Clinical trial NCT03108027
Conditions: Asthma
Keywords: QVM149, asthma, allergic asthma, allergy triggered asthma, reactive asthma, asthma attack, difficulty breathing
Sponsor: Novartis Pharmaceuticals
Start date: 2017-06-26; Completion date: 2018-02-24
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This was a randomized, placebo-controlled, double-blind, six-sequence, three-period cross-over study in asthma patients. The study consisted of a 14-day screening period, followed by a 14-day run-in period, and a treatment epoch which consists of three treatment periods, with a minimum duration of 14 days each followed (for the 2 first treatment periods) by a wash-out period. The duration of each treatment period may be extended up to a duration of 18 days if needed for operational reasons. The third treatment period was followed by a Study Completion evaluation at 1-7 days following the last dose. The treatment periods were separated by wash-out periods of 14 to 21 days duration.

Detailed description:

Arms: arm 1: Patients will receive in a sequential order the following interventional treatments: A,B and C. arm 2: Patients will receive in a sequential order the following interventional treatments: B, A and C. arm 3: Patients will receive in a sequential order the following interventional treatments: C, B and A. arm 4: Patients will receive in a sequential order the following interventional treatments : C, A and B. arm 5: Patients will receive in a sequential order the following interventional treatments: A, C and B. arm 6: Patients will receive in a sequential order the following interventional treatments: B, C and A.
Interventions: intervention 1: Treatment A: Matching placebo (morning dose) and QVM149 150/50/80 μg (evening dose) intervention 2: Treatment B: QVM149 150/50/80 μg (morning dose) and matching placebo (evening dose) intervention 3: Treatment C: Placebo (morning dose) and placebo (evening dose)
Intervention descriptions: intervention 1: Matching placebo (morning dose) and QVM149 150/50/80 μg (evening dose) intervention 2: QVM149 150/50/80 μg (morning dose) and matching placebo (evening dose) intervention 3: Placebo (morning dose) and placebo (evening dose)

Protocol documents:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
QVM149
Clinical Trial Protocol CQVM149B2209
A randomized, double-blind, repeat dose cross-over study 
to assess the bronchodilator effects of once daily QVM149 
following morning or evening dosing for 14 days compared 
to placebo in patients with asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
2017-000644-17
Version number:
v00 (Original Protocol)
Clinical Trial Phase:
II
Release date:
08-Mar-2017
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Clinical Trial Protocol (Version 00)
Protocol No. CQVM149B2209
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 Clinical Trial 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 Chief Medical Office and Patient Safety 
(CMO&PS) 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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Clinical Trial Protocol (Version 00)
Protocol No. CQVM149B2209
Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................7
List of figures......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................13
1 Introduction.......................................................................................................................16
1.1
Background............................................................................................................16
1.3
Clinical data...........................................................................................................19
1.3.1
Human safety and tolerability data.......................................................19
1.3.2 
Human pharmacokinetic data................................................................20
1.3.3
Human pharmacodynamic data.............................................................20
1.4
Study purpose........................................................................................................21
2 Objectives and endpoints...................................................................................................21
2.1
Primary objective(s)...............................................................................................21
2.2
Secondary objective(s)...........................................................................................21
3 Investigational plan...........................................................................................................23
3.1
Study design...........................................................................................................23
3.2
Rationale for study design.....................................................................................27
3.3 
Rationale for dose/regimen, route of administration and duration of treatment....28
3.4
Rationalefor choice of comparator.......................................................................31
3.6
Risks and benefits..................................................................................................31
3.6.1
Blood sample volumes..........................................................................34
4 Population..........................................................................................................................34
4.1
Inclusion criteria....................................................................................................35
4.2
Exclusion criteria...................................................................................................36
5 Restrictionsfor studypatients...........................................................................................40
5.1
Contraception requirements...................................................................................40
5.2
Prohibited treatment...............................................................................................
Corporate Confidential Information
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Corporate Confidential Information
Corporate Confidential Information


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Protocol No. CQVM149B2209
5.3
Dietary restrictions and smoking...........................................................................42
5.4
Other restrictions ...................................................................................................42
6
Treatment...........................................................................................................................42
6.1
Study treatment......................................................................................................42
6.1.1
Investigational and control drugs..........................................................42
6.1.2
Additional study treatment....................................................................43
6.2
Treatment arms ......................................................................................................43
6.3
Treatment assignment and randomization.............................................................43
6.4
Treatment blinding.................................................................................................44
6.5
Treating the patient................................................................................................45
6.6
Permitted dose adjustments and interruptions of study treatment.........................46
6.7
Emergency breaking of assigned treatment code ..................................................46
6.8
Treatment exposure and compliance .....................................................................47
6.9
Recommended treatment of adverse events ..........................................................47
6.10
Rescue medication.................................................................................................47
6.11
Concomitant treatment...........................................................................................47
7
Study completion and discontinuation ..............................................................................48
7.1
Study completion and post-study treatment ..........................................................48
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
Patient screening....................................................................................................57
8.4
Patient 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 .............................................................................57
8.6
Safety.....................................................................................................................58
8.6.1
Physical examination ............................................................................58
8.6.2
Vital signs..............................................................................................58


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Protocol No. CQVM149B2209
8.6.3
Height and weight.................................................................................58
8.6.4
Laboratory evaluations..........................................................................58
8.6.5
Electrocardiogram (ECG).....................................................................59
8.6.6
Pregnancy and assessments of fertility.................................................59
8.6.7
Patient Diary (e-Diary)..........................................................................60
8.7
Pharmacokinetics...................................................................................................60
9 Safety monitoring..............................................................................................................60
9.1
Adverse events.......................................................................................................60
9.2
Serious adverse event reporting.............................................................................62
9.2.1 
Definition of Serious Adverse Event (SAE).........................................62
9.2.2
SAE reporting........................................................................................63
9.3
Liver safety monitoring.........................................................................................64
9.4
Reporting of study treatment errors including misuse/abuse................................65
9.5
Pregnancy reporting...............................................................................................66
9.6
Prospective suicidality assessment........................................................................66
9.7
Early phase safety monitoring...............................................................................66
10 Data review and database management.............................................................................67
10.1 Site monitoring......................................................................................................67
10.2 Data collection.......................................................................................................67
10.3 Database management and quality control............................................................68
10.4 Data Monitoring Committee..................................................................................69
10.5 Adjudication committee.........................................................................................69
11 Data analysis......................................................................................................................69
11.1 Analysis sets..........................................................................................................69
11.2 Patient demographics and other baseline characteristics.......................................69
11.3 Treatments.............................................................................................................69
11.4 Analysis of the primary variable(s).......................................................................69
11.4.1
Primary Variable(s)...............................................................................69
11.4.2
Statistical model, hypothesis, andmethod of analysis..........................70
11.4.3
Handling of missing values/censoring/discontinuations.......................70
11.4.4
Sensitivityanalyses...............................................................................70
11.5 Analysis of secondary variable(s)..........................................................................70
11.5.1
Efficacy / Pharmacodynamics...............................................................
Corporate Confidential Information
70


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Protocol No. CQVM149B2209
11.5.2
Safety.....................................................................................................71
11.5.3
Other assessments.................................................................................71
11.7 Sample size calculation..........................................................................................72
11.8 Power for analysis of key secondary variables......................................................72
12 Ethical considerations........................................................................................................72
12.1 Regulatory and ethical compliance........................................................................72
12.2 Responsibilities of the investigator and IRB/IEC..................................................73
12.3 Publication of study protocol and results...............................................................73
12.4 Quality control and quality assurance....................................................................73
13 Protocol adherence............................................................................................................74
13.1 Protocol amendments.............................................................................................74
14 References.........................................................................................................................75
15 Appendix 1: Liver event definitions and follow-up requirements....................................77
16 Appendix 2: Instruction for Use of Concept1...................................................................
Corporate Confidential Information
79
Corporate Confidential Information


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Protocol No. CQVM149B2209
List of tables
Table 3-1
Study Treatments ..................................................................................25
Table 3-2
Comparison of the comparable MF component doses between 
Asmanex® Twisthaler®, QMF149 and QVM149 drug products...........30
Table 5-1
Withholding period of bronchodilators prior to spirometry..................40
Table 5-2
Prohibited asthma medication during treatment period ........................40
Table 5-3
Prohibited treatments, cessation periods...............................................41
Table 5-4
Medication allowed under certain conditions if taken as follows.........41
Table 6-1
Overview of study medication ..............................................................42
Table 6-2
Definition of treatment sequences.........................................................43
Table 6-3
Randomization assignment numbering.................................................43
Table 6-4
Blinding and unblinding plan................................................................45
Table 8-1
Assessment schedule.............................................................................51
Table 8-2
Spirometry.............................................................................................55
Table 9-1
Guidance for capturing study treatment errors......................................66
Table 15-1
Liver event definitions ..........................................................................77
Table 15-2
Actions required for liver events...........................................................77
Table 15-3
Exclusion of underlying liver disease ...................................................78
List of figures
Figure 3-1
Study design..........................................................................................23


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Protocol No. CQVM149B2209
List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
coefficient of variation
ECG
Electrocardiogram
EDC
Electronic Data Capture
eSource
Electronic Source
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBsAg
Hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long-acting beta adrenoceptor agonists
LAMA
Long-acting muscarinic antagonist


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Protocol No. CQVM149B2209
LFT
Liver function test
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
LLN
lower limit of normal
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
NCDS
Novartis Clinical Data Standards
PA
posteroanterior
PC
personal computer
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PIP
pediatric investigation plan
p.o.
oral(ly)
PSD
Premature patient discontinuation
PT
prothrombin time
RBC
red blood cell(s)
RDC
Remote Data Capture
SABA
Short acting beta 2 agonist
SAE
serious adverse event
SAMA
Short acting muscarinic antagonist
S
Source documents
s.c.
subcutaneous
sCR
serum creatinine
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TD
Study Treatment Discontinuation
ULN
upper limit of normal


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Clinical Trial Protocol (Version 00)
Protocol No. CQVM149B2209
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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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 patients fulfilling certain criteria
Control drug
Any drug(s) (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 patient in a time unit 
(e.g. 100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of 
clinical study data using data collection systems, such as 
Web-based applications, interactive voice response systems and 
clinical laboratory interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) 
which are used to capture data transcribed from paper source 
forms used at the point of care.
Enrollment
Point/time of patient entry into the study at which informed 
consent must be obtained (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.
Healthy volunteer
A person with no known significant health problems who 
volunteers to be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; 
this definition is consistent with US Code of Federal Regulation
(CFR) 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational 
Medicinal Product," or “test substance”
Medication pack number
A unique identifier on the label of each drug package in studies 
that dispense study treatment using an Interactive Response 
Technology (IRT) system
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.


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Patient
An individual with the condition of interest
Randomization number
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Run in Failure
A patient who is screened but not randomized/treated after the 
run-in period (where run-in period requires adjustment to 
patient’s medications or other intervention) 
Screen Failure
A patient who is screened but is not treated or randomized 
Patient
A trial participant (can be a healthy volunteer or a patient)
Patient number
A unique number assigned to each patient upon signing the 
informed consent. This number is the definitive, unique 
identifier for the patient and should be used to identify the 
patient throughout the study for all data collected, sample labels, 
etc.
Source Data/Document
Source data refers to the initial record, document, or primary 
location from where data comes. The data source can be a 
database, a dataset, a spreadsheet or even hard-coded data, such 
as paper or eSource.
Study treatment
Any drug or combination of drugs administered to the study 
participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Study treatment 
discontinuation
When the patient 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 
patient does not want to participate in the study any longer, and
does not want any further visits or assessments, and does not 
want any further study related contact, and does not allow 
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Protocol summary
Protocol number
CQVM149B2209
Full Title
A randomized, double-blind, repeat dose cross-over study to assess the 
bronchodilator effects of once daily QVM149 following morning or evening 
dosing for 14 days compared to placebo in patients with asthma.
Brief title
Assess the bronchodilator effect of QVM149 dosed once daily either in the 
morning or in the evening compared to placebo in patients with asthma. 
Sponsor and Clinical 
Trial Phase
Novartis 
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
This study will provide evidence of the comparability of lung function effects 
of QVM149 (indacaterol acetate / glycopyrronium bromide / mometasone 
furoate) irrespective of the administration schedule. It is considered important 
for the overall QVM149 development program to demonstrate lung function 
benefits of QVM149 compared to placebo irrespective of time of dosing. 
Flexibility in dosing schedule may confer benefit to the patient by facilitating 
treatment compliance with subsequent lung function improvement and 
asthma control.
Primary Objective
To investigate the potential influence of time of dosing (morning or evening) 
on the bronchodilator effect of once daily orally inhaled QVM149 compared to 
placebo.
Secondary 
Objectives

To investigate the potential influence of time of dosing (morning or 
evening) on trough FEV1 of once daily orally inhaled QVM149 compared 
to placebo.

To investigate the potential influence of time of dosing (morning or 
evening), on peak expiratory flow rate (PEF) of once daily orally inhaled 
QVM149 compared to placebo.

To evaluate safety and tolerability of QVM149 when dosed in the 
morning or in the evening in patients with asthma after during two weeks 
of treatment in each treatment period. 
Study design
This is a randomized, placebo-controlled, double-blind, six-sequence, 
three-period cross-over study in asthma patients. The study will consist of a 
14-day screening period, followed by a 14-day run-in period,  and a treatment 
epoch which consists of three treatment periods, with a minimum duration of 
14 days each followed (for the 2 first treatment periods) by a wash-out period. 
The duration of each treatment period may be extended up to aduration of 18 
days if needed for operational reasons. The third treatment period will be 
followed by a Study Completion evaluation at 1-7 days following the last 
dose. The treatment periods will be separated by wash-out periods of 14 to 
21 days duration.
The total duration of the study is approximately 13 weeks (minimum) to 
19 weeks (maximum) for each patient.


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Population
The study population will be comprised of male and female patients aged 18 
and above with asthma. Approximately 36 adult patients will be randomized 
with the intention that at least 30 patients complete the study.
Key Inclusion 
criteria

Patients with a documented physician diagnosis of asthma and who 
additionally meet the following criteria:
−
patients receiving daily treatment with an inhaled corticosteroid 
at a low or medium daily dose 
−
on a stable regimen for at least 4 weeks prior to screening.

Pre-bronchodilator FEV1 ≥ 60 % and < 100% of the predicted normal 
value for the patient during screening.

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 patients must perform a reversibility 
test at Screening.

At screening, and baseline (day 1 pre-dose time) of the first treatment 
period, vital signs (systolic and diastolic blood pressure and pulse rate) 
will be assessed in the sitting position and again in the standing position 
as outlined in the SOM. Sitting and standing vital signs should be within 
the following ranges:
−oral body temperature between 35.0-37.5 °C
−systolic blood pressure, 90-159 mmHg
−diastolic blood pressure, 50-99 mmHg
−pulse rate, 40-90 bpm

Hypertensive patients must have been on stable antihypertensive therapy 
for at least 4 weeks prior to screening to be included in the trial.

Patients must weigh at least 50 kg at screening to participate in the 
study, and must have a body mass index (BMI) within the range of 18 to 
40 kg/m2.
Key Exclusion 
criteria

Contraindicated for treatment with, or having a history of reactions/ 
hypersensitivity to any of the drugs of a similar class

Patients who have had an asthma attack/exacerbation requiring systemic 
steroids or hospitalization or emergency room visit within 1 year of 
Screening. 

Patients who have had previous intubation for a severe asthma 
attack/exacerbation.

Patients with a history of clinically relevant bronchoconstriction upon 
repeated forced expiratory maneuvers.

History of paradoxical bronchospasm in response to inhaled medicines.

Patients who during the run-in period prior to randomization require the 
use of ≥12 puffs / 24 hours of rescue medication for 48 hours (over two 
consecutive days) or who have a decline in PEF from  the reference PEF 
of ≥ 30% for 6 consecutive scheduled PEF readings 

Patients who do not maintain regular day/night, waking/sleeping cycles 
(e.g., night shift workers).
Study treatment

QVM149  once daily in the morning 

QVM149 once daily in the evening

Placebo
Pharmacokinetic 
assessments

Not applicable


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Protocol No. CQVM149B2209
Efficacy/PD 
assessments

Spirometry; FEV1 over 24 hours

Peak expiratory flow
Key safety 
assessments

Physical examination

Vital signs

Laboratory evaluations; hematology, blood chemistry and urinalysis

Electrocardiogram (ECG)

Peak flow measures
Other assessments

Patient diary to record rescue medication use, study treatment
administration (am and pm),  PEF measurements (am and pm)
Data analysis
The primary objective is to investigate the potential influence of time of dosing 
(morning or evening) on the bronchodilator effect of once daily orally inhaled 
QVM149 compared to placebo.
The primary variable is the weighted mean forced expiratory volume in 1 
second (FEV1) over 24 hours (AUC0-24h) following 14 days of treatment with 
QVM149 dosed in the morning, QVM149 dosed in the evening and placebo. 
The primary variable will be determined for each patient on day 14/15 on 
each treatment using the linear trapezoidal rule.
The primary variable, FEV1 weighted mean (0- 24 h) (AUC0-24h), will be 
analyzed using a linear mixed model The model will include period, treatment 
(QVM149 morning, QVM149 evening, placebo), and sequence as fixed effect 
factors. 
The 
patient 
effect 
will 
be 
assumed 
to 
be 
random. 
Restricted maximum likelihood method will be used. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. 
From these analyses, point estimates and their associated 90% confidence 
intervals will be constructed for each treatment. The difference between 
adjusted means and the corresponding two-sided 90% confidence interval for 
morning dose versus placebo, evening dose versus placebo will be 
presented.  In addition, difference between adjusted means and the 
corresponding two-sided 90% confidence interval for morning versus evening 
doses will be presented.
The secondary endpoints are:

FEV1 at approximately 5 min. before last p.m. or penultimate a.m. dose 
obtained from spirometry data.

Daily morning and evening peak expiratory flow (PEF) rate from Day 2 to 
Day 14 during the three treatment periods
FEV1 (mL) will be analyzed by fitting the same model as described for the 
primary endpoint above in addition to summary statistics. 
PEF (L/min) will be analyzed separately for morning and evening values. 
The morning/evening PEF (L/min) will be averaged between days 2 to 14 of 
each treatment period for each patient. Morning and evening PEF data 
averaged over the days of run-in period will be used as baseline values. 
The change from baseline in average mean morning/evening PEF score 
between days 2 to 14 in each period will be analyzed using the same model 
as for the primary endpoint and summarized by treatment.
Key words
Asthma, FEV1, spirometry, peak flow


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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 (GINA 2016).
Despite existing therapies there is still significant unmet medical need in asthma, with an 
estimated 300 million people affected worldwide. The Global Burden of Asthma Report 
estimates that 15 million disability–adjusted life years (DALYs) are lost annually due to 
asthma, representing 1% of the total global burden. Annual worldwide deaths have been 
estimated at 250,000 (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, 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.
The clinical presentation of asthma is characterized by diurnal variation: symptoms of asthma 
typically worsen and lung function decreases
during the
night (Muers 1984).
The pathogenesis to diminished airway caliber during the night is not fully understood but has 
been linked, among other factors, to the diurnal rhythm of endogenous cortisol levels
(Barnes et al 1980, Landstra et al 2007). In previous studies various ICS have been administered 
at different times of the day. Results are not uniform but suggest that time of administration may


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influence the efficacy of ICS. Fluticasone furoate at a dose of 100 μg via the Ellipta® device 
showed similar gains in lung function when administered in
the morning (77 mL 
compared to placebo in 24 hours weighted means FEV1) or in the evening (105 mL) 
(Kempsford et al 2016). A less consistent picture has been described for Fluticasone furoate 
delivered with a Diskus® inhalation device (Woodcock et a. 2011). 
MF formulated as Asmanex® Twisthaler® if prescribed once-daily, is recommended to be 
dosed in the evening evening (Asmanex® Twisthaler® SmPC). Clinical studies suggest that 
MF can also be administered once daily in the morning to convey clinical benefit to patients 
in terms of lung function (Noonan et al 2001) and asthma symptoms (Zetterstrom et al 2008).
Individual patients may like to choose at what time of the day they take their medication. 
Therefore, having the flexibility of dosing either in the morning or evening may be more 
convenient for the patient and may further improve treatment adherence and the management
of asthma.
Indacaterol
Indacaterol maleate delivered via Concept1 (Onbrez® Breezhaler®) is approved in over
110 countries worldwide at doses of 150 μg to 300 μg once daily for 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 doses of 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 (CQAB149B2102) with no 
impact on efficacy, safety or systemic exposure (CQAB149D2301). Indacaterol acetate 
bronchodilator effects, control of asthma symptoms and safety of indacaterol acetate (150 μg 
or 75 μg o.d.; on top of MF background medication) were further substantiated in study 
QMF149E2203 in patients with asthma. Therefore, the acetate salt is being used as the LABA 
component in the QVM149 fixed-dose combination.
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 improvements in lung function in COPD patients which is sustained over 24 hours 
and provides significant symptomatic benefits with a favorable safety and tolerability profile 
efficacy was maintained with once-daily dosing for treatment periods of up to a year with 
good safety and tolerability.


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The fixed dose combination of indacaterol maleate and glycopyrronium bromide (QVA149) is 
also registered in the EU as Ultibro® Breezhaler® with the delivered doses as proposed for
QVM149. 
Mometasone furoate (MF)
MF is marketed in inhalation, nasal, cream, ointment and lotion formulations. The inhalation 
powder formulation which may be administered once or twice daily is marketed as a multi 
dose dry powder inhaler (MDDPI) called Asmanex® Twisthaler® for the treatment of asthma.
Asmanex® Twisthaler® is currently approved in the United States for the treatment of asthma 
in adults and children ≥ 4 years of age and is approved in over 55 countries world-wide for the 
treatment of asthma in adults and adolescents ≥ 12 years of age. The recommended daily 
doses of Asmanex® Twisthaler® range from 200 μg to 800 μg.
MF delivered via Concept1 device
To deliver a matching dose of MF via Concept1 compared to Twisthaler® a dose adjustment 
for the MF component needed to be made. Primarily to account for differences in inhalation 
device performance the nominal dose of MF in Concept1 needed to be adjusted to match the 
MF dose delivered by the Twisthaler® device. 
In a 4-week study in patients with persistent asthma (Study CQMF149E2201), MF doses of 
80 μg and 320 μg delivered once daily via Concept1 showed comparable efficacy and 
systemic exposure to MF doses of 200 μg and 800 μg (2 x 400 μg) d elivered once daily via 
Twisthaler® confirming appropriate dose adjustment of the MF component in the Concept1 
device. MF low (200), mid (400) and high (800) μg doses delivered via Twisthaler®
(approved doses) are considered to be comparable to 80, 160 and 320 μg MF doses via 
Concept1, respectively based on the results of  Study CQMF149E2101 and in vitro fine 
particle mass  adjustment. These are the MF doses used in the LABA/ICS dual combination of 
indacaterol and MF (QMF149).   
QVM149
An alteration in fine particle mass of MF in the QVM149 combination product compared to 
the corresponding MF dose in the QMF149 (LABA/ICS dual combination) combination 
product (matched to Asmanex® Twisthaler®) has been observed.  Fine particle mass is 
considered as the appropriate in-vitro quality parameter to adjust the dose of the affected 
MF component in the QVM149 combination product to match the corresponding doses of MF 
in the QMF149 combination product, in order to achieve comparable aerosol performance 
(with respect to FPM) (Table 3-2).
Thus the mid and high nominal of MF in QVM149 are 80 μg and 160 μg to ensure that the 
fine particle mass (FPM, in-vitro aerosol performance) in the lactose blend formulation for
QVM149 is similar to the nominal MF doses of 160 μg and 320 μg used for QMF149
(Section 3.3).


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No adjustmentstothe dosesofindacaterolorglycopyrroniumintheFDC QVM149 
combination are required.Additional detail is provided inSection 3.3discussing the dose 
rationale ofthisstudy
.
The most relevant data for the present study are summarized in the sections below. 
Fordetailed information, please refer to the Investigator
's Brochure.
1.3
Clinical data
1.3.1
Human safety and tolerability data
Corporate Confidential Information
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.


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For indacaterol, the characteristic adverse effects of inhaled β2-adrenergic agonists can occur 
as a result of activation of systemic β-adrenergic receptors. The most common adverse effects 
include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum 
potassium and increases in plasma glucose.
For glycopyrronium, adverse experiences typically associated with muscarinic antagonists 
such as dry mouth, gastro-intestinal disturbances and urinary retention/ difficulty voiding 
urine were reported at low rates. The frequency of cardiovascular related adverse experiences 
was generally low, however a higher rate of atrial fibrillation was observed with
glycopyrronium than with placebo in COPD patients. The COPD population investigated in
this context, however, had a high prevalence of cardiovascular comorbidity.
For MF, the characteristic adverse effects of ICS can occur. The most prominent of these 
include oral candidiasis following local deposition of the steroid in the oropharynx.
Systemic effects can also occur. These may include Cushing's syndrome, Cushingoid
features, adrenal suppression, growth retardation in children and adolescents, decrease in 
bone mineral density, cataracts, glaucoma, and yet more rarely, a range of psychological or 
behavioral effects. 
Up to now no additional risks have been identified in completed and ongoing clinical studies 
with the monocomponents and the FDCs which might occur when the three components are 
administered concurrently or from the same inhaler.
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 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 as
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).


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The available asthma clinical trial data suggest that a LAMA may confer bronchodilator 
effects in terms of improved lung function when used in addition to ICS alone or in 
conjunction with LABA/ICS  
(i.e., “free combination” or “loose” triple therapy) 
(Fardon 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 additional treatment option to theophylline, systemic 
corticosteroids or biologics for GINA Step ≥4 asthma patients.
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.
1.4
Study purpose
The purpose of this study is to assess the bronchodilator effects of QVM149 dosed once daily 
either in the morning or in the evening for 2 weeks compared to placebo. It will provide 
evidence of the comparability of lung function effects of QVM149 irrespective of the 
administration schedule. It is considered important for the overall QVM149 development 
program to demonstrate lung function benefits of QVM149 compared to placebo irrespective 
of time of dosing because in all other planned and ongoing studies QVM149 is dosed in the 
evening. Flexibility in dosing schedule may confer benefit to the patient by facilitating 
treatment compliance with subsequent lung function improvement and asthma control.
2
Objectives and endpoints
2.1
Primary objective(s)
Objective
Endpoint

To investigate the potential influence of 
time of dosing (morning or evening) on 
the bronchodilator effect of once daily 
orally inhaled QVM149 compared to 
placebo 

Weighted mean forced expiratory volume 
in 1 second (FEV1) over 24 h (AUC0-24h) 
following 14 days of treatment with 
QVM149 dosed in the morning, QVM149 
dosed in the evening and placebo.
2.2
Secondary objective(s)
Objective
Endpoint

To investigate the potential influence of 
time of dosing (morning or evening) on 
trough FEV1 of once daily orally inhaled 
QVM149 compared to placebo.

FEV1 at approximately 24 h after the last 
p.m. or penultimate a.m. dose.

To investigate the potential influence of 
time of dosing (morning or evening), on 

Daily morning and evening peak 
expiratory flow rate from Day 2 to Day 


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Objective
Endpoint
peak expiratory flow rate (PEF) of once 
daily orally inhaled QVM149 compared 
to placebo (all administered via the 
Concept1 inhalation device).
14 during the three treatment periods
To evaluate safety and tolerability of 
QVM149 when dosed in the morning or 
in the evening in patients with asthma 
during two weeks of treatment in each 
treatment period.
Adverse events
Hematology
Blood chemistry
Urinalysis
Vital signs
ECG
Corporate Confidential Information


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3
Investigational plan
3.1
Study design
Figure 3-1
Study design
This is a randomized, placebo-controlled, double-blind, six-sequence, three-period cross-over 
study in asthma patients. The study will consist of a 14-day screening period, followed by a 
14-day run-in period,  and a treatment epoch which consists of three treatment periods, with a 
minimum duration of 14 days each followed (for the 2 first treatment periods) by a wash-out 
period. The duration of each treatment period may be extended up to a duration of 18 days if 
needed for operational reasons. The third treatment period will be followed by a 
Study Completion evaluation at 1-7 days following the last dose. The treatment periods will 
be separated by wash-out periods of 14 to 21 days duration.
The total duration of the study is approximately 13 weeks (minimum) to 19 weeks (maximum) 
for each patient.
Screening
Before any screening assessment and asthma drug cessation, patient has to agree to the study 
and complete informed consent process and provide written informed consent. 
Screening assessments can be performed over a 2-week period maximum. Inclusion and 
exclusion criteria will be checked to confirm patient’s eligibility.


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At beginning of screening period, patient will be provided with a PEF-meter and a patient-
diary for recording the measurements. At screening, only PEF need to be recorded with the 
device. A minimum of 5 days screening is required to allow for PEF reference calculation. 
Patients who meet the eligibility criteria at screening will undergo run-in period.
Run-in
On Day 1 of the run-in period, patients will discontinue their previous asthma medication and 
remain off this medication throughout the run-in period. Patients will be provided with the 
short-acting β2-agonist (SABA) salbutamol (dose strength of 100 μg/puff; an equivalent 
SABA may be dispensed based on local availability) at the beginning of the run-in period. 
Patients should use this provided SABA as rescue medication throughout the trial. 
Patients are required to measure their PEF twice per day (morning and evening) during the all 
run-in period.
Patient will also record their use of rescue medication during the run-in phase (SABA during 
run-in and wash-out; SABA and study medication during treatment periods) as well as asthma 
symptoms if any. This will allow for continuous monitoring of PEF, rescue medication use 
and asthma symptoms from the start of the run-in period to completion of the treatment epoch 
(end of treatment period three).
After approximately 7 days into the 14-day run-in period, patients will attend to the site for an 
outpatient visit. Site staff will control patient’s PEF measurements and rescue medications use 
records as well as collect blood safety which will support patient eligibility for randomization.
Baseline is defined by the assessments to be performed at pre-dose treatment period 1 Day 1
only. 
These assessments will confirm patient eligibility before randomization.
All run-in and baseline (day 1 pre-dose, treatment period 1) safety evaluation results must be 
available prior to randomization.
Randomization
At the end of the run-in period, patients will be randomized to one of 6 possible treatment 
sequences (Figure 3-1), each consisting of 3 double-blind treatment periods. Each treatment 
sequence will have approximately 6 patients. . Randomization will take place only if the 
patient tolerated withdrawal of controller medication (as judged by use of SABA, rescue 
medication use and PEF; details provided in Section 4, exclusion criteria)
Details of study drug administration procedures are provided in Section 6 of the protocol and 
in the Study Operations manual.


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Study treatments
The treatments are:
1. QVM149 150/50/80 μg o.d. (indacaterol acetate 150 μg/ glycopyrronium bromide 50 μg/ 
MF 80 μg once daily) administered in the morning (plus matching placebo in the evening)
2.
QVM149 150/50/80 μg o.d. (indacaterol acetate150 μg/ glycopyrronium bromide 50 μg/ 
MF 80 μg once daily) administered in the evening (plus matching placebo in the morning)
3.
placebo administered in the morning and in the evening.
To facilitate double-blind administration of study medication all patients will be dosed twice 
daily in all treatment periods as detailed in Table 3-1 below:
Table 3-1
Study Treatments
Dosing time
Treatment options
a.m. dosing
p.m. dosing
QVM149 morning dose
QVM149
Placebo
QVM149 evening dose
Placebo
QVM149
Placebo
Placebo
Placebo
Treatment period Day 1
On Day 1 of each treatment period patients will attend the site for an outpatient visit in the 
afternoon (approximately 1 to 2 hours before the first scheduled evening dose). Only the 
evening dose will be administered on Day 1. 
Day 1 pre-dose assessments will be performed. Patient will be evaluated for randomization 
eligibility (but only at treatment period 1), trained /re-trained on the use of the Concept1 
inhalation device and will administer the study drug or placebo under the guidance and 
supervision of site personnel at approximately 19:00 hours
Treatment period Day 2 to Day 13
The first morning dose of each treatment period will be administered on Day 2 of each 
treatment period. Patients will self-administer study drug on Days 2 to 13 of each treatment
period at home. 
Patients will be instructed to take the study medication in the morning (at approximately
07:00 hours) and in the evening (at approximately 19:00 hours) and to record their 
pre-treatment morning and evening PEF throughout the study in a diary. 
Site staff will call the patient once a week during the treatment and during washout periods to 
verify patient well-being and to ensure none of the study discontinuation criteria (Section 7.2) 
are met.
Treatment period Day 14 and Day 15
Patients will attend to the site in the morning of Day 14 of each treatment period to inhale the 
morning dose of study medication or placebo under the guidance and supervision of site staff. 


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Site personnel will also review PEF measures and rescue medication intake as well as study 
drug compliance. Patients can stay on site for the remainder of Day 14.
Patient will be re-trained on the use of the Concept1 inhalation device under the guidance of 
site personnel. 
Patients will then be admitted in the afternoon of Day 14 of each treatment period 
approximately 4 hours prior to Day 14 assessments in each treatment period. This time is 
required to ensure that patient will not take any rescue medication within 4 hours prior 
spirometry starts. 
The last evening and morning dose of study drug or placebo will be administered under the 
guidance and supervision of site personnel at approx. 19:00 hours on Day 14 and approx. 
07:00 hours on Day 15. For 24 hour repeated spirometric assessments, patients will remain 
domiciled (1 night). Spirometry will be performed from Day 14 starting before the evening 
dose (at approximately -5 min in relation to planned evening dosing time, i.e. at 
approximately 19:00 h) and then every 3 hours after administration of the evening dose until 
24 hours after the Day 14 evening dose, i.e. until approximately 19:00 hours on Day 15.
After spirometry ended and last Day 15 visit assessment performed, the patient will be 
discharged and will start the wash-out period.
Wash-out (duration 14 to 21 days)
During the wash-out period, patient will continue to measure PEF and register rescue 
medication intake. Site personnel will call the patient weekly to check patient’s well-being.
Procedures in treatment periods two and three are identical to the procedures of treatment 
period one apart from:

Check of eligibility which occurs only prior to randomization on Day 1 of treatment 
period 1. 

At the end of treatment period three, the patient will complete end of study visit 
assessments instead of entering into a wash-out period.
Study completion
At the end of the last treatment period, patients will then undergo Study Completion 
evaluations and will be discharged from the study. The study design is shown in Figure 3-1.


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3.2
Rationale for study design
This short-term treatment cross-over design is chosen to characterize the bronchodilator 
effects of once daily QVM149 (indacaterol/glycopyrronium/MF 150/50/80 µg) either dosed in 
the morning or in the evening compared to placebo 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 within the 
defined 2-week screening period. 
The 2-week run-in period will allow for an assessment of likely study adherence in the 
population of asthma patients since patients will be using short-acting rescue medication only. 
The run-in period will thereby help to ensure that patients who cannot tolerate withdrawal 
from ICS for a short period of time will not be randomized. . The maximum duration that 
patients are on SABA only and off ICS (and other asthma medication) is 6 to 8.5 weeks 
(2 to 3 weeks of wash-out, 2 to 2.5 weeks during the placebo treatment period and 2 to 
3 weeks during washout). This is in-line with previous studies conducted in comparable 
patient populations that showed that such duration of time off controller medication is 
tolerable for patients with the investigated severity of asthma (Kempsford et al 2013, 
Kempsford et al 2016). If a patient's condition should deteriorate during the study the 
comprehensive rules on "Discontinuation of study treatment" (Section 7.2) will help ensure 
patient safety throughout the trial. Patients with more severe asthma are excluded from this 
study.
The run-in period of 2 weeks before the first treatment period as well as the washout periods 
of 2 to 3 weeks between the treatment periods will allow for pharmacodynamic assessments 
on Day 14/15 of each treatment period without any carry-over effect from previous 
medications present. Run-in and washout periods of approximately two-week duration have been 
successfully used in similar trials with a LABA/ICS combination (Kempsford et al 2013) or with 
an ICS (Kempsford et al 2016). For glycopyrronium, based on 24 hour spirometry data, the 
half-life of the bronchodilatory effect is estimated to be ≤ 80 hours. Therefore the 
bronchodilatory effect is expected to be washed-out at the very latest following 17 days after 
last dose administration. Consequently, the proposed minimum 2 weeks washout plus 2 weeks 
of treatment in the next following treatment period are sufficient to avoid a carry-over 
pharmacodynamic effect between treatment periods for glycopyrronium as well. The duration 
of the washout periods of 2 to maximally 3 weeks is considered adequate to not put patients at 
undue risk for deterioration of their disease.
The crossover design (rather than a parallel group design) was chosen because within patient 
variability is expected to be less than between-patient 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.


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3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The components of QVM149 at the daily dose investigated in this trial are approved for 
COPD or asthma. QVM149 is 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® (indacaterol maleate) and Seebri Breezhaler®
(glycopyrronium bromide) 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.
In order to allow for placebo to be used in this trial patients with relatively mild asthma 
(low to mid-dose ICS use before enrollment, pre-bronchodilator FEV1 ≥ 60 % and ≤ 100% of 
the predicted normal value for the patient, no systemic corticosteroids for asthma over the 
year preceding the study; further details available in Section 4) will be enrolled (please compare 
section on definition of patient population below). It is expected that patients generally can tolerate 
being off any controller medication and use SABA only for the short periods of time as required 
under this study protocol. Similar study designs have been employed in comparable patient 
populations in the past (Kempsford et al 2013; Kempsford et al 2016). Furthermore, given the 
good tolerability profile of the components of QVM149, it is deemed acceptable to administer 
the triple fixed-dose combinations to the relatively mild asthmatics enrolled for the duration 
of 2 weeks each in the respective treatment periods.
Details justifying the dose of 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 (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. 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 trough 
FEV1, PEF and rescue medication use compared with indacaterol acetate 75 μg and 
significantly improved lung function compared to placebo. Therefore, a dose of indacaterol 
acetate 150 µg o.d. has been selected for use in the QVM149 program.


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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 
Phase III development program in COPD supports the efficacy and safety of glycopyrronium 
bromide 50 µg once daily. It has demonstrated clinically meaningful and statistically 
significant improvements in lung function in COPD patients which were sustained over 
24 hours and provided significant symptomatic benefits with a favorable safety and 
tolerability profile. Lung function improvements were comparable to tiotropium 18 µg 
administered via HandiHaler®.
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 (CNVA237A2205, CNVA237A2303). It is therefore expected that 
glycopyrronium bromide 50 µg once-daily will provide similar efficacy in an asthma 
population as Triotropium Respimat® 5 μg once-daily (considered equivalent to tiotropium 
18 µg administered via HandiHaler® and  has recently been approved in Europe for treatment 
of asthma).
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, we conducted a 3 step bridging approach to determine the MF dose (to be 
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 in device performance characteristics between the Twisthaler® and Concept1 
devices.
Step 1: pharmacokinetic bridging utilizing pharmacokinetic characterization in study 
CQMF149E2101 followed by in-vitro fine particle mass adjustment (step 2) and finally 
pharmacodynamic evaluation of efficacy in asthma patients in study CQMF149E2201 (step 3).
For Step 1 and 2, the data of study CQMF149E2101, along with in-vitro fine particle mass 
adjustments have led to the selection of 80, 160 and 320 µg as doses of MF in Concept1 
device that are comparable to the approved doses 200 µg, 400 µg and 800 µg ( 2x400 µg) MF 
in Twisthaler®.
For Step 3, two of the MF doses in Twisthaler® and Concept1 were further evaluated for 
pharmacodynamic and clinical comparability in a 4-week study (CQMF149E2201) in patients 
with persistent asthma. MF doses of 80 μg and 320 μg delivered once daily via Concept1 


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showed comparable efficacy in trough FEV1 and slightly lower systemic exposure compared 
to MF doses of 200 μg and 800 μg (2 x 400 μg) delivered once daily via Twisthaler ®
confirming the selected doses for MF Concept1 are appropriate for further QMF149 Concept1 
development.
In summary, MF doses of 200 µg o.d, 400 µg o.d. and 400 µg b.i.d. delivered by Twisthaler ®
are comparable with MF doses of 80 µg o.d, 160 µg o.d. and 320 µg o.d., respectively in 
QMF149 delivered by Concept1.
For QVM149, 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 have 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 Concept1 (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.
QVM149 is available in two formulations that differ by MF dose strength only. 
The indacaterol and glycopyrronium dose is constant. In this study the dose containing 80 μg
MF is investigated. This is the lower of the two MF doses within the available formulations of 
the QVM149 FDC that is investigated in the ongoing phase III program. . It is expected that a 
potential differential effect of morning and evening dosing of QVM149 on lung function 
compared to placebo would be less easily detectable with the high MF dose. This is based on 
earlier study results using MF (in a different formulation and delivered with the Twisthaler®
inhalation device) in asthma patients in which there was a trend toward some separation in 
lung function effect following morning and evening dosing of MF which seemed to be more 
visible at lower MF doses (Noonan et al 2001).
Table 3-2
Comparison of the comparable MF component doses between 
Asmanex® Twisthaler®, QMF149 and QVM149 drug products
MF dose level
Asmanex® Twisthaler®
MF in QMF149 
MF in QVM149
Low
200 µg
80 µg
not applicable
Mid
400 µg
160 µg
80 µg
High 
800 µg
320 µg
160 µg
Duration of treatment
The entire treatment epoch consists of 3 treatment periods of 14 days each (up to 18 days if 
required for operational reasons; this added flexibility is not expected to impact on lung 
function read-outs as evidenced by earlier studies investigating lung function effects of ICS or 
ICS/LABA).


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A 2-week treatment per period is considered sufficient to investigate the effect of a.m. and 
p.m. dosing of QVM149 in comparison to placebo. Based on available data for indacaterol in 
COPD patients it is not expected that indacaterol exerts a differential effect on lung function 
by time of dosing (study QAB149B2305). Since the bronchodilator effects of indacaterol are 
largely evident after the first few days of dosing the treatment duration of 2 weeks is 
considered sufficient. These aspects hold true for glycopyrronium as well, however, a study 
investigating both, morning and evening dosing has not been conducted. Data on time to 
maximal effect is available from studies in COPD patients but not asthma (NVA237A2205, 
NVA237A2208). Supportive evidence is available from a study that investigated effect of timeof 
dosing of tiotropium, another LAMA, on lung function parameters. This study suggests that 
once-daily L
AMAscan be administered any time of the day (Calverley et al 2003). For ICS a 
plateau in lung function effect may be achieved only later than after two weeks 
(Correnetal2003). However, in study QMF149E2201 which investigated MF delivered via 
the Concept1 and the Twisthaler® inhalation devices the majority of the increase in FEV1 
from baseline was already evident after 2 weeks of treatment with only small incremental 
additional lung-function benefit until the end of week 4. This confirmed an earlier study in 
which different doses of mometasone furoate (delivered by the Twisthaler®inhalation device) 
were given over 12 weeks. The change from baseline FEV1 after 2 weeks of treatment was 
approximately 71% to 83% of the effect seen after 12 weeks of treatment (D’Urzo et al 2005).
Similarly, Karpel et al 2005described approximately 76% and 80% of maximal lung function 
effect of MF delivered by the TH after 12 weeks as either b.i.d. or o.d. dose. In addition, the 
approach to assess ICS treatments in comparison to placebo over two week treatment periods 
has been used successfully with clear differentiation of lung function profiles compared to 
placebo (Kempsford et al 2016,Kempsford et al 2013).
3.4
Rationale for choice of comparator
This is a placebo-controlled trial to establish assay sensitivity and to allow for an 
unbiasedassessmentof the lung function effect of a.m. and p.m. dosing of QVM149. 
Without theplacebo control an assessment of the overall absolute effect of morning and 
evening dosing ofQVM149could not be established. Precedence in the literature and 
inregulatory documents substantiates this approach (Kempsford
et al 2013, 
Kempsfordetal2016, European Public Assessment Report on Relvar Ellipta 2013). 
3.6
Risks and benefits
Corporate Confidential Information
The risks to which patients participating 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).


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Risks associated with study conduct
Patients will be required to perform repetitive lung function measurements during the study, 
and these can lead to cough, shortness of breath, dizziness, or exhaustion. Since patients only 
carry out full forced maneuvers during clinic visits (not at home), these will be performed 
under medical supervision to ensure availability of immediate aid if required. Considering the 
2 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.
Risks associated with investigational treatment (QVM149)
In light of their underlying asthma disease and the inclusion requirements in this study, 
patients have been exposed to ICS and likely ß2-agonist bronchodilators (e.g. SABA) before 
entering the trial.
MF, the ICS component of QVM149 is approved for the treatment of asthma. 
The safety and tolerability profile of indacaterol, the LABA component in QVM149 is 
comparable to that of other medications of the same classes (e.g. formoterol, salmeterol). 
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 patients and COPD patients across 
34 completed studies. Addition of LAMA (Spiriva® 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 risk-benefit 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. Patients 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 patients 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®). Patients participating in this trial may experience these adverse effects. 


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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.
During the run-in period, the washout period between treatment periods as well as the 
treatment period in which the patient will receive placebo the patient will be without asthma 
controller medication (no background ICS, only SABA as rescue medication is available 
throughout the trial). This change in asthma treatment may lead to worsening of lung function 
and/or asthma symptoms.
Management and mitigation of risks
Frequent and regular contacts between patients and study staff will occur in terms of clinic 
visits and intermittent telephone calls throughout the treatment periods. . The site will contact 
the patient approximately once per week to ensure adequate clinical monitoring of 
participating patients. In addition, safety monitoring (e.g. collection of symptoms and rescue 
medication use via the combined device PEF-patient 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. Furthermore, comprehensive stopping criteria have been defined (Section 7.2) to 
ensure a patient safety.
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 (Section 7.2).
In this clinical study all patients will receive the glucocorticosteroid MF (ICS component of 
QVM149). Since glucocorticosteroids are teratogenic in rodents and rabbits, only women of 
childbearing potential (WOCBP) who agree to use highly effective methods of contraception 
(see Section 4.2 eligibility criteria) will be permitted to participate in the study. Women of 
child bearing potential will 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 (Section 4.2). If there is any question that the patient will not 
reliably comply, they will not be entered in the study.
QVM149 is 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 may be unknown risks of QVM149 which may be serious.


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Benefits
There is no intended benefit for the patients in this study and the study is not designed to 
provide substantial benefit for the patient. Benefits may, however, 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 QVM149 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.
Conclusion
In conclusion, the risk-benefit assessment for this study suggests that the patients 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.
3.6.1
Blood sample volumes
A maximum of 100 mL of blood is planned to be collected over a period of 13 to 19 weeks 
from each patient as part of the study. Additional samples may be required for safety 
monitoring.
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. Instructions for all sample 
collection, processing, storage and shipment information is also available in the SOM and 
central Laboratory Manual.
See Section 8.9 regarding the potential use of residual samples. 
4
Population
The study population will be comprised of male and female patients aged 18 and above with 
asthma. Approximately 36 adult patients will be randomized with the intention that at least 
30 patients complete the study.
The investigator must ensure that all patients being considered for the study meet eligibility 
criteria. No additional exclusions should be applied by the investigator.
Patient selection is to be established by checking through all inclusion and exclusion criteria 
at screening and at the first baseline visit. Source documentation relating to eligibility must be 
stored at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
Patients who are prematurely withdrawn from the study for any reasons will not be replaced.


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4.1
Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients aged ≥ 18 and above
3. Patients with a documented physician diagnosis of asthma and who additionally meet the 
following criteria:
patients receiving daily treatment with an inhaled corticosteroid at a low or medium 
daily dose as defined by GINA guidance (GINA 2016, Box 3-6),
on a stable regimen (dose unchanged) for at least 4 weeks prior to screening.
4. Pre-bronchodilator FEV1 ≥ 60 % and < 100% of the predicted normal value for the patient 
(after withholding bronchodilators) during screening.
Withholding period of bronchodilators prior to spirometry (also applicable for 
Reversibility testing) are given in Table 5-1.

Corporate Confidential Information
Re-testing is allowed once. Re-assessment of percentage predicted FEV1 should be 
done in an ad-hoc visit to be scheduled on a date that would provide sufficient time to 
receive confirmation from the spirometry data central reviewer of the validity of the 
assessment before randomization
5. Patients who demonstrate an increase in FEV1 of ≥ 12 % and ≥ 200 mL after 
administration of 400 µgsalbutamol/360 µg albuterol(orequivalent dose) at Visit 1
(Screening). All patients must perform a reversibility test at Visit 1.
If reversibility is not demonstrated at Screening, then, reversibility testing may be repeated 
once during the screening epoch on a date that would provide sufficient time to receive 
confirmation from the spirometry data central reviewer of the validity of the assessment 
before randomization.  
If reversibility is not demonstrated after repeated assessment, patients must be screen 
failed.
6. At screening, and baseline (day 1 pre-dose time) of the first treatment period, vital signs 
(systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position 
and again in the standing position as outlinedin the SOM. 
 
7. Hypertensive patients must have been on stable antihypertensive therapy for at least 4 
weeks prior to screening to be included in the trial.


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8. Patients must weigh at least 50 kg at screening to participate in the study, and must have a 
body mass index (BMI) within the range of 18 to 40 kg/m2.
9. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to randomization. If the 
repeat value remains outside of the specified ranges, the patient must be excluded from the 
study.
1. Contraindicated for treatment with, or having a history of reactions/ hypersensitivity to 
any of the following inhaled drugs, drugs of a similar class, or any component thereof.

Sympathomimetic amines / adrenoreceptor agonist agents

Antimuscarinic agents

Lactose or any of the other excipients of the study drug (including patients with 
history of galactose intolerance, Lapp lactase deficiency or glucose-galactose 
malabsorption)
2. Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 1 year of Screening. 
3. Patients who have had a respiratory tract infection or asthma worsening within 4 weeks 
prior to Screening. Patients may be re-screened 4 weeks after recovery from their 
respiratory tract infection or asthma worsening.
4. Patients who have had previous intubation for a severe asthma attack/exacerbation.
5. 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.
6. Patients with a history of clinically relevant bronchoconstriction upon repeated forced 
expiratory maneuvers.
7. History of paradoxical bronchospasm in response to inhaled medicines.
8. 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.
9. Patients who during the run-in period require the use of ≥12 puffs / 24 hours of rescue 
medication for 48 hours (over two consecutive days) or who have a decline in PEF from 
the reference PEF (PEF reference during screening period defined in Section 8.5.2) of 
≥30% for 6 consecutive scheduled PEF readings (including readings taken in the morning 
and evening).


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10. History or current diagnosis (at Screening and prior to randomization) of any the 
following ECG abnormalities:

Clinically significant cardiac arrhythmias (for example sustained ventricular 
tachycardia, and second or third degree AV block)

History of familial long QT syndrome or known family history of Torsades de Pointes

Paroxysmal (e.g., intermittent) atrial fibrillation.

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., cardioselective 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 screening with a resting ventricular rate < 100/min.

Any other clinically significant ECG abnormality
11. Concomitant use of an agent known to prolong the QT interval unless it can be 
discontinued for the duration of study.
12. Patients with a history of long QT syndrome or whose QTc measured at Screening 
(Fridericia method) is prolonged (> 450 msec for males and > 460 msec for females).
13. Patients with a history of myocardial infarction within the previous 12 months.
14. 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
15. 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.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
17. In this study QVM149 which contains an ICS is administered during two of the three 
treatment periods. Therefore, women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 4 weeks after stopping of investigational 
drug are excluded. 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 
investigational drug.  In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.


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
Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that 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 pill 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 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential. Refer to Section 8.6.6 (Pregnancy and Assessments of 
Fertility).
A pregnancy test will be performed for 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.
18. Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c> 9%) at screening.
19. Plasma donation > 150 mL within 7 days prior to first dosing.
20. Donation or loss of 400 mL or more of blood within eight (8) weeks prior to initial dosing, 
or longer if required by local regulation.
21. Other significant illness which has not resolved within two (2) weeks prior to initial 
dosing. Patients may be re-screened 4 weeks after recovery from their illness.
22. Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g., 
recurrent episodes of fainting, palpitations, etc.).
23. Patients receiving medications in the classes listed in Section 5.2 (Prohibited treatment) 
should be excluded.
24. Use of other investigational drugs at screening, or within 30 days or 5 half-lives of 
enrollment, whichever is longer; or longer if required by local regulations, and for any 
other limitation of participation in an investigational trial based on local regulations.
25. Current smokers and patients who have smoked or inhaled tobacco products within the 
6 month period prior to Screening, 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.).
26. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such 
abuse as indicated by the laboratory assays conducted during screening.


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27. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in 
case of participation in the study. The Investigator should make this determination in 
consideration of the patient’s medical history and/or clinical or laboratory evidence of any 
of the following:

Inflammatory bowel disease, peptic ulcers, gastrointestinal including rectal bleeding;

Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel 
resection;

Pancreatic injury or pancreatitis;

Liver disease or liver injury as indicated by abnormal liver function tests. ALT 
(SGPT), AST (SGOT), γ-GT, alkaline phosphatase and serum bilirubin will be tested 
during screening epoch.
28. Patients with seasonal allergy whose asthma is likely to deteriorate during the study period.
29. Patients on Maintenance Immunotherapy (desensitization) for allergies for less than 
3 months prior to randomization or patients on Maintenance Immunotherapy for more 
than 3 months prior to randomization but expected to change throughout the course of the 
study.
30. Patients with evidence upon visual inspection (laboratory culture is not required) of 
clinically significant (in the opinion of investigator) oropharyngeal candidiasis during 
Screening, with or without treatment. Patients may be re-screened once their candidiasis 
has been treated and has resolved.
31. Patients who have a clinically significant laboratory abnormality at Screening epoch in the 
opinion of the investigator (one re-test is allowed before the randomization).
32. Patients with a serum potassium or magnesium level below the laboratory limit of normal 
at screening.
33. History of being immunocompromised; immunodeficiency diseases.
34. No person who is considered vulnerable or person who is in detention may participate in 
this study.
35. 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.
36. Patients unable to use the Concept1 dry powder inhaler or a metered dose inhaler.
37. Patients with narcolepsy and/or insomnia.
38. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
39. Patients who are directly associated with any members of the study team or their family 
members
40. Patients incapable of understanding the nature, significance and implications of the 
clinical trial and therefore incapable of giving consent personally
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 patients
For the duration of the study, the patients should 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 contraception requirement outlined 
in the Section 4.2 (Exclusion Criteria). If there is any question that the patient will not reliably 
comply, they should not be entered or continue in the study.
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 spirometry
Class of Medication
Minimum cessation prior spirometry
SABA
≥ 6 h
SAMA
≥ 8 h     (only applicable at screening)
LABA or fixed dose combination of ICS/LABA b.i.d.
≥ 24 h (only applicable at screening)
LABA or fixed dose combination of ICS/LABA o.d. or 
tiotropium
≥ 48 h   (only applicable at screening)
Xanthines
≥ 7 days   (only applicable at screening)
Table 5-2
Prohibited asthma medication during treatment period
Medication
Action to be taken
Long-acting anti-cholinergic agents (other than study drug)
patient to be withdrawn 
Short-acting anti-cholinergics
patient to be withdrawn 
Fixed-combinations of long-acting β2-agonists and inhaled corticosteroids
patient to be withdrawn 
Long-acting β2-agonists (other than study drug)
patient to be withdrawn 
Short acting β2-agonists (other than those prescribed in the study)
patient to be withdrawn 
Theophylline and other xanthines
patient to be withdrawn 
Inhaled (other than study drug), parenteral or oral corticosteroids 
patient to be withdrawn
Newly introduced or increased dose leukotriene antagonists, ketotifen, 
inhaled nasal cromolyn, nedocromil, inhaled nasal corticosteroid
patient to be withdrawn*
*Leukotriene antagonists, ketotifen, inhaled nasal cromolyn, nedocromil, inhaled nasal 
corticosteroid are allowed for the treatment of asthma or allergic conditions during the study if 
taken regularly every day as part of the patient’s treatment regime, and if treatment has been 
stable for 4 weeks prior to screening.


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Table 5-3
Prohibited treatments, cessation periods
Medication*
Minimum cessation period prior to Day 1 
or as indicated 
Non-potassium sparing diuretics (unless administered 
as a fixed-dose combination with a potassium 
conserving drug)
7 days prior to Day 1
Non-selective systemic β –blocking agents
7 days prior to Day 1
Cardiac anti-arrhythmics Class Ia
7 days prior to Day 1
Cardiac anti-arrhythmics Class III
7 days, amiodarone 3 months prior to Day 1
All antipsychotic agents (first, second and third 
generation, inclusive of atypical antipsychotics). 
Combinations of antipsychotic agents with 
antidepressants are prohibited
14 days prior to Day 1
Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)
14 days prior to Day 1
Monoamine-oxidase inhibitors
14 days prior to Day 1
Systemic anticholinergics
7 days prior to Day 1
Mizolastin or terfenadine (H1 antagonists)
5 days prior to Day 1
Strong inhibitors of cytochrome P4503A 
e.g.ketoconazole
7 days prior to Day 1
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 Day 1
Other investigational drugs
30 days or 5 half-lives, whichever is longer 
prior to Day 1
Parenteral or oral corticosteroids
Within 30 days prior to Day 1
Noradrenaline reuptake inhibitors
7 days prior to Day 1
Live attenuated vaccine
30 days prior to Day 1
* Informed consent needs to be signed before to cessation period starts.
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, patients should refrain from the following:

Coffee, tea, chocolate, cola and other caffeine-containing beverages and foods and ice-
cold beverages  for at least 4 hours prior to spirometry

Alcohol for at least 4 hours prior to spirometry

Strenuous activity for at least 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 patients) strenuous physical exercise (e.g. weight training, aerobics, 
football) 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 patient numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational and control drugs
Table 6-1
Overview of study medication
Study drug name Formulation
Appearance
Unit dose
Packaging
Provided by
QVM149 and 
Concept1 Inhaler
Capsules with 
powder for 
Inhalation 
Hard capsules 150/50/80µgProvided as single blind 
supplies including 
Concept1 devices
Novartis Drug 
Supply 
Management
Placebo to 
QVM149 and 
Concept1 Inhaler
Capsules with 
powder for 
Inhalation 
Hard capsules 0µg
Provided as single blind 
supplies including 
Concept1 devices
Novartis Drug 
Supply 
Management
Placebo to 
QVM149 and 
Concept 1 Inhaler 
as training kit
Capsules with 
powder for 
Inhalation
Hard capsules 0µg
Blister +Inhaler
Novartis Drug 
Supply 
Management
Concept1 device
NA
Single-dose 
dry powder 
inhaler
NA
Inhaler
Novartis Drug 
Supply 
Management


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6.1.2
Additional study treatment
No additional treatment beyond investigational drug and control drug are included in this trial.
Rescue medications are described in Section 6.10.
6.2
Treatment arms
Study treatments are defined as:

A:  Matching placebo (am); QVM149 150/50/80 μg (pm)

B:  QVM149 150/50/80 μg (am); Matching placebo (pm)

C:  Placebo (am); Placebo (pm)
Patients 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
B
A
C
3
C
B
A
4
C
A
B
5
A
C
B
6
B
C
A
6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual patients by way of a randomization 
number, which will be in the range of 5101-5136. 
The randomization number is only used to identify which treatment the patients have been 
randomized to receive.  The Patient number assigned to a patient at screening remains the 
unique identifier for the patient throughout the study. For information on patient numbering, 
please see ‘Patient numbering’ section in the SOM.
The table below details the general details of the numbering of the patients once randomized 
to treatment:
Table 6-3
Randomization assignment numbering
Cohort
Randomization numbers
I (n=36)
5101 – 5136
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient
randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient
numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. 


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The randomization scheme for patients 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 patients.
The investigator will enter the screening number and medication number in the eCRF.
IRT will assign to the patient a unique patient identification number at screening. This unique 
patient number will be used throughout all the study and no randomization will be entered in 
the eCRF.
6.4
Treatment blinding
This is a patient, investigator and sponsor-blinded study. Patients, 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.
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 patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site (see Section 6.7).
Drug product will be supplied in single-blind patient packs, so an unblinded pharmacist who 
is independent of the study team will be required in order to maintain the blind. 
This unblinded pharmacist will receive a randomization list or treatment allocation cards from 
Drug 
Supply 
Management 
with 
the 
appropriate 
treatment 
allocation 
numbers. 
Appropriate measures must be taken by the unblinded pharmacist to ensure that the treatment 
assignments are concealed from the rest of the site staff.
Sponsor staff
The following unblinded sponsor roles are required for this study:
Unblinded clinical staff managing drug re-supply to site
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors are not provided with a randomization list directly but will be 
unblinded through review of source documentation compiled by the unblinded pharmacist, 
which details treatment allocation to individual patients. 
Sponsor clinical staffs are required to assist in the management and re-supply of 
investigational drug product. These individuals are not provided with randomization lists 
directly, but may be unblinded through communication of drug re-supply needs via the 
unblinded site pharmacists. 
For interim analysis purpose, the Independent Statistician / Programmer / Modeler will 
receive unblinded sample data from the sample analysts to report results for review.




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From Day 2 to Day 13
In each treatment period, from Day 2 to Day 13, administration of study medication should 
occur within ± 1h of the time of dosing on Day 1 (for evening dose) and Day 2 (for morning 
dose) in Treatment period 1. Morning and evening dosing should be approximately 12 hours 
apart. 
On Day 14 and Day 15
On Days 14 and 15 study drug must be administered at 07:00h and 19:00h with a time 
window of ± 30 min. There must be 12 hours in between morning and evening doses on 
Days 14 and 15. A deviation of ± 15 min is acceptable.
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 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the 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 at any time in case of emergency.  The investigator will need to 
provide:

protocol number

study drug name (if available)

patient number. 
In addition, the investigator must provide oral and written information to inform the patient
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 patient.


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6.8
Treatment exposure and compliance
For treatment administration 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 patient to take the study treatment exactly as 
prescribed and by stating that compliance is necessary for the patient’s safety and the validity 
of the study. The patient must also be instructed to contact the investigator if he/she is unable 
for any reason to take the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using 
capsule counts and information provided by the patient. 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 electronic patient diary in which all patients 
will record administration each day on morning and evening. 
6.9
Recommended treatment of adverse events
Medication used to treat adverse events (AEs) must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF.
6.10
Rescue medication
At Day 1 of the run-in period, all patients will be provided with a short acting β2-agonist 
(100 μg salbutamol/90 μg albuterol or equivalent dose). Patients will be instructed to use it 
throughout the study as rescue medication on an ‘as needed basis’. Patients will be advised 
that between visits they can take their rescue medication for symptoms of intercurrent 
bronchospasm. No other rescue treatment is permitted. Also refer to Section 3.1
(Study design), Section 4.2 (Exclusion criteria), Section 5.2 and Section 7.2 (Discontinuation 
of study treatment) for details.
6.11
Concomitant treatment
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. 
All 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 patient
or, if the patient is already enrolled, to determine if the patient should continue participation in 
the study.


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7
Study completion and discontinuation 
7.1
Study completion and post-study treatment
Each patient 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 patient 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 randomized and/or treated patients should have a safety follow-up call conducted 30 days 
after last administration of study treatment. 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 patient
should be recorded in the source documentation.
7.2
Discontinuation of study treatment 
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by 
either the patient or the investigator.
Study treatment must be discontinued and the patient withdrawn from the study under the
following circumstances:

Patient decision - patients may choose to discontinue study treatment for any reason at any 
time.

The investigator believes that continuation would negatively impact the safety of the 
patient or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the patient’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 outlined in Section 5.2 (Prohibited treatment)  

For liver event occurs, refer to Appendix 1: Liver Event Definitions and Follow-up 
Requirements

≥ 3 consecutive days  in any one treatment period in which ≥12 inhalations/day of SABA 
rescue medication were used

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.
Emergence of the following adverse events:

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


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
Reflex bronchoconstriction or other severe intolerance reaction to study drug inhalation

If the absolute QTcF is >500 msec or an increase from pre-dose Treatment Period 1 
of >60 msec on two adequate ECGs at least a minute apart, second (if Mobitz Type 2) or 
third degree AV block, atrial or ventricular arrhythmias (as judged clinically significant by 
the investigator).

Clinical asthma worsening which required additional asthma treatment other than study 
medication or study-defined rescue medication in any one treatment or washout period.
Any of the following laboratory abnormalities:

Random (non-fasting) plasma glucose greater than 15 mmol/L

Serum potassium below the lower limit of the laboratory reference range if confirmed by a 
repeat test to exclude laboratory error

Urine cotinine > than the laboratory’s lowest level of quantification (LoQ of 500 ng/mL or 
lower) after randomization (a positive test at screening would preclude inclusion into the 
study)
Discontinuation of study treatment and patient withdrawal will be at the discretion of the 
Investigator, under the following circumstances:

Clinically significant abnormal laboratory value(s) (as judged clinically significant by the 
investigator).

The Investigator deems discontinuation is necessary for the safety of the patient.
The appropriate personnel from the site and Novartis will assess whether investigational drug 
treatment should be discontinued for any patient whose treatment code has been broken 
inadvertently for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason 
for the patient’s premature discontinuation of study treatment and record this information on 
the Dosage Administration CRF.
Patients who discontinue study treatment or who decide they do not wish to participate i n 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 patient/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 patient’s discontinuation from study 
treatment.
Patients who are prematurely withdrawn from the study for any reasons will not be replaced.


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7.3
Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material. 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
7.4
Lost to follow-up
For patients 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 patient, e.g. dates of 
telephone calls, registered letters, etc. A patient 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 two 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, 
patients must be seen as soon as possible and treated as a prematurely discontinued patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. 
The investigator will be responsible for informing Institutional Review Board/Independent 
Ethics Committee (IRBs/IECs) of the early termination of the trial.








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11If urinalysis at run-in is done within 7 days prior to Day 1 treatment period 1, Day 1 treatment period 1 urineanalysis doesn
't need to be repeated.
12Both standing and supine/sitting blood pressure measurements are required at Screening and Baseline of the first treatment period. Only sitting or 
supine blood pressure measurements are required at the other visits. Patients
' positions during measurement collections should be consistent between 
visits (sitting or supine throughout the study).
13Vital signs will be measured before study drug intake.
14ECG to be done before study drug intake.
15If hematology at run-in is done within 7 day
s prior to Day 1 treatment period 1, Day 1 treatment period 1 hematology doesn
't need to be repeated.
16If clinical chemistry at run-in is done within 7 days prior to Day 1 treatment period 1, Day 1 treatment period 1 clinical chemistry analysis doesn
't need
to be repeated.
18Patient will be re-trained to inhalation technique to Concept 1 device at the beginning and at the end of each treatment period (Day1 and Day 14). 
19Patient will be admitted in the afternoon in order to have assessments performed before randomization. Day 1 first dose will be administered on site 
around 7 pm.
20Drug will be taken at home from Day 2 am to Day 13 pm. 
21Study drug morning dose intake on site at Day 14. Patient can be discharged or stay on site up to evening dosing.
22At Day 14, evening dose will be taken at 7 pm -The first spirometry assessment will be -5 minutes before evening dose.
23Study drug morning intake on site at Day 15. There is no drug intake on the evening of Day 15, washout starts from Day 15 evening. 
24Morning dose will be around 7 am.
25Patient status information will be collected at the end of each epoch (early discontinuation or Study completion), completed in Summary eCRF page.
26A call to follow-up on patientsafety will be performed at least 30 days after last study treatment administration.
27
Corporate Confidential Information
From the start of the screeningperiod to completion of the treatment epoch (end of 3rd treatment period).
Note: If several assessments are scheduled at the same time point, please see the SOM for guidance on recommendedsequence of assessments.


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Table 8-2
Spirometry
For each treatment period
Spirometry
(timing in relation to study drug administration )
Day 14
(Visit 102)
(Visit 202)
(Visit 302)
Timing prior to study drug administration
  -5 min
Study drug - evening dose Day 14 – 19:00
Timing post evening dose
+  3 h  (Day 14 – 22:00)
Day 15 
(Visit 103)
(Visit 203)
(Visit 303)
+  6 h   (Day 15 – 01:00)
+  9 h   (Day 15 – 04:00)
+ 12 h  (Day 15 – 06:55 ) – before Day 15 am dose
Study drug morning dose Day 15 – 07:00
+ 15 h  (Day 15 – 10:00)
+ 18 h  (Day 15 – 13:00)
+ 21 h  (Day 15 – 16:00)
+ 23h55min (Day 15 – 18:55)- before Day 15 am dose
Post Day 15 morning dose 
Study drug – morning dose Day 15 – 07:00
After Day 15 morning dose intake, wash-out start.  


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8.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Ifapplicable, in cases where the patient’s representative gives consent (if allowed according 
to local requirements), the patientmust be informed about the study to the extent possible 
given his/her understanding. If the patientis capable of doing so, he/she must indicate assent 
by personally signing and dating the written informed consent document or a separate assent 
form. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patientsource documents. 
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 patientagrees to future research.  
Theprocedures set out in the main consent form concerning the storage, maintenance of 
privacy, and release of the data or specimens for the main study will also be adhered to for 
any future research. Any changes 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 investigationaldrug can be 
found in the Investigator
's Brochure (IB). This information will be included in the patient
informed consent and should be discussed with the patientduring 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 patient.
Ensure patients are informed of the contraception requirements outlined in the Section4.2
(Exclusion criteria) and in Section 5.1
Corporate Confidential Information
(Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included 
in this study.


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8.3
Patientscreening
Re-screening is allowed under certain circumstances. Please refer to Section 4.2(Exclusion 
criteria) for details. 
Information on what data should be collected for screening failures isoutlined in the Site 
Operations Manual.
8.4
Patientdemographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all patients.  
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 patients will be screened for substances of abuse and cotinine. See the Site Operations 
Manual for details.
8.4.2
Reversibility
Reversibility is to be measured at Visit 1(Screening). Refer to Section 4.1(Inclusion criteria) 
for details. Respective washout period of bronchodilators must be fulfilledprior to 
reversibilitytesting. Please refer to Table 5-1and Study Operations manual for details.
8.5
Efficacy / Pharmacodynamics 
Pharmacodynamic assessments (spirometry) will be collected at the timepoints defined in the 
Assessmentschedule.
Pharmacodynamic (PD) assessments will be performed and evaluated in all patients at all 
dose levels, including the placebo group. 
8.5.1
Spirometry
Refer to Section 2.1(Primary objectives), Section 2.2(Secondary objectives), Section 2.3
(Exploratory objectives),Table 8-2(Spirometry) and Study Operations Manual for details.
8.5.2
Peak expiratory flow
PEF will be measured on all
Corporate Confidential Information
days from Screeningto completion of the treatment epoch 
(endof 3rd treatment period). 
The screening reference PEF will be determined by calculating the average of PEF values 
over the screening period (minimum of 5days required).


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Please refer to Section 3.1 (Study design) and Study Operations Manual for details.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule (Section 8.1) detailing when each 
assessment is to be performed.
8.6.1
Physical examination
See the Site Operations Manual for details.
8.6.2
Vital signs

Body temperature

Blood pressure (BP) 

Pulse 
8.6.3
Height and weight

Height

Body weight

Body mass index (BMI) will be calculated as (Body weight (kg) / [Height (m)]2)
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.
8.6.4.1
Hematology
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differentials and platelet count will be measured. Coagulation testing including prothrombin 
time (PT) also reported as International Normalized Ratio (INR) and activated partial 
thromboplastin time (aPTT) will be measured.
8.6.4.2
Clinical chemistry
Sodium, potassium, creatinine, blood urea nitrogen (BUN)/urea, uric acid, chloride, albumin, 
calcium, alkaline phosphatase, total bilirubin, bicarbonate/HCO3, LDH, G-GT, AST, ALT, 
CK, glucose, total cholesterol, triglycerides. HbA1c will be included in the screening panel 
only.
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, 
direct and indirect reacting bilirubin should be differentiated.


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8.6.4.3
Urinalysis
Dipstick measurements for protein, blood, and WBC/leukocytes, nitrite, pH, glucose, ketones, 
urobilinogen, bilirubin will be performed. 
If dipstick measurement results are positive (abnormal), results will be captured in the CRF.
Microscopy must be assessed following an abnormal dipstick test with results captured in the 
CRF.
8.6.5
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
Site Operations Manual.
The CRF will contain: PR interval, QRS duration, heart rate, RR interval, QT interval, QTc
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the 
ECG machine, the investigator must calculate QTcF at the Screening and/or Baseline visit(s) 
(as applicable) to assess eligibility. See the Site Operations Manual for additional details.
Clinically significant abnormalities must be reported in the AE CRF.
8.6.6
Pregnancy and assessments of fertility
Pregnancy Testing
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 negative. 
*Additional pregnancy testing might be performed if requested per local requirements.  
Refer to Section 9.6 for details on Reporting Pregnancy.
Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy 

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
patient, regardless of reported reproductive/menopausal status at Screening/Baseline.  


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8.6.7
Patient Diary (e-Diary)
Each patientwill be provided with an electronic diary to record study assessments while at 
home from Run in to completion of the treatment epoch (end of 3rdtreatment period).
Pleaserefer to Section 3.1(Study design) and Study Operations Manual for details.
8.7
Pharmacokinetics
Not applicable.
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 or disease) in a patient
afterproviding written informed consent
Corporate Confidential Information
for participation in the studyuntil 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.


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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 patient
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination 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 patients with underlying disease. 
Investigators have the responsibility for managing the safety of individual patient and 
identifying adverse events. Alert ranges for liver related events are included in Appendix 1.
Adverse events should 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 

Yes or 

No
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).


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Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications.  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 patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection 
for patients that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of Serious Adverse Event (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

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH-E2D Guideline 2004).


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Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (please refer to ICH-E2D Guideline 2004).
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 Chief Medical Office and Patient Safety (CMO&PS) as per 
Section 9.2.2.
9.2.2
SAE reporting
Screen Failures & Run-In Failures
Note the following requirement for Screen Failures: SAEs occurring after the patient has 
provided informed consent until the time the patient is deemed a Screen Failure must be 
reported to Novartis.
For patients considered Run-In Failures, SAEs occurring after the patient has provided 
informed consent until the time the patient is deemed a Run-In Failure must be reported to 
Novartis.
Randomized Patients
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last administration of study treatment 
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. 
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 
patient 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.
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 Chief Medical Office 
and Patient Safety (CMO&PS) Department associate may urgently require further information 


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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 patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
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 G-GT) 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 patient. 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.
If the initial elevation is confirmed, close observation of the patient 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 patient if appropriate

Causality assessment of the liver event 


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
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 Gamma-glutamyl transferase (GGT). 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 
patient 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. Refer to the Site Operations Manual for additional details. 
9.4
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/patient
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
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 Chief Medical Office and Patient Safety (CMO&PS) department if the treatment 
error is associated with an SAE. 
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 Chief Medical Office and Patient Safety 
(CMO&PS). As such, instances of misuse or abuse are also to be reported using the SAE 
form/CRF. Table 9-1 summarizes the reporting requirements.


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Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose 
Administration 
(DAR) CRF 
Document in 
Adverse Event CRF
Complete Serious 
Adverse Event form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an Adverse 
Event
Only if associated with a 
Serious Adverse Event
Misuse/Abuse
Yes
Yes 
Yes, even if not associated 
with an Serious Adverse 
Event
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 patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to 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 Chief Medical Office and Patient Safety (CMO&PS) 
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 an SAE form.
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.
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.


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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 data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The monitor will visit the site to check the completeness of patient records, the accuracy of 
data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and 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 patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and 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 eCRFs are performed according to the study-specific monitoring plan. 
No information in source documents about the identity of the patients will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF) 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 patient 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 (Section 8.1) and can be recorded directly on the eCRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the eCRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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10.3
Database management and quality control
Corporate Confidential Information
Novartis staff review the data entered into the eCRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. 
Designatedinvestigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff 
who will make the correction to the database. The signed copy of the Data Query Form is kept 
at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
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.
Diary data will be entered into anelectronic diary by the patient. The system will be supplied 
by a vendor, who will also manage the database. The database will be sent electronically to 
Novartis.
Randomization codes and data about all study drug(s) dispensed to the patientand all dosage
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis.
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 relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Anychanges to the database after that time can only be made after written agreement by 
Novartis management.


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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 patient 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, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
The PD analysis set will include all patients with available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data.
11.2
Patient demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
patient. Summary statistics will be provided for all patients, 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 patient.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment sequence and patient.
11.4
Analysis of the primary variable(s)
The primary objective is to investigate the potential influence of time of dosing (morning or 
evening) on the bronchodilator effect of once daily orally inhaled QVM149 (150 μg 
indacaterol / 50 μg glycopyrronium / 80 μg MF) compared to placebo (all administered via the 
Concept1 inhalation device).
11.4.1
Primary Variable(s)
The primary variable is the weighted mean forced expiratory volume in 1 second (FEV1) over 
24 hours (AUC0-24h) following 14 days of treatment with QVM149 dosed in the morning, 
QVM149 dosed in the evening and placebo. The primary variable will be determined for each 
patient on day 14 on each treatment using the linear trapezoidal rule.


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11.4.2
Statistical model, hypothesis, and method of analysis
The primary variable, FEV1 weighted mean (0- 24 h) (AUC0-24h), will be analyzed using a 
linear mixed model. The model will include period, treatment (QVM149 morning, QVM149 
evening, placebo), and sequence as fixed effect factors. The patient effect will be assumed to 
be random. Restricted maximum likelihood method will be used. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. From these analyses, 
point estimates and their associated 90% confidence intervals will be constructed for each 
treatment. The difference between adjusted means and the corresponding two-sided 90% 
confidence interval for morning dose versus placebo, evening dose versus placebo will be 
presented. In addition, difference between adjusted means and the corresponding two-sided 
90% confidence interval for morning versus evening doses 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
Sensitivity analyses will be performed on a subset of patients where patients having drug 
administered outside of the allowed time window on day 14 or 15 will be excluded. 
Spirometry data assessed outside of the allowed time window will also be excluded.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
The secondary endpoints are:

FEV1 at approximately 5 min. before last p.m. or penultimate a.m. dose obtained from 
spirometry data.

Daily morning and evening peak expiratory flow (PEF) rate from Day 2 to Day 14 during 
the three treatment periods
FEV1 (mL) will be analyzed by fitting the same model as described for the primary endpoint 
above in addition to summary statistics. 
PEF 
(L/min) 
will 
be 
analyzed 
separately 
for 
morning 
and 
evening 
values. 
The morning/evening PEF (L/min) will be averaged between days 2 to 14 of each treatment 
period for each patient. The average morning/evening PEF score between days 2 to 14 in each 
period will be analyzed using the same model as for the primary endpoint and summarized by 
treatment.


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11.5.2
Safety
All safety parameterswill be summarized on the safety set.
Vital signs
All vital signs data will be listed by treatment sequence, patient, and visit/timeand if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. 
Summarystatistics will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment sequence, patientand 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, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a patientwith 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 andpatient.
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 patients 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 epoch and continuing into the next epoch is counted only in the onset 
epoch. A patientwith multiple adverse events within a body system and treatment epoch is 
only counted once towards the total of this body system and treatment.
11.5.3
Other assessments
Corporate Confidential Information
Not Applicable.


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11.7
Sample size calculation
With a sample size of 30 completers (5 patients per sequence), a two-sided 90% confidence 
interval for the difference between QVM149 pm/am and placebo in weighted mean FEV1 
over 24 hours(AUC
0-24h)after 2 weeks of treatment will have an interval that extends no more 
than 88ml from the observed difference in means. This calculation assumes a within-patient 
standard deviation of 200 ml in weighted mean FEV1 over 24 hours (AUC
0-24h)
(historicalstudy HZA114624 -Fluticasone furoate and vilanterol (Kempsford et al 2013)).
To ensure at least 30 patients complete the study, 36 patients will be enrolled assuming a 
drop-out rate of up to 20% and assuming equal assignment to the 6 sequences.
11.8
Power for analysis of key secondary variables
Not applicable.
12
Ethical considerations
12.1
Regulatory and ethical compliance
Corporate Confidential Information
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.
Corporate Confidential Information


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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, patient recruitment 
procedures (e.g. advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by 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.
12.4
Quality control and quality assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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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 patients 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.
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 patients may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
References are available upon request
Barnes P, FitzGerald G, Brown M, et al (1980) Nocturnal asthma and changes in circulating 
epinephrine, histamine, and cortisol. N Engl J Med; 303(5):263-7.
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; 128:315-22.
Beasley R (2004) The Global Burden of Asthma Report, Global Initiative for Asthma (GINA). 
Available from www.ginasthma.org
Befekadu E, Onofrei C, Colice GL (2014) Tiotropium in asthma, a systemic review. JAA; 
7:11-21.
Calverley PMA, Lee A, Towse L, et al (2003) Effect of tiotropium bromide on circadian 
variation in airflow limitation in chronic obstructive pulmonary disease. Thorax; 58:855-860.
Corren J, Berkowitz R, Murray JJ, et al (2003) Comparison of once-daily mometasone furoate 
versus once-daily budesonide in patients with moderate persistent asthma. Int J Clin Pract; 
57(7):567-72. Erratum in: Int J Clin Pract. 2007 Feb; 61(2):352. Dosage error in article text.
D'Urzo A, Karpel JP, Busse WW, et al (2005) Efficacy and safety of mometasone furoate 
administered once-daily in the evening in patients with persistent asthma dependent on 
inhaled corticosteroids. Curr Med Res Opin; 21(8):1281-9.
European Medicines Agency (2013) Assessment Report on Relvar Ellipta (Internet) Available 
from
<http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/002673/WC500157635.pdf> (Accessed 09 March 2017).
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.
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Available from: 
<http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500002807.pdf> (Accessed 09 March 2017).
Karpel JP, Busse WW, Noonan MJ, et al (2005) Effects of mometasone furoate given once 
daily in the evening on lung function and symptom control in persistent asthma. Ann 
Pharmacother; 39(12):1977-83.


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Kempsford RD, Oliver A, Bal J, et al (2013) The efficacy of once-daily fluticasone 
furoate/vilanterol in asthma is comparable with morning or evening dosing. Respir Med; 
107(12):1873-80.
Kempsford RD, Bal J, Baines A, et al (2016) The efficacy of fluticasone furoate administered 
in the morning or evening is comparable in patients with persistent asthma. Respir Med;
112:18-24
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; 367:1198-207.
Landstra AM, Postam DS, Boezen HM et al (2007) Role of Serum Cortisol Levels in Children 
with Asthma. Am J Resp Crit Care Med; 165:708-712.
Muers MF (1984) Diurnal variation in asthma. Arch Dis Childhood; 59:898-901.
Noonan M, Karpel JP, Bensch GW, et al (2001) Comparison of once-daily to twice-daily 
treatment with mometasone furoate dry powder inhaler. Ann Allergy Asthma Immunol;
86:36-43.
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 from <http://www.cromsource.com> (Accessed 09 
March 2017).
Zetterstrom O, Dahl R, Lindqvist A, et al (2008) Comparable morning versus evening 
administration of once-daily mometasone furoate dry powder inhaler. Resp Med; 102,1406-
1411.


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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 elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN 

5 x ULN < ALT/AST 8 x ULN

3 x ULN < ALT/AST 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
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* 
*Liver event guidance for CRF completion is available in the Site Operations Manual
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, GGT, 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 14 (up to 18) days. Dispose of each inhaler after 
the end of a treatment period of 14 (up to 18) 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.

SAP_000.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
QVM149
CQVM149B2209
A randomized, double-blind, repeat dose cross-over study 
to assess the bronchodilator effects of once daily QVM149 
following morning or evening dosing for 14 days compared 
to placebo in patients with asthma
Statistical Analysis Plan (SAP)
Document type: 
SAP Documentation –NIBR 
Document status:
Final version 3.0Amendment 2
Release date:
27-Mar-2018
Number of pages:
15
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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SAP 
CQVM149B2209


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SAP 
CQVM149B2209
Corporate Confidential Information


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SAP 
CQVM149B2209
able of contents
able of contents.................................................................................................................4
ist of tables........................................................................................................................4
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study obectives.......................................................................................................5
1.3.1 
Primary obective(s)................................................................................5
1.3.2 
Secondary obective(s)............................................................................5
1.4
Study design and treatment......................................................................................
2 First interpretable results (FIR)...........................................................................................7
3 Interim analyses...................................................................................................................7
4 Statistical methods: Analysis sets........................................................................................7
5 Statistical methods for Pharmacoinetic (P) parameters..................................................8
Statistical methods for Pharmacodynamic (PD) parameters...............................................8
.1
Primary obective.....................................................................................................8
.1.1 
Variables.................................................................................................9
.1.2 
Descriptive analyses................................................................................9
.1.3 
Statistical model, assumptions and hypotheses.......................................9
.2
Secondaryobectives.............................................................................................11
.2.1 
Variables...............................................................................................11
.2.2 
Descriptive analyses..............................................................................11
.2.3 
Statistical model, assumptions and hypotheses.....................................11
7 Statistical methods for safety and tolerability data............................................................12
7.1
Variables................................................................................................................12
7.2
Descriptive analyses..............................................................................................13
7.3
raphical presentation...........................................................................................15
8 Statistical methods for biomarer data..............................................................................15
ist of tables
able 4-1 
Protocol deviation codes and analysis sets..............................................
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SAP 
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1 
Introduction 
1.1 
Scopeof document
he RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial CQVM149B2209.
he Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2 
Study referencedocumentation
his SAP is based on the final version of the following study documents:
the study protocol, v00, 08 March 2017
the S M, v00, 08 March 2017
1.3 
Study obectives
1.3.1 
Primary obective(s)
bective
ndpoint
o investigate the potential influence of 
time of dosing (morning or evening) on 
the bronchodilator effect of once daily 
orally inhaled QVM149 compared to 
placebo 
eighted mean forced epiratory 
volume in 1 second (F V1) over 24 h 
(A C
0-24h) following 14 days of 
treatment with QVM149 dosed in the 
morning, QVM149 dosed in the evening 
and placebo.
1.3.2 
Secondary obective(s)
bective
ndpoint
o investigate the potential influence of 
time of dosing (morning or evening) on 
trough F V1 of once daily orally inhaled 
QVM149 compared to placebo.
F V1 at approimately 24 h after the 
last p.m. or penultimate a.m. dose.
o investigate the potential influence of 
time of dosing (morning or evening), on 
pea epiratory flow rate (P F) of once 
daily orally inhaled QVM149 compared 
to placebo (all administered via the 
Concept1 inhalation device).
Daily morning and evening pea 
epiratory flow rate from Day 2 to Day 
14 during the three treatment periods


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SAP 
CQVM149B2209
bective
ndpoint
o evaluate safety and tolerability of 
QVM149 when dosed in the morning or 
in the evening in patients with asthma 
during two wees of treatment in each 
treatment period.
Adverse events
ematology
Blood chemistry
rinalysis
Vital signs
C
1.4 
Study design and treatment
his is a randomized, placebo-controlled, double-blind, si-seuence, three-period cross-over 
study in asthma patients. he study will consist of a 14-day screening period, followed by a 14-
day run-in period,  and a treatment epoch which consists of three treatment periods, with a 
minimum duration of 14 days each followed (for the 2 first treatment periods) by a wash-out 
period. he duration of each treatment period may be etended up to aduration of 18 days if 
needed for operational reasons. he third treatment period will be followed by a Study 
Completion evaluation at 1-7 days following the last dose. he treatment periods will be 
separated by wash-out periods of 14 to 21 days duration.
he total duration of the study is approimately 13 wees (minimum) to 19wees (maimum) 
for each patient.
he study population will be comprised of male and female patients aged 18 and above with 
asthma. Approimately 3 adult patients will be randomized with the intention that at least 30 
patients complete the study.
Study treatments are defined as:
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A:  Matching placebo (am) QVM149 150/50/80 g(pm)


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SAP 
CQVM149B2209
B:  QVM149 150/50/80 g (am) Matching placebo (pm)
C:  Placebo (am) Placebo (pm)
Patients will be randomized to one of the following  treatment seuences (defined according 
to a illiams design for 3 treatments and 3 periods) in the ratio of 1:1:1:1:1:1.
2 
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for this trial.
3 
Interim analyses 
4 
Statistical methods: Analysis sets
For subects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
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SAP 
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For subects for which the actual seuence of treatments received does not match the 
randomized seuence of treatments, the actual seuence will be used for analysis involving a 
seuence component (e.g. AN VAs with a seuence effect) if the actual seuence is one of the 
seuences planned in the study design. If the actual seuence is not one of the seuences 
planned in the study design, the randomized seuence will be used for analysis involving a 
seuence component but data points from periods in which the subect has not received the 
randomized treatment will be ecluded from the analysis. 
he safety analysis set will include all subects that received any study drug.
he PD analysis set will include all subects with any available PD data, 
who received any study 
drugand eperienced no protocol deviations with relevant impact on PD data.
Anyone who did not complete an informed consent will not have their data reported.
he analysis sets and protocol deviation codes are related as follows:
able 4-1 
Protocol deviation codes and analysis sets
Category
Deviation code
et description of deviation
Data eclusion
Subects are ecluded from all (safety)analysis in case of 
these PDs: 
clude subect from all (safety)
analysis set 
INC 01
ritten informed consent was not 
obtainedprior to performing study 
assessment
clude from Safety set
Subects are ecluded from PD analysis in case of these 
PDs:
clude subect from PD analysis 
set
INC01
ritten informed consent was not 
obtainedprior to performing study 
assessment
clude from PD set
If updates to this table are needed,anamendment tothe SAP needs tobe implemented priorto
DB .
5 
Statistical methods for Pharmacoinetic (P) parameters
Not applicable.
Statistical methods for Pharmacodynamic (PD) parameters
.1 
Primary obective
he primary obective is to investigate the potential influence of time of dosing (morning or 
evening) on the bronchodilator effect of once daily orally inhaled QVM149 (150 g indacaterol 
/ 50 g glycopyrronium / 80 g MF) compared to placebo (all administered via the Concept1 
inhalation device).


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.1.1 
Variables 
he primary variable is the weighted mean forced epiratory volume in 1 second (F V1) over 
24 hours (AC0-24h) following 14 days of treatment with QVM149 dosed in the morning, 
QVM149 dosed in the evening and placebo.
he primary variable will be determined for each patient on day 14 on each treatment using the 
linear trapezoidal rule. F V
1measurements are taen 5 min before the evening dose on day 14 
then, 3h, h, 9h, 12h, 15h, 18h, 21h and 23h55 (timing from the post-evening dose).
he weighted mean will be calculated as the A C0-24hdivided by the t
f-t
lhours time interval 
for each subect (t
ftime of the first observation, tlis the time for the last observation).
where,
Ci the highest value at planned relative timepoint i
t
i the actual time for planned relative timepoint i
i  the planned relative time of assessment
f thefirst i
l the last i.
.1.2 
Descriptive analyses
A C0-24h F V1 will be calculated and listed by treatment seuence and subect, and 
summarized by treatment.
.1.3 
Statistical model, assumptions and hypotheses
he primary variable, F V1 weighted mean (0-24 h) (A C
0-24h), will be analyzed using a linear 
mied model. he model will include period, treatment (QVM149 morning, QVM149 evening, 
placebo), and seuence as fied effect factors. he patient effect will be assumed to be random. 
Restricted maimum lielihood method will be used. he enward-Roger approimation will 
be used to estimate denominator degrees of freedom. From these analyses, point estimates and 
their associated 90 confidence intervals will be constructed for each treatment. he difference 
between adusted means and the corresponding two-sided 90 confidence interval for morning 
dose versus placebo, evening dose versus placebowill be presented. In addition, difference 
between adusted means and the corresponding two-sided 90 confidence interval for morning 
versus evening doses will be presented.
.1.3.1 Model checing procedures
Missing values
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If a patient taes rescue medication within  hours prior to the spirometry assessments and the 
visitis not rescheduled to the net 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 taen 
during the 24-hour spirometry assessment then from the time of the rescue medication intae, 
all post-timepoint spirometry assessments will be considered as missing in this treatment period
and A C(0-24hr) will be considered as missing.
Sensitivity analyses 
Sensitivity analyses will be performed on a subset of patients where patients having drug 
administered outside of the allowed time window on day 14 or 15 will be ecluded. Spirometry 
data assessed outside of the allowed time window will also be ecluded.
n Day 14 in the morning, study drug must be administered at 07:00h with a time window of 
 30 min i.e. .307.30. here must be 12 hours in between morning and evening doses on 
Days 14 and 15 with an acceptable deviation of  15 min.
For eample:
If on Day 14, study drug is given at 7.30 am then study drug must be given between 7.15 pm 
7.45 pm on day 14 in the evening and between 7:00am 8:00am on day 15 in the morning.
If on Day 14, study drug is given at .30 amthen study drug must be given between .15 pm 
.45 pm on day 14 in the evening and between :00am 7:00am on day 15 in the morning.
Supportive analysis
Repeated measures of F V1 will be analyzed using a mied model for repeated measures 
(MMRM) with period, seuence, visit and treatment as factors having fied effects and period 
specific baseline F V1 as covariate. he modeling will assume an unstructured variance 
covariance matri to account for the correlations between assessments over time points. 
Average treatment effect on the overall F V1 profile over 0-24hr will be estimated in terms of 
adusted mean difference between morning dose vs. placebo and evening dose vs. placebo with 
corresponding 2-sided 90 CIs. he inference is valid under Missing at Random (MAR) 
assumption on missingness mechanism and provides evidence on robustness of the primary 
analysis results to the missing value handling techniues
Subgroup analysis
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he primary analysis will be performed by subgroup of patients based on their compliance of 
study medication within the 7 days before the spirometry assessment: if spirometry assessment 
is done on the evening of day 14, then compliance will be calculated between day 8 and day 14 
on a total number of 14 doses.


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his 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 eual a total number of 12 doses)
.1.3.2
raphical presentation of results
Plot of treatment differenceswith 90 CI for A C0-24hF V1, and plot by treatment and 
additionally by period and seuence of the mean of F V1 and 90 CIover the 24h after the 
evening dose given on day 14 will be displayed.
.2 
Secondary obectives
.2.1 
Variables 
he secondary endpoints are:
rough F V1 at approimately 24 h after the last p.m. or penultimate a.m. dose.
Daily morning and evening pea epiratory flow (P F) rate from Day 2 to Day 14 during 
the three treatment periods
.2.2 
Descriptive analyses
he a.m.trough F V1 is defined for each subect as the F V1 measurement at day 15,12h
(timing from the post-evening dose on day 14)(before Day 15 amdose).
he p.m.trough F V1 is defined as the F V1 measurement at day 15, 23h55 (timing from 
the post-evening dose on day 14).
hemorning/evening P F (/min) will be averaged between days 2 to 14 of each treatment 
period for each patient.
Summary statisticsof a.m. and p.m. trough F V1and average morning/evening P Fscore 
between days 2 to 14 willbe presented by treatment.
.2.3 
Statistical model, assumptions and hypotheses
he a.m.and p.m. trough F V1 (m) will be analyzed by fitting the same model as described 
for the primary endpoint above. 
P F (/min) will be analyzed separately for morning and evening values. hemorning/evening 
P F (/min) will be averaged between days 2 to 14 of each treatment period for each patient. 
he average morning/evening P F score between days 2 to 14 in each period will be analyzed 
using the same model as for the primary endpoint.


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.2.3.1 Model checing procedures
Missing values
If a patient taes rescue medication within  hours prior to the spirometry assessments and the 
visitis not rescheduled to the net day then a.m. and p.m. trough F V1 for this treatment period 
will be set to missing.If rescue medication is taen during the 24-hour spirometry assessment 
then from the time of the rescue medication intae, all post-timepoint spirometry assessments 
will be considered as missing in this treatment period.
.2.3.2
raphical presentation of results
Plot of mean morning/evening P F and 90 CI over time between day 2 to14by treatment, 
and plot of treatment differences with 90 CI for mean morning/evening P Fand treatment 
differences with 90 CI for a.m. and p.m. trough F V1will be displayed.
7 
Statistical methods for safety and tolerability data
7.1 
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), C intervals, 
laboratory measurements, as well as subect demographics, baseline characteristics, and 
treatment information.
he last daily dose of inhaled corticosteroids taen before being enrolled into the study will be 
categorized into three categories: ow, medium and high defined based on 2017 INA report.
http://ginasthma.org/2017-gina-report-global-strategy-for-asthma-management-and-
prevention/
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7.2 
Descriptive analyses
Subect demographics and other baseline characteristics
All data for bacground and demographic variables will be listed by treatment seuence and 
subect. Summary statistics will be provided for all subects, as well as for each treatment 
seuence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment seuence and subect.
Subect disposition
A disposition summary will be presented for all subects. his table will present the number and 
percentage of subects who completed each study epoch and discontinued early for each epoch, 
along with the reasons for early discontinuation. 
he number and percentage of subects in each analysis set will be summarized for all subects. 
All analysis set results will be presented in listings by treatment seuence and subect. A 
separate listing of all subects ecluded from any analysis set and the reasons for their eclusion 
will be provided. 
All study epoch completion data will be listed by treatment seuence and subect.
reatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment seuence andsubect.
Vital signs
All vital signs data will be listed by treatmentseuence, subect, 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.


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C evaluations
All C data will be listed by treatmentseuence, subect 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 treatmentseuence, subect, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subect 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 andsubect.
he number and percentage of subects with treatment emergent adverse events will be 
tabulated by body system and preferred term with a breadown 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 net 
period is counted only in the onset period.A subect 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 eample, if A occurs during the washout period ust after treatment period 1 will 
be counted under treatment epoch 1.
For the legal reuirements of Clinicalrials.gov and udraC, two reuired tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5 and on treatment emergent serious adverse events and SA 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 As (irrespective of study treatment causality, 
seriousness and severity) occurred with the same S C and P:
a single occurrence will be counted if there is  1 day gap between the end date of the 
preceding A and the startdate of the consecutive A
more than one occurrence will be counted if there is  1 day gap between the end date 
of the preceding A and the start date of the consecutive A.
For occurrence, the presence of at least one SA / SA suspected to be related to study 
treatment / non SA has to be checed in a bloc e.g., among A s in a  1 day gap bloc, if at 
least one SA is occurring, then one occurrence is calculated for that SA.
he number of deaths resulting from SAs suspected to be related to study treatment and SAs 
irrespective of study treatment relationship will be provided by S C and P. 
Protocol Deviations
Protocol deviations will be listed by treatment seuence and subect.


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iver events
iver event data may be reported in listings and summariesif data is collected during thestudy.
7.3 
raphical presentation 
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Boplots to visualize trends in longitudinal safety data (vitals, C , lab parameter) will be 
created.