients with a history of clinically relevant bronchoconstriction upon repeated forced 
expiratory maneuvers.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the requirement for highly effective 
contraception requirement for the duration of the study. If there is any question that the 
effective subject will not reliably comply, they should not be entered or continue in the study.
There is no requirement for males to use contraception. 
5.2
Prohibited treatment
Restrictions for medications other than study drug apply according to below tables:
Table 5-1
Withholding period of bronchodilators prior to any spirometry
assessment during the trial
Class of Medication
Minimum cessation prior spirometry
SABA
≥ 6 hrs
SAMA
≥ 8 hrs.
LABA or fixed dose combination of ICS/LABA b.i.d
≥ 24 hrs.
LABA or fixed dose combination of ICS/LABA o.d 
≥ 48 hrs.
LAMA
≥ 48 hrs.
xanthines
≥ 7 days
Table 5-2
Prohibited asthma medication during treatment period
Medication
Action to be taken
Long-acting anti-cholinergic agents (e.g. tiotropium bromide)
subject to be withdrawn 
Short-acting anti-cholinergics
subject to be withdrawn 
Fixed-combinations of long-acting β2-agonists and inhaled corticosteroids
subject to be withdrawn 
Long-acting β2-agonists (other than study drug)
subject to be withdrawn 
Short acting β2-agonists (other than those prescribed in the study)
subject to be withdrawn 
Theophylline and other xanthines
subject to be withdrawn 
Parenteral or oral corticosteroids
subject to be withdrawn
Leukotriene antagonists, ketotifen, inhaled cromolyn, nedocromil
subject to be withdrawn 


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Table 5-3
Prohibited treatment, cessation periods
Medication
Minimum cessation period prior to 
Baseline or as indicated 
Non-potassium sparing diuretics (unless administered 
as a fixed-dose combination with a potassium 
conserving drug)
7 days prior to Baseline
Non-selective systemic β –blocking agents
7 days prior to Baseline
Cardiac anti-arrhythmics Class Ia
7 days prior to Baseline
Cardiac anti-arrhythmics Class III
7 days, amiodarone 3 months prior to 
Baseline 
All antipsychotic agents (first, second and third 
generation, inclusive of atypical antipsychotics). 
Combinations of antipsychotic agents with 
antidepressants are prohibited
14 days prior to Baseline
Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)
14 days prior to Baseline
Monoamine-oxidase inhibitors
14 days prior to Baseline
Systemic anticholinergics
7 days prior to Baseline
Mizolastin or terfenadine (H1 antagonists)
5 days prior to Baseline
Strong inhibitors of cytochrome P4503A 
e.g.,ketoconazole
7 days prior to Baseline
Tricyclic antidepressants (Please note that tetracyclics 
which are similar in class with regards to drug 
interaction are also to be excluded)
14 days prior to Baseline
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
prior to Baseline
Parenteral or oral corticosteroids
Within 30 days prior to baseline
Noradrenaline reuptake inhibitors
7 days prior to Baseline
Live attenuated vaccine
not within 30 days prior to 1st dose and
anytime thereafter during the trial
Table 5-4
Medication allowed under certain conditions if taken as follows
Class of Medication
Condition under which medication is permitted
Selective Serotonin Reuptake 
Inhibitors
Stable dose for at least 30 days prior to the Screening and during 
the trial.
Topical corticosteroids for skin 
disease
Stable dose for at least 30 days prior to Screening.
H1-antagonists except mizolastin 
or, terfenadine
Stable dose/regimen for at least 5 days prior to Screening
Inactivated influenza, 
pneumococcal or any other 
inactivated vaccine
Not administered 48 hours prior to the 1st dose in treatment period 
1 and anytime thereafter during the trial. Vaccinations within 48 
hours and afterward are not allowed.


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5.3
Dietary restrictions and smoking
On study days when spirometry will be performed, subjects 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 4 hours of spirometry

Exposure to environmental smoke, dust or areas with strong odors within at least 4 hours 
of spirometry 
5.4
Other restrictions
No unusual (for individual subjects) strenuous physical exercise for 7 days before first dosing
of Treatment Period 1, until after Study Completion evaluation.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational and control drugs
The investigational drug, QVM149 (indacaterol acetate/glycopyrronium bromide/MF) 
150/50/80 µg, 150/50/160 µg and salmeterol xinafoate/fluticasone propionate 50/500 µg as 
well as their respective matching placebos will be prepared by Novartis and supplied to the 
Investigator as single blind patient kits with a tear off label.
Table 6-1
Overview of study medication
Study drug name
Formulation
Unit dose
Packaging
Provided by
QVM149 and Concept1 
Inhaler
Capsules with 
powder for Inhalation 
150/50/80µg
Provided as single blind 
supplies including Concept1 
devices
Novartis Drug Supply 
Management
QVM149 and Concept1 
Inhaler
Capsules with 
powder for Inhalation 
150/50/160µg
Provided as single blind 
supplies including Concept1 
devices
Novartis Drug Supply 
Management
Placebo to QVM149 and 
Concept1 Inhaler
Capsules with 
powder for Inhalation 
0µg
Provided as single blind 
supplies including Concept1 
devices
Novartis Drug Supply
Management
salmeterol xinafoate/ 
fluticasone propionate 
Inhalation powder, 
pre-dispensed in
inhalation device
50/500µg
Provided  as single blind 
supplies devices
Novartis Drug Supply 
Management
Placebo to salmeterol 
xinafoate/ fluticasone 
propionate
Inhalation powder, 
pre-dispensed in 
inhalation device
0µg
Provided as single blind 
supplies devices
Novartis Drug Supply 
Management


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Study drug name
Formulation
Unit dose
Packaging
Provided by
Placebo to QVM149 and 
Concept 1 Inhaler as 
training kit
Capsules with 
powder for Inhalation
0µg
Blister +Inhaler
Novartis Drug Supply
Management
Placebo to salmeterol 
xinafoate/ fluticasone 
propionate as training kit
Inhalation powder, 
pre-dispensed in 
inhalation device
0µg
Supplied  as training  
inhalation devices
Novartis Drug Supply 
Management
6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
6.2
Treatment Arms
Study treatments are defined as:

A:  QVM149 150/50/80 μg o.d.

B:  QVM149 150/50/160 μg o.d. 

C:  salmeterol/fluticasone FDC 50/500 μg b.i.d.
Subjects will be randomized to one of the following 6 treatment sequences (defined according 
to a Williams design for 3 treatments and 3 periods) in the ratio of 1:1:1:1:1:1.
Table 6-2
Definition of treatment sequences
Sequence
Period 1
Period 2
Period 3
1
A
B
C
2
A
C
B
3
B
C
A
4
B
A
C
5
C
A
B
6
C
B
A
6.3
Treatment assignment and randomization
At the randomization visit, all eligible subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or delegate will contact the 
IRT after confirming that the subject fulfills all the eligibility criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm. 
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 subjects and investigator staff. 
A subject randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers (not needed). A separate medication list will be produced by or 
under the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to packs containing the 
investigational drug(s).


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The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.
The investigator will enter the screening number and medication number in the eCRF.
IRT will assign subject ID at screening – will be kept throughout the study – no medication 
number.
6.4
Treatment blinding
This is a subject, investigator and sponsor-blinded study. Subjects, investigators and sponsor 
will remain blinded to study treatment throughout the study, except where indicated below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
A double-dummy design is used because the identity of the study treatments cannot be 
disguised due to their different forms.
Site staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff
The following unblinded sponsor roles are required for this study:
Sponsor clinical staffs are required to assist in the management and re-supply of 
investigational drug product. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions. Sample data may be provided to 
the independent committee/analysis team, if used, under unblinded conditions. 
All other sponsor staff (study statistician, study programmer, biomarker expert, clinical trial 
team, decision boards etc) will stay blinded to treatment assignments (except in the case of a 
safety event necessitating unblinding) until database lock.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure until clinical database lock. 
Following final database lock all roles may be considered unblinded.  See Table 6-3 for an 
overview of the blinding/unblinding plan.




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Subjects 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). Subjects 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 of either salmeterol/fluticasone or placebo.
The evening dose (to be taken between 05:00 and 08:00 pm) will consist of sequential single 
inhalations: 

One inhalation of either QVM149 or placebo 

One inhalation of 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 the device by which the FDC of salmeterol/fluticasone are administered are
given in Appendix 2 and Appendix 3. Further details are provided in the SOM.
Administration of study medication at the same time of Day on Day 21 and 22 of each 
treatment period +/- 1 h will ensure that corresponding assessments are done at approximately 
the same time of the day in each treatment period.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted.
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject 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 subject, he/she must provide
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The investigator will then receive details of the investigational drug 
treatment for the specified subject and a fax or email confirming this information. The system 
will automatically inform the study monitor for the site and the Study Team that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will need to provide:

protocol number

study drug name (if available)

subject number. 


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In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.8
Treatment exposure and compliance
For all study drug treatment administered at the site, compliance will be ensured by 
administration under the guidance and direct supervision of the investigator/designee. 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and the 
validity of the study. The subject must also be instructed to contact the investigator if he/she is 
unable for any reason to take the study treatment as prescribed at home.
For QVM149 doses administered at the site, after inhalation in each treatment period, the capsule 
shell will be checked for residual powder. If residual powder is found the inhalation procedure will 
be repeated up to a maximum of 3 times provided that total inhalation time does not exceed 
2 minutes. The finding will be recorded in the drug administration section of the (e)CRF. 
For Salmeterol xinafoate/fluticasone propionate, a dose indicator on its device indicates the 
number of doses left.
Compliance will be assessed by the Investigator and/or study personnel at each visit using 
capsule counts, device indicator and information provided by the subject. This information 
should be captured in the source document at each visit. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log.
Furthermore, compliance with the intake of rescue medication and study drug treatment at 
home will be monitored closely by a review of a subject diary in which all subjects will record 
administration each day. 
6.9
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.10
Rescue medication
At Visit 1, all subjects will be provided with a short acting β2-agonist (100 μg 
salbutamol/90 μg albuterol). Subjects will be instructed to use it throughout the study as 
rescue medication on an ‘as needed basis’. Subjects will be advised that between visits they 
can take their rescue medication for symptoms of intercurrent bronchospasm. No other rescue 
treatment is permitted. 
In order to standardize measurements, subjects will be instructed to abstain from taking rescue 
medication (salbutamol/albuterol) within 6 hours of the start of each visit during which 
spirometry is being performed unless absolutely necessary. If rescue medication is taken 
within 6 h prior to the first spirometry assessments, then the visit should be rescheduled to the 
next day if possible and within permitted windows (Day 21 plus up to 4 days). 


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Bronchodilator medications that the subjects used prior to Visit 1 must be recorded in the 
asthma-related prior/concurrent medication page of the e-CRF. For screening spirometry 
assessments cessation periods in accordance with Table 5-1 must be adhered to. 
After screening spirometry until randomization subjects may take the asthma medication they 
had before 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 will be recorded by the subject in their 
electronic diary.
The rescue salbutamol/albuterol will be provided to the subjects by the study center and 
reimbursed locally by Novartis or supplied to the investigator sites locally by Novartis.
6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or allowing a new medication to be started, or if the subject is already enrolled, to determine if 
the subject should continue participation in the study.
7
Study Completion and Discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. 
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All subjects should have a safety follow-up call conducted 30 days after last visit. 
The information collected is kept as source documentation.  All SAEs reported during this 
time period must be reported as described in Section 9.2 and the Site Operations Manual. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation.


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7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator. 
Study treatment must be discontinued and the subject withdrawn from the study under the 
following circumstances:

Subject decision - subjects may choose to discontinue study treatment for any reason at 
any time

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation

Any protocol deviation that results in a significant risk to the subject’s safety

Any severe or serious adverse event considered at least possibly related to the study 
medications
Pregnancy (see Section 8.6 (Safety), and Section 9.5 (Pregnancy reporting)

Use of prohibited treatment as per recommendations in Section 5.2 (Prohibited Treatment)
For liver events, refer to Section 15-Appendix 1: Liver Event Definitions and Follow-up 
Requirements)

Emergence of the following adverse events:

on two ECGs at least a minute apart:

absolute QTcF  > 500 msec or an increase from screening of > 60 msec is noted 

treatment-emergent second or third degree AV block, clinically relevant atrial or 
ventricular arrhythmias.

Reflex bronchoconstriction or other severe intolerance reaction to study drug 
inhalation

Paradoxical bronchospasm as evidenced either by a significant increase in wheeze and 
dyspnea shortly after the administration of study drug or a fall in FEV1 of >20% 
within 30 minutes of administration of study drug

Patients who have a decline in PEF from the reference PEF (during screening period) 
of ≥ 30% for 6 consecutive scheduled PEF readings (including readings taken in the 
morning and evening) at any point during the study.

≥ 3 days in any one treatment period in which ≥12 inhalations/day of 
albuterol/salbutamol were used

Clinical asthma worsening which required additional asthma treatment other than 
study medication or study-defined rescue medication (albuterol/salbutamol)

The following deviations from the prescribed dose regimen for the study drug:

Subject missed more than 6 consecutive doses of study medication in any one 
treatment period

Any of the following laboratory abnormalities:

Random (non-fasting) plasma glucose greater than 15 mmol/L


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
Serum potassium below the lower limit of the laboratory reference range if confirmed 
by a repeat test to exclude laboratory error
Discontinuation of study treatment and subject withdrawal will be at the discretion of the 
Investigator, under the following circumstances: 

Positive drug screen (suspected related to drug abuse): Drugs of abuse (DOA) testing 
maybe performed anytime at the discretion of the investigator. 

Any of the following laboratory abnormalities:

clinically significant abnormal laboratory value(s) or test procedure e.g. subjects 
with hemoglobin levels below 11.0 g/dL may be withdrawn from the study at the 
discretion of the investigator

Use of concomitant treatment that would confound the interpretation of the 
pharmacodynamic data (after consultation with Novartis medical expert)
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason 
for the subject’s premature discontinuation of study treatment and record this information on 
the Dosage Administration CRF. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3, Withdraw of Informed Consent). Where possible, they should 
return for the assessments indicated by an asterisk (*) in the assessment table. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) 
should be made to contact the subject/pre-designated contact as specified in Section 7.4
(Lost to follow-up). This contact should preferably be done according to the study visit 
schedule,
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
Subjects who are prematurely withdrawn from the study for reasons other than safety may be 
replaced on a case by case basis.


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7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material. 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.
7.5
Study stopping rules
The study will be halted with no further recruitment and dosing suspended for all study 
participants pending a safety review if three or more study-drug related SAEs are reported or 
if the aggregate of severity, frequency, and/or drug relatedness of AEs, in the opinion of the 
investigator or Novartis, merit halting the study. Further dosing may only commence if 
deemed safe after a full safety review by the Novartis Translational Medical Expert (TME) 
and investigator.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including slow 
enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must be seen as 
soon as possible and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator will be responsible for informing 
IRBs/IECs of the early termination of the trial.








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Footnotes
1Visit structure given for internal programming purpose only –Visits windows are defined in the Study Operations Manual.
2   Screening visit assessments can be performed at different days within 14 day screening period.
3   Day 14 of each treatment period will be a visit on the phone to assess subjectsafety.
4   
6   Review of inclusion/exclusion criteria and current medical conditions is required at baseline before the randomization.
7  If hematology at screening is done within 7 days prior to baseline, baseline hematology doesn
't need to be repeated.
8  If blood chemistry at screening is done within 7 days prior to baseline, baseline blood chemistry doesn
't need to be repeated.
9  Only required during treatment period 2 and 3.
10Subjectdischarged from the site after completion of last assessments.
11 First study drug intake at Day 1 will be on site and after all other visit assessments have been completed. 
12 For each treatment period, study drug administration at subject’s home from Day 1 evening to Day 21 morning.
13Day 22 should also be considered as first treatment day of the subsequent treatment period.
14Include Peak flow meter, e-Diary and inhalation devices training.These data remains at source.
15Completed daily.
16Spirometry for eligibility: reversibility testing can be repeated once during the screening period if necessary
17 Refer to Table 8-2Spirometry Assessments for detailed time-points.
18Refer to concomitant treatment section for rescue medication details.
19 Serum pregnancy test at screening and urinary pregnancy test at baseline and at end of trial.Additional pregnancy testing can be performed if required by local 
regulations.
20Assessments to be performed if subject terminates early or at V399 Study completion (for a continuing subject the required assessments are completed under the first 
visit of treatment period 2 or 3.
21These data remains at source.
22 Both standing and supine/sitting blood pressure measurements are required at this time point. Only sitting or supine blood pressure measurements are required at the
other visits. Subjects
' positions during measurement collections should be consistent between visits (sitting or supine throughoutthe study).
23  HbA1c will be collected at 
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Table 8-2
Spirometry – Assessments
For each treatment period
Spirometry
(timing in relation to study drug administration )
Day 21
(Visit 103)
(Visit 203)
(Visit 303)
Timing prior to study drug administration
  -45 min
  -15 min
Study drug - evening dose Day 21 
Timing post evening dose
+  5 min
+ 15 min
+ 30 min
+ 1 h
+ 2 h
+ 3 h
+ 4 h
Day 22 
Day 22 
(Visit 104)
(Visit 204)
(Visit 304)
Timing post evening dose day 21
+  8 h
+ 10 h
+ 11 h 55 min
Study drug morning dose
+ 14 h
+ 18 h
+ 21 h 
+ 23 h 15 min
+ 23 h 45 min
Day 22
Day 22 = Day 1 of the subsequent treatment 
period
First evening dose of the next study period


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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
ofthe procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF. 
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
Anychanges to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator
's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Anynew information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section4.2
(Exclusion criteria) and in Section 5.1(Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
Re-screening is allowed under certain circumstances. Please refer to Section 3.1Study design
and Section 4.2
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Exclusion criteria(2, 5, and 6) for details. 
Information on what data should be collected for screening failures is outlined in the 
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8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Alcohol test, Drug screen, Urine cotinine 
All subjects will be screened substances of abuse and cotinine. See the Site Operations 
Manual for details.
8.4.2
Reversibility
To be measured during screening. If reversibility is not achieved then the reversibility 
assessment may be repeated onceprior the randomization.
All reversibility evaluations should follow the recommendations of the Milleretal2005a
unless otherwise indicated by inclusion/exclusion criteria of the study.
A spirometry assessment should be performed at screening after respectivewashout period of
bronchodilators is fulfilled. Please refer to Table 5-1for details.
400 µg (4 x 100 µg) of salbutamol is then administered following completion of the baseline 
assessment. A second spirometry assessment is then performed starting within 30 minutes of 
the administration of the salbutamol.
Reversibility (%) is calculated as: 
(FEV
1 (post-bronchodilator) –FEV1(pre-bronchodilator) x 100)/ FEV1(pre-bronchodilator)
The findings of the reversibility evaluations will be recorded in the CRF.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamic assessments will be conducted at the timepoints defined in the 
Assessmentschedule. Follow instructions outlined in the Site Operations Manual.
Pharmacodynamic (PD) assessmentswill be obtained andevaluated in all subjects for all 
treatment periods.
8.5.1
Spirometry
Forced Expiratory Volume in 1 second (FEV
1
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), 
 
ForcedVital Capacity (FVC), 
 will be 
measured at screening, pre-dose, and specific time points for approximately 24 hours post 
dose (on Days 21 and 22) in each treatment period. 
 
 
 
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For each subject,the spirometric measurementsshouldbe taken at approximately the same 
correspondingtime of day in each treatment periodas closely as practically possible. 
Predose FEV1, 
 FVC, 
assessments will be conducted before the 
first on-site administration of study medication intreatment period 1. Timing is minus 45 min 
andminus 15 min in relation to first inhalation of study medication.
Spirometry timepoints following the last dose of study medication in each treatment period 
are as follows:
Day 21 pre-dose: -45 min and -15 min 
Day 21/22 post-dose: 5 min, 15 min, 30 min, 1h, 2 h, 3 h, 4 h, 8 h, 10 h, 11 h 55 min, 14h, 
18 h, 21 h, 23 h 15 min, 23 h 45 min
All spirometry evaluations should follow the recommendations of the (ATS/ERS 2005 Task 
force: Standardization of Lung Function Testing Miller et al 2005a).
The spirometry equipment used during the trial must meet or exceed the minimal 
ATS/ERSrecommendations for diagnostic spirometry equipment as defined in the guideline 
(Milleretal2005b). Calibrationof the spirometry equipment is mandatory on all visit days 
and must be performed before the first study measurement. All calibration reports and subject
spirometry reports should be stored as source data.
The same spirometry equipment should be used for all assessments performed by a subject. 
Alimited number of staff, as designated by the investigator, will evaluate all subjects at all 
visits throughout the entire trial. Where possible the same technician should perform all 
maneuvers for an individual subject. All staff conducting the spirometry tests must have 
received appropriate training which must be documented.
Results for spirometryassessmentsare highly dependent on effort and cooperation from the 
subject. Thus, throughout the maneuver, enthusiastic coaching of the subject is required. 
All spirometry maneuvers should be performed in sitting position whilst wearing nose-clips. 
At least three acceptable maneuvers should be performed for each time point, and the results 
must meet within-test and between-test criteria for acceptability. A maximum of eight 
maneuvers should be performed at any time point.
The highest value obtained of FEV1
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Information
, 
and FVC from any of the three maneuvers 
that meet acceptability criteria (can be from different curves) will be recorded on the CRF. 
Alldisplaceable volumes will be reported in liters (L) at body conditions: normal body 
temperature (37°C), ambient pressure, saturated with water vapor (BTPS).
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If 
t
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The following data will be collected:
The time at which the first determination of FEV1, 
took place
FEV1, 
measurements
FVC measurement
FEV1% predicted
FVC% predicted
FEV1/FVC ratio
8.5.2
Peak expiratory flow
PEF will be measured on alldays from screening through the end of study visit. The PEF will 
be measured twice daily, once in the morning prior to asthma medication usage during the 
screening period and prior to study drug during treatment periods and once in the evening, 
approximately 12 hours later again prior to asthma medication usage during the screening 
period and prior to study drug during treatment periods. 
Each subject will be provided with a PEFmeter and diary into which they will record their 
results (this may be done electronically) and the use of rescue medication. PEF meter training 
should occur at screening and repeated at the beginning of each treatment period. 
PEFmeasurements should be taken prior to pre-dose assessments.
Subjects should measure PEF in triplicate and record the best value. The diary data will be 
available to the Investigator for review to monitor subjectsafety and compliance (to verify 
subjects are performing the assessments twice daily as instructed). The Investigator must 
make all efforts to achieve compliance from their subjects.
The PEF value recorded at the first screening visit will become the reference value for PEF 
safety monitoring. This value should be recorded on the subjectdiary and the subjects should 
monitor their PEF readings using this value to detect a decline. The investigator should 
instruct the subjectto call the site if the PEF drops below the limit required for 
discontinuation (see Section 7.2Discontinuation of study treatment) and this should be 
tracked by the site to track when the subjectmeets stopping criteria.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with theAssessment Schedule(Section 8.1)detailing when each 
assessment is to be performed.
8.6.1
Physical examination
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See the Site Operations Manual for details.
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8.6.2
Vital signs

Body temperature

Blood pressure (BP) 

Pulse rate
8.6.3
Height and weight

Height in cm.

Body weight in kg.
8.6.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differentials,
platelet count, aPTT and PT/INR will be measured.
Clinical chemistry
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, LDH, GGT, AST, ALT, CK, glucose, total cholesterol, 
triglycerides. If the total bilirubin concentration is increased above 1.5 times the upper limit of 
normal, direct and indirect reacting bilirubin should be differentiated. HbA1c will be included 
in the screening panel only.
Urinalysis
Urine test by dipstick e.g. Combur9: leucocytes, nitrite, pH, protein, glucose, ketones, 
urobilinogen, bilirubin, blood/ hemoglobin 
If the dipstick result is positive for protein, nitrite, leucocytes or blood, the sample will be sent 
for microscopic analysis of WBC, RBC and casts.
8.6.5
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the
Site Operation Manual.
The CRF will contain: PR interval, QRS duration, heart rate, RR, QT, QTc
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Clinically significant abnormalities must be reported in the AE CRF.


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8.6.6
Pregnancy and assessments of fertility
Women of child-bearing potential are not eligible to participate in this study unless they are 
using highly effective methods of contraception during dosing of study treatment and up to 
30 days after completion of study medication as defined in Section 4.2 Exclusion criteria. 
In all enrolled women, including postmenopausal and surgically sterile women, a serum 
pregnancy is performed at screening. At baseline and at the end of trial a urinary pregnancy 
test is performed.
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  
See the Assessment Schedule, Section 8.1, for timing of the protocol required pregnancy 
testing; additional pregnancy testing may be performed to meet local requirements*. 
A positive urine pregnancy test requires immediate interruption of study treatment until serum 
β-hCG is performed and found to be negativeα. 
*If additional pregnancy testing is needed per local requirements, those additional results will 
be kept as source documentation only. 
8.7
Pharmacokinetics
Not applicable.
8.8
Other assessments
8.8.1
Patient diary
Each subject will be provided with an electronic diary to record study assessments while at 
home (from screening through treatment periods).
Subjects will record:

Rescue medication use

Study treatment administration: am and pm

PEF measurements: am and pm
The diary will contain instructions for the subjects to perform PEF measurements prior to the 
intake of study treatment. Whilst it is preferred that PEF measurements are made prior to 
(6-hours) the administration of salbutamol (as rescue medication), subjects should not 
withhold their rescue medication in the event that their clinical condition deemed the 
immediate use of medication.
Subjects will be informed of their alert values for PEF at screening and after randomization so 
that if they meet stopping criteria related to PEF measurements whilst at home, they can 
contact 
the 
clinic 
immediately 
and 
appropriate 
action 
taken 
for 
review 
and 
withdrawal/ongoing management of their asthma.


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8.8.2
Device training
Corporate Confidential Information
Subjects will be providedwith device training for the e-diary/peak flow meter device. 
Theelectronic device will be used to collect information on rescue medication use and to 
store PEF meter measurements. Subject will also be trained with inhalation devicesusing 
respective training kits.


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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom of disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual subject and identifying adverse events. Alert ranges for liver related events are 
included in Appendix 1.
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. 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
2. its relationship to the study treatment 

No Relationship to study treatment or other investigational treatment or

Relationship to study treatment  or

Relationship to other investigational treatment or 

Relationship to both study treatment and other investigational treatment or 
indistinguishable


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3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness 
criteria have been met 
5. Action taken regarding investigational treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (e.g. further observation only) 

investigational treatment dosage increased/reduced 

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)   
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). Once an adverse event is detected, it must 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 investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
9.2
Serious adverse event reporting
9.2.1
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 

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug


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
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 subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject 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 subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (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 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment. 
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the 
Site Operations Manual.
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.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis.  Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 15-1-Appendix 1 for complete definitions of liver events. 
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γGT) to confirm 
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with 
the results provided via the standard electronic transfer.  If results will not be available from 
the central laboratory within 24 hours, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unscheduled local laboratory CRF.


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If the initial elevation is confirmed, close observation of the subject will be initiated, including:

Consideration of treatment interruption if deemed appropriate

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate 

Hospitalization of the subject if appropriate

Causality assessment of the liver event 

Thorough follow-up of the liver event should include

Repeating liver chemistry tests two or three times weekly. Testing should include 
ALT, AST, ALP, PT/INR, and γGT. If total bilirubin is elevated > 2 x ULN, 
fractionation into direct and indirect bilirubin is required. To rule out muscular origin 
of transaminase elevations, CPK should be measured along with liver chemistry tests. 
Frequency of retesting can decrease to once a week or less if abnormalities stabilize 
or the study drug has been discontinued and the subject is asymptomatic. 
Retesting should be continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases. 

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 

Exclusion of underlying liver disease, as specified in Table 15-3.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents. 

Considering gastroenterology or hepatology consultations. 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
9.4
Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF. Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with an SAE. 


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All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Drug Safety and Epidemiology. As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-1
summarizes the reporting requirements.
Table 9-1
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose 
Administration 
(DAR) CRF 
Document in AE 
CRF
Complete SAE form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes 
Yes, even if not associated 
with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.5
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued. 
9.6
Prospective suicidality assessment
Not required. 
9.7
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.


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When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
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 monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject 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 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
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 eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety 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 subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Novartis. 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 subject data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.


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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Corporate Confidential Information
Novartis staff or CRO working on behalf of Novartis 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. 
Concomitant medications entered into the databasewill be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions 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 or designated CRO.
Diary data will be entered into an electronic diary by the subject. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis or designated CRO.
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an InteractiveResponse Technology (IRT). Thesystem will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis or designated CRO.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
Thecode break functionality will remain available until study shut down or upon request of 
Novartis.
Theoccurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. 
Anychangesto the database after that time can only be made by joint written agreement 
between the COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.


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10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment received.
All subjects that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set.
The PD analysis set will include all subjects with any available PD data, who received any 
study drug and experienced no protocol deviations with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment sequence and subject.
11.4
Analysis of the primary variable(s)
The primary objective is to demonstrate superiority in peak bronchodilator effect of QVM149 
at a dose of 150/50/160 μg o.d. and 150/50/80 μg o.d. compared to a FDC of 
salmeterol/fluticasone at a dose of 50/500 μg b.i.d. after 3 weeks of treatment in patients with 
asthma.
11.4.1
Variable(s)
The primary endpoint is the peak FEV1 (mL) defined as the highest bronchodilatory effect on 
FEV1 during a period of 5 min to 4 h after the last evening dose of the preceding 3-week 
treatment period.


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11.4.2
Statistical model, hypothesis, and method of analysis
The following hypothesis will be tested for each of QVM149 doses versus 
salmeterol/fluticasone separately:
H0: There is no difference in terms of the peak FEV1 after 21 days of treatment between:
QVM149 (150/50/160 µg) and salmeterol/fluticasone 
OR
QVM149 (150/50/80 µg) and salmeterol/fluticasone 
H1: There is a difference in terms of the peak FEV1 after 21 days of treatment between:
QVM149 (150/50/160 µg) and salmeterol/fluticasone 
AND 
QVM149 (150/50/80 µg) and salmeterol/fluticasone 
Each test will be conducted at a one-sided 2.5% level.
The primary variable will be analyzed using a linear mixed model. The model will include 
period, treatment, and sequence as fixed effect factors and patient as a random effect. 
Restricted maximum likelihood method will be used. The Kenward-Roger approximation will 
be used to estimate denominator degrees of freedom. 
No adjustment for multiplicity is planned because both tests are required to be positive.
The pairwise treatment differences of each QVM149 dose versus salmeterol/fluticasone along 
with the corresponding 2-sided 95% confidence intervals will be presented.
11.4.3
Handling of missing values/censoring/discontinuations
If a patient takes rescue medication within 6 hours prior to the spirometry assessments and the 
visit is not rescheduled to the next day then all spirometry assessment data from this visit and 
the following visits in this treatment period will be set to missing.
11.4.4
Sensitivity analyses
A sensitivity analysis will be conducted to evaluate the presence of any potential carry-over 
effects by applying the same model as described above and adding a factor modeling the 
carry-over effects.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
The secondary endpoints obtained from spirometry data are:

FEV1, FVC and FEV1/FVC ratio at the following timepoints in relation to evening dose
at Day 21:  -45 min, -15 min, 5 min, 15 min, 30 min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 
11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min

Standardized AUC in FEV1 across different time intervals (5 min – 1 h, 5 min – 4 h, 5 min 
– 23h 45 min) at Day 21


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
Trough FEV1 (mL; mean of FEV1 at 23 h 15 min and 23 h 45 min post-dose) at Day 21
Standardized AUC in FEV1 (5 min-23 h 45 min), AUC in FEV1 (5 min - 1 h), AUC in FEV1
(5 min - 4 h) and trough FEV1 will be analyzed by fitting the same model as described for the 
primary endpoint above in addition to summary statistics. The standardized AUCs are derived 
using the linear trapezoidal rule and adjusting for the length of the assessment interval.
Other secondary endpoints including FEV1, FVC and FEV1/FVC will be reported using 
descriptive statistics by treatment. 
11.5.2
Safety
All safety parameters will be summarized on the safety set.
Clinical laboratory evaluations
All laboratory data will be listed by treatment sequence, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Vital signs
All vital signs data will be listed by treatment sequence, subject, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. 
Summary statistics will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment sequence, subject and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
All study emergent adverse events 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 of the first period will be classified as a prior adverse event.
The number and percentage of subjects with treatment emergent adverse events will be 
tabulated by body system and preferred term with a breakdown by treatment. An adverse 
event starting in one period and continuing into the next period is counted only in the onset 
period. A subject with multiple adverse events within a body system and treatment period is 
only counted once towards the total of this body system and treatment.
11.5.3
Other assessments
Not Applicable.


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11.7
Sample size calculation
The sample size was chosen to provide at least 80% power for comparing peak FEV1 in both 
QVM149 doses vs. salmeterol/fluticasone.
For the treatment differences in peak FEV1 the following effects are expected:
at least 100 mL after treatment with QVM149 150/50/160 μg vs. treatment with 
salmeterol/fluticasone
and at least 80 mL after treatment with QVM149 150/50/80 μg vs. treatment with 
salmeterol/fluticasone.
The assumptions of the variability were based on the historical cross-over studies 
QVA149A2210 and tiotropium (Beeh et al 2014
Corporate Confidential Information
). The within subject standard deviations 
observed in these above studies varied between ~98 mL and ~210 mL. Based on this a 
standard deviation of 190mL is used for powering the current study.With 95 patients 


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completing the study the power for both doses of QVM149 vs salmeterol/fluticasone inpeak 
FEV1 to become significant on a 1-sided 2.5% alpha would be at least 80%.
To ensure at least 95patients complete the study approximately 114patients will be enrolled 
assuming a drop-out rate of up to 15% and ensuring equal assignment to the 6 sequences. 
11.8
Power for analysis of key secondary variables
Corporate Confidential Information
Not applicable.


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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
13
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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.


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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
References are available upon request
Bateman ED, Kornmann O, Schmitt P, 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.
Beasley R (2004) The Global Burden of Asthma Report, Global Initiative for Asthma (GINA). 
Available from www.ginasthma.org
Beeh KM, Moroni-Zentgraf P, Ablinger O, et al (2014) Tiotropium Respimat® in asthma: a 
double-blind, randomised, dose-ranging study in adult patients with moderate asthma.
Respir Res. 2014; 15(1): 61.
Befekadu E, Onofrei C, Colice GL (2014) Tiotropium in asthma, a systemic review. JAA; 7: 11-21.
Fardon T, Haggart K, Lee DK, 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.
GINA (2016) Global Initiative for Asthma. Global Strategy for Asthma Management and 
Prevention. 
Guyer AC, Long AA (2013) Long-acting anticholinergics in the treatment of asthma. Allergy 
Clin Immunol; 13:392-398.
Kerstjens HAM, Disse B, Schröder-Babo W, 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, Engel M, Dahl R, et al (2012) Tiotropium in Asthma Poorly Controlled with 
Standard Combination Therapy. N Engl J Med; 367: 1198-1207.
Kieser M, Friede T (2003) Simple procedures for blinded sample size adjustment that do not 
affect the type I error rate. Statistics in Medicine; 22: 35-3581.
Miller MR, Crapo R, Hankinson J, et al ATS ERS task force (2005a) General considerations 
of lung function testing.  Eur Respir J 2005; 26: 153–161.
Miller MR, Hankinson J, Brusasco V, et al, ATS ERS task force (2005b) Standardization of 
spirometry. Eur Respir J 2005; 26: 319–338.
Peters SP, Kunselman S, Icitovic N, et al (2010) Tiotropium bromide as step-up therapy for 
adults with uncontrolled asthma. N Engl J Med; 363(18): 1715-1726.
Testi R (2014) White Paper, Long Acting Muscarinic Agent (LAMA). A new Frontier for 
COPD and Asthma Treatment. Available on www.cromsource.com


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15
Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or
eosinophilia

ALT or AST > 8 × ULN 

5 x ULN < ALT/AST 8 x ULN

3 x ULN < ALT/AST 5 x ULN

ALP > 2 × ULN (in the absence of known bone pathology)

Any clinical event of jaundice (or equivalent term)
Any adverse event potentially indicative of liver toxicity
ALT or AST elevation with 
coagulopathy
ALT or AST elevation accompanied 
by symptoms
Isolated ALT or AST elevation
Isolated ALP elevation
Others
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance
ALT or AST elevation with 
coagulopathy
ALT or AST elevation accompanied 
by symptoms
Isolated ALT or AST elevation > 8 × 
ULN
Jaundice
Isolated ALT or AST elevation > 5 to 
≤ 8 × ULN

If confirmed, consider interruption or discontinuation of 
study drug

If elevation persists for more than 2 weeks, discontinue the 
study drug

Establish causality

Complete CRFs per liver event guidance
Isolated ALT or AST elevation > 3 to 
≤ 5 × ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; 
if >50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance


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Criteria
Actions required
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or discontinuation 

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance
Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, γGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin


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16
Appendix 2: 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.

Always use the new inhaler that comes with your new medication pack. 

Use the same inhaler throughout a treatment period of 21 days. Dispose of each inhaler 
after the end of a treatment period of 21 days.

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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17
Appendix 3: How to Use salmeterol xinafoate/ fluticasone 
propionate and its inhaler
Instructions for use
Follow the instructions below for using your inhalation device. You will breathe in (inhale) 
the medicine from the inhaler. Do not use the inhaler 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 inhaler
Take the inhaler out of the medication pack given to you. The inhaler will be in the closed 
position. The dose indicator on the top of the inhaler tells you how many doses are left. 
The dose indicator number will decrease each time you use the inhaler. After you have used 
55 doses from the inhaler, 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 inhaler


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Taking a dose from the inhaler requires the following 3 steps: Open, Click, Inhale.
1. OPEN
Hold the inhaler 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 inhaler 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 inhaler 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 
inhaler is ready:

Do not close the inhaler.

Do not tilt the inhaler.

Do not play with the lever.

Do not move the lever more than once.


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3. INHALE
Before inhaling your dose from the inhaler, breathe out (exhale) fully while holding the 
inhaler level and away from your mouth (see Figure 5). Remember, never breathe out into 
the inhaler mouthpiece.
Figure 5
Exhaling
Put the mouthpiece to your lips (see Figure 6). Breathe in quickly and deeply through the 
inhaler. Do not breathe in through your nose.
Figure 6
Inhaling
Remove the inhaler from your mouth. Hold your breath for about 10 seconds, or for as long as 
is comfortable. Breathe out slowly. The inhaler 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 inhaler
if you do not feel or taste the medicine.


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4. CLOSE
Close the inhaler when you are finished taking a dose so that the inhaler 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 inhaler will click shut. The lever will 
automatically return to its original position. The inhaler is now ready for you to take your next 
scheduled dose, due in about 12 hours. (Repeat steps 1 to 4 at that time).
Figure 7
Closing the Mouthpiece Cover
Remember:

Never breathe into the inhaler.

Never take the inhaler apart.

Always ready and use the inhaler in a level, flat position.

Do not use the inhaler with a spacer device.

Never wash the mouthpiece or any part of the inhaler. Keep it dry.

Always keep the inhaler in a dry place.

Never take an extra dose, even if you did not taste or feel the medicine.

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
QVM149
CQVM149B2208
A randomized, double-blind, double dummy, active-
controlled, 3-period completecross-over study to assess 
the bronchodilator effect and safety of two doses of 
QVM149 compared to a fixed dose combination of 
salmeterol/fluticasone in patients with asthma
Statistical Analysis Plan (SAP)
Document type: 
SAP Documentation –NIBR 
Document status:
Final4.0Amendment 3
Release date:
06-Sep-2018
Number of pages:
20
Personal Data
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CQVM149B2208
Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................3
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary objective(s)................................................................................5
1.3.2
Secondary objective(s)............................................................................5
1.4
Study design and treatment......................................................................................8
2 First interpretable results (FIR).........................................................................................10
4 Statistical methods: Analysis sets......................................................................................11
5 Statistical methods for Pharmacokinetic (PK) parameters................................................11
6 Statistical methods for Pharmacodynamic (PD) parameters.............................................12
6.1
Primary objective...................................................................................................12
6.1.1
Variables...............................................................................................12
6.1.2
Descriptive analyses..............................................................................12
6.1.3
Statistical model, assumptions and hypotheses.....................................12
6.2
Secondary objectives.............................................................................................14
6.2.1
Variables...............................................................................................14
6.2.2
Descriptive analyses..............................................................................15
6.2.3
Statistical model, assumptions and hypotheses.....................................15
7.1
Variables................................................................................................................17
7.2
Descriptive analyses..............................................................................................17
7.3
Graphical presentation...........................................................................................19
9 Reference list.....................................................................................................................20
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................
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1
Introduction 
1.1
Scope of document
The Statistical analysis plan (SAP) documents contain detailed information to aid the 
production of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CQVM149B2208”.
SAP describes the implementation of the statistical analysis planned in the protocol.
1.2
Study reference documentation
This SAP is based on the final version of the following study documents:

the study protocol, v00, 20 March 2017

the SOM, v00, 30 January 2017
1.3
Study objectives
1.3.1
Primary objective(s)
Objective
Endpoint

To demonstrate superiority in peak 
bronchodilator effect of QVM149 at a 
dose of 150/50/160 μg o.d. and 
150/50/80 μg o.d. compared to a FDC of 
salmeterol/fluticasone at a dose of 
50/500 μg b.i.d. after 3 weeks of 
treatment in patients with asthma

Peak FEV1 (mL) defined as the highest 
bronchodilatory effect on FEV1 during a 
period of 5 min to 4 h after the last 
evening dose of each treatment period.
1.3.2
Secondary objective(s)
Objective
Endpoint

To evaluate the bronchodilator effect of 
each dose of QVM149 compared to 
salmeterol/fluticasone FDC after 3 
weeks of treatment.

FEV1, Forced Vital Capacity (FVC), 
and FEV1/FVC ratio at the following 
timepoints in relation to evening dose :
-  45 min, -15 min, 5 min, 15 min, 30 
min, 1 h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h
55 min, 14 h, 18 h, 21 h, 23 h 15 min,
23 h 45 min.

To evaluate the bronchodilator effect of 
each dose of QVM149 compared to 
salmeterol/ fluticasone FDC by
measuring standardized FEV1 AUCs 
after 3 weeks of treatment respective 
period.

FEV1AUC 5 min - 1 h (Day 21)

FEV1AUC 5 min - 4 h (Day 21)

FEV1AUC 5 min (Day 21) - 23 h 45 min
(Day 22)

To evaluate post-dose trough 
bronchodilator effect of each dose of 

Trough FEV1 (mL; mean of FEV1 at
23 h 15 min and 23 h 45 min post-dose)


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Objective
Endpoint
QVM149 compared to 
salmeterol/fluticasone FDC after 3 
weeks of treatment in the respective 
treatment period.

To evaluate safety and tolerability of 
each dose of QVM149 and salmeterol/ 
fluticasone FDC when administered for 
3 weeks.

Hematology

Blood chemistry

Urine analysis

Vital signs

ECG

Adverse events 


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1.4
Study design and treatment
This is a confirmatory, randomized, double-blind, double-dummy, active-controlled, 3-period 
complete cross-over study. During the 2-week screening period, patients will be required to 
abstain from using any asthma medication before screening lung function assessments in line 
with cessation periods. Patients are allowed to use their previous asthma medication between 
screening spirometry and randomization but need to stop at randomization when study drug 
administration commences.
Short-acting beta-2-agonist bronchodilators will be provided to each patient to be used as rescue 
medication throughout the trial. Rescue medication use will be recorded in the patient diary.
The 2-week screening period may be divided into more than one visit for operational reasons 
with the informed consent being obtained prior to any study related activities.
Eligible subjects may be re-screened once if they are not included in the study within the 
allowed 2 week screening period.  Subjects may also be re-screened at the discretion of the 
Investigator, and following discussion with the Medical Monitor and/or Sponsor, if the reason 
for screen failure was considered temporary in nature.  All screening data must be obtained 
within 2 weeks prior to administration of study medication, as stipulated above.  Subjects who 
are re-screened will re-consented and will be allocated a new screening number.
At the end of the screening period, patients will be randomized to one of 6 possible treatment 
sequences), each consisting of 3 double-blind, double-dummy treatment periods of 21 days 
(cross-over design). There is no washout period between treatments periods since drug effects 
from the previous period are not expected to be present after 3 weeks with current treatment in 
each period.
The treatments are:
1. QVM149 150/50/160 μg o.d. (indacaterol acetate 150 μg/ glycopyrronium bromide 50 
μg/ MF 160 μg once daily) – QVM149 high dose
2. QVM149 150/50/80 μg o.d. (150 μg/ 50 μg/ 80 μg once daily) - QVM149 mid dose
3. salmeterol/fluticasone FDC 50/500 μg b.i.d.
4.
Double blind and double dummy study drug administration schedule
Each treatment sequence will have approximately 19 subjects.


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Procedures in treatment periods two and three are identical to the procedures of treatment period 
one. At the end of the last treatment period, subjects will then undergo Study Completion 
evaluations and will be discharged from the study site. 
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry and urinalysis), adverse event and
serious adverse event monitoring.
The study population will consist of male and female patients aged between 18 and 75 years 
with asthma and who have been treated with ICS and LABA for at least 12 months prior to 
screening.
A total of approximately 114 patients will be enrolled and randomized with the intention that 
at least 95 patients complete the study. Patients dropped out may be replaced if the drop-out 
rate reaches 10%.


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Spirometry –Assessments
For each treatment period
Spirometry
(timinginrelationtostudydrugadministration)
Day 21
(Visit 103)
(Visit 203)
(Visit 303)
Timing priortostudydrugadministration
  -45 min
  -15 min
Study drug -evening dose Day 21 
Timing post evening dose
+  5 min, + 15min, + 30 min, + 1h, + 2h, + 3 h, + 4h
Day 22 
Day 22 
(Visit 104)
(Visit 204)
(Visit 304)
Timing post evening dose day 21
+  8h, + 10 h, + 11 h 55 min
Study drug morning dose
+ 14 h, + 18 h, + 21 h, + 23 h 15 min, + 23 h 45 min
Day 22
Day 22 = Day 1 of the subsequent treatment 
period
First evening dose of the next study period
2
First interpretable results (FIR)
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First interpretable results (FIR) will be provided for this trial.
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4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment received.
All subjects that received study drug will be included in the safety analysis set.
The PD analysis set will include all subjects with any available PD data, who received any study 
drug and experienced no protocol deviations withrelevant impact on PD data.
Anyone who did not complete an informed consent will not have their data reported.For 
subjects for which the actual sequence of treatments received does not match the randomized 
sequence of treatments, the actual sequence willbe used for analysis involving a sequence 
component (in the linear mixed modelwith a sequence effect) if the actual sequence is one of 
the sequences planned in the study design. If the actual sequence is not one of the sequences 
planned in the study design, the randomized sequence will be used for analysis involving a 
sequence component but data points from periods in which the subject has not received the 
randomized treatment will be excluded from the analysis. 
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these 
PDs:
Exclude subject from PD analysis 
set
INCL01
Written informed consent was not 
obtainedprior to performing study 
assessment
Exclude from PD set
If updates to this table are needed,anamendment tothe SAP needs tobe implemented priorto
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
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6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective is to demonstrate superiority in peak bronchodilator effect of QVM149 
at a dose of 150/50/160 μg o.d. and 150/50/80 μg o.d. compared to a FDC of 
salmeterol/fluticasone at a dose of 50/500 μg b.i.d. in patients with asthma.
6.1.1
Variables 
The primary endpoint is the peak FEV1 (mL) defined as the highest bronchodilatory effect on 
FEV1 during a period of 5 min to 4 h after the last dose of the preceding 3 week treatment 
period.
6.1.2
Descriptive analyses
The primary variable will be determined after the last dose of the preceding 3 week treatment. 
FEV1 measurements to consider defining peak FEV1 are on day 21 +5 min, +15 min, +30 min, 
+1h, +2h, +3h and +4h (timing from the post-evening dose). Peak FEV1 will be listed by 
treatment sequence and subject, and summarized by treatment.
6.1.3
Statistical model, assumptions and hypotheses
The following hypothesis will be tested for each of QVM149 doses versus 
salmeterol/fluticasone separately:
H0: There is no difference in terms of the peak FEV1 after 21 days of treatment between:
the QVM149 high dose and salmeterol/fluticasone 
OR 
the QVM149 mid dose and salmeterol/fluticasone 
H1: There is a difference in terms of the peak FEV1 after 21 days of treatment between:
the QVM149 high dose and salmeterol/fluticasone 
AND 
the QVM149 mid dose and salmeterol/fluticasone 
Each test will be conducted at a one-sided 2.5% level.
The primary variable will be analyzed using a linear mixed model. The model will include 
period, treatment, and sequence as fixed effect factors and patient as a random effect. Restricted 
maximum likelihood method will be used. The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom. 
The pairwise treatment differences of each QVM149 dose versus salmeterol/fluticasone along 
with the corresponding 2-sided 95% confidence intervals will be presented. In addition, 
difference between adjusted means and the corresponding two-sided 95% confidence interval 
for QVM high versus mid doses will be estimated.
No adjustment for multiplicity is planned because both tests are required to be positive.


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6.1.3.1 Model checking procedures
Missing values
If a patient takes rescue medication within 6h prior to the spirometry assessments and the visit
is not rescheduled to the next day then all spirometry assessment datafrom this visit and the 
following visits in this treatment period will be set to missing.If rescue medication is taken 
during the 24-hour spirometry assessment then from the time of the rescue medication intake, 
all post-timepoint spirometry assessments will be considered as missing in this treatment period.
Sensitivity analyses
A sensitivity analysis will be conducted to evaluate the presence of any potential carry-
overeffects by applying the same model as described above and adding a factor modeling 
thefirst order carry-over effects.
Note:In a 3-treatments×3-periods crossover, carry-over is not confounded with sequence.
Calculate carry-over term: the value of the treatment for the preceding period. It should be 
done at the dataset level before running the modelwith this additional “carryover” term. 
SAS LAG() function should be used. 
Proc sort data=a;
by subject period;
Data cross3;
set a;
carryover = lag (trt);
if (period=1) then carryover = 1;
 
 
# one of the treatment levels
LAG() gives the preceding value of the argument variable, so the data must besorted in 
the correct order. The first period has no carry-over.
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Subgroup analysis
The primary analysis will be performed by subgroup of patients based on their compliance of 
study medication within the 7 days before the spirometry assessmentwithin the treatment 
period: if spirometry assessment is done on the evening of day 21of the treatment period, then 
compliance will be calculated between day 15and day 21on a total number of 14 doses.
This analysis will be provided per compliance of study medication within the 7 days before 
spirometry assessment defined as follows:
<80% Compliance of study medication within the 7 days before spirometry assessment (less
than a total number of 12 doses)
80-100% Compliance of study medication within the 7 days before spirometry assessment
(more or equal a total number of 12 doses)
6.1.3.2 Graphical presentation of results
Plot of the pairwise treatment differences of each QVM149 dose versus salmeterol/fluticasone 
andQVM149 high versus mid dose along with the corresponding 2-sided 95% confidence 
intervalsat day 21willbe displayed.
6.2
Secondary objectives
6.2.1
Variables 
The secondary endpoints are:
FEV1, Forced Vital Capacity (FVC), and FEV1/FVC ratio
Standardized AUC in FEV1 across different time intervals (5 min –1 h, 5 min –4 h, 5
min –23h 45 min) at Day 21(FEV1AUC(5 min -1 h), FEV1AUC(5 min -4 h)
FEV1AUC(5 min-23 h 45 min))
Trough FEV1 (mL)
FEV1, Forced Vital Capacity (FVC), and FEV1/FVC ratio are collected at the following 
timepoints in relation to evening dose on day 21: -45 min, -15 min, 5 min, 15 min, 30 min, 1 
h, 2 h, 3h, 4 h, 8 h, 10 h, 11 h 55 min, 14 h, 18 h, 21 h, 23 h 15 min, 23 h 45 min.
Trough FEV1 (mL) is defined as the mean of FEV1at 23 h 15 min and 23 h 45 min post-dose
from the last evening dose of each period, i.e. on day 21.
For FEV1AUC(5 min-23 h 45 min), FEV1AUC(5 min -1 h), FEV1AUC(5 min -4 h), the 
standardized AUCsare derived using the linear trapezoidal rule and adjusting for the length of 
the assessment interval.
Itwill be calculated as the AUC0-24h divided by the t
f-t
lhours time interval for each subject 
(t
f=time of the first observation, tl
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where,
Ci = the highest value at planned relative timepoint i
ti = the actual time for planned relative timepoint i
i = the planned relative time of assessment
f =the first i
l =the last i.
6.2.2
Descriptive analyses
All secondary endpoints, FEV1, Forced Vital Capacity (FVC), FEV1/FVC, standardized AUC 
in FEV1 (5 min-23 h 45 min), in FEV1 (5 min - 1 h), in FEV1 (5 min - 4 h) and trough FEV1 
will be listed by treatment sequence and subject, and reported using summary statistics by 
treatment.
6.2.3
Statistical model, assumptions and hypotheses
The secondary endpoints standardized AUC in FEV1 (5 min-23 h 45 min), in FEV1 (5 min - 1 
h), in FEV1 (5 min - 4 h) and trough FEV1 will be analyzed by fitting the same model as 
described for the primary endpoint above.
6.2.3.1
Model checking procedures
Missing values
If an observation is missing between two non-missing observations, the AUC will be linearly 
interpolated between the two non-missing values i.e. the subject’s profile will be assumed to be 
linear between the two available values. Multiple occurrences of such missing values (an 
observation missing between adjacent non-missing observations) will be handled in a similar 
manner. But in case of missing consecutive assessments, then the patient profile will be 
excluded from analysis. No imputation will be made if either the first or the last observation is 
missing and AUC (0-24hr) is calculated from the available part of the profile ignoring the first 
and last time points.
If a patient takes rescue medication within 6h prior to the spirometry assessments and the visit
is not rescheduled to the next day then all spirometry assessment data from this visit and the 
following visits in this treatment period will be set to missing. If rescue medication is taken 
during the 24-hour spirometry assessment then from the time of the rescue medication intake, 
all post-time point spirometry assessments will be considered as missing in this treatment period.
AUC FEV1 will only be calculated if the last time point in AUC is prior to intake of rescue 
medication (e.g. if a patient takes rescue medication at 2hrs, then FEV1 AUC(5min-1h) will be 
computed with FEV1 AUC( 5min – 4h) and FEV1 AUC (5min – 23h 45min) set to missing.)


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6.2.3.2 Graphical presentation of results
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Plot of the pairwise treatment differences of standardized AUC in FEV1(5 min-23 h 45 min),
in FEV1(5 min -1 h), in FEV1(5 min -4 h) and trough FEV1 of each QVM149 dose versus 
salmeterol/fluticasone and for QVM149 high versus mid dose along with the corresponding 2-
sided 95% confidence intervalsat day 21willbe displayed.
Additionally, Plots (Mean (SD) and boxplots) of FEV1, Forced Vital Capacity (FVC), and 
FEV1/FVC ratio overthe 24h after the evening dose given on day 21 will be produced by 
treatment, in addition plot of mean of FEV1by period and sequence will be displayed.
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7
Statistical methods for safety and tolerability data
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.
The last daily dose of inhaled corticosteroids (ICS) taken before being enrolled into the study 
will be categorized into three categories: Low, medium and high defined based on 2017 GINA 
report.
http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-
prevention/
7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
Subject disposition
A disposition summary will be presented for all subjects. This table will present the number and 
percentage of subjects who completed each study epoch and discontinued early for each epoch, 
along with the reasons for early discontinuation. 
The number and percentage of subjects in each analysis set will be summarized for all subjects. 
All analysis set results will be presented in listings by treatment sequence and subject. A 


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separate listing of all subjects excluded from any analysis set and the reasons for their exclusion 
will be provided. 
All study epoch completion data will be listed by treatment sequence and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment sequence and subject.
Vital signs
All vital signs data will be listed by treatment sequence, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment sequence, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment sequence, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with treatment emergent adverse events will be 
tabulated by body system and preferred term with a breakdown by treatment. Adverse events 
starting on or after the time of the first inhalation of study drug will be classified as a treatment 
emergent adverse event. An adverse event starting in one period and continuing into the next 
period is counted only in the onset period. A subject with multiple adverse events within a body 
system and treatment period is only counted once towards the total of this body system and 
treatment.
Any adverse event occurring during the washout period is counted under the current treatment 
epoch. For example, if AE occurs during the washout period just after treatment period 1, it will 
be counted under treatment epoch 1.For the legal requirements of ClinicalTrials.gov and 
EudraCT, two required tables on treatment emergent adverse events which are not serious 
adverse events with an incidence greater than 2% and on treatment emergent serious adverse 
events and SAE suspected to be related to study treatment will be provided by system organ 
class and preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


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a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE
's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to studytreatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Rescue medication
Rescue medications use collected during the entire treatment duration will be listed by treatment 
sequence, subject. 
The number of patients using rescue medication (salbutamol/albuterol)over the last week of 
thetreatment periodand the mean of the number of puffs per subject taken over the last week 
of treatment will be summarized by treatment.
Protocol Deviations
Protocol deviations will belisted by treatment sequence and subject.
Liver events
Liver event data may be reported in listings and summaries if data is collected during the study.
7.3
Graphical presentation 
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Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
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Reference list
Kieser M, Friede T (2003) Simple procedures for blinded sample size adjustment that do not
affect the type I error rate. Statistics in Medicine; 22: 35-3581.