Conditions: Asthma
Keywords: asthma, asthma attack, difficulty breathing, bronchial diseases, lung, lung diseases, inhaled drugs, bronchodilator, inhaled corticosteriod
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 54
Healthy volunteers: no

Brief summary:
This study is a randomized, double-blind, placebo-controlled, three-period cross-over study in approximately 54 subjects with asthma.

Detailed description:
This is a randomized, double-blind, placebo-controlled, three-period cross-over study in asthma patients. The study will consist of a screening epoch, followed by a treatment epoch which consists of three treatment periods, and will conclude with an end of study epoch.

Each subject will be assigned to 1 of 6 treatment sequences and will sequentially receive the investigational products and placebo during the trial.

Arms:
arm 1: A-B-C arm 2: B-C-A arm 3: C-A-B arm 4: A-C-B arm 5: B-A-C arm 6: C-B-A

Interventions: intervention 1: Indacaterol maleate intervention 2: Indacaterol acetate intervention 3: Placebo
Intervention descriptions: intervention 1: 150 μg via Concept1 device intervention 2: 150 μg via Concept1 device intervention 3: Capsule containing no active ingredients delivered via Concept1 device

Protocol document:
Prot_001.pdf: 
Novartis Institutes for BioMedical Research
QVM149
Clinical Trial Protocol CQVM149B2203
A randomized, double-blind, placebo-controlled, 
three-period cross-over study to assess the 
pharmacodynamics, safety, tolerability, and 
pharmacokinetics of two orally inhaled indacaterol salts
(maleate and acetate) delivered via the Concept1 inhalation 
device in patients with asthma
Document type:
Clinical Trial Protocol
EUDRACT number:
Not applicable
Version number:
v00 (Original Protocol)
Clinical Trial Phase:
II
Release date:
27-Feb-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct.
Notification of serious adverse events
Refer to Section 9.2 of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Drug Safety 
and Epidemiology Department and notify the Clinical Trial Leader.).
Contact information is listed in the Site Operations Manual. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents.................................................................................................................3
List of tables........................................................................................................................6
List of figures......................................................................................................................7
List of abbreviations............................................................................................................8
Pharmacokinetic definitions and symbols.........................................................................11
Glossary of terms...............................................................................................................12
Protocol synopsis...............................................................................................................14
1 Introduction.......................................................................................................................17
1.1
Background............................................................................................................17
1.3
Clinical data...........................................................................................................18
1.3.1
Human safety and tolerability data.......................................................18
1.3.2 
Human pharmacokinetic data................................................................20
1.3.3
Human pharmacodynamic data.............................................................22
1.4
Study purpose........................................................................................................24
2 Study objectives and endpoints.........................................................................................25
2.1
Primary objective(s)...............................................................................................25
2.2
Secondary objective(s)...........................................................................................25
3 Investigational plan...........................................................................................................27
3.1
Study design...........................................................................................................27
3.2
Rationale of study design.......................................................................................28
3.3
Rationale for dose/regimen, route of administration and duration of treatment....29
3.4 
Rationale for choice of comparator.......................................................................30
3.5
Rationale for choice of background therapy..........................................................30
3.6
Purpose and timing of interim analyses/design adaptations..................................30
3.7
Risks and benefits..................................................................................................30
3.7.1
Blood sample volumes..........................................................................31
4 Population..........................................................................................................................32
4.1
Inclusion criteria....................................................................................................32
4.2
Exclusion criteria...................................................................................................33
5 Restrictions for Study Subjects.........................................................................................
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5.1
Contraception requirements...................................................................................37
5.2
Prohibited treatment...............................................................................................38
5.3
Dietary restrictions and smoking...........................................................................39
5.4
Other restrictions ...................................................................................................40
6
Treatment...........................................................................................................................40
6.1
Study treatment......................................................................................................40
6.1.1
Investigational treatment and control drugs..........................................40
6.2
Treatment arms ......................................................................................................41
6.3
Treatment assignment and randomization.............................................................42
6.4
Treatment blinding.................................................................................................42
6.5
Treating the subject................................................................................................43
6.6
Permitted dose adjustments and interruptions of study treatment.........................44
6.7
Emergency breaking of assigned treatment code ..................................................44
6.8
Treatment exposure and compliance .....................................................................44
6.9
Recommended treatment of adverse events ..........................................................45
6.10
Rescue medication.................................................................................................45
6.10.1
Salbutamol usage ..................................................................................45
6.11
Concomitant treatment...........................................................................................46
7
Study completion and discontinuation ..............................................................................47
7.1
Study completion and post-study treatment ..........................................................47
7.2
Discontinuation of study treatment........................................................................47
7.3
Withdrawal of informed consent ...........................................................................49
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.................................................................................58
8.3
Subject screening...................................................................................................58
8.4
Subject demographics/other baseline characteristics.............................................59
8.4.1
Hepatitis and HIV Screen......................................................................59
8.4.2
Reversibility..........................................................................................60
8.5
Efficacy / Pharmacodynamics ...............................................................................60
8.5.1
Spirometry.............................................................................................60
8.5.2
Peak expiratory flow .............................................................................62
8.6
Safety.....................................................................................................................62
8.6.1
Physical examination ............................................................................62


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8.6.2
Vital signs..............................................................................................62
8.6.3
Height and weight.................................................................................62
8.6.4
Laboratory evaluations..........................................................................62
8.6.5
Electrocardiogram (ECG).....................................................................64
8.6.6
Pregnancy and assessments of fertility.................................................64
8.7
Pharmacokinetics...................................................................................................64
8.8
Other assessments..................................................................................................65
8.8.1
Patient diary..........................................................................................65
8.8.2
Device training......................................................................................65
8.9
Use of residual biological samples........................................................................66
9 Safety monitoring..............................................................................................................66
9.1
Adverse events.......................................................................................................66
9.2
Serious adverse event reporting.............................................................................68
9.2.1
Definition of SAE.................................................................................68
9.2.2
SAE reporting........................................................................................69
9.3
Liver safety monitoring.........................................................................................69
9.4
Reporting Medication errors including misuse/abuse...........................................71
9.5
Pregnancy reporting...............................................................................................71
9.6
Prospective suicidality assessment........................................................................72
9.7
Early phase safety monitoring...............................................................................72
10 Data review and database management.............................................................................72
10.1 Site monitoring......................................................................................................72
10.2 Data collection.......................................................................................................73
10.3 Database management and quality control............................................................73
10.4 Data Monitoring Committee..................................................................................74
10.5 Adjudication Committee........................................................................................74
11 Data analysis......................................................................................................................74
11.1 Analysis sets..........................................................................................................74
11.2 Subject demographics and other baseline characteristics......................................75
11.3 Treatments.............................................................................................................75
11.4 Analysis of the primary variable(s).......................................................................75
11.4.1
Variable(s).............................................................................................75
11.4.2
Statistical model, hypothesis, and method of analysis..........................75
11.4.3
Handling of missing values/censoring/discontinuations.......................76
11.4.4
Summary statistics of safety..................................................................76
11.4.5
Summary statistics of pharmacokinetics...............................................
C
 
 
76
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11.4.6
Sensitivity analyses...............................................................................76
11.5 Analysis of secondary variable(s)..........................................................................76
11.5.1
Efficacy / Pharmacodynamics...............................................................76
11.5.2
Safety.....................................................................................................77
11.5.3
Pharmacokinetics..................................................................................78
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................79
11.7 Sample size calculation..........................................................................................80
11.8 Power for analysis of key secondary variables......................................................80
12 Ethical considerations........................................................................................................81
12.1 Regulatory and ethical compliance........................................................................81
12.2 Responsibilities of the investigator and IRB/IEC..................................................81
12.3 Publication of study protocol and results...............................................................81
13 Protocol adherence............................................................................................................81
13.1 Protocol Amendments...........................................................................................82
14 References.........................................................................................................................83
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................84
16 Appendix 2: Concept1 Platform Inhaler: Instructions for use of medical devices for 
investigational human use Instructions for using inhaler and capsules.............................86
List of tables
Table 5-1
Withholding period of bronchodilators prior to spirometry..................38
Table 5-2
Prohibited asthma medication during treatment period........................38
Table 5-3
Prohibited treatments, cessation periods...............................................39
Table 6-1
Overview of study medication..............................................................41
Table 6-2
Definition of treatment sequences.........................................................41
Table 6-3
Treatment Assignment Numbering.......................................................42
Table 6-4
Blinding levels......................................................................................43
Table 8-1
Assessment Schedule............................................................................51
Table 9-1
Summary of reporting requirements for medication errors...................71
Table 15-1
Liver Event and Laboratory Trigger Definitions..................................84
Table 15-2
Actions required for Liver Events.........................................................84
Table 15-3
Exclusion of underlying liver disease...................................................
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List of figures
Figure 3-1 Study Design...........................................................................................................27


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


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Protocol No. CQVM149B2203
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
i.v.
intravenous
IB
Investigator's Brochure
IBD
International birthdate
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICS
inhaled corticosteroid
IEC
Independent Ethics Committee
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
kg
kilogram
LABA
Long-acting β2 agonist
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LLOQ
lower limit of quantification
MDDPI
multidose dry powder inhaler
mg
milligram(s)
ml
milliliter(s)
o.d.
once a day
OTC
over-the-counter
p.o.
oral
PD
pharmacodynamic(s)
PEF
peak expiratory flow
PI
post-inhalation
PK
pharmacokinetic(s)
pMDI
pressurized metered-dose inhaler
RBC
red blood cell(s)


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REB
Research Ethics Board
SABA
Short acting beta2 agonist
SAE
serious adverse event
SD
standard deviation
SDDPI
single-dose dry powder inhaler
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
γ-GT
gamma-glutamyl transferase
μg
microgram


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Pharmacokinetic definitions and symbols
AUC0-24h,ss
The area under the plasma concentration-time curve from time zero to 
24 hour post dose [pg.h/mL], at steady state
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the end of the dosing interval tau at steady state [mass 
x time / volume]
Cav,ss
The average steady state plasma (or serum or blood) concentration 
during multiple dosing
Cmax,ss
The observed maximum plasma (or serum or blood) concentration 
following drug administration at steady state [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
Frel
Relative bioavailability of indacaterol acetate compared to indacaterol 
maleate
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]
T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax,ss
The time to reach the maximum concentration after drug administration 
at steady state [h]


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Glossary of terms
Baseline
Period after screening and  prior to the first dose of Treatment period 1 
Control drug
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug.
Enrollment
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol).
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes any 
placebos, any active controls, as well as approved drugs used outside 
of their indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system.
Period
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned.
Randomization 
number
A 
unique 
identifier 
assigned 
to 
each 
randomized 
subject, 
corresponding to a specific treatment arm assignment
Stage
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal.


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Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part 
of the required study procedures; includes investigational drug, active 
drug run-ins or background therapy.
Subject
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient.
Subject number
A number assigned to each subject who enrolls in the study. 
When combined with the center number, a unique identifier is created 
for each subject in the study.
Variable
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points.


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Protocol synopsis
Protocol number
CQVM149B2203
Title
A randomized, double-blind, placebo-controlled, three-period cross-over study 
to assess the pharmacodynamics, safety, tolerability, and pharmacokinetics of 
two orally inhaled indacaterol salts (maleate and acetate) delivered via the 
Concept1 inhalation device in patients with asthma
Brief title
Pharmacodynamics, safety, tolerability, and pharmacokinetics of two orally 
inhaled indacaterol salts in adult subjects with asthma.
Sponsor and 
Clinical Phase
Novartis 
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
This study is designed to determine the pharmacodynamics, safety, tolerability, 
and systemic pharmacokinetics of indacaterol maleate 150 μg (approved 
product Onbrez® Breezhaler®) and indacaterol acetate 150 μg (development 
formulation), at steady state, in subjects with asthma.
Primary 
Objective(s)
To assess the bronchodilator effect of orally inhaled indacaterol salts (maleate 
and acetate) compared to placebo in subjects with asthma as measured by 
trough Forced Expiratory Volume in 1 second (FEV1) after 14 days of treatment. 
Trough is defined as the mean of FEV1 at 23 h 15 min and 23 h 45 min 
post-dose.
Secondary 
Objectives
To assess the steady state pharmacokinetics of orally inhaled indacaterol salts 
(maleate and acetate) following 14 days of treatment in subjects with asthma
To assess the bronchodilator effect of orally inhaled indacaterol salts (maleate 
and acetate) compared to placebo in subjects with asthma as measured by: 

Time to peak FEV1 on Day 14.

FEV1, forced vital capacity (FVC), and forced expiratory flow (25-75%)
(FEF25-75%) at each post-dose time point after 14 days of treatment.

Standardized FEV1 AUC between baseline (pre-dose) and 4 hr post-dose 
on Day 14 of treatment.

Morning (pre-dose) and evening peak expiratory flow (PEF) measurements 
for indacaterol salts (maleate and acetate) in comparison to placebo

To assess day and night rescue medication usage for indacaterol salts 
(maleate and acetate) in comparison to placebo

To assess the safety and tolerability of indacaterol salts (maleate and 
acetate) in comparison to placebo in terms of the number and percentage of 
adverse events, laboratory results, vital signs (blood pressure and pulse 
rate) and ECGs.
Study design
This study is a randomized, double-blind, placebo-controlled, three-period 
complete block cross-over study in approximately 54 subjects (42 completers) 
with asthma.
Population
The study population will be comprised of male and female patients aged 18 
and above with asthma. Approximately 54 adult subjects will be randomized 
with the intent of having at least 42 subjects complete the study.


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Inclusion criteria
Male and female patients with asthma, aged 18 or above, diagnosed according 
to documented physician diagnosis of asthma and who additionally meet the 
following criteria:

Patients receiving daily treatment with an inhaled corticosteroid up to the 
maximum dose per day as indicated in the package leaflet and on a stable 
regimen for at least 4 weeks prior to screening.

Patients with a pre-bronchodilator FEV1 at screening of ≥50% and ≤90% of 
the predicted normal value for the patient. This criterion for FEV1 will have 
to be demonstrated after a washout period withholding of bronchodilators.

Patients who demonstrate an increase of ≥12% and ≥200 mL in FEV1 within 
30 minutes after inhaling a total of 400 μg of salbutamol/360 μg albuterol or 
equivalent dose (the reversibility test) as per ATS/ERS Task force: 
Standardization of Lung Function Testing guidelines (Miller et al 2005a). 
Reversibility will have to be demonstrated after an appropriate washout 
period.
Exclusion criteria
History of hypersensitivity to any of the study drugs or to drugs of similar 
chemical classes.
A history of clinically significant ECG abnormalities, (including past medical 
history of life-threatening arrhythmias or a history, or family history, of long QT 
syndrome or Torsades de Pointes, and paroxismal atrial fibrillation) 

Patients diagnosed with COPD as defined by the (GOLD Guidelines 2017).

Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c <9%
at screening).

Patients who have had a severe asthma attack/exacerbation requiring 
hospital admission in the 6 weeks prior to screening

Patients who have had previous intubation for a severe asthma 
attack/exacerbation.

Patients with concomitant pulmonary disease, pulmonary tuberculosis 
(unless confirmed by chest X-ray to be no longer active) or clinically 
significant bronchiectasis.
Investigational 
and reference 
therapy

Indacaterol Maleate 150 μg

Indacaterol Acetate 150 μg

Placebo
Efficacy/PD 
assessments

Spirometry

PEF

Rescue medication use
Safety 
assessments

Hematology

Blood chemistry

Urinalysis

Adverse events

Serious adverse events

Vital signs (blood pressure and pulse rate)

ECG
Other 
assessments
Pharmacokinetic assessments for indacaterol:

Day 14: pre-dose (-15 minutes), 5 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 
8 h, 12 h, and 24 h post-dose.


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Data analysis
The primary endpoint is trough FEV1 after 14 days of treatment. Trough FEV1 is 
defined as the mean of the FEV1 measurements at 23 h 15 min and 23 h 45 min 
post dose. The trough FEV1 will be analyzed using an analysis of variance 
(ANOVA) with treatment, period and sequence as fixed effects and subject 
nested within sequence as random effect. Treatment contrasts will be 
constructed to compare each indacaterol salt (maleate and acetate) with 
placebo, the results will be expressed as estimates and their two sided 95% 
confidence intervals and P-value, without adjustment for multiplicity.
Additionally as a secondary consideration, an estimate of the differences in 
trough FEV1 between indacaterol acetate (test) and indacaterol maleate 
(reference) will be calculated together with the corresponding two sided 95% 
confidence intervals.
Pharmacokinetic analysis
The log transformed pharmacokinetic parameters AUC0-24h,ss and Cmax,ss 
will be compared for indacaterol acetate (test) relative to indacaterol maleate 
(reference) using a mixed effects model with sequence, treatment and period as 
fixed effects and subject nested within sequence as random effect. Body weight 
may be included as a covariate and applied as a fixed effec t in the model. 
Ratios of the geometric means together with their corresponding 90% 
confidence intervals will be provided for each of the PK parameters above.
Key words
Asthma, indacaterol, bronchodilator, pharmacokinetics, pharmacodynamics, 
tolerability


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1
Introduction
1.1
Background
Asthma is a chronic inflammatory disorder of the lungs characterized by variable airflow 
limitation and hyper-responsiveness. It is a common disorder with an estimated worldwide 
prevalence of 300 million. It impacts morbidity, witha substantial socioeconomic burden.
QVM149 is a fixed dose combination (FDC) of an inhaled long-acting β2-agonist 
(indacaterolacetate), an inhaled long-acting antimuscarinic (glycopyrronium bromide) and an 
inhaled corticosteroid (mometasone furoate) thatis currently being developed as a 
lactose-blended dry powder for the once-daily maintenance treatment of asthma GINA step 
≥4 and administered via the Concept1 single-dose dry powder inhaler (SDDPI). All three 
mono-components, indacaterol (as the maleate salt), glycopyrronium bromide, and 
mometasone furoate have previously been developed and approved as individual drugs for 
either chronic obstructive pulmonary disease (COPD) or asthma. Indacaterol maleate, 
delivered via Concept1, aSDDPI (Onbrez® Breezhaler
®), is approved in over 110countries 
worldwide for the once daily maintenance bronchodilator treatment of airflow obstruction in 
patients with COPD. 
During the clinical development of indacaterol maleate, a small proportion of subjects 
(including healthy volunteers and patients with asthma,and COPD) developed a 
postinhalation (PI) cough. This was of rapid onset, short-lived,and with no adverse impact on 
safety, efficacy or tolerability. This PI cough was not dose dependent. In Study 
CQAB149D2301,an early proof-of-concept type formulationwas used andpost-inhalation 
cough was observed in 45% to 59% of subjects receiving indacaterol maleate whereas only 
7% to 14% of subjects receiving indacaterol acetate experienced post-inhalation cough. Hence, 
theacetate salt of indacaterol reduced the incidence of post-inhalation cough compared to the 
maleate salt whilst demonstrating similar efficacy, safety,and systemic exposure. Due to 
likely patient preference of a product which does not cause PI cough,all ongoing and future 
QVM149 studies will be performed using the indacaterol acetate salt.
This study is designed to determine the pharmacodynamics, safety, tolerability, and systemic 
pharmacokinetics of indacaterol maleate 150 μg (the salt form of the approved product 
Onbrez®Breezhaler®
Corporate Confidential Information
) and indacaterol acetate 150 μg at steady state, in subjects with asthma.


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1.3
Clinical data
1.3.1
Human safety and tolerability data
Indacaterol maleate
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Indacaterol has been studied in healthy subjects, adult subjects with COPD, and adult, 
adolescent,and pediatric subjects with asthma. In total, over 28,000 subjects were included in 
the indacaterol clinical development program. 
Indacaterol, at doses from 75 μg to 300 μg once daily, has been approved for the treatment of 
COPD in over 110 countries worldwide including those of European Economic Area, USA 
and Japan. The lowest dose approved for the maintenance therapy for COPD outside of the 
US and Canada is 150 μg given once daily. 
The cumulative patient exposure since the International Birth Date until 30 Nov 2015 of the 
product is estimated to be approximately 2,236,431.77 patient years. About 76.2% of the 
cumulative exposure to indacaterol maleate was related to the 150 μg dose strength.  


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Overall, the safety profile of indacaterol is similar to that of other LABAs at therapeutic doses, 
with the added benefit that the drug is administered once daily. The most common adverse 
reactions at the recommended doses were nasopharyngitis, upper respiratory tract infection, 
cough, headache, and muscle spasms. These were in the vast majority mild or moderate and 
became less frequent if treatment was continued.
At recommended doses, the adverse reaction profile of Onbrez® Breezhaler® in patients with 
COPD shows clinically insignificant systemic effects of β2-adrenergic stimulation. Mean heart 
rate changes were less than one beat per minute, and tachycardia was infrequent and reported 
at a similar rate as under placebo treatment. Relevant prolongations of QTcF were not 
detectable in comparison to placebo. The frequency of notable QTcF intervals (i.e. >450 ms 
(males) and >470 ms (females)) and reports of hypokalemia were similar to placebo. 
The mean of the maximum changes in blood glucose were similar between Onbrez ®
Breezhaler® and placebo.
The effects of indacaterol on QT intervals were assessed in healthy subjects, COPD subjects, 
and asthma subjects. In a thorough QT study (CQAB149B2339) conducted in compliance 
with current ICH guidance, indacaterol treatment with multiple daily doses (150, 300, and 
600 μg) was assessed as safe and well tolerated. Maximum mean prolongations of QTcF 
intervals were <5 msec (the regulatory threshold of concern) and the upper limit of the 90% 
confidence interval was below 10 msec for all time matched comparisons versus placebo at 
the investigated doses. This shows that there is no concern for QTcF prolongation in the 
investigated dose range.
Administration of indacaterol at daily doses of up to 600 μg for up to one year of exposure 
was safe and well tolerated. There were no notable differences between the safety profiles of 
indacaterol once daily and other LABAs given twice daily. Post-marketing data from 
countries where indacaterol is approved for the treatment of COPD do not reveal any new 
safety concerns and have not led to any regulatory or manufacturer actions being taken for 
safety reasons.
For further detailed information on the pharmacodynamic profile of indacaterol, please refer 
to the (Indacaterol (QAB149) Investigator’s Brochure (IB)) and Onbrez® SmPC.
Indacaterol acetate
To date, three studies (CQAB149B2102, CQAB149D2301, and CQMF149E2203 (as part of 
the development program for the FDC of indacaterol acetate with mometasone furoate)), in a 
total of 463 subjects with asthma have been completed using indacaterol acetate. So far, one 
study with indacaterol acetate as one of the study arms has been concluded in a total of 
64 healthy subjects (CQMF149E2102, as part of the development program for the FDC of 
indacaterol acetate with mometasone furoate).
Study CQAB149B2102 was a multi-center, randomized, single-dose, double-blind, 4-way 
cross-over study to evaluate tolerability following treatment with indacaterol salts 
(maleate, xinafoate, and acetate using the Aerolizer™ device, a SDDPI) in comparison to 
placebo in 98 subjects with mild to moderate persistent asthma.


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All three indacaterol salts were generally safe and well tolerated. There were no deaths or 
serious adverse events. Two subjects withdrew due to adverse events. These were not 
suspected to be study drug related. The most common adverse event was cough. This was 
predominantly mild or moderate. There were no cough-related study withdrawals.
There was a marked increase in the incidence of cough 5 minutes after inhalation 
(as evaluated by direct and targeted observation by the investigator) of each of the indacaterol 
salts compared to placebo; the incidence rates following inhalation of indacaterol maleate, 
indacaterol acetate, indacaterol xinafoate, and placebo were 69%, 28%, 20%, and 7%, 
respectively. There was a significantly lower incidence of PI cough with the xinafoate and 
acetate salts in comparison to the maleate salt. The cough was characterized by a rapid onset, 
short duration and was predominantly mild to moderate in severity.
Study CQAB149D2301 was a multi-center, randomized, double-blind, placebo-controlled, 
multiple-dose, 4-way cross-over study consisting of four treatments namely indacaterol 
maleate, indacaterol xinafoate, indacaterol acetate (each at 400 μg) and matching placebo 
inhaled via the Concept1 device in 30 subjects with persistent asthma. Indacaterol, in all three 
salt forms, was well tolerated by subjects with no unexpected events observed and no subject 
having a serious adverse event. Only one subject was withdrawn from the study for severe 
adverse events that were not considered to be related to study drug. There were no clinically 
relevant changes in laboratory values or in ECG and vital signs. Cough within 5 minutes of 
dosing affected up to 59% subjects in the indacaterol maleate group. These coughs were 
mainly of moderate severity on day 1 but mainly mild thereafter. The incidence of cough was 
lower with the other two salts (14% patients in each group on Day 7).
Study CQMF149E2203 was a multicenter, randomized, double-blind, placebo-controlled, 
12-week treatment, parallel-group study to assess the efficacy, safety, and pharmacokinetics 
of indacaterol acetate (75 and 150 μg o.d.) inhaled via the Concept1 device in patients with 
persistent asthma. Both indacaterol acetate treatment groups were safe and well tolerated. 
There were no deaths in this study. Besides one subject who discontinued the study due to an 
AE (asthma), there were no SAEs or discontinuations due to SAEs in the indacaterol acetate 
150 μg group. The frequency of SAEs and discontinuations to AEs or SAEs was similar 
across the indacaterol acetate 75 μg and the placebo groups. The incidence of AEs and 
discontinuations from study was lower in indacaterol acetate 150 μg treatment group 
compared with the indacaterol acetate 75 μg and placebo groups.
1.3.2
Human pharmacokinetic data
1.3.2.1
Indacaterol Maleate
Absorption
The median time to reach peak serum concentrations of indacaterol delivered as lactose dry 
powder formulation in the Concept1 device was approximately 15 minutes after single or 
repeated inhaled doses. Systemic exposure increased with increasing dose (from 150 μg to 
600 μg) in a dose proportional manner on repeated once-daily dosing via Concept1 and was 
about dose-proportional in the dose range of 75 µg to 150 µg Accumulation factors (Racc; i.e. 
Day 14/Day 1 or Day 15/Day 1 ratios) for AUC and Cmax were in the range of 2.9 to 3.8 and 


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1.6 to 2.8, respectively at steady-state of once-daily doses between 75 μg and 600 μg. 
Apparent systemic clearance (CL/F) did not appear to change on repeated dosing. 
Absolute bioavailability of an inhaled dose was on average 43%-45%.
Distribution
The high apparent volumes of distribution (Vz/F) seen in all studies indicated that inhaled 
indacaterol once absorbed into systemic circulation was distributed extensively throughout the 
body. After intravenous infusion the volume of distribution (Vz) was 2,557 L thus confirming 
extensive distribution of indacaterol throughout the body. The in vitro human serum and 
plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively, consistent with ex vivo 
protein binding measurements. Mild-to-moderate hepatic impairment did not alter the protein 
binding of indacaterol. Indacaterol had an in vitro blood-to-plasma concentration ratio of 1.2.
Biotransformation/Metabolism
After oral administration of radiolabeled indacaterol in a human ADME study, indacaterol 
itself was the main component in serum, accounting for over one-third of the total drug related 
AUC0-24h. A hydroxylated derivative was the most prominent metabolite in serum. A direct 
phenyl-O-glucuronide and hydroxylated glucuronide were also prominent metabolites. 
A diastereoisomer of the hydroxylated derivative, an N-glucuronide of indacaterol and C- and 
N-dealkylated products were further metabolites identified.
The key enzymes responsible for metabolic clearance of indacaterol are UGT1A1 and 
CYP3A4. In vitro investigations indicated that UGT1A1 was the only UGT isoform that 
metabolized indacaterol to the phenolic-O-glucuronide. The oxidative metabolites were found 
in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. It was concluded that 
CYP3A4 is the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro 
investigations further indicated that indacaterol is a low affinity substrate for the efflux pump 
P-glycoprotein (P-gp).
Clinical drug interaction studies were carried out using potent and specific inhibitors of 
CYP3A4 
and 
P-gp 
(i.e. 
ketoconazole 
(Study 
QAB149A2311), 
erythromycin 
(Study QAB149B2220), 
ritonavir 
(Study 
QAB149B2107) 
and 
verapamil 
(Study QAB149B2216)). Verapamil was used as the prototypic inhibitor of P-gp and resulted 
in 1.4- to 2-fold increase in AUC and 1.5-fold increase in Cmax. Co-administration of 
erythromycin resulted in an increase of 1.4- to 1.6-fold for AUC and 1.2-fold for Cmax. 
Combined inhibition of P-gp and CYP3A4 by the very strong dual inhibitor ketoconazole 
caused a 1.9-fold and 1.3-fold increase in AUC and Cmax respectively. Concomitant 
treatment with another dual inhibitor of CYP3A4 and P-gp, ritonavir, resulted in a 1.7-fold 
increase in AUC, whereas Cmax was virtually unaffected. Given the safety data of study 
QAB1492339 and of the pivotal studies (which both confirmed safe use of a 600 μg o.d. 
dosage regimen), the magnitude of exposure increases due to drug-interactions do not raise 
any safety concerns for therapeutic doses of 75 μg o.d. or 150 μg o.d.
In-vitro investigations have indicated that indacaterol is devoid of any potential to cause 
metabolic drug interactions (by inhibition or induction of cytochrome P450 enzymes, or 
induction of UGT1A1) with medications at the systemic exposure levels achieved in clinical 
practice.


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Elimination
The available data suggest that elimination of systemically available indacaterol is due to a 
variety of processes, including 1) P-gp transport of indacaterol, 2) O- and N-glucuronidation 
of indacaterol (UGT1A1), 3) oxidative metabolism by CYP3A4, possibly followed by 
glucuronidation, 4) biliary excretion of glucuronides into the gut, where indacaterol and 
hydroxylated metabolites are liberated and excreted with the feces, and 5) renal excretion. 
The quantitative contribution of each hepatobiliary elimination process cannot be assessed. 
However, the clinical drug interaction studies suggest that P-gp mediated transport and 
CYP3A4-metabolism are major processes. Mild and moderate hepatic impairment did not 
change systemic clearance to a clinically meaningful extent.
Indacaterol serum concentrations declined in a multiphasic manner. The apparent terminal 
half-life determined in individual studies, depending on the sampling time interval and the 
assay sensitivity, ranged from 45.5 to 126 h. The effective half-life for accumulation was 
calculated according to a method (Boxenbaum and Battle 1995) based on the actually 
observed accumulation of indacaterol after repeated dosing. The results indicated that the 
effective half-life ranged from 40 to 56 hours for once-daily doses between 75 μg and 600 μg. 
This is consistent with the observed time to steady state of approximately 12 to 15 days.
1.3.2.2
Indacaterol acetate
Study CQAB149D2301 was conducted with an early proof-of-concept type formulation 
(see Section 1.3.1). Following oral inhalation of 400 μg indacaterol via the Concept1, the 
pharmacokinetic profiles and systemic exposures of indacaterol acetate and indacaterol 
maleate in plasma were similar. The ratio of geometric means on Day 7 for AUC0 -24h 
(acetate vs. maleate) was 0.975 [90% CI: (0.908, 1.046)] and for Cmax 0.976 [90% CI: (0.885, 
1.077)].This result showed that the PK profile for indacaterol was similar following oral 
inhalation as acetate or maleate via the Concept 1 device, which allowed for bridging to the 
existing human PK data for indacaterol maleate.
1.3.3
Human pharmacodynamic data
1.3.3.1
Indacaterol maleate
A number of clinical trials have investigated the efficacy of inhaled indacaterol maleate in 
subjects with obstructive airway diseases, specifically asthma and COPD. A number of single 
and multiple dose dry powder and pressurized metered dose inhaler (pMDI) devices have 
been employed and doses of up to 3000 μg (single dose) and 800 μg (multiple dose for 
28 days)/600 μg (multiple dose for 52-weeks) have been evaluated.
Data from an extensive clinical development program demonstrate that indacaterol maleate is 
an effective bronchodilator with a rapid onset and full 24 h duration of action in both asthma 
and COPD (approved indication for Onbrez® Breezhaler® (indacaterol maleate)). 
The bronchodilator effect data in subjects with asthma are also summarized below as this 
reflects the target population in this current study.


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Indacaterol maleate in patients with COPD
Lung function
Onbrez® Breezhaler®, administered once a day at doses of 150 μg and 300 μg, demonstrated 
clinically meaningful improvements in lung function. At the 12-week primary endpoint 
(24-hour trough FEV1), the 150 μg dose resulted in a 130-180 mL increase compared to 
placebo (p<0.001) and a 60 mL increase compared to salmeterol 50 μg twice a day (p<0.001). 
The 300 μg dose resulted in a 170-180mL increase compared to placebo (p<0.001) and a 
100 mL increase compared to formoterol 12 μg twice a day (p<0.001). Both doses resulted in 
an increase of 40-50mL over open-label tiotropium 18 μg once a day (150 μg, p=0.004; 
300 μg, p=0.01). The 24-hour bronchodilator effect of Onbrez® Breezhaler® was maintained 
from the first dose throughout a one-year treatment period with no evidence of loss in efficacy 
(tachyphylaxis) (Indacaterol (QAB149) IB).
Symptomatic benefits
Both doses demonstrated statistically significant improvements in symptom relief over 
placebo for dyspnea and health status (as evaluated by Transitional Dyspnea Index [TDI] and 
St. George's Respiratory Questionnaire [SGRQ], respectively). The magnitude of response 
was generally greater than seen with active comparators (salmeterol and tiotropium). 
In addition, patients treated with Onbrez® Breezhaler® required significantly less rescue 
medication, had more days when no rescue medication was needed compared to placebo and 
had a significantly improved percentage of days with no daytime symptoms.
Pooled efficacy analysis over 6 months treatment demonstrated that the rate of COPD 
exacerbations 
was 
statistically 
significantly 
lower 
than 
the 
placebo 
rate. 
Treatment comparison compared to placebo showed a ratio of rates of 0.68 (95% CI 
[0.47, 0.98]; p-value 0.036) and 0.74 (95% CI [0.56, 0.96]; p-value 0.026) for 150 μg and 
300 μg, respectively (Indacaterol (QAB149) IB) (Onbrez® Breezhaler® SmPC).
Indacaterol maleate in subjects with asthma
The completed clinical studies have demonstrated the efficacy of indacaterol in subjects with 
asthma. Collectively, these studies show that indacaterol provides efficacious bronchodilation 
in subjects with asthma similar to that achieved in subjects with COPD. 
The efficacy of indacaterol in subjects with asthma has been investigated across a broad range 
of variables including trough FEV1, peak FEV1, time to onset of action, and AUC at specified 
time points.
Randomized trials in subjects with asthma compared the impact of indacaterol on lung 
function in terms of FEV1. Clinically significant improvements in trough FEV1, FEV1(AUC22-
24h), FEV1(AUC0-4h), and peak FEV1 were observed with once-daily indacaterol 100, 200, 300,
400 and 600 µg vs. placebo. Indacaterol 300 and 600 µg q.d. showed significantly greater 
improvements in trough FEV1 than formoterol 12 µg b.i.d. (p<0.01).


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A rapid onset of action has been demonstrated for indacaterol compared with placebo. 
Significant improvements in FEV1 were observed with indacaterol 200 and 400 µg within 
5 min post-dose vs. placebo (p<0.05). Indacaterol has also been shown to have a more rapid 
onset of action compared with salmeterol and a comparable onset versus the short-acting 
β2-agonist, salbutamol. A clinically relevant increase in mean FEV1 was seen at 5 min 
post-dose for salbutamol 200 µg, between 15 and 30 min post-dose for indacaterol 200 µg and 
between 1 and 2 h post-dose for salmeterol 50 µg. 
Clinically significant improvements in FEV1 achieved with indacaterol therapy post-dose 
were maintained for at least 24-h compared with placebo. A single 200 µg dose of indacaterol 
demonstrated a prolonged duration of action (FEV1) when compared to a single 50 µg dose of 
salmeterol and a single 200 µg dose of salbutamol.
Indacaterol acetate in subjects with asthma
Studies conducted with indacaterol acetate show similar improvements in lung function and 
therefore suggest that the efficacy of indacaterol is independent from the used salt form.
Study CQAB149D2301, is a randomized, double-blind, placebo-controlled, multiple-dose, 
4-way cross-over study consisting of four treatments namely indacaterol maleate, indacaterol 
xinafoate, indacaterol acetate (each at 400 μg) and matching placebo inhaled via the Concept1 
device in 30 subjects with persistent asthma. The acetate salt, in this population, resulted in a 
change in FEV1 similar to that of the maleate salt with no differences in systemic exposure or 
safety parameters.
In Study CQMF149E2203, a randomized, double-blind, placebo-controlled, 12-week 
treatment, parallel-group study to assess the efficacy, safety and pharmacokinetics of 
indacaterol acetate (75 and 150 µg o.d.) in 335 subjects with persistent asthma, indacaterol 
acetate 150 μg and 75 μg both showed statistically significant superiority of trough FEV 1 to 
placebo at Week 12. The increase in LS mean of trough FEV 1 at Week 12 in the indacaterol 
acetate 150 μg group was 106 ml and 80 ml in the indacaterol acetate 75 μg group compared 
with placebo.  
1.4
Study purpose
This study is designed to determine the steady-state pharmacodynamics, safety, tolerability, 
and systemic pharmacokinetics of indacaterol maleate 150 μg (the salt form used in the 
approved product Onbrez® Breezhaler®) and indacaterol acetate 150 μg ( the salt form used in 
clinical development of QVM149 and QMF149 as a FDC with mometasone furoate) in 
subjects with asthma. The data from this study will support clinical development and 
registration of QMF149 and QVM149 by enabling bridging to the safety database of the 
approved monotherapy product, indacaterol maleate.


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2
Study objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the bronchodilator effect of orally 
inhaled indacaterol salts (maleate and 
acetate) in subjects with asthma compared to 
placebo as measured by trough FEV1 after 
14 days of treatment.

Trough FEV1 (mean of FEV1 at 23 h 
15 min and 23 h 45 min post-dose) 
after 14 days of treatment
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary 
objective(s)

To assess the steady state pharmacokinetics 
of indacaterol after 14 days of treatment of 
orally inhaled indacaterol salts (maleate and 
acetate) in subjects with asthma.

AUC0-24h,ss and Cmax,ss,Tmax,ss, 
Cmin,ss, Cav,ss and Frel 

To assess the bronchodilator effect of orally 
inhaled indacaterol salts (maleate and 
acetate) in subjects with asthma compared to 
placebo as measured by:

Time to peak FEV1 on Day 14

FEV1, FEV1 (% predicted), FVC, FVC 
(% predicted), FEV1/FVC, and FEF25-
75% at each post-dose time point after 14 
days of treatment

Standardized FEV1 AUC from pre-dose 
to 4 h post-dose on Day 14 of treatment

FEV1, FVC, and FEF25-75%  after 
14 days of each treatment period

To assess the bronchodilator effect of 
indacaterol acetate, indacaterol maleate, and 
placebo by comparing the pre-medication 
(morning (pre-dose) and evening) peak 
expiratory flow (PEF) rate collected between 
days 8 and 14 of each treatment. 

Peak expiratory flow rate collected 
daily between days 8 and 14 during all 
three treatment periods (indacaterol 
acetate, indacaterol maleate, and 
placebo)

To assess rescue medication usage for 
indacaterol salts (maleate and acetate) in 
comparison to placebo.

Usage of rescue medications as 
reported by subjects via diary during 
each treatment arm


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Secondary objective(s)
Endpoints related to secondary 
objective(s)
To assess the safety and tolerability of 
indacaterol salts (maleate and acetate) in 
comparison to placebo of14 days of 
treatment in each treatment period.
Safetyassessments during each 
treatment period including:
Adverse Events and Serious 
Adverse Events
Vital signs
Hematology
Blood Chemistry
Urinalysis
ECG evaluation
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3
Investigational plan
3.1
Study design
Figure 3-1 Study Design
This is a confirmatory, randomized, double-blind, placebo-controlled, three-period complete 
block, cross-over study in approximately 54 subjects with asthma.
Once informed consent is obtained, subjects will be assessed for study eligibility during the 
14 day screening epoch. Subjects are only eligible to participate in the study if their inhaled 
corticosteroid (ICS) dose has been stable for at least 4 weeks prior to screening. During this 
time, subjects will continue their ICS regimen but will be required to abstain from using any 
other asthma medication as well as lung function assessments following the cessation periods
as detailed in Section 5.3 and Table 5-2.
Short-acting β2-agonist bronchodilators will be provided to be used as rescue medication 
throughout the trial, as detailed in Section 5.3 and Table 5-1. Rescue medication use will be 
recorded in the patient diary.
The 2-week screening epoch may be divided into more than one visit for logistical reasons.  
Eligible subjects may be re-screened in case they are not included in the study within the 
allowed 2-week screening epoch.  Subjects may also be re-screened at the discretion of the 
investigator, and following discussion with the Medical Monitor and/or Sponsor, if the reason 
for screen failure was considered temporary in nature.  All screening data must be obtained 
within 2 weeks prior to administration of study medication.  Subjects who are re-screened will 
re-consent and be allocated a new screening number. 


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During screening, subjects will be provided with an electronic device to collect information 
on rescue medication use, mouth rinsing, ICS use compliance, and will collect and store PEF 
meter measurements. All subjects will be trained on the use of this device. Diary entries will 
be made daily throughout the entire study duration (including washout periods). Stopping 
rules with regard to rescue medication and PEF rate should be adhered to by the investigator 
to ensure the patient remains stable. Training of the Concept1 inhalation device will occur at 
screening and then will be reinforced at each onsite study visit. Subjects who are unable to 
demonstrate correct use of the Concept1 device will not be eligible to enter the treatment 
epoch.
Subjects who meet all of the eligibility criteria will be randomized to one of six treatment 
sequences as described in Figure 3-1. They will receive their first dose on the morning of 
Day 1. Subjects will be dosed between 06:00 a.m. and 10:00 a.m. under the guidance and 
supervision of the investigator or designee after an additional training for correct use of the 
Concept1 inhalation device. Dosing of investigational product and background ICS 
medication should occur at approximately the same time of the day throughout the study. 
For details of administration of investigational product please refer to Section 6.5. PEF 
measurements (if not already performed at home on the morning of Day 1 or Day 14) should 
be taken prior to pre-dose spirometry and safety assessments 
For further details, refer to the Assessment schedule.
On Day 1, subjects will leave the clinic after the completion of the required asses sments and 
will dose at home once daily in the morning on Days 2 to 13. During days 2 -13, subjects will 
record drug administration, PEF measurements, mouth rinsing, and rescue medication use in 
their diary. Subjects will be domiciled at the clinic on the morning of Day 14, for drug 
administration and Day 14 visit assessments. For details, refer to the Assessment schedule. 
Subjects will be discharged on Day 15 following the final PK and safety blood sample dr aw 
and completion of Day 15 assessments.
A washout period of 7 - 14 days will separate each treatment period. Apart from the pre-dose 
spirometry and safety assessments on Day 1 which will only be done before Treatment period 
1, the assessments for Treatment Periods 2 and 3 will be identical to Treatment period 1 
(refer to the Assessment schedule for Treatment periods 2 and 3 assessments).
Epoch Completion assessments must be conducted for subjects who complete all three 
treatment periods or at any time a subject early terminates from the trial. . The last visit (Day 
65) of Treatment period 3 will also be the end of study visit. For assessments that are listed in 
both Day 65 and in Epoch completion, the assessment is to be completed once. Subjects 
should be discharged from the site after the completion of Day 15 assessments for all 3 
periods. Serious Adverse Event (SAE) reporting after the End of Study visit is described in
Section 9.2.2 (SAE reporting).
3.2
Rationale of study design
Long action ß2 agonists are recommended in asthmatics not adequately controlled with ICS 
alone. In addition, long-acting ß2 agonists are not recommended in asthmatics without ICS 
background therapy. Therefore subjects with asthma requiring daily treatment with an ICS (i.e. 
maintenance treatment) to achieve control have been specifically selected for this study.


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A 14-day treatment crossover design is chosen to characterize lung function effects of once 
daily indacaterol maleate and indacaterol acetate compared to placebo in subjects with asthma. 
Bronchodilator effects of indacaterol are expected to reach steady state with no additional 
improvements in lung function after 14 days of treatment. For further details please refer to 
Section 3.3. 
The crossover design has been selected for this study as the intra-subject variability of the 
primary endpoint (FEV
1) islower than the inter-subject variability in this patient population 
thereby allowing the total number of subjects studied to be minimized without impacting 
statistical power. The utilization of a Williams design is efficient with the use of six sequences 
of seven subjects/sequence allowing balance for first order carryover. For once daily dosing 
regimens of indacaterol, the effective half-life of accumulation (T1/2,acc), of indacaterol 
rangesfrom40 to 56hours. Therefore, the maximum expected washout period based on 
T1/2,acc would need to be approximately 12 days [(5 x T1/2)/24]. Aspharmacokinetic 
assessments will only be completed at steady state i.e. at the end of each treatment period, the 
duration between PKassessments in successive treatment periods in this study will be 
effectively 21to 28-days (14 days treatment periods separated by 7-14 day washout periods). 
In addition, this washout is considered appropriate with regards to the measured primary PD 
effect (trough FEV1), with the effect of indacaterol on FEV1 lasting for approximately 
48-hours after the last dose (Study CQAB149B2223).
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The lowest dose of indacaterol approved for the maintenance therapy for COPD in the EU,
Japan,and other countries worldwide (outside of the US and Canada) is 150 μg given once 
daily. This dose is proposed to be used as part of the FDC in both asthma and COPD. 
Thisdose has been discussed and agreed for evaluation in Phase III studies with competent 
authorities. Therefore, this dose and regimen are considered appropriate and relevant for 
evaluating the comparability of indacaterol maleate and indacaterol acetate in this study.
The duration of treatment per treatment period is 14 days. Indacaterol maleate achieves 
PD(Studies CQAB149B2357 and CQAB149B2235S) and PK steady state 
(StudyCQAB149B2339) within 14 days. The PD and PK steady state were confirmed in a 
12week, lung function study (CQMF149E2203) with indacaterol acetate in subjects with 
asthma.  In this study, a near maximal FEV1
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effect was observed on Day 2 of treatment. 
While there are no further primary data establishing the PD and PK steady states for 
indacaterol acetate, based on the comparability of the two salts from the 7-day PD and 
systemic exposure data from Study CQAB149D2301 indacaterol maleate and acetate are not 
expected to differ with regards to PD and PK following administrationof an identical nominal 
dose.


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3.4
Rationale for choice of comparator
A placebo control is included to allow calibration of the overall bronchodilator response for 
indacaterol when formulated as either salt delivered via the Concept1 in subjects with asthma. 
Indacaterol maleate is considered an active calibrator rather than a comparator in this study 
because the study is not adequately powered for a direct comparison of the two salts.
3.5
Rationale for choice of background therapy
Subjects will continue on stable background ICS therapy as established prior to study entry, 
thereby justifying treatment with placebo. Subjects will maintain their preexisting, stable 
medical regimen for treatment of preexisting medical conditions throughout the study.
3.6
Purpose and timing of interim analyses/design adaptations
No interim analysis has been planned.
3.7
Risks and benefits
The risks to which subjects 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 treatments indacaterol acetate and maleate.
Subjects 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 subjects 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 PK assessments and safety laboratory. Puncturing of the veins can 
cause discomfort, pain, hematoma, or in rare cases lead to an infection.
Indacaterol acetate, administered at doses of up to 400 μg (and for up to 12 weeks) via the 
Concept1 inhalation device has been shown to be safe and well tolerated in previous studies 
conducted in subjects with asthma (QAB149B2102 - single dose; QAB149D2301 – 1 week; 
QMF149E2203 – 12 weeks). This is substantiated with studies using indacaterol maleate, 
which, administered at doses of up to 600 μg (and for up to 6-months) via the Concept1 have 
been shown to be safe and well tolerated in previous studies conducted in subjects with 
asthma (QAB149B2102 - single dose; QAB149D2301 – 1 week; QAB149B2357 – 2 weeks; 
QAB149B2223 – 2 weeks: QAB149B2338 – 6 months). Overall, the safety and tolerability 
profile of indacaterol is consistent with the known profile of the class of ß2 agonist agents.
In principle, the characteristic adverse effects of inhaled β2-adrenergic agonists can occur as a
result of activation of systemic β-adrenergic receptors after inhalation of indacaterol.
The most common adverse effects include skeletal muscle tremor and cramps, insomnia,
tachycardia,
decreases
in
serum 
potassium,
and 
increases 
in 
plasma
glucose. 
Detailed information is available in the IB and in the SmPC for Onbrez® Breezhaler®.
The most common adverse reactions of indacaterol observed in clinical trials at the 
recommended doses were nasopharyngitis, upper respiratory tract infection, cough, headache, 


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and muscle spasms. Thevast majorityof these cases wasmild or moderate and became less 
frequent if treatment was continued.
There may be a potential risk related to changing patient treatment as they need to comply 
with allowed concomitant medication and bronchodilator washouts.  The risk of clinical 
deterioration will be minimized by the following eligibility criteria and assessments 
completed from screening and throughout the study including washout periods:
For this study, only subjects who have been on a stable dose of ICS for at least 4weeks 
prior to screening are eligible for participation. Subjects will be required to continue their 
stable steroid dose throughout the study. 
Subjects who were previously intubated for severe asthma, recently hospitalized for 
asthma exacerbation, or treated for a lower respiratory tract infection, will not be allowed 
to participate in the study.
The PEF rate will be assessed throughout the study (including washout periods). 
Withdrawal criteria related to this assessment will mitigate risk of clinical deterioration.
The dose and frequency ofShort Acting Beta Agonists(SABAs)administered will be 
monitored throughout the study. Subjects who note excessive use of SABAs will be 
withdrawn from the study. 
There may be a small potential risk of a hypersensitivity reaction (including anaphylactoid 
reactions and anaphylaxis) to either indacaterol maleate, indacaterol acetate, or one of the 
excipients of the formulations. The risk will be limited by the exclusion of individuals with 
prior hypersensitivity to indacaterol, drugs of the same class or with similar chemical structure 
or its excipients.
Reflex bronchoconstriction can occur as an unspecific intolerance reaction to inhaled drugs. 
Subjects are under clinical observation at the site when inhaling the drugs for the first time so 
an intolerance reactioncan be detected. When indacaterol is inhaled,subjects may react with 
short-lasting cough immediately after inhalation; this post-inhalational cough was not 
associated with other symptoms or bronchial obstruction in previous studies.
There may be unknown risks of indacaterolwhich may be serious.
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and following study discontinuation criteria.
3.7.1
Blood sample volumes
A maximum of approximately 250mL of blood 
 is planned to be collected over a period of approximately 90days, from each subject 
as part of the study. Additional samples for monitoring of any safety findings would be in 
addition to this. This is not considered to be a risk for this population.
Timing of blood sample collection isoutlined in Section 8.1(Assessment schedule).
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage,and shipment information.
See Section 8.9
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regarding the potential use of residual samples. 


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4
Population
Asthma patients
The study population will be comprised of male and female patients aged 18 and above with 
asthma. Approximately 54 adult patients will be randomized with the intention that at least 
42 subjects complete the study. 
The investigator must ensure that all subjects being considered for the study meet eligibility 
criteria. No additional exclusions should be applied by the investigator.
Subject selection is to be established by checking through all inclusion and exclusion criteria 
throughout the screening epoch and prior to the first dose in Treatment period 1. 
Source documentation relating to eligibility must be stored at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
4.1
Inclusion criteria
Asthma 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 for a period of at least 1 year 
prior to screening and who additionally meet the following criteria:

Patients receiving daily treatment with an inhaled corticosteroid up to the maximum dose 
per day (as indicated in the package leaflet), on a stable regimen (dose cannot have changed 
within 4 weeks prior to screening) for at least 4 weeks prior to screening.
4. Pre-bronchodilator FEV1 ≥50 % and ≤ 90% 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

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 within 30 minutes 
after administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at 
screening. All patients must perform a reversibility test at Visit 1 (screening). 
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.
Spacer devices are not permitted during reversibility testing.


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At screening, and prior to the first dose of Treatmentperiod 1, vital signs (systolic and 
diastolicblood pressure and pulse rate) will be assessed in the sitting position and again 
(when required) in the standing position as outlined in the SOM. 
 
Hypertensive subjects should have been on stable antihypertensivetherapy for at least 4 
weeks prior to screening to be included in the trial.
6. Subjects 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/m
2.
7. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
4.2
Exclusion criteria
Asthma patients fulfilling any of the following criteria are noteligible for inclusion in this 
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 / adrenoceptoragonist agents

Corporate Confidential Information
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 6 weeks of screening. If patients 
experience an asthma attack/exacerbation requiring systemic steroids or hospitalization or 
emergency room visit during the screening epoch, they may be re-screened 6 weeks after 
recovery (intheinvestigator
's judgment) from the exacerbation.
3. Patients who have had previous intubation for a severe asthma attack/exacerbation.
4. 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.
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.


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6. Patients with any chronic conditions affecting the upper respiratory tract (e.g. chronic 
sinusitis) which in the opinion of the investigator may interfere with the study evaluation 
or optimal participation in the study.
7. Patients who have a decline in PEF from the reference PEF (taken at screening) of ≥30% 
for 5 of 6 consecutive scheduled PEF readings (readings taken at morning and evening) 
during at least 3 days of screening epoch prior to randomization.
8. Patients who require the use of ≥12 puffs / 24 hours of rescue medication for 48 hours 
(over two consecutive days) during screening prior to randomization.
9. Patients with a history of clinically relevant bronchoconstriction upon repeated forced 
expiratory maneuvers.
10. History of paradoxical bronchospasm in response to inhaled medicines.
11. History or current diagnosis of 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.
12. Patients with a history of myocardial infarction within the previous 12 months.
13. Patients who have a clinically significant ECG abnormality (as determined by the 
investigator) at screening and prior to randomization.
14. 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).
15. Patients who, either 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.
16. Concomitant use of an agent known to prolong the QT interval unless it can be 
discontinued for the duration of study.
17. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
of whether there is evidence of local recurrence or metastases.


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18. 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.

In this study, ICS background therapy is required throughout the study. 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 2 weeks after stopping of investigational drug. Highly effective 
contraception methods include:

Total abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug.  In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or 
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.
A pregnancy test will be done on all female patients regardless of reported reproductive 
status at specified time points throughout the study.
If requested by local authorities, additional and more frequent pregnancy testing may be 
performed.
19. Patients with Type I diabetes or uncontrolled Type II diabetes (HbA1c > 9%) at screening.
20. Plasma donation > 150 mL within 7 days prior to first dosing.
21. 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.
22. Hemoglobin levels below the laboratory lower limit of normal and considered clinically 
significant at screening.
23. Significant illness which has not resolved within two (2) weeks prior to initial dosing.
24. Recent (within the last three years) and/or recurrent history of autonomic dysfunction (e.g., 
recurrent episodes of fainting, palpitations, etc.).


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25. Patients receiving medications in the classes listed in Section 5.2 (Prohibited treatment)
should be excluded.
26. 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.
27. Current smokers (urine cotinine > than the laboratory’s lowest level of quantification 
(LoQ of 500 ng/mL or lower)) 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.).
28. Any surgical or medical condition that might significantly alter the absorption, distribution, 
metabolism, or excretion of drugs, or which may jeopardize the subject in case of 
participation in the study. The investigator should make this determination in 
consideration of the subject’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
at screening.
29. Patients who have a clinically significant laboratory abnormality at screening in the 
opinion of the investigator (one re-test is allowed before the randomization). If the retest is 
outside the reference range but is not clinically significant in the opinion of the 
investigator, the patient can be enrolled.
30. Patients with a serum potassium or magnesium level below the laboratory limit of normal 
at screening.
31. History of being immunocompromised; immunodeficiency diseases, including a positive 
HIV (refer to Section 6.2) test result at screening.
32. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result at screening.
33. 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.
34. 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.
35. Patients with seasonal allergy whose asthma is likely to deteriorate during the study period
in the investigator’s judgment.
36. No person who is considered vulnerable or person who is in detention may participate in 
this study.


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37. 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.
38. Patients unable to use the Concept1 dry powder inhaler or a metered dose inhaler.
39. 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.
40. Patients with narcolepsy and/or insomnia.
41. Patients who are directly associated with any members of the study team or their family 
members
42. Patients who do not maintain regular day/night, waking/sleeping cycles (e.g., night shift 
workers).
43. Subjects incapable of understanding the nature, significance and implications of the 
clinical trial and therefore incapable of giving consent personally
44. No additional exclusions may be applied by the investigator, to ensure that the study 
population will be representative of all eligible patients.
5
Restrictions for Study Subjects
During recruitment, screening, and informed consent review, subjects must be informed and 
reminded of the restrictions outlined in this section. 
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. 
As ICS background therapy is required throughout this study, women of childbearing 
potential cannot participate unless they agree to use highly effective measures of 
contraception. Please refer to Section 4.2 (Exclusion criteria) for details of contraception 
requirements for the study.


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5.2
Prohibited treatment
Restrictions for medications other than study drug and background ICS therapy apply 
according to below tables:
Table 5-1
Withholding period of bronchodilators prior to spirometry
Class of Medication
Minimum cessation prior 
spirometry
SABA
≥ 6 hrs
SAMA
≥ 8 hrs.
LABA or fixed dose combination of ICS/LABA b.i.d.
≥ 24 hrs.
LABA or fixed dose combination of ICS/LABA o.d. or tiotropium
≥ 48 hrs.
xanthines
≥ 7 days
Table 5-2
Prohibited asthma medication during treatment period
Medication
Action to be taken
Long-acting anti-cholinergic agents (e.g. tiotropium bromide)
subject to be withdrawn 
Short-acting anti-cholinergics
subject to be withdrawn 
Fixed-combinations of long-acting β2-agonists and inhaled 
corticosteroids
subject to be withdrawn 
Long-acting β2-agonists (other than study drug)
subject to be withdrawn 
Short acting β2-agonists (other than those prescribed in the study)
subject to be withdrawn 
Theophylline and other xanthines
subject to be withdrawn 
Parenteral or oral corticosteroids  
subject to be withdrawn
Newly introduced or increased dose leukotriene antagonists, 
ketotifen, inhaled nasal cromolyn, nedocromil, inhaled nasal 
corticosteroid
subject to be withdrawn *
* Leukotriene antagonists, ketotifen, inhaled nasal cromolyn, nedocromil and inhaled nasal 
corticosteroids 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 
Baseline or as indicated 
Non-potassium sparing diuretics (unless administered as a 
fixed-dose combination with a potassium conserving drug)
7 days prior to Baseline
Non-selective systemic β –blocking agents
7 days prior to Baseline
Cardiac anti-arrhythmics Class Ia
7 days prior to Baseline
Cardiac anti-arrhythmics Class III
7 days, amiodarone 3 months prior 
to Baseline 
All antipsychotic agents (first, second, and third generation, 
inclusive of atypical antipsychotics). Combinations of 
antipsychotic agents with antidepressants are prohibited
14 days prior to Baseline
Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)
14 days prior to Baseline
Monoamine-oxidase inhibitors
14 days prior to Baseline
Systemic anticholinergics
7 days prior to Baseline
Mizolastin or terfenadine (H1 antagonists)
5 days prior to Baseline
Strong inhibitors of cytochrome P4503A e.g.ketoconazole
7 days prior to Baseline
Tricyclic antidepressants (Note that tetracyclics that are similar 
in class with regards to drug interaction are also to be
excluded)
14 days prior to Baseline
Other investigational drugs
30 days or 5 half-lives, whichever is 
longer prior to Baseline
Parenteral or oral corticosteroids
Within 30 days prior to baseline
Noradrenaline reuptake inhibitors
7 days prior to Baseline
Live attenuated vaccine
Must not administered within 30 days
prior to 1st dose and anytime 
thereafter during the trial.
5.3
Dietary restrictions and smoking
On study days when spirometry will be performed, patients should refrain from the following:

Alcohol for 4 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 

Strenuous activity for 12 hours prior to spirometry 

Intake of  xanthine (e.g. caffeine) containing food or beverages (i.e. coffee, tea, soda, 
chocolate) is not permitted at any time while the subjects are domiciled. During the 
out-patient phase of the study (Days 2-13), caffeinated beverages will be restricted to no 
more than 4 cups/day until after all assessments on Day 15 (for each Treatment period) 
are complete.

No grapefruit or grapefruit juice can be consumed for 14 days prior to the first dose ot 
Treatment period 1 until 24 hours following the last dose of Treatment period 3.


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
All subjects will fast overnight from midnight on Day 13 (water allowed). Dosing will 
occur in the morning of Day 14, between the hours of 06:00 and 10:00. On day 14, a 
standard lunch will be served at approximately 4 hours post-dose (i.e. between the hours 
of 10:00 and 14:00) and dinner will be provided at approximately 9 hours post-dose 
(i.e. between the hours of 16:00 and 19:00). When meal and blood draw times coincide, 
blood should be drawn before the meal is provided. On Day 14, no fluids are permitted for 
1 hour before and 1 hour after study drug administration, with the exception of fluid given 
for mouth rinsing following the inhalations. Otherwise, subjects should have a fluid intake 
of approximately 200 mL every 4 hours during waking hours on day 14 in addition to 
fluid taken with meals and medication. There are no fluid restrictions at any other times.
If a deviation occurs for any of the restrictions above, it must be noted in the CRF.
5.4
Other restrictions
No unusual (for individual patients) strenuous physical exercise for 7 days before first dosing 
of Treatment period 1 until after Study Completion evaluation.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drugs
Indacaterol maleate 150 μg, indacaterol acetate 150 μg, and matching placebo capsules will be 
prepared by Novartis and supplied to the investigator as single-blind patient kits with a tear 
off label along with the Concept1 devices.
Additional placebo capsules and Concept1 inhalation devices will also be supplied to train site 
staff and to allow the study subjects to ‘practice’ inhalation.
All patients must be trained on the use of the Concept1 during the screening epoch, with additional 
training provided throughout the study in accordance with the Assessment schedule.
A separate manual will be provided detailing instructions for use of the Concept1 inhalation 
device.


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Table 6-1
Overview of study medication
Study drug 
name
Formulation
Unit 
dose
Packaging
Provided by
Indacaterol 
maleate
Capsules with 
powder for 
inhalation
150 mcg
Supplied in single-blind patient
pack including Concept1 
devices
Novartis Drug Supply 
Management
Indacaterol 
acetate
Capsules with 
powder for 
inhalation
150 mcg
Supplied in single-blind patient
pack including Concept1 
devices
Novartis Drug Supply 
Management
Placebo
Capsules with 
powder for 
inhalation
0 mcg
Supplied in single-blind patient
pack including Concept1 
devices
Novartis Drug Supply 
Management
Concept1 
device
N/A
N/A
Supplied with IP
Novartis Drug Supply 
Management
Additional study treatment
All subjects participating in the study will continue to use an inhaled corticosteroid and 
remain on a stable dose and regimen throughout the study including the washout between 
treatment periods. These corticosteroids will be used according to their approved labels. 
The subjects' ICS compliance will be reviewed by the site in the medication diary.
All subjects participating in the study will be provided (locally sourced by the si te) with an 
inhaled, short-acting β2-agonist (salbutamol or any other short-acting β2-agonist at matching 
dose-strength) and allowed to use this throughout the study as needed. Use of salbutamol 
(or any other short-acting β2-agonist at matching dose-strength) will be recorded in a daily 
diary and if any patient meets stopping criteria (Section 7.5 (Study Stopping rules)) related to 
excessive use of salbutamol or any other short-acting β2-agonist at matching dose-strength, 
they will be withdrawn.
6.2
Treatment arms
Study treatments are defined as:

A: indacaterol maleate 150 μg via Concept1 device

B: indacaterol acetate 150 μg via Concept1 device

C: matching placebo capsules to indacaterol via Concept1 device
Subjects will be randomized to one of the following six 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
C
A
3
C
A
B
4
A
C
B
5
B
A
C
6
C
B
A


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6.3
Treatment assignment and randomization
At the randomization visit, all eligible subjects will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or delegate will contact IRT 
after confirming that the subject fulfills all eligibility criteria. IRT will assign a randomization 
number to the subject, that will be used to specify a treatment arm and the unblinded 
pharmacist will provide the correct medication. The medication will be provided as a single 
label tear off to maintain the blind outside of the pharmacy. The randomization number will 
not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigative staff.
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms. A separate 
medication list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to packs containing the investigational drug(s).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of patients.
The investigator will enter the screening number which will be kept throughout the study in 
the eCRF.
Table 6-3
Treatment Assignment Numbering
Randomization numbers
Replacement randomization numbers
5101 – 5166
6101 – 6166
6.4
Treatment blinding
This is a subject, investigator, and sponsor-blinded study. Subjects, investigators and sponsor 
will remain blinded to study treatment throughout the study, except where indicated below. 
At database lock, all roles can be unblinded. 
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 subject at a site for safety reasons (necessary for subject management) 
will occur via the process defined in (Section 6.7 (Emergency breaking of assigned treatment 
code)).


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Table 6-4
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & dosing
Safety event (single 
subject unblinded)
Subjects/Patients
B
B
UI
Site staff
B
B
UI
Unblinded site staff (see text for details) 
B
UI
UI
Drug Supply and Randomization Office
UI
UI
UI
Unblinded sponsor staff 
(see text for details)
B
UI
UI
Statistician/statistical programmer/data 
analysts
B
B
UI
Independent committees used for 
assessing interim results
B
B
UI
All other sponsor staff not identified above
B
B
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
6.5
Treating the subject
Indacaterol maleate, indacaterol acetate, and placebo will be administered via the Concept1 
inhalation device.  IP administration will occur at the site by the subject on Day 1 and Day 14 
under the guidance and supervision of site staff and will be administered by the subject at the 
subject's home on study days 2-13 for each treatment period.
Investigational product should be administered approximately between 6:00 a.m. and 
10:00 a.m. every day of each treatment period.
On Day 1 and 14 of Treatment period 1, investigational product (and background ICS 
medication) should be administered between 06:00 a.m. and 10:00 a.m and within ± 1h of 
each other. This means that time of dosing between Day 1 and Day 14 should not differ by 
more than one hour. On Day 1 and Day 14 of Treatment periods 2 and 3, investigational 
product (and background ICS medication) should be administered within ± 1h of the time of
study medication administration of Day 1 and Day 14 of Treatment period 1 respectively. 
This will ensure that assessments are done at approximately the same time of the day in each 
treatment period.
After each dose inhalation, subjects should rinse their mouths with water. Water used for 
mouth rinsing should be spat out and should not be swallowed.
One Concept1 inhalation device will be provided for each treatment period for a total of 3 
devices dispensed for the duration of the study. Subjects should re-use the Concept1 device 
for 14 sequential doses for each treatment period. 
The last dose on Day 14 should be taken at the site. An extra medication kit (in addition to 
the one dispensed to the subject) will be assigned for the Day 14 dosing, which will not be 
dispensed to the subject but kept at the site. On Day 14, one capsule should be taken from the 
kit kept at the site, and the subject should administer the capsule using the same Concept1 
device used during Days 1-13. No new device should be provided for the Day 14 dose.


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Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
See the Site Operations Manual for further details.
6.6
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted.
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must occur only when it is required to treat the subject safely. 
Most often, study treatment discontinuation and knowledge of the possible treatment 
assignments are sufficient to treat a study subject who presents with an emergency condition. 
Emergency treatment code breaks are performed using IRT. When the investigator contacts 
the system to break a treatment code for a subject, he/she must provide the requested subject 
identifying information and confirm the necessity to break the treatment code for the subject. 
The investigator will then receive details of the investigational drug treatment for the 
specified subject and a fax or email confirming this information. The system will 
automatically inform the study monitor for the site and the Study Team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to IRT in case of an emergency.   The investigator will need to provide: 

protocol number

study drug name (if available)

subject number
In addition, the investigator must provide oral and written information to inform the subject 
how to contact the investigator's backup in case of emergency when he/she is unavailable to 
ensure that un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject. 
6.8
Treatment exposure and compliance
For all study drug treatment administered in the clinic, compliance will be adhered to by 
administration under the guidance and direct supervision of the investigator/designee. 
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. 
For doses administered at the site, after inhalation in each treatment period, the capsule shell 
will be checked for residual powder. If residual powder is found, the inhalation procedure will 
be repeated up to a maximum of 3 times provided that total inhalation time does not exceed 
2 minutes. The finding will be recorded in the drug administration section of the (e)CRF. 
Compliance will be assessed by the investigator and/or designee
at each visit. 
This information should be captured in the source document at each visit. All study treatment 
dispensed and returned must be recorded on the Drug Accountability Log.


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Furthermore, compliance with the intake of inhaled corticosteroid and study drug treatment at 
home will be monitored closely by a review of a patient diary in which all subjects will record 
administration each day (washout periods). The subject must also be instructed to contact the 
investigator if he/she is unable to take the study treatment as prescribed at home. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
subjects on Day 14 of each treatment period during which they were treated with indacaterol 
acetate and indacaterol maleate, as detailed in Section 8.7 (Pharmacokinetics).
6.9
Recommended treatment of adverse events
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies eCRF.
6.10
Rescue medication
At screening, all patients will be supplied with an inhaled short-acting β2-agonist (100 μg/puff 
salbutamol or other short-acting β2-agonist at matching dose strength) which they will be 
instructed to use throughout the study as rescue medication. Rescue medication will be 
procured by the investigative site. Subjects should be instructed to abstain from taking rescu e 
medication within 6 hours of the start of each site visit unless absolutely necessary. If a 
subject does use their rescue medication within 6 hours of the spirometry assessments on 
Day 14 in either of the three treatment periods, the spirometry assessments should continue as 
planned, with the rescue medication usage recorded in the CRF and the data will be excluded 
from the PD analysis set.
During the study, subjects will record use of rescue medication in a patient diary. Patients 
should monitor this use carefully and if they use more than ≥12 puffs (100 μg/puff) over 
24 hours then they should call the site and inform the site personnel. If rescue medication use 
continues at this level for another 48 hours on two consecutive days then the patient will meet 
withdrawal criteria (Section 7.5 Study Stopping rules). 
Use of rescue medication must be recorded in the patient diary from screening until Day 15 of 
the Treatment period 3. Concomitant medications and significant non-drug therapies will be 
collected in the eCRF from screening through completion of the study.
6.10.1
Salbutamol usage
Rescue medication allowed during the conduct of the study is salbutamol (100 µg/puff) or any 
other short-acting β2-agonist at matching dose strength. Daily use of rescue medication will be 
recorded in the patient diary and this should be recorded in the rescue medication eCRF from 
screening until discharge of patients from the site on Day 15 of Treatment period 3.


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6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. 
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation 
in the study.
Regular asthma treatment
To be eligible patients must have received inhaled corticosteroids (ICS) at a regimen that has 
remained stable for at least 4 weeks prior to screening. Patients must continue their individual 
ICS dosing regimen and it must remain unchanged throughout the study.
The only exception allowed is:

When, in the medical opinion of the investigator, the patient experiences an asthma 
exacerbation requiring the use of additional anti-inflammatory therapy. If an exacerbation 
occurs during the screening epoch, the patient may be re-screened 6 weeks after resolution 
of the exacerbation. If the patient experiences an asthma exacerbation after randomization 
that requires the use of additional anti-inflammatory therapy, the patient must be 
withdrawn from the study and treated as clinically indicated.
In addition, SABA rescue medication supplied to the patient at screening may be used, as 
needed, for any asthma symptoms that may occur.
The following medications 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 stabilized (stable dose regimen for 4 weeks) prior to screening:

Topical corticosteroids in recommended doses and dosage regimens will be allowed for 
the treatment of eczema.

Antihistamines, inhaled nasal cromolyn, nedocromil, and inhaled nasal corticosteroids 
In addition these are allowed concomitant medications:

Maintenance immunotherapy (desensitization) for allergies is allowed if treatment has 
been stabilized for at least 3 months prior to screening, and remains unchanged throughout 
the course of the study.

Influenza and pneumonia vaccination is acceptable provided it is administered >48 hours 
prior to the first dose of Treatment period 1. Vaccinations within 48 hours and after are 
not allowed for this study.  


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
Selective Serotonin Reuptake Inhibitors at stable dose for at least 30 days prior to 
screening and during the trial.

Topical corticosteroids for skin disease at stable dose for at least 30 days prior to 
screening. 

H1-antagonists except mizolastin or terfenadine at stable dose/regimen for at least 5 days 
prior to screening.  
Adjustments to long acting β2–agonist
The use of any long-acting β2–agonist must be stopped during the screening epoch in 
accordance with Table 5-1.
Subjects using long-acting β2-agonists and combination medicines containing LABA must be 
switched to the as-needed use of short acting β2-agonist (i.e. salbutamol MDI) with cessation 
periods prior to lung function testing in accordance with Table 5-1. 
The steroid component of any fixed combination (ICS and β 2-agonist) therapy must be 
replaced with the equivalent monotherapy ICS plus the as needed use of a short-acting β2-
agonist that is provided to the patient at screening.
7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. 
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the investigator, or in the event of an early study termination decision, the 
date of that decision.
All subjects should have a safety follow-up call conducted 30 days after last visit. 
The information collected is kept as source documentation.  All SAEs reported during this
period must be reported as described in Section 9.2 and the Site Operations Manual.  
Documentation of attempts to contact the subject should be recorded in the source 
documentation.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration. Discontinuation of study treatment can be decided 
by either the subject or the investigator.
Study treatment must be discontinued and the subject withdrawn from the trial under the 
following circumstances:

Any severe or serious adverse event considered at least possibly related to the study 
medications.

Any other protocol deviation that results in a significant risk to the subject’s safety


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
Subject decision - subjects may choose to discontinue study treatment or withdraw 
informed consent for any reason at any time.

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation.

Pregnancy (see Section 8.6) and Section 9.6 (Pregnancy reporting)

Use of prohibited treatment as per recommendations in Section 5.2

For liver events, refer to Section 15-Appendix 1: Liver Event Definitions and Follow-up 
Requirements).

Patients who have a decline in PEF from the reference PEF (taken at screening) of ≥30% 
for 5 of 6 consecutive scheduled PEF readings (includes readings taken at morning and 
evening) at any point during the study (Section 4.2).  

≥ 3 consecutive days  in any one treatment period in which ≥12 inhalations/day of SABA 
rescue medication were used

Emergency department therapy resulting in the use of oral, parenteral, or non-study related 
inhaled corticosteroids therapy related to the treatment of worsened asthma.

Use of prohibited treatment as per Section 5.2 (Prohibited treatment).
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

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 period.
If a liver event occurs, follow guidelines outlined in Appendix 1 regarding discontinuation of 
study treatment. 
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 subject 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.


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The appropriate personnel from the site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently 
for any reason.
If discontinuation of study treatment occurs, investigator must determine the primary reason 
for the subject’s premature discontinuation of study treatment and record this information on 
the Dosage Administration eCRF.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should not be considered withdrawn from the study unless they withdraw their 
consent (see Section 7.3). Where possible, they should return for the assessments conducted 
on Day 15/End of Study Visit. If they fail to return for these assessments for unknown reasons, 
every 
effort 
(e.g. 
telephone, 
e-mail, 
letter) 
should 
be 
made 
to 
contact 
the 
subject/pre-designated contact as specified in Section 7.4. (Lost to follow-up). This contact 
should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact until the subject's end of 
study visit:

new /change in concomitant treatments

adverse events/serious adverse events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
Subjects who are prematurely withdrawn from the study for reasons other than safety may be 
replaced on a case by case basis.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material.
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.


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7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not 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, 
subjects must be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.










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1Visit structure given for internal programming purpose only
2After informed consent, screening procedures may be performed over more than 1 day/visitas long as it is completed during the defined screening epoch.
3A washout (minimum of 7days and maximum of 14 days from last dose on Day 14) must occur after completion of Treatment period 1 prior to beginning Treatment 
period 2 and after completion of Treatment period 2 prior to beginning Treatment period 3. There is no washout after Day 15 of Treatment period 3. A + 2 days washout 
window is allowed for each treatment.Study days are based on a 10 days washout period, Visit days may be adapted as per the actual washout period; 7-14 days 
allowed per protocol.  
4Assessments to be performedif subject terminates early or at V399 Study completion. 
5Pre-dose assessments on Day 1 may be completed any time on Day 1 prior to first dose.  For Treatment period 1 only: Pre-dose, Day 1 assessments (with the 
exception of blood pressure, pulse, spirometry, PEF, diary entry, and device training) do not need to be repeated if screening assessments were completed within 7 days 
of Day 1 in Treatment period 1.  All Day 1, pre-dose assessments must be completed for Treatment period 2 and 3.
6Pre-dose assessments with the exception of spirometry may be completed any time on Day 14 prior to dosing
7
9Pregnancy assessments may be performed at a greater frequency if required by local regulations.
10Serum pregnancy test
11Urine pregnancy test.
12For Treatment periods 2 and 3, dosing on site on Day 1 should be between 06:00am and 10:00am and +/-1h of the time on dosing on Day 1 of Treatment period 1.
13For Treatment periods 1,2 and 3 dosing on site on Day 14 should be between 06:00am and 10:00am and +/-1h of the time of dosing on Day 1 of the current Treatment 
Period.
14At home study drug administration should be between 06:00am and 10:00am and +/-1h of the time on dosing on Day 1 of Treatment period 1.
15Can be repeated once during screening if necessary
16Both standing and supine/sitting blood pressure measurements are required at screening and at pre-dose Treatment period 1 only.  Only sitting or supine blood 
pressure measurements are required for other visits. Subjects’ positions during bloodpressure collections should remain consistent between visits (sitting or supine 
throughout the study).
17This assessment is completed on Day 65of Treatment period 3 only
18If value is outside the acceptable reference range, this assessment may be retested
19Subject status information will be collected at the end of each epoch(screening, after each treatment period and at early discontinuation or study completion), inthe
Summary eCRF page.
20Subjects will complete these assessments when a subject early terminates or after the subject has completed Treatment periods1, 2, and 3. These assessments are 
completed one time only. 
21SAE monitoring is to be conducted from informed consent signature to 30 days after the last IP administration.
22
Corporate Confidential Information
For Treatment period 3 only, assessments listed in Epoch completion will be completed in addition to assessments listed for Day 65. For assessments that are listed in 
both Day 65and in Epoch completion, the assessment is to be completed once. 




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1 If value is outside the acceptable reference range, this assessment may be retested
2 After informed consent, screening procedures may be performed over more than 1 day/visit as long 
as it is completed during the defined screening epoch.
3 A washout (minimum of 7 days and maximum of 14 days from last dose on Day 14) must occur after 
completion of Treatment period 1 prior to beginning Treatment period 2 and after completion of 
Treatment period 2 prior to beginning Treatment period 3. There is no washout period after Day 65 of 
Treatment period 3. A + 2 days washout window is allowed for each treatment. Study days are based 
on a 10 days washout period, Visit days may be adapted as per the actual washout period; 7-14 days 
allowed per protocol.  
4 Pre-dose assessments on Day 1 may be completed any time on Day 1 prior to first dose.  
For Treatment period 1 only: Pre-dose, Day 1 assessments (with the exception of blood pressure, 
pulse, spirometry, PEF, diary entry, and device training) do not need to be repeated if screening 
assessments were completed within 7 days of Day 1 in Treatment period 1.  All Day 1, pre-dose 
assessments must be completed for Treatment period 2 and 3. 
5 Collected on Day 1 of Treatment period 1 only
6 Pre-dose assessments with the exception of spirometry may be completed any time on Day 14 prior 
to dosing
7 Early discontinuation or Epoch completion assessments should be completed after completion of 
each treatment period or at any time a subject early terminates from the study (does not complete 
Treatment period 1, 2, or 3 per protocol). Day 65 of Treatment period 3 will also be the end of study 
visit. Subjects should be discharged from site after completing Day 65/Epoch completion visit. 


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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed,where 
required by law or regulation), IRB/IEC-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e.all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provideinvestigators a proposed informed consent form that complies with the 
ICH E6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
Anychanges to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Anynew information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an Investigator Notification or an Aggregate 
Safety Finding. New information might require an update to the informed consent and then 
must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in theSection4.2
(Exclusion criteria)and in Section 5.1(Contraception requirements).
A copy of the approved version of all consent forms must be provided to Novartisor designee
after IRB/IEC approval.
8.3
Subject screening
See 
Corporate Confidential Information
Section 3.1


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8.4
Subject demographics/other baseline characteristics
Demographics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Details are outlined in the Site Operations Manual.
Relevant medical history / Current medical conditions
Relevant medical history and current medical conditions will be recorded in the CRF until 
informed consent. Where possible, diagnoses instead of symptoms should be recorded. Any 
event or change in the subject’s condition or health status occurring prior to informed consent 
will be reported in the Relevant medical history / Current medical conditions section of the 
CRF.
Alcohol test, Drug screen, Smoking History, Urine Cotinine
Subjects will be tested for substance abuse (e.g., alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates).
Results will be available as Source data and will not be recorded within the CRF.
Each subject will also be tested for urine cotinine levels. Cotinine levels will be checked at 
screening. Subjects with levels greater than the level indicated in the exclusion criteria will be 
considered smokers and thereby not included. A cotinine level exceeding this value after 
randomization will result in withdrawal of the subject (see Section 7.2 (Discontinuation of 
study treatment)). Unscheduled urine cotinine testing may be done at the discretion of the 
investigator at any time during the study.
Smoking history, including number of pack years will be completed in the CRF. Pack years is 
calculated by multiplying the number of packs of cigarettes smoked per day by the number of 
years the person has smoked. (e.g. 1 pack year is equal to smoking 1 pack per day for 1 year, 
or 2 packs per day for half a year).
8.4.1
Hepatitis and HIV Screen
All subjects will be tested for Hepatitis B, Hepatitis C, and HIV seropositivity during the 
screening epoch. Hepatitis B will be evaluated using the Hepatitis B surface antigen (HBsAg). 
Screening for Hepatitis C will be based on HCV antibodies. Evaluation for HIV seropositivity 
will be performed, and if positive, confirmation by a second technique available at the 
laboratory site, e.g., Western blot or as specified by local regulation.
Appropriate counseling will be made available by the investigator in the event of a positive 
finding. Notification of state and federal authorities, as required by law in the US, will be the 
responsibility of the investigator.
Results will be available as source data and will not be recorded within the clinical database.


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8.4.2
Reversibility 
To be measured during screening. If reversibility is not achieved then the reversibility 
assessment may be repeated once prior the randomization.
All reversibility evaluations should follow the recommendations of the Miller et al 2005b
unless otherwise indicated by inclusion/exclusion criteria of the study.
A spirometry assessment should be performed at screening after a washout period of at least
(see Table 5-1 Withholding period of bronchodilators prior to spirometry for more details):

6 hours for short-acting bronchodilators

24 hours for long-acting β2-agonist containing medications administered b.i.d. 
(e.g. salmeterol, formoterol and combinations using these, e.g. LABA/ICS)

48 hours for long-acting β2-agonist containing medications administered o.d. 
(e.g. indacaterol, vilanterol, and combinations using these, e.g. LABA/ICS) and for 
tiotropium.
400 µg (4 x 100 µg) of salbutamol is then administered following completion of the baseline 
assessment. A second spirometry assessment is then performed starting within 30 minutes of 
the administration of salbutamol.
Reversibility (%) is calculated as: 
(FEV1 (post-bronchodilator) – FEV1 (pre-bronchodilator) x 100)/ FEV1 (pre-bronchodilator)
The findings of the reversibility evaluations will be recorded in the CRF.
8.5
Efficacy / Pharmacodynamics
Pharmacodynamic samples will be collected at the timepoints defined in the 
Assessment schedule, Section 8.1. Follow instructions outlined in the Site Operations Manual 
regarding sample collection, numbering, processing, and shipment.
To better define the PD profile, the timing of the sample collection may be altered based on 
emergent data. The number of samples/blood draws and total blood volume collected should
not exceed those stated in the protocol.
Pharmacodynamic (PD) samples will be obtained and evaluated in all subjects at all dose levels. 
8.5.1
Spirometry
Forced Expiratory Volume in 1 second (FEV1), 3 seconds (FEV3), 6 seconds (FEV6), 
Forced Vital Capacity (FVC), and Forced Expiratory Flow 25-75% (FEF25-75%) will be 
measured at screening, pre-dose, and specific time points for approximately 24 hours post 
dose (on Days 14 and 15) in each treatment period. Additional lung function parameters will 
be derived mathematically from the listed measurements (e.g. FEV1/FVC, FEV1/FEV6, 
FEV3/FVC, FEV3/FEV6, 1-FEV3/FVC, 1-FEV6/FVC). 
For each patient, the spirometric measurements must be taken at approximately the same 
corresponding time of day in each treatment period as closely as practically possible. 
Pre-bronchodilator FEV1, FEV3, FEV6, FVC, and FEF25–75 assessments will be conducted at 
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Spirometry timepoints following the last dose of study medication in each treatment period 
are as follows:
Day 14 predose: -45 min and -15 min 
Day 14/15 post-dose: 5 min, 15 min, 30 min,1 h, 2 h, 3h, 4 h, 8 h, 12 h, 23 h 15 min, 
23 h 45 min
All spirometry evaluations should follow the recommendations of the ATS/ERS 2005 Task 
force: Standardization of Lung Function Testing (Milleretal2005a).
The spirometry equipment used during the trial must meet or exceed the minimal ATS/ERS 
recommendations for diagnostic spirometry equipment as defined in the guideline
(Milleretal2005b).Calibrationof the spirometry equipment is mandatory on all visit days 
and must be performed before the first study measurement. All calibration reports and patient 
spirometry reports should be stored as source data.
The same spirometry equipment should be used for all assessments performed by a subject. 
Alimited number of staff, as designated by the investigator, will evaluate all patients at all 
visits throughout theentire trial. Where possible the same technician should perform all 
maneuvers for an individual subject. All staff conducting the spirometry tests must have 
received appropriate training which must be documented.
Results for spriometry assessmentsare highly dependent on effort and cooperation from the 
subject. Thus, throughout the maneuver, enthusiastic coaching of the subject is required. 
All spirometry maneuvers should be performed in sitting position whilst wearing nose-clips. 
At least three acceptable maneuvers should be performed for each time point, and the results 
must meet within-test and between-test criteria for acceptability. A maximum of eight 
maneuvers should be performed at any time point.
The highest value obtained of FEV1
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and FVC from any of the three maneuvers that meet 
acceptability criteria (can be from different curves) will be recorded on the CRF. 
Alldisplaceable volumes will be reported in liters (L) at body conditions: normal body 
temperature (37°C), ambient pressure, saturated withwater vapor (BTPS).


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8.5.2
Peak expiratory flow
PEF will be measured on all days from screening through the end of study visit. The PEF will 
be measured twice daily, once in the morning (between 06:00 am and 10:00 am) prior to ICS 
treatment and prior to study drug during treatment periods) and once in the evening, 
approximately 12 hours later (between 6:00 pm and 10:00 pm) and prior to ICS treatment. 
Each subject will be provided with a PEF meter and diary into which they will record their 
results and the use of rescue medication. PEF meter training should occur at screening. 
PEF measurements should be taken prior to pre-dose assessments.
Patients should measure PEF in triplicate and record the best value. The diary data will be 
available to the investigator for review to monitor subject safety and compliance (to verify 
that subjects are performing the assessments twice daily as instructed). The investigator must 
make all efforts to achieve compliance from their subjects.
The PEF value recorded at the first screening visit will become the reference value for PEF 
safety monitoring. This value should be recorded on the patient diary and the patients should 
monitor their PEF readings using this value to detect a decline. The investigator should 
instruct the patient to call the site if the PEF drops below the limit required for discontinuation 
(see Section 7.1) and this should be tracked by the site to track when the patient meets 
stopping criteria.
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 (oral or tympanic) 35.0-37.5°C.

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
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening, the assessment may be repeated once 
(for the purpose of inclusion), and in any case, prior to enrollment/randomization, to rule out 
laboratory error. If the repeat value remains outside of protocol-specified ranges, the subject 
should be excluded from the study.


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In the case where a laboratory range is not specified by the protocol, but is outside the 
reference range for the center at screening, a decision regarding whether the result is of 
clinical significance or not shall be made by the investigator and shall be based, in part, upon 
the nature and degree of the observed abnormality. The assessment may be repeated once 
(for the purpose of inclusion) and in any case, prior to enrollment/randomization, to rule out 
laboratory error.
In all cases, the investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the subject to continue in the study.
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. When in doubt, Novartis personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(i.e., neutrophils, basophils, eosinophils, monocytes, and lymphocytes) platelet, aPTT, 
PT/INR, count will be measured.
Clinical chemistry
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, amylase, lipase, CK, 
glucose, total cholesterol, triglycerides. If the total bilirubin concentration is increased above 
1.5 times the upper limit of normal, direct and indirect reacting bilirubin should be 
differentiated. HbA1c will be included in the panel at screening only.
Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments, and allow proper assessments.
A semi-quantitative ‘dipstick’ evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes, and blood.
If the dipstick result is positive for protein, leucocytes and/or blood, the sample will be sent 
for microscopic analysis of WBC, RBC, and casts.
Dipstick measurements for specific gravity, albumin, protein, glucose and blood will be 
performed. Microscopy, WBC, RBC and sediments will also be assessed in case of an 
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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 following ECG parameters will be captured in the CRF: heart rate, PR interval, QRS 
duration, QT interval, RR interval, and QTc.
The Fridericia QT correct formula (QTcF) should be used for clinical decisions. 
Clinicallysignificant abnormalities must be reported in the AE CRF. 
8.6.6
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will havepregnancy testing.  
Seethe Assessment Schedule, Section 8.1, for timing of the protocol required pregnancy 
testing; additional pregnancy testing maybe performed to meet local requirements*.   
Apositive urine pregnancy test requires immediate interruption of study treatment until serum 
β-hCG is performed and found to be negative.
*If additional pregnancy testing is needed per local requirements, those additional results will 
be kept as source documentation only. 
8.7
Pharmacokinetics
Timing of pharmacokinetic blood sample collection isoutlined in the AssessmentSchedule, 
Section 8.1
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.
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects administered all 
forms of indacaterol.
Untreated samples (placebo) will not be analyzed.
Concentrations will be expressed in mass per volume units and will refer to the free base of 
indacaterol.
Details of the analytical methods, the validation method, and the analytical within-study 
quality control procedures, together with the data, will be provided in the Bioanalytical Data 
Report. Concentrations below the LLOQ will be reported as “zero” in summary statistics of 
concentration data as well as PK parameter calculations and missing data will be labeled as 
such in the Bioanalytical Data Report.
PK samples remaining after completion of the determination of parent may be used for 
exploratory assessment of metabolites or other bioanalytical purposes (e.g. cross check 
between different sites, stability assessment). Given the exploratory nature of the work, the 
analytical method used for those assessments will not be validated.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.


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Other pharmacokinetic parameters may be determined as appropriate. Pharmacokinetic 
parameters will be determined by non-compartmental methods using Phoenix WinNonlin 
(Version 6.4 or higher).
8.8
Other assessments
8.8.1
Patient diary
Each subject will be provided with a diary to record study assessments while at home 
(fromscreening, through alltreatment periods including washout periods).
Subjects will record:
Use of ICS
Rescue medication use
PEF measurements:am and pm
Mouth rinsing
The diary will contain instructions for the subjects to perform PEF measurements prior to the 
intake of ICS. Whilst it is preferred that PEFmeasurements are made prior to (6-hours) the 
administration of salbutamol (as rescue medication), subjects should not withhold their rescue 
medication in the event that their clinical condition deemsthe immediate use of medication.
Subjects will be informed of their alert values for PEF at screening and after randomization so 
that if theymeet stopping criteria related to PEF measurements whilst at home, they can 
contact the clinic immediately and appropriate action taken for review and 
withdrawal/ongoing management of their asthma.
8.8.2
Device training
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Subjectswill be provided with device training for the e-diary/peak flow meter device. 
Theelectronic device will be used to collect information on rescue medication use and to 
store PEF meter measurements.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a subject or 
clinical investigation subject after providing written informed consentfor participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5
(Reporting Medication errors including misuse/abuse) for an overview of thereporting 
requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
they induce clinical signs or symptoms,
they are considered clinically significant,

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they require therapy.


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Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from
baseline or the previous visit, or values which are considered to be non-typical in subjects 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual subjects and identifying adverse events. Alert ranges for liver related events are 
included in Section 15-Appendix 1: Liver Event Definitions and Follow-up Requirements).
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:

the severity grade  

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment 

study treatment (no/yes), or

other treatment (no/yes), or

both or indistinguishable

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (Section 9.2.1 (Definition of SAE)) and 
which seriousness criteria have been met

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 adjusted/temporarily interrupted 

investigational treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

subject hospitalized/subject’s hospitalization prolonged (Section 9.2.1 (Definition of SAE))

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Information about common side effects already known about the investigational drug can be 
found in the IB.  Once an adverse event is detected, it must be followed until its resolution or 
until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
Investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.


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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
A 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 subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2
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9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last IP administration, 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 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment a Drug Safety and Epidemiology Department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an 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.   SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring, and completion 
of the standard base liver CRF pages
Refer to Table 15-1-Appendix 1 for complete definitions 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. 


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
Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and γGT) to confirm 
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with 
the results provided via the standard electronic transfer.  If results will not be available from 
the central laboratory within 24 hours, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unscheduled local laboratory CRF.
If the initial elevation is confirmed, close observation of the subject will be initiated, 
including:

Consideration of treatment interruption if deemed appropriate

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study 
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include: 

Repeating liver chemistry tests two or three times weekly. Testing should include ALT, 
AST, ALP, PT/INR, and 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 subject is asymptomatic. Retesting 
should be continued up to resolution. 

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets.

Exclusion of underlying liver disease, as specified in Table 5-3.

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.


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9.4
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with a 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 Drug Safety and Epidemiology. As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-1
summarizes the reporting requirements.
Table 9-1
Summary of reporting requirements for medication errors
Treatment error type
Document in Dose
Administration (DAR) CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.5
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.


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The study drug must be discontinued, though the subject may stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The subject may continue all other protocol assessments.
9.6
Prospective suicidality assessment
Not Applicable. 
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.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRF's must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).


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The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRF's are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Novartis. The investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive a CD-ROM or paper copies of the subject data for archiving at the investigational 
site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule and can be recorded directly on the CRF's. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or designee review the data entered into the CRFs by investigational staff for 
completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data.
Concomitant medications entered into the 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 or designee. 
Diary data will be entered into an electronic diary by the subject. The system will be supplied 
by a vendor(s), who will also manage the database. The database will be sent electronically to 
Novartis or designee. 
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using the Novartis IRT system. The system will be supplied by a 
vendor, who will also manage the database. The database will be sent electronically to 
Novartis or designee.


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Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. 
Data quality processesand query generation and resolution procedures will be provided in 
vendors
' manuals. 
10.4
Data Monitoring Committee
Not required
10.5
Adjudication Committee
Not required
11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation.
11.1
Analysis sets
Corporate Confidential Information
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who receive any study drug and no major 
protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with available PD parameter data who received 
any study drug and experienced no major protocol deviations with relevant impact on PDdata. 
Any PD data for the primary endpoint obtained within 6 hours after rescue medication use or 
within 7 days of systemic corticosteroid will be set to missing.


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11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject. 
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment sequence and subject.
11.4
Analysis of the primary variable(s)
11.4.1
Variable(s)
The primary variable is trough FEV1 to assess the bronchodilator effect of orally inhaled 
indacaterol salts (maleate and acetate) in subjects with asthma compared with placebo. 
Trough FEV1 is defined as the average of the FEV1 measurements at 23 h 15 min and 23 h 45 
min post dose.
11.4.2
Statistical model, hypothesis, and method of analysis
The following hypothesis will be tested for each of indacaterol salts (acetate and maleate) 
versus placebo separately:

HA1: Indacaterol acetate is different to placebo in terms of the trough FEV1 after 
14 days of treatment

HA2: Indacaterol maleate is different to placebo in terms of the trough FEV1 after 
14 days of treatment
The trough FEV1 after 14 days of treatment will be analyzed using an analysis of variance 
(ANOVA) with treatment, period and sequence as fixed effects and subject nested within 
sequence will be included as a random effect. The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom.
The final model estimates will include the LS mean for each treatment (indacaterol acetate, 
maleate and placebo) together with standard error (SE), the adjusted mean difference between 
indacaterol salts (acetate and maleate) and placebo, and corresponding two-sided 95% 
confidence intervals and P-value for the differences (acetate vs placebo and maleate vs 
placebo) using placebo as reference treatment. Additionally as a secondary consideration, an 
estimate of the differences in trough FEV1 between indacaterol acetate (test) and indacaterol 
maleate (reference) will be calculated together with the corresponding two sided 95% 
confidence intervals.
Trough FEV1 will be listed by treatment sequence, subject and visit/time and descriptive 
summary statistics will be provided by treatment and visit/time. Summary statistics will 
include arithmetic mean, SD, CV (arithmetic), median, minimum and maximum.
Graphical methods will be employed to show mean and individual figures for trough FEV1


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No adjustments will be made for multiplicity because the objective is to prove that both 
formulations must be statistically significantly different from placebo each at 2 sided 5% level 
of significance.
11.4.3
Handling of missing values/censoring/discontinuations
Subjects withdrawn for any reasons other than safety and tolerability may be replaced on a 
case by case basis. 
If one of the 23h 15 min and 23h 45 min values are missing (or set to missing) then the 
remaining non-missing value will be taken as trough FEV1. If both values are missing, or if 
the subject withdrew from the study, regardless of the reason for discontinuation, then trough 
FEV1 will be regarded as missing.
If any of the values used in the trough FEV1 are collected within six hours of rescue 
medication then the individual FEV1 value will be set to missing and the imputation rules 
stated above will then be applied.
11.4.4
Summary statistics of safety
Not applicable
11.4.5
Summary statistics of pharmacokinetics
Not Applicable
11.4.6
Sensitivity analyses
Not Applicable
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
FEV1, FEV1% predicted, FVC, FVC% predicted, FEF25-75% after 14 days of treatment will be 
analyzed using the same model as for the primary analysis with the additional fixed effects for 
time and treatment by time interaction term. Time will be repeated within each subject*period 
interaction term. An unstructured covariance matrix will be applied.
Peak FEV1 (maximum FEV1 post treatment) and Standardized FEV1 AUC0-4h between 
screening (pre dose) and 4h post dose on Day 14 of treatment will be analyzed using the same 
model as for the primary analysis.
All subjects will be instructed to record PEF twice daily using a Peak Flow Meter device, 
once in the morning and once approximately 12 h later in the evening from screening and 
throughout the study. The morning/evening and the overall PEF (L/min) will be averaged 
between days 8 to 14 of each treatment period for each subject. Mean morning/evening and 
overall PEF will be analyzed using the same model as for the primary analysis and 
summarized by treatment.


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Time to peak FEV1 on Day 14 will be analyzed using non-parametric methods. The median 
difference and the two sided 95% confidence interval of the median difference in time to peak 
FEV1 will be estimated using Hodges-Lehmann estimation procedure.
The number of puffs of the rescue medication use is recorded twice (morning/evening) by 
subjects in the eDairy. The average number of puffs of rescue medication use will be
calculated as the number of puff >0 divided by days (14-8) for morning/evening and overall 
number of puffs of each treatment period for each subject and will be used for statistical 
analysis. The mean morning/evening and overall number of puffs of rescue medication use 
will be analyzed using the same model as for the primary analysis and summarized by 
treatment. The number and percentage of subjects with rescue medications, together with the 
number of events, were tabulated by treatment.
All the above secondary variables will be listed by treatment sequence, subject and visit/time 
and descriptive summary statistics will be provided by treatment and visit/time. 
Summary statistics will include arithmetic mean, SD, CV (arithmetic), median, minimum and 
maximum.
Graphical methods will be employed to show mean and individual figures for all parameters.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment sequence, subject, and visit/time and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment sequence, subject and visit/time, abnormalities will 
be flagged. Summary statistics will be provided by treatment and visit/time. Summary table 
for percentage and number of subjects with abnormal values <40 /40-90 />90 bpm in heart 
rate and summary table for percentage and number of subjects with notable values increase 
>30 / increase >60 / >450 />480/>500 msec in QTcF interval will be provided.
Clinical laboratory evaluations
All laboratory data will be listed by treatment sequence, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
Summary table for percentage and number of subjects with notable values for serum 
potassium (<3 /3-<3.5 />5.5 mmol/L) and plasma glucose (>10-15 />15 mmol/L) will be 
provided.


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Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
All study emergent adverse events will be summarized. 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 a washout period will be assigned to the
treatment period just prior to that washout period. Any adverse events that started during the 
study before the time of the first inhalation of study drug of the first period will be classified 
as a prior adverse event. 
The number and percentage of subjects with treatment emergent adverse event summaries will 
be produced, overall by system organ class and preferred term, overall by system organ class, 
preferred term and maximum severity, suspected drug-related adverse events by system organ 
class and preferred term, serious adverse events by system organ class and preferred term, and 
adverse events leading to permanent discontinuation of study drug by system organ class and 
preferred term with a breakdown by treatment. A subject with multiple adverse events within 
a body system and treatment period is only counted once towards the total of this body system 
and treatment.
Concomitant medications / Significant non-drug therapies
All concomitant therapies will be listed by treatment sequence and subject.
11.5.3
Pharmacokinetics
Statistical methods for pharmacokinetic analysis
The log transformed pharmacokinetic parameters AUC0-24h,ss and Cmax,ss on day 14 will 
be compared for indacaterol acetate (test) relative to indacaterol maleate (reference) using a 
mixed effects model with sequence, treatment and period as fixed effects and subject nested 
within sequence as random effect. Body weight assessed in period 1 may be included as a 
covariate and applied as a fixed effect in the model. The estimates of the treatment differences 
(indacaterol acetate (test) vs. maleate (reference); Frel) along with their 90% confidence 
intervals will be obtained. The estimates and confidence intervals will be transformed back to 
the original scale to provide ratios of the geometric means together with their corresponding 
90% confidence intervals.
Tmax,ss will be analyzed using non-parametric methods. The median difference and the 
90% confidence interval of the median difference in Tmax,ss will be estimated using Hodges-
Lehmann estimation procedure.
Handling of missing values/censoring/discontinuations
All subjects with evaluable PK parameters data for at least one study treatment will be 
included for this analysis


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Summarystatistics for pharmacokinetic data
Indacaterol plasma concentrations will be listed by treatment sequence, subject, profile day, 
and sampling time point. Descriptive summary statistics will be provided by treatment, profile 
day, and sampling time point. Summary statistics will include mean (arithmetic and 
geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. 
Concentrations below LLOQ will be treated as zero in summary statistics. Ageometric mean 
will not be reported if the dataset includes zero values.
Pharmacokinetic parameters will be calculated as described in Section 8.7(Pharmacokinetics)
and will be listed by treatment sequence, profile day, and subject. Descriptive summary 
statistics will be provided by treatment and profile day. Summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax where median, minimum and maximum will be 
presented.
Graphical methods will be employed to show mean and individual time-concentration profiles.
Pharmacokinetic parameters will be determined using WinNonlin Phoenix (version 6.4 or 
higher).
11.5.4
Pharmacokinetic / pharmacodynamic interactions
Not Applicable.
11.5.5
Other assessments
Corporate Confidential Information
Not Applicable. 


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11.7
Sample size calculation
Sample size calculations are based on the primary endpoint of trough FEV1. Trough FEV1is 
defined as the average of the FEV1measurements at 23 h 15 min and 23 h 45 min post-dose.
The primary objectiveis to prove that the test formulation (the one included in the 
combination therapy which is acetate and maleate salt) must be better than placebo. Using an 
estimate of within subject standard deviation of 230 mL from Study QAB149D2301 and 
assuming the data are normally distributed, 42 (7 per sequence) subjects are required to detect 
the difference of 170 mL in trough FEV1with 90% power in each test (acetate vs placebo and 
maleate vs placebo). 
No adjustment will be made for multiplicity because the objective is to obtain a statistical 
separation from placebo for both the comparisons.
The power where both tests are required to meet the overall objective is >81% power, with a 
two-sided test at a significance level of 5%. 
Allowing for a 20% drop out rate, a total sample size of 54 (9 per sequence) subjects will be 
randomized to six treatment sequences.
11.8
Power for analysis of key secondary variables
The sample size was estimated based on the primary endpoint of trough FEV1
Corporate Confidential Information
is also adequate 
from a pharmacokinetic bioequivalence perspective. The intra-subject CV (coefficient of 
variation) of Cmax and AUC0-24h in Study CQAB149D2301 was 14% and 20%, 
respectively. Assuming a maximum intra-subject CV of 20% for AUC0-24h (based on 7-day 
dosing in asthma subjects in Study CQAB149D2301), a sample size of 42 completers will 
provide at least 95% power to achieve [90% CI for geometric mean ratio (test/reference) 
within the interval of 0.80-1.25] with respect to the AUC0-24h,ss of indacaterol, if the true 
geometric meanratio is 1.


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


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


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14
References
Boxenbaum H, Battle M (1995) Effective half-life in clinical pharmacology. J Clin Pharmacol
Aug;35(8): 763-6.
Global Initiative for Chronic Obstructive Lung Disease (GOLD); Global Initiative for Chronic 
Obstructive Lund Disease (2017 report).
Miller MR, Crapo R, Hankinson J, et al (2005a) General considerations for lung function 
testing. Eur. Respir. J. Jul;26(1); 153-61.
Miller MR, Hankinson J, Brusasco V, et al (2005b) Standardisation of spirometry. Eur. Respir. 
J. Aug;26(2): 319-38.


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


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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, GT, 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: Concept1 Platform Inhaler: Instructions for use 
of medical devices for investigational human use
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 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.
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.


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REMEMBER:

Do not swallow capsules.

Only use the inhaler contained in this pack.

Capsules must always be stored in the blister, and only removed immediately before 
use.

Never place a capsule directly into the mouthpiece of the inhaler.

Do not press the side buttons more than once.

Never blow into the mouthpiece of the inhaler.

Always release the push buttons before inhalation.

Never wash the inhaler with water. Keep it dry. See “How to clean your inhaler”.

Never take the inhaler apart.

Always use the new inhaler that comes with your new medication pack. Dispose of 
each inhaler after the number of uses identified by your physician.

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.
Manufactured by:
Novartis Pharma AG, Switzerland
© Novartis

SAP_000.pdf: 
Novartis Institutes for BioMedical Research
QVM149
CQVM149B2203
A randomized, double-blind, placebo-controlled, 
three-period cross-over study to assess the 
pharmacodynamics, safety, tolerability, and 
pharmacokinetics of two orally inhaled indacaterol salts
(maleate and acetate) delivered via the Concept1 inhalation 
device in patients with asthma
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation –NIBR 
Document status:
Final2.0 Amendment 1
Release date:
16-Apr-2018
Number of pages:
17
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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For business use only
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SAPAmendment 1
CQVM149B2203
Corporate Confidential Information


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For business use only
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CQVM149B2203
Table of contents
Table of contents.................................................................................................................3
List of tables........................................................................................................................4
1 Introduction.........................................................................................................................5
1.1
Scope of document..................................................................................................5
1.2
Study reference documentation...............................................................................5
1.3
Study objectives.......................................................................................................6
1.3.1
Primary objectives...................................................................................6
1.3.2
Secondary objective(s)............................................................................6
1.4
Study design and treatment......................................................................................6
2 First interpretable results (FIR)...........................................................................................7
4 Statistical methods: Analysis sets........................................................................................7
5 Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses................................................................................................9
5.3
Statistical model, assumptions and hypotheses.......................................................9
5.3.1
Model checking procedures....................................................................9
5.3.2
Graphical presentation of results...........................................................10
6 Statistical methods for Pharmacodynamic (PD) parameters.............................................10
6.1 
Primary objective...................................................................................................10
6.1.1
Variables...............................................................................................10
6.1.2
Descriptive analyses..............................................................................10
6.1.3
Statistical model, assumptions and hypotheses.....................................10
6.2
Secondary objectives.............................................................................................12
6.2.1
Variables...............................................................................................12
6.2.2
Descriptive analyses..............................................................................13
6.2.3
Statistical model, assumptions and hypotheses.....................................13
6.3
Exploratory objectives...........................................................................................14
6.3.1
Variables...............................................................................................14
6.3.2
Descriptive analyses..............................................................................14
7 Statistical methods for safety and tolerability data............................................................14
7.1
Variables................................................................................................................14
7.2
Descriptive analyses..............................................................................................15
7.3
Graphical presentation...........................................................................................
C
 
 
17
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List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................8


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CQVM149B2203”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol is finalized at the time of the finalization of Statistical Analysis Plan.
This SAP Amendment 1 is based on the final version of the

Study protocol, v00, 28 Feb 2017


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1.3
Study objectives
1.3.1
Primary objectives
To assess the bronchodilator effect of orally inhaled indacaterol salts (maleate and acetate) 
in subjects with asthma compared to placebo as measured by trough FEV1 after 14 days of 
treatment
1.3.2
Secondary objective(s)
To assess the steady state pharmacokinetics of indacaterol after 14 days of treatment of 
orally inhaled indacaterol salts (maleate and acetate) in subjects with asthma.
To assess the bronchodilator effect of orally inhaled indacaterol salts (maleate and acetate) 
in subjects with asthma compared toplacebo as measured by:
Time to peak FEV1 on Day 14
FEV1, FEV1 (% predicted), FVC, FVC (% predicted), FEV1/FVC, and FEF25-
75% at each post-dose time point after 14 days of treatment
Standardized FEV1 AUC from pre-dose to 4 h post-dose on Day 14 of treatment
To assess the bronchodilator effect ofindacaterol acetate, indacaterol maleate, andplacebo 
by comparing the pre-medication(morning (pre-dose) and evening) peakexpiratory flow 
(PEF) rate collected betweendays 8 and 14 of each treatment.
To assess rescue medication usage for indacaterol salts (maleate and acetate) in 
comparison to placebo.
To assess the safety and tolerability of indacaterol salts (maleate and acetate) in 
comparison to placebo of 14 days of treatment in each treatment period.
1.4
Study design and treatment
Figure 1-1
Study design
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This is a confirmatory, randomized, double blind, placebo-controlled, three-period complete
block, crossoverstudy in patientswith asthma.
Subjects who meet all of the eligibility criteria will be randomized to one of six treatment
sequences as described in Figure 3-1. They will receive their first dose on the morning ofDay 
1. Subjects will be dosed between 06:00 a.m. and 10:00 a.m. under the guidance andsupervision 
of the investigator or designee after an additional training for correct use of theConcept1 
inhalation device. Dosing of investigational product and background ICSmedication should 
occur at approximately the same time of the day throughout the study.PEFmeasurements (if 
not already performed at home on the morning of Day 1 or Day 14) shouldbe taken prior to 
pre-dose spirometry and safety assessments.
On Day 1, subjects will leavethe clinic after the completion of the required assessments and
will dose at home once daily in the morning on Days 2 to 13. During days 2 -13, subjects will
record drug administration, PEF measurements, mouth rinsing, and rescue medication use in
their diary. Subjects will be domiciled at the clinic on the morning of Day 14, for drug
administration and Day 14 visit assessments.Subjects will be discharged on Day 15 following 
the final PK and safety blood sample drawand completion of Day 15 assessments.
Awashout period of 7 -14 days will separate each treatment period. 
Epoch Completion assessments must be conducted for subjects who complete all three
treatment periods or at any time a subject early terminates from the trial. . The last visit (Day
65) ofTreatment period 3 will also be the end of study visit. Subjectsshould be discharged from 
the site after the completion of Day 15 assessments for all 3periods.
2
First interpretable results (FIR)
First interpretable results (FIR) willbe provided for thistrial.
4
Statistical methods: Analysis sets
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For all analysis sets, subjects will be analyzed according to the study treatment(s) received. 
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The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no major protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data.
The PD analysis set will include all subjects with available PD parameter data who received
any study drug and experienced no major protocol deviations with relevant impact on PD data. 
Any PD data for the primary endpoint obtained within 6 hours after rescue medication use or
within 7 days of systemic corticosteroid will be set to missing.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from Safety analysis in case of these 
PDs: 
Exclude subject from Safety
analysis set 
INCL01
Deviation from inclusion criteria: In the 
unlikely event that a subject was included 
without written informed consent, then 
their data will not be used
Yes
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
INCL01
Deviation from inclusion criteria: In the 
unlikely event that a subject was included 
without written informed consent, then 
their data will not be used
Yes
Subjects are excluded from PK analysis in case of these PDs:
Exclude subject from PK 
analysis sets
INCL01
Deviation from inclusion criteria: In the 
unlikely event that a subject was included 
without written informed consent, then 
their data will not be used
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to
DBL.


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5
Statistical methods for Pharmacokinetic (PK) parameters
5.1
Variables 
The concentrations of indacaterol in plasma will be determined by a validated LC-MS/MS
method;
Other pharmacokinetic parameters may be determined as appropriate. 
5.2
Descriptive analyses
Indacaterol plasma concentrations will be listed by treatment sequence, subject, profile day,and 
sampling time point. Descriptive summary statistics will be provided by treatment, profileday, 
and sampling time point. Summary statistics will include mean (arithmetic andgeometric), SD, 
CV (arithmetic and geometric), median, minimum and maximum.
Concentrations below LLOQ will be treated as zero in summary statistics. A geometric mean
will not be reported if the dataset includes zero values.
Pharmacokinetic parameters will be listed by treatment sequence, profile day, and subject. 
Descriptive summarystatistics will be provided by treatment and profile day. Summary 
statistics will include mean(arithmetic and geometric), SD, and CV (arithmetic and geometric), 
median, minimum andmaximum. An exception to this is Tmax where median, minimum and 
maximum will bepresented.
5.3
Statistical model, assumptions and hypotheses
The log transformed pharmacokinetic parameters AUC0-24h,ssand Cmax,sson day 14 willbe 
compared for indacaterol acetate (test) relative to indacaterol maleate (reference) using amixed 
effects model with sequence, treatment and period as fixed effects and subject nestedwithin 
sequence as random effect. Body weight assessed in period 1 will beincluded as acontinuous 
covariate and applied as a fixed effect in the model. The estimates of the treatment differences
(indacaterol acetate (test) vs. maleate (reference); Frel) along with their 90% confidence
intervals will be obtained. The estimates and confidence intervals will be transformed back to
the original scale to provide ratios of the geometric means together withtheir corresponding
90% confidence intervals.
Tmax,ss will be analyzed using non-parametric methods. The median difference and the90% 
confidence interval of the median difference in Tmax,ss will be estimated using Hodges-
Lehmann estimation procedure.
5.3.1
Model checking procedures
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All drug concentrations below the lower limit of quantification (LLOQ) will be reported as 
“zero” and will be treated as zero for calculation of PK parameters.
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Subjects with missing PK parameters (e.g. Cmax,ss, and AUC0-24h,ss) in some but not all 
periods will be included in a mixed model analysis.
5.3.2
Graphical presentation of results
Individual concentration-time profiles and mean profiles with SD bars will be presented for Day 
14 PK data.
6
Statistical methods for Pharmacodynamic (PD) parameters
6.1
Primary objective
The primary objective is to assess the bronchodilator effect of orally inhaled indacaterol salts 
(maleate and acetate) in subjects with asthma compared with placebo as measured by trough 
FEV1 after 14 days of treatment.
6.1.1
Variables 
The primary variable is trough FEV1 after 14 days of treatment. Trough FEV1 is defined as the 
average of the FEV1 measurements at 23 h 15 min and 23 h 45 min post dose.
6.1.2
Descriptive analyses
Trough FEV1 will be listed by treatment sequence, subject and visit/time and descriptive
summary statistics will be provided by treatment and visit/time. Summary statistics will include 
arithmetic mean, SD, CV (arithmetic), median, minimum and maximum.
6.1.3
Statistical model, assumptions and hypotheses
The following hypothesis will be tested for each of indacaterol salts (acetate and maleate) versus 
placebo separately:
H0 (Null Hypothesis): There is no difference in terms of the trough FEV1 after 14 days of 
treatment between:
                                      Indacaterol acetate and placebo                  
                                                          OR
                                    Indacaterol maleate and placebo
H1 (Alternative Hypothesis): There is a difference in terms of the trough FEV1 after 14 days 
of treatment between:                        
                                     Indacaterol acetate and placebo                  
                                                  AND
                               Indacaterol maleate and placebo
No adjustments will be made for multiplicity because the objective is to prove that both
formulations must be statistically significantly different from placebo each at 2-sided 5% level
of significance.


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The trough FEV1 after 14 days of treatment will be analyzed using an analysis of variance 
(ANOVA) with treatment, period and sequence as fixed effects and subject nested within 
sequence will be included as a random effect. The Kenward-Roger approximation will be used 
to estimate denominator degrees of freedom. 
The final model estimates will include the LS mean for each treatment (indacaterol acetate, 
maleate and placebo) together with standard error (SE), the adjusted mean difference between 
indacaterol salts (acetate and maleate) and placebo, and corresponding two-sided 95% 
confidence intervals and P-value for the differences (acetate vs placebo and maleate vs placebo) 
using placebo as reference treatment. 
Additionally as a secondary consideration, an estimate of the differences in trough FEV1 
between indacaterol acetate (test) and indacaterol maleate (reference) will be calculated 
together with the corresponding two sided 95% confidence intervals.
6.1.3.1
Model checking procedures
Subjects withdrawn for any reasons other than safety and tolerability may be replaced on a case 
by case basis.
If one of the 23h 15 min and 23h 45 min values are missing (or set to missing) then the
remaining non-missing value will be taken as trough FEV1. If both values are missing, or if the 
subject withdrew from the study, regardless of the reason for discontinuation, then trough FEV1 
will be regarded as missing.
If any of the values used in the trough FEV1 are collected within six hours of rescue medication 
or 7 days of systemic corticosteroid then the individual FEV1 within 6 hours after rescue 
medication use or within 7 days of systemic corticosteroid will be set to missing. If rescue 
medication is taken during the 24 hour spirometry assessments then from the time of the rescue 
medication intake, all post-time point  spirometry assessments will be considered as missing in 
this treatment period.
Subgroup analysis:
The primary analysis will be performed by subgroup of patients based on their compliance of 
study medication within the 7 days before the spirometry assessment: if spirometry assessment 
is done during day 14, then compliance will be calculated between day 8 and day 14 on a total 
number of 7 doses.
This analysis will be provided per compliance of study medication within the 7 days before
spirometry assessment defined as follows:

<80% Compliance of study medication within the 7 days before spirometry assessment 
(less than a total number of 5 doses)

80-100% Compliance of study medication within the 7 days before spirometry assessment
(more or equal a total number of 5 doses)


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6.1.3.2
Graphical presentation of results
Individual time profiles and the results of statistical analysis will also be presented in a graphical 
representation called forest plot showing the estimated mean differences indacaterol salts 
(acetate and maleate) to placebo and estimated difference between acetate and maleate salts and 
their confidence intervals per time point for each comparison.
6.2
Secondary objectives
6.2.1
Variables 
Forced Expiratory Volume in 1 second (FEV1), 3 seconds (FEV3), 6 seconds (FEV6), FEV1% 
predicted, Forced Vital Capacity (FVC), FVC% predicted and Forced Expiratory Flow 25-75% 
(FEF25-75%) will be measured at screening, pre-dose, and specific time points for 
approximately 24 hours post dose (on Days 14 and 15) in each treatment period. Additional 
lung function parameters will be derived mathematically from the listed measurements (e.g. 
FEV1/FVC, FEV1/FEV6, FEV3/FVC, FEV3/FEV6, 1-FEV3/FVC, 1-FEV6/FVC).
For each patient, the spirometric measurements must be taken at approximately the same
corresponding time of day in each treatment period as closely as practically possible.
Pre-bronchodilator FEV1, FEV3, FEV6, FVC, and FEF25–75 assessments will be conducted 
at screening.
Spirometry timepoints following the last dose of study medication in each treatment period are 
as follows:

Day 14 predose: - 45 min and -15 min 

Day 14/15 post-dose: 5 min, 15 min, 30 min,1 h, 2 h, 3h, 4 h, 8 h, 12 h, 23 h 15 
min, 23 h 45 min
Time to peak FEV1 (maximum FEV1 post treatment) on Day 14 will be derived from the 
spirometry timepoints following the last dose of the study medication in each treatment period.
Standardized FEV1 AUC (0-4hr) (i.e. Area Under Curve between 5 min (=time 0h) and 4h post 
dose) on Day 14 of treatment. Area under curve for FEV1 from Spirometry data and will be 
calculated by trapezoidal rule as follows:
	 =
∑
()∗()



,
  =    = 	
Where ‘t’ is time-point and ‘c’ is FEV1 at time-point t.
T0 is initial time-point, Tn is the last time point of interest.
Peak FEV1 defined as the highest bronchodilatory effect on FEV1 during a period of 5 min to 
4h on Day 14 of treatment. FEV1 measurements to consider defining peak FEV1 are on day 14 
+5 min, +15 min, +30 min, +1h, +2 h, +3h, +4h.
PEF will be recorded twice daily using a Peak Flow Meter device, once in the morning and 
once approximately 12 h later in the evening. The morning/evening and overall (average of both 
morning and evening) PEF measurements will be averaged separately between days 8 to 14 of 
each treatment period and each subject.


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The number of puffs of rescue medication takenis recorded twice (morning/evening) by
subjects in the eDiary.The morning/evening and overall (both morning and evening) number 
of puffs of rescue medication will beaveragedseparately between days 8 to 14 of each treatment 
period and each subject.
Below is an example for averaging the rescue medication for each treatment period and subject.
6.2.2
Descriptive analyses
All the above secondary variables will be listed by treatment sequence, subject and visit/time
and descriptive summary statistics will be provided by treatment and visit/time.Summary 
statistics will include arithmetic mean, SD, CV (arithmetic), median, minimum andmaximum.
The mean morning/evening and overall numberof puffs of rescue medication usewill be listed 
by treatment sequence and subject and summarystatistics bytreatment. The number and 
percentage of subjects with rescue medications, together with thenumber of puffs, will be
tabulated by treatment.
The average morning/evening and the overall PEF (L/min) will be listed by treatment sequence 
andsubject and summary statisticsby treatment.
6.2.3
Statistical model, assumptions and hypotheses
All the above secondary variables(Section 6.2.1) for spirometry (excludingTime to peak FEV1, 
Standardized FEV1 AUC (0-4hr), Peak FEV1, Averagerescue medication for morning/evening 
and Average PEF measurements for morning/evening) after 14 days of treatment will be
analyzed using repeated measures of ANOVA including treatment, period,sequence, time, 
treatment by timeas fixed effects and subject nested within sequence will be included as a 
random effect. Time will be repeated within each subject*periodinteraction term.An 
unstructured variance unstructured covariance matrixwill be applied.
Standardized FEV1 AUC(0-4hr)betweenbaseline(pre dose) and 4h post dose and peak FEV1 
on Day 14 of treatment will be analyzed using the samemodel (ANOVA) as for the primary 
analysis.
Averaged morning/evening and overall number of puffs of rescue medication and average 
morning/evening and overall number of PEF measurements will be analyzed using the same 
model (ANOVA) as for primary analysis.
Time to peak FEV1 on Day 14 will be analyzed using non-parametric methods. The median
difference and the two-sided95% confidence interval of the median difference in time to peak
FEV1 will be estimated using Hodges-Lehmann estimation procedure.
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6.2.3.1
Model checking procedures
For the FEV1 AUC (0-4hr) if an observation is missing between two non-missing observations, 
the AUC will be linearly interpolated between the two non-missing values i.e. the subject‘s 
profile will be assumed to be linear between the two available values. Multiple occurrences of 
such missing values (an observation missing between adjacent non-missing observations) will 
be handled in a similar manner. But in case of missing consecutive assessments, then the patient 
profile will be excluded from analysis. No imputation will be made if either the first or the last 
observation is missing and AUC (0-4hr) is calculated from the available part of the profile 
ignoring the first and last time points. 
For all secondary end points, if a patient takes rescue medication within 6h prior to the 
spirometry assessments and the visit is not rescheduled to the next day then all spirometry 
assessments data from this visit and the following visits in this treatment period will be set to 
missing. If rescue medication is taken during the 24 hour spirometry assessments then from the 
time of the rescue medication intake, all post-time point  spirometry assessments will be 
considered as missing in this treatment period and AUC (0-4hr) will be considered as missing.
6.2.3.2
Graphical presentation of results
Individual time profiles and Mean (SD) plots for all secondary parameters will be presented by 
treatment group and time.
The results of statistical analysis will also be presented in a graphical representation called forest 
plot showing the estimated mean differences indacaterol salts (acetate and maleate) to placebo 
and estimated difference between acetate and maleate salts and their confidence intervals per 
time point for each comparison including studentized residual plots.
6.3
Exploratory objectives
6.3.1
Variables 
Not Applicable
6.3.2
Descriptive analyses
Not Applicable
7
Statistical methods for safety and tolerability data
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, and 
treatment information.


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7.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
Subject disposition
A disposition summary will be presented for all subjects. This table will present the number and 
percentage of subjects who completed each study epoch and discontinued early for each epoch, 
along with the reasons for early discontinuation. 
The number and percentage of subjects in each analysis set will be summarized for all subjects. 
All analysis set results will be presented in listings by treatment sequence and subject. A 
separate listing of all subjects excluded from any analysis set and the reasons for their exclusion 
will be provided. 
All study epoch completion data will be listed by treatment sequence and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment sequence and subject.
Vital signs
All vital signs data will be listed by treatment sequence, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment sequence, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. Summary table for 
percentage and number of subjects with abnormal values <40 /40-90 />90 bpm in heart rate and 
summary table for percentage and number of subjects with notable values increase >30 / 
increase >60 / >450 />480/>500 msec in QTcF interval will be provided.
Clinical laboratory evaluations
All laboratory data will be listed by treatment sequence, subject, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Summary table for percentage and number of subjects with notable values for serum potassium 
(<3 /3-<3.5 />5.5 mmol/L) and plasma glucose (>10-15 />15 mmol/L) will be provided.


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Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
All treatment emergent adverse events will be summarized. 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 a washout period will be assigned to the treatment 
period just prior to that washout period. 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 and will not be summarized.
The number and percentage of subjects with treatment emergent adverse event will be 
summarized by treatment, overall by system organ class and preferred term, overall by system 
organ class, preferred term and maximum severity, suspected drug-related adverse events by 
system organ class and preferred term, serious adverse events by system organ class and 
preferred term, and adverse events leading to permanent discontinuation of study drug by 
system organ class and preferred term with a breakdown by treatment. A subject with multiple 
adverse events within a body system and treatment period is only counted once towards the 
total of this body system and treatment.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety analysis set 
population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
Protocol Deviations
Protocol deviations will be listed by treatment sequence and subject.
Liver events
Liver event data may be reported in listings and summaries if data is collected during the study.


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7.3
Graphical presentation 
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Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.