Conditions: Asthma
Keywords: indacaterol acetate, asthma, GINA 2015, pediatrics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 79
Healthy volunteers: no

Brief summary:
This study is designed to explore lung function effects of two doses of indacaterol acetate, 75 μg and 150 μg, in pediatric asthma patients 6-11 years old, and to compare the systemic exposure to indacaterol in plasma with historical data in adults, to identify an appropriate dose to Phase III evaluation.

Detailed description:

Arms:
arm 1: Indacaterol acetate 75 μg o.d. delivered via Concept1 inhaler arm 2: Indacaterol acetate 150 μg o.d. delivered via Concept1 inhaler

Interventions: intervention 1: Indacaterol acetate 75 μg intervention 2: Indacaterol acetate 150 μg
Intervention descriptions: intervention 1: Indacaterol acetate 75 μg o.d. delivered via Concept1 inhaler intervention 2: Indacaterol acetate 150 μg o.d. delivered via Concept1 inhaler

Protocol document:
Prot_001.pdf: 
Global Clinical Development - General Medicine 
QMF149/ Indacaterol acetate 
CQMF149G2202 / NCT02892019
A multicenter, randomized, double-blind, active-controlled, 
2 week treatment, parallel-group study to assess the 
efficacy and safety of indacaterol acetate delivered via the 
Concept1 inhalation device in children greater or equal to 6 
and less than 12 years of age with asthma 
Document type: 
Clinical Trial Protocol 
PIP 
EMEA-001217-PIP01-11 
EUDRACT number: 
2016‐002113‐21 
Version number: 
00 (Original Protocol) 
Clinical trial phase: 
IIb 
Release date: 
28-Jun-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.1 (February 2016) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Protocol summary ................................................................................................................ 9 
1 
Introduction ....................................................................................................................... 12 
1.1 
Background ............................................................................................................ 12 
1.2 
Purpose .................................................................................................................. 14 
2 
Study objectives and endpoints ......................................................................................... 14 
2.1 
Primary objective(s) ............................................................................................... 14 
2.2 
Secondary objective(s) ........................................................................................... 14 
2.3 
Exploratory objectives ........................................................................................... 14 
3 
Investigational plan ........................................................................................................... 14 
3.1 
Study design........................................................................................................... 14 
3.2 
Rationale for study design ..................................................................................... 18 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 19 
3.4 
Rationale for choice of comparator ....................................................................... 20 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 20 
3.6 
Risks and benefits .................................................................................................. 20 
4 
Population .......................................................................................................................... 21 
4.1 
Inclusion criteria .................................................................................................... 21 
4.2 
Exclusion criteria ................................................................................................... 22 
5 
Treatment ........................................................................................................................... 24 
5.1 
Study treatment ...................................................................................................... 24 
5.1.1 
Investigational and control drugs .......................................................... 24 
5.1.2 
Additional treatment .............................................................................. 24 
5.2 
Treatment arms ...................................................................................................... 25 
5.3 
Treatment assignment and randomization ............................................................. 25 
5.4 
Treatment blinding ................................................................................................. 25 
5.5 
Treating the patient ................................................................................................ 26 
5.5.1 
Patient numbering ................................................................................. 26 
5.5.2 
Dispensing the study drug ..................................................................... 26 
5.5.3 
Handling of study and additional treatment .......................................... 26 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 27 


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5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 28 
5.5.6 
Rescue medication ................................................................................ 28 
5.5.7 
Concomitant medication ....................................................................... 29 
5.5.8 
Prohibited medication ........................................................................... 29 
5.5.9 
Emergency breaking of assigned treatment code .................................. 30 
5.6 
Study completion and discontinuation ................................................................... 31 
5.6.1 
Study completion and post-study treatment .......................................... 31 
5.6.2 
Discontinuation of study treatment ....................................................... 31 
5.6.3 
Withdrawal of informed consent ........................................................... 32 
5.6.4 
Lost to Follow-up .................................................................................. 33 
5.6.5 
Early study termination by the sponsor ................................................. 33 
6 
Visit schedule and assessments ......................................................................................... 33 
6.1 
Information to be collected on screening failures .................................................. 42 
6.2 
Patient demographics/other baseline characteristics ............................................. 42 
6.3 
Treatment exposure and compliance ..................................................................... 42 
6.4 
Efficacy .................................................................................................................. 43 
6.4.1 
Spirometry assessments ........................................................................ 43 
6.4.2 
Patient reported outcomes (PRO) .......................................................... 43 
6.4.3 
Electronic Diary .................................................................................... 44 
6.4.4 
Peak expiratory flow ............................................................................. 44 
6.4.5 
Rescue medication usage ...................................................................... 44 
6.4.6 
Appropriateness of efficacy assessments .............................................. 45 
6.5 
Safety ..................................................................................................................... 45 
6.5.1 
Physical examination ............................................................................ 45 
6.5.2 
Vital signs.............................................................................................. 45 
6.5.3 
Height and weight ................................................................................. 45 
6.5.4 
Laboratory evaluations .......................................................................... 46 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 46 
6.5.6 
Worsening of asthma ............................................................................. 47 
6.5.7 
Asthma Exacerbation ............................................................................ 48 
6.5.8 
Pregnancy and assessments of fertility ................................................. 49 
6.5.9 
Appropriateness of safety measurements .............................................. 49 
6.6 
Other assessments .................................................................................................. 49 
6.6.1 
Pharmacokinetics .................................................................................. 49 
7 
Safety monitoring .............................................................................................................. 49 
7.1 
Adverse events (AEs) ............................................................................................ 49 


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7.2 
Serious adverse events (SAEs) .............................................................................. 51 
7.2.1 
Definition of SAE ................................................................................. 51 
7.2.2 
SAE reporting........................................................................................ 52 
7.2.3 
Pneumonia reporting ............................................................................. 53 
7.3 
Liver safety monitoring ......................................................................................... 53 
7.4 
Reporting of study treatment errors including misuse/abuse ................................ 54 
7.5 
Pregnancy reporting ............................................................................................... 54 
8 
Data review and database management ............................................................................. 55 
8.1 
Site monitoring ...................................................................................................... 55 
8.2 
Data collection ....................................................................................................... 56 
8.3 
Database management and quality control ............................................................ 56 
8.4 
Data Monitoring Committee .................................................................................. 57 
8.5 
Adjudication Committee ........................................................................................ 57 
9 
Data analysis ...................................................................................................................... 57 
9.1 
Analysis sets .......................................................................................................... 57 
9.2 
Patient demographics and other baseline characteristics ....................................... 58 
9.3 
Treatments ............................................................................................................. 58 
9.4 
Analysis of the primary variable(s) ....................................................................... 58 
9.4.1 
Variable(s) ............................................................................................. 58 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 58 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 59 
9.4.4 
Sensitivity analyses ............................................................................... 59 
9.5 
Analysis of secondary variables ............................................................................ 59 
9.5.1 
Efficacy variables .................................................................................. 59 
9.5.2 
Safety variables ..................................................................................... 60 
9.5.3 
Pharmacokinetics .................................................................................. 62 
9.5.4 
PK/PD ................................................................................................... 62 
9.6 
Interim analyses ..................................................................................................... 63 
9.7 
Sample size calculation .......................................................................................... 63 
10 Ethical considerations ........................................................................................................ 63 
10.1 
Regulatory and ethical compliance ........................................................................ 63 
10.2 
Informed consent procedures ................................................................................. 63 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 64 
10.4 
Publication of study protocol and results............................................................... 64 
10.5 
Quality Control and Quality Assurance ................................................................. 64 
11 Protocol adherence ............................................................................................................ 64 


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11.1 
Protocol Amendments ........................................................................................... 65 
12 References ......................................................................................................................... 65 
13 Appendices ........................................................................................................................ 67 
Appendix 1: Instruction for Use of Concept1 ................................................................... 67 
Appendix 2: How to Use an Accuhaler®/ Diskus® ............................................................ 72 
Appendix 3: Spirometry Guidance .................................................................................... 76 
Appendix 4: Patient Asthma Control e-Diary ................................................................... 78 
Appendix 5: ACQ-IA ........................................................................................................ 79 
Appendix 6: Clinically notable laboratory values and vital signs ..................................... 84 
Appendix 7: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements ..................................................................................................................... 85 
 
List of tables 
Table 5-1 
Prohibited asthma-related medications ................................................. 29 
Table 5-2 
Medications allowed under certain conditions ...................................... 30 
Table 5-3 
Other prohibited medications ................................................................ 30 
Table 6-1 
Assessment schedule ............................................................................. 35 
Table 6-2 
Timed assessment schedule (Visit 199) ................................................ 41 
Table 6-3 
Timing of key visit procedures during treatment .................................. 41 
Table 13-1 
Liver Event and Laboratory Trigger Definitions .................................. 85 
Table 13-2 
Follow Up Requirements for Liver Events and Laboratory Triggers ... 85 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 18 
 


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List of abbreviations 
 
ACQ-IA 
Interviewer-administered Asthma Control Questionnaire 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
b.i.d. 
twice a day 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CFR 
US Code of Federal Regulations  
CHMP 
Committee for Medicinal Products for Human Use 
COPD 
Chronic Obstructive Pulmonary Disease 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
DAR 
Dose administration record 
DPI 
Dry powder inhaler 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
e-Diary 
Electronic Diary 
EOT 
End of Treatment 
ERS 
European Respiratory Society 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GTL 
Global Trial Leader 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICS 
Inhaled Corticosteroid 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine System 
LABA 
Long Acting Beta-2 Agonist 
LAMA 
Long Acting Muscarinic Antagonist 


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LFT 
Liver function test  
LTRA 
Leukotriene Receptor Antagonist 
MAP 
Master analysis plan 
MDDPI 
Multi dose dry powder inhaler 
MDI 
Metered-dose inhaler 
MedDRA 
Medical dictionary for regulatory activities  
OC/RDC 
Oracle Clinical/Remote Data Capture 
o.d. 
once a day 
PDCO 
EU Pediatric Committee 
PEF 
Peak Expiratory Flow 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PRO 
Patient Reported Outcome 
QTc 
Corrected QT interval 
RAN 
Randomized Set 
SABA 
Short Acting Beta-2 Agonist 
SAE 
Serious Adverse Event 
SAMA 
Short Acting Anticholinergics 
SAP 
Statistical Analysis Plan 
SCS 
Systemic Corticosteroids 
SDDPI 
Single Dose Dry Powder Inhaler 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TD 
Study Treatment Discontinuation 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
 
Cohort  
A specific group of patients/subjects fulfilling certain criteria 
Control drug 
Drugs(s) 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 
Dosage 
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol) 
Epoch 
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and Follow-up 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication pack number 
A unique identifier on the label of each investigational drug package 
Part  
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects 
with established disease and in those with newly-diagnosed disease. 
Patient/subject ID  
A unique number assigned to each patient upon signing the informed 
consent  
Randomization number 
A unique identifier assigned to each randomized patient, corresponding 
to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the patient as 
part of the required study procedures; includes investigational drug(s), 
placebo/comparator active drug Run-in or background therapy 
Study Treatment 
Discontinuation (TD) 
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent 
(WoC) 
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material 
 


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Protocol summary 
 
Protocol number 
QMF149G2202 
Title 
A multicenter, randomized, double-blind, active-controlled, 2 week 
treatment, parallel-group study to assess the efficacy and safety of 
indacaterol acetate delivered via the Concept1 inhalation device in 
children greater or equal to 6 and less than 12 years of age with 
asthma 
Brief title 
 
Efficacy and safety of indacaterol acetate delivered via the Concept1 
inhalation device in children greater or equal to 6 and less than 12 
years of age with asthma  
Sponsor and Clinical 
Phase 
Novartis Phase II  
 
Investigation type 
Drug and Concept1 Device (Breezhaler®) 
Study type 
Interventional  
Purpose and rationale 
This study is designed to explore lung function effects of two doses 
of indacaterol acetate, 75 µg and 150 µg, in pediatric asthma 
patients, and to compare the systemic exposure to indacaterol in 
plasma with historical data in adults, to identify an appropriate dose 
for Phase III evaluation. 
Primary Objective(s)  
The primary objective of this study is to evaluate indacaterol acetate 
75 µg o.d and 150 µg o.d. in terms of change from baseline in pre-
dose trough FEV1 after 2 weeks of treatment. 
Secondary Objectives 
One secondary objective is to evaluate the systemic exposure to 
indacaterol in plasma following sparse pharmacokinetic (PK) 
sampling on Day 1 and Day 14 after oral inhalation of indacaterol 
acetate 75 µg and 150 µg. 
Other secondary objectives include the evaluation of clinical effects 
and pharmacodynamics of indacaterol acetate (75 μg and 150 μg 
o.d.) after 2 weeks of treatment in terms of: ACQ-IA score, lung 
function parameters, rescue medication usage and symptoms as 
recorded by patient e-diary.  
Safety (including labs, vital signs, ECG, adverse events), and 
tolerability of indacaterol acetate (75 and 150 μg o.d.) over 2 weeks 
of treatment will be evaluated. 
Study design 
A multicenter, randomized, double-blind, active-controlled, 2 week 
treatment, parallel-group study  
Population 
The study population will consist of approximately 80 male and 
female children ≥ 6 years and < 12 years with persistent asthma 
Key Inclusion criteria 
1. Male and female children ≥ 6 years and < 12 years with 
confirmed diagnosis of asthma for at least 1 year prior to study 


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enrollment. 
2. Written informed consent by parent(s)/legal guardian(s) and 
depending upon their age and local requirements a consent or 
assent for the patient. 
3. Patients receiving daily treatment with a stable low dose Inhaled 
Corticosteroid (ICS) (with or without additional controller), or 
patients receiving daily treatment with a stable mid-dose ICS 
(monotherapy or together with LTRA) for at least 4 weeks prior 
to Screening, and able to tolerate fluticasone propionate 100 µg 
b.i.d. inhaler starting at Visit 1 (or soon after).  
4. Patients with a pre-bronchodilator FEV1 ≥ 50% and ≤ 90% of the 
predicted normal value for the patient at the start and end of 
Run-in (Visits 101 and 199). 
• Withholding period of bronchodilators prior to spirometry at 
Visit 101: SABA for ≥ 6 hours and FDC or free combinations of 
ICS/ Long Acting Beta-2 Agonist (LABA) for ≥ 48 hours, o.d. 
LABA for at ≥ 14 days,  SAMA for ≥ 8 hours, LAMA for ≥ 7 
days, xanthines ≥ 7 days 
• One-time re-testing of pre-bronchodilator FEV1 is allowed only 
at Visit 101. Re-assessment should be done in an ad-hoc visit 
before randomization. 
5. Patients who demonstrate an increase in FEV1 of ≥ 12% within 
30 minutes after administration of 400 µg salbutamol/360 µg 
albuterol (or equivalent dose) at Visit 101. All patients must 
perform a reversibility test at Visit 101. Use of spacer devices is 
mandatory. Reversibility may be repeated once. 
6. A single parent/legal guardian must be designated to complete all 
e-Diary entries and attend all clinic visits with the patient. 
Key Exclusion criteria 
1. Patients taking a mid-dose ICS (per GINA guidelines) in 
combination with LABA or any patient taking high-dose ICS.  
2. Evidence of unstable disease within 4 weeks prior to Screening 
(Visit 1). 
3. Patients who have had an asthma attack/exacerbation requiring 
systemic steroids (SCS) or hospitalization or emergency room 
visit within 3 months prior to Visit 1 (Screening) or more than 3 
separate exacerbations in the 12 months preceding Visit 1. If 
patients experience an asthma attack/exacerbation requiring SCS 
or hospitalization between Visit 1 and Visit 199 they may be re-
screened 3 months after recovery from the exacerbation. 
4. Suspected or documented bacterial or viral infection of the upper 
or lower respiratory tract, sinus or middle ear that is not resolved 
within 4 weeks of Screening (Visit 1). 
5. Prior intubation for asthma  


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6. Patients who, in the opinion of the investigator, are not able to be 
compliant with study treatments, properly use study drug devices 
(e.g. DPI, MDI, Concept1, peak flow meter), or who have any 
medical or mental disorder, situation, or diagnosis which could 
interfere with the proper completion of the protocol requirements. 
Study treatment 
• Indacaterol acetate 75 µg capsules for inhalation, delivered via 
Concept1 
• Indacaterol acetate 150 µg capsules for inhalation, delivered via 
Concept1 
Efficacy assessments 
• Spirometry  
• Pediatric ACQ-IA 
• Asthma symptoms based on e-Diary 
• Peak Expiratory Flow (PEF) 
• Rescue Medication Use 
Key safety 
assessments 
• Medical history and physical examination including 
oropharyngeal examination 
• Vital signs 
• Hematology, blood chemistry, urine dipsticks 
• Electrocardiogram (ECG) 
• Adverse events (AEs) including asthma exacerbations, worsening 
asthma, and serious adverse events (SAEs) 
Other assessments 
Pharmacokinetic (PK) analysis will be conducted in all patients 
Data analysis 
The primary endpoint is change from baseline in pre-dose trough 
FEV1 (mL) after 2 weeks of treatment. Summary statistics (n, mean, 
25th percentile, median, 75th percentile, standard deviation, minimum 
and maximum) by treatment group will be provided for change from 
baseline in pre-dose trough FEV1 as well as pre-dose trough FEV1 
after 2 weeks of treatment. Inferential testing statistics will not be 
performed since the sample size is small and power is limited. 
For secondary endpoints (Spirometry, Pediatric ACQ-IA, Asthma 
symptoms recorded in e-Diary, Peak Expiratory Flow, Rescue 
Medication Use), summary statistics will be provided by treatment 
group. 
Key words 
indacaterol acetate, asthma, GINA 2015, pediatrics 


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1 
Introduction 
1.1 
Background  
Asthma is a chronic inflammatory disorder of the airways associated with hyper- 
responsiveness of airways that leads to recurrent episodes of wheezing, breathlessness, chest 
tightness, and coughing, particularly at night or in the early morning.  These episodes are 
usually associated with widespread but variable airflow obstruction within the lung that is 
often reversible either spontaneously or with treatment.  Airflow limitation occurs as a result 
of obstruction or narrowing of the airways when exposed to precipitating factors. Although 
exacerbations of asthma are episodic, inflammation is chronic (GINA Global strategy for 
Asthma management and prevention, 2015).  Asthma is defined by its clinical, physiological, 
and pathobiological characteristics.  The wide clinical spectrum of asthma is highly variable, 
and although different cellular patterns have been observed in asthmatic airways, the presence 
of airway inflammation remains a consistent feature. 
Despite persistent airway inflammation, asthma symptoms are episodic and the relationship 
between the intensity of inflammation and the severity of asthma is not clearly established. In 
most patients, the inflammation affects all airways including the upper respiratory tract and 
nose, but the physiological effects are most pronounced in medium-sized bronchi.  Despite the 
cellular heterogeneity of inflammatory response, the pattern of inflammation in the airways 
appears to be similar in all clinical forms of asthma at all ages, whether allergic, non-allergic, 
or aspirin-induced (GINA 2015). 
Asthma most often starts early in life and has variable courses and unstable phenotypes which 
may progress or remit over time.  Despite advances in medical management, childhood 
asthma continues to be a leading cause of emergency department visits, hospitalizations, and 
school days missed.  Children afflicted with uncontrolled asthma have difficulty exercising, 
sleeping, and participating in the normal activities of childhood (Runge and Hill 2009).  
Asthma is the most common childhood chronic disease (Bastain et al 2011) and its prevalence 
has increased especially among children (GINA 2014). Children under 18 years represent 
one-third of all asthmatics according to the MMWR Surveillance summary - National 
surveillance for asthma 1980 to 2004 (United States) (Moorman et al 2007), with data 
showing that the incidence and prevalence of asthma is increasing more rapidly in children 
than that in adults, particularly in children under 15 years (Masoli et al 2004). 
Due to this high impact of asthma on the quality of life of pediatric patients and caregivers, as 
well as is costs, several guidelines exist to support clinical care of pediatric asthmatics.  Two 
types of medications are used to treat asthma: long-term control (“prevention”) medications 
and quick-relief medications, which reverse acute airflow obstruction.  All children who have 
persistent asthma should be started on a long-term control (“prevention”) medication.  Such 
anti-inflammatory medications are taken daily to reduce airway inflammation.  The 
recommended type and dose of long-term control medication depends on the level of asthma 
severity and the age of the child. For persistent asthma, these guidelines recommend step wise 
intensification of asthma controller medications.  Combinations of different controller 
medications are recommended as preferred treatment options by various guidelines (NIH, 
GINA, ICON).  Especially fixed dose combinations (FDC) products containing a LABA plus 


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ICS have been shown to be safe and effective in the management of asthma and 
recommended by GINA as preferred controller therapy ≥ Step 3 for adult and pediatric 
population. In older children and adults, ICS/LABA combinations have been shown to 
improve asthma outcomes to a better extent than higher doses of ICS. ICS/LABA 
combinations are recommended as the preferred add-on treatment in children >5 years (SIGN, 
GINA), or >12 years (NAEPP), in other studies they are suggested as an option for 
children >5 years (AAMH, NAEPP) or at any age (JGPA) (Woolcock et al 1996, Greening et 
al 1994, Ducharme et al 2010). However, most of the currently available FDC products (e.g. 
salmeterol xinafoate/ fluticasone propionate) require twice a day (b.i.d.) dosing to achieve an 
optimum therapeutic effect in asthma.  
Novartis is developing QMF149 which is a fixed-dose combination (FDC) of indacaterol 
acetate (inhaled LABA with 24 hour duration of action) and mometasone furoate (MF, ICS) 
for once-daily maintenance treatment of asthma in both adults and children 6 years of age and 
above.  The mono-components are approved medications: indacaterol as the maleate salt for 
the treatment of chronic obstructive pulmonary disease (COPD) in adults, and MF for the use 
in asthma in adult and pediatric patients (Asmanex® Twisthaler®). 
QMF149 FDC has been used in clinical trials in healthy volunteers, and adult and adolescent 
asthma patients. Indacaterol acetate has been investigated in healthy volunteers and adult 
asthma patients and demonstrated a lower incidence of post-inhalation cough compared to 
indacaterol maleate in asthma patients, while maintaining bronchodilator efficacy, with a very 
similar safety profile (study CQAB149D2301). 
Studies CQMF149E2203 and CQAB149B2357 evaluated indacaterol acetate and maleate, 
respectively delivered via the Concept1 (Breezhaler®) inhaler in patients with asthma. These 
two studies support selection of indacaterol dose 150 µg once daily in the adult and adolescent 
population.  
A dose-ranging study of indacaterol maleate in adult asthmatic patients demonstrated that a 
dose of 150 µg o.d. was safe and effective (Study CQAB149B2357). The dose of indacaterol 
acetate was investigated in Study CQMF149E2203 in adult asthma patients, where indacaterol 
acetate 150 μg and 75 μg was delivered via Concept1 compared to placebo. The study 
demonstrated that both 150 μg and 75 μg doses were found to be superior to placebo and 
indacaterol acetate 150 µg showed positive trends in terms of trough forced expiratory volume 
in 1 second (FEV1), peak expiratory flow (PEF), and rescue medication use compared with 
indacaterol acetate 75 μg.  
This study is part of the pediatric development plan for QVM149 and is designed based on 
agreement with EU Pediatric Committee (PDCO). Prior to progressing into Phase III testing 
of QMF149 in ≥6, <12-year-old children, a dose selection study of indacaterol in this 
population is needed. The objective of the study is to assess the benefit of two doses of 
indacaterol when added to baseline ICS therapy to identify an appropriate dose to carry 
forward for Phase III evaluation. This will be achieved by assessing the totality of lung 
function data, symptoms and systemic exposure to indacaterol in 6 to 11-year-old children 
compared with historical PK data collected in adults.  
 


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1.2 
Purpose  
This study is designed to explore lung function effects of two doses of indacaterol acetate, 
75 µg and 150 µg, in pediatric asthma patients 6-11 years old, and to compare the systemic 
exposure to indacaterol in plasma with historical data in adults, to identify an appropriate dose 
to Phase III evaluation. 
2 
Study objectives and endpoints 
2.1 
Primary objective(s) 
To evaluate indacaterol acetate 75 µg o.d and 150 µg o.d. in terms of change from baseline in 
pre-dose trough FEV1 after 2 weeks of treatment. 
2.2 
Secondary objective(s) 
• To evaluate the systemic exposure to indacaterol in plasma following sparse 
pharmacokinetic (PK) sampling on Day 1 and Day 14 after oral inhalation of indacaterol 
acetate 75 µg and 150 µg  
• To evaluate the clinical effects and pharmacodynamics of indacaterol acetate (75 μg and 
150 μg o.d.) after 2 weeks of treatment in terms of: 
• Pediatric interviewer-administered Asthma Control Questionnaire (ACQ-IA) score at 
Week 2  
• FEV1 and forced vital capacity (FVC) rate at 30 minutes and 1-hour post dose at 
Week 2 
• Rescue medication usage over 2 weeks of treatment as determined by patient diary 
data 
• Symptoms as recorded by patient e-diary  
• Pre-dose morning and evening peak expiratory flow (PEF) over 2 weeks of treatment 
as determined by electronic peak flow meter data. 
• To evaluate the safety (including labs, vital signs, ECG, adverse events), and tolerability 
of indacaterol acetate (75 and 150 μg o.d.) over 2 weeks of treatment.  
2.3 
Exploratory objectives 
Not applicable 
3 
Investigational plan 
3.1 
Study design 
This study uses a randomized, multicenter, double-blind, active-controlled study design.  The 
primary endpoint will be evaluated after 2 weeks of treatment with indacaterol acetate as 
change from baseline in children ≥6 years and <12 years (GINA step 2 & 3). Study treatment 
will be administered on top of background asthma ICS controller therapy (fluticasone 
propionate 100 µg b.i.d. or dose equivalent). This study will consist of 4 epochs: Screening, 
Run-in, Treatment, and Follow-up (telephone contact for safety).  


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Screening (Visit 1) 
At an initial Screening visit (Visit 1) informed consent is obtained from the parent(s)/legal 
guardian(s).  Additionally, a patient assent is obtained before any study-related assessments or 
procedures are performed (according to locally accepted policy/practice).  Patients will be 
screened to determine eligibility (Section 4.1 and 4.2). Where appropriate, concomitant 
medications are adjusted at this visit and washout begins for any prohibited medications. The 
window between Visit 1 and 101 (Screening Epoch) is to complete all Screening measures 
and to washout prohibited medications (Table 5-1, Table 5-2 and Table 5-3). It can be as short 
as necessary and last up to 30 days. 
Patients meeting Screening eligibility will receive the following at the Screening visit (Visit 
1): 
• Fluticasone propionate 100 µg b.i.d. delivered via Diskus®/ Accuhaler® (if not available in 
a specific country, fluticasone propionate 125 µg b.i.d. via MDI inhaler; if these 
formulations are not available, then the closest equivalent to fluticasone propionate 100 µg 
b.i.d. should be given; MDI can be used with spacer).  
The child’s parent/ legal guardian will be instructed that their child discontinue their 
current ICS and be placed on fluticasone propionate. If their child has already taken his/ 
her ICS prior to arriving at the site, then the child should begin using the provided 
fluticasone inhaler the next day.  Patients will be instructed to take their fluticasone inhaler 
daily in the morning and evening, in place of their previous ICS.   
• The patient’s parent/ legal guardian must be instructed that the patient should NOT take 
fluticasone on the mornings before arriving at the site for their study visits.  They will take 
their morning fluticasone dose at the site on those days.  Therefore, it is important that 
they bring the fluticasone inhaler with them to every study visit.  If it is found that a 
patient did take the fluticasone morning dose prior to arriving at the site, this should be 
documented in the patient’s source and the visit will go on as scheduled. 
• Patients will receive the short acting β2-agonist (SABA) salbutamol/albuterol to use as 
rescue medication throughout the study.  Parents/ legal guardians must be instructed that 
their child NOT take rescue salbutamol/albuterol for at least 6 hours prior to any of their 
study visits (unless they are experiencing symptoms that mandate salbutamol/albuterol 
inhalation, in which case the visit would be re-scheduled).  Spacers are allowed for the 
rescue medication use. No other rescue medication is allowed in the study. 
• Patients/ patient’s parent/legal guardian will be issued an electronic diary (e-Diary) to 
record asthma symptoms and rescue medication use, which will be completed by the 
patient’s parent/legal guardian.  The patient’s parent/legal guardian will be instructed to 
bring the e-Diary with them to every study visit. 
• Patients will also be issued an electronic Peak Flow meter (part of e-Diary) to record 
their Peak Expiratory Flow (PEF) rate. The patient and his/her parent/legal guardian 
will be instructed on how to use this device. 
• Patients are allowed to use a spacer while taking their inhaled medication and must use a 
spacer for reversibility testing. 
 


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Visit 1 should be conducted up to 30 days before Visit 101.  Visit 1 and 101 may occur on the 
same day, as long as no washout is required (no short-acting rescue medication taken within 6 
hours, and appropriate washout of prohibited treatment in Table 5-1, Table 5-2 and Table 5-
3). 
Patients should bring their ICS (fluticasone propionate) inhaler, rescue salbutamol/albuterol, 
PEF and e-Diary, and all study medications with them to every study visit.  
Run-in epoch (Visit 101-Visit 199) 
Once patients’ concurrent medications comply with the requirements of the study (Section 
5.5.6 and 5.5.8) patients will enter a Run-in epoch.  
The Run-in epoch is 2 weeks in duration (Visit 101 and 199) and will be used to further assess 
eligibility (including meeting reversibility and FEV1 criteria, collecting baseline patient 
characteristics, and reviewing fluticasone and rescue salbutamol/albuterol use).   
Patients are instructed NOT to take their fluticasone inhaler in the morning of these study 
visits, and should bring it with them to the site.  The patients should take their fluticasone 
inhaler at the beginning of each study visit, under supervision of the site staff.  The patient 
will take their fluticasone inhaler back home with them and be instructed to take it as directed.   
During Visit 101, study staff will administer the pediatric Asthma Control Questionnaire to 
the child.  The Asthma Control Questionnaire – interviewer-administered (ACQ-IA) is further 
discussed in Section 6.4.2.  
Approximately two weeks after the start of the Run-in epoch (Visit 101 + 14 days), the patient 
will return to the clinic in the morning for Visit 199 (end of Run-in), to have all eligibility 
criteria reviewed along with their e-Diary and PEF meter and complete another ACQ-IA.  If 
the patient continues to meet eligibility criteria (no salbutamol/albuterol taken within 6 hours 
of this visit and FEV1 ≥50% and ≤ 90% of the predicted normal value for the patient) the 
patient will immediately continue to Visit 201 (Randomization/ Day 1).   
If the patient’s FEV1 and/or reversibility do not meet criteria at Visit 101, these assessments 
can be repeated one time, on a different day. For learning purposes, spirometry training can be 
provided prior to actual measurements.   
Table 6-1 displays all Run-in procedures. 
For all subsequent study visits, the patient’s parent(s)/legal guardian(s) should be instructed 
that their child does NOT take the morning dose of fluticasone, as they will take this dose at 
the site and the investigator will observe the inhalation technique of the child.  Additionally, 
patients should NOT take any rescue salbutamol/albuterol for a minimum of 6 hours prior to 
arriving for their next study visit.  If rescue medication is taken within 6 hours of a study visit, 
the visit must be rescheduled. 
NOTE: Since the first spirometry measurement is 45 minutes prior to inhalation of 
study medication (Visit 199), and study medication is administered in the morning, it is 
important to schedule the remaining study visits early enough so the patient will have 
enough time to take their fluticasone on site, have other study assessments done (vital 
signs and lab) and have the first spirometry 45 minutes prior to inhalation of study 
medication.  Refer to Table 6-2 and Table 6-3 for details.   


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Treatment epoch (Visit 201-Visit 299) 
If the patient continues to meet eligibility criteria, Visit 201 (randomization/ Day 1) occurs on 
the same day as Visit 199.  Qualifying patients will be randomized to one of the two treatment 
groups below, with an equal (1:1) randomization ratio: 
• Indacaterol acetate 75 µg delivered via Concept1 o.d. in the morning 
• Indacaterol acetate 150 µg delivered via Concept1 o.d. in the morning 
The treatment epoch will last 2 weeks.  Patients will receive their first dose of study 
medication at the site, and the patient’s parent/legal guardian should be instructed to give their 
child study medication at approximately the same time each day.  Patients will return to the 
clinic 2 weeks later for the end of treatment visit (Visit 299).   
All patients will be required to attend the clinic visits (Visit 201 and 299) where they will take 
their morning fluticasone dose, have pre-dose trough measurements of lung function prior to 
taking the study medication, and post-dose measurements. 
Parents/legal guardian(s) will be instructed to record the time of their child’s last dose of 
study medication taken the day prior (~Day 13) to their final treatment visit (Visit 299/Day 
14).  Additionally, parents/legal guardians should be instructed that their child should not take 
the last dose of study medication on the day of the last clinic visit (Visit 299/ end of 
treatment).  Rather, the patient (parent/legal guardian) should bring their medication with 
them to the clinic and this dose will be administered under the supervision of study personnel. 
If study medication has not been taken in the morning on day 13 (last day before end of 
treatment Visit 299), the visit has to be rescheduled.  
PK sampling (taken ≤ 2 hours pre-dose and at 15 minutes and 1 hour post-dose) will be 
performed at Visit 199/201 and 299 (Table 6-1 through 6-3).  The ACQ-IA will also be done 
at Visit 299. 
Patients should be seen for all visits on the designated day or as close as possible.   
Follow-up epoch 
A final telephone contact must be conducted at 30-days after last treatment date (telephone 
Visit 301). Patients who discontinue their study treatment prematurely will return to the clinic 
for Visit 299 as a Discontinuation visit and then directly move to Follow-up and disclose with 
Visit 301. 
Figure 3-1 shows the study design. 
 


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Figure 3-1 
Study design  
 
3.2 
Rationale for study design 
This study is a randomized, double-blind, parallel-group study, with a 2-week treatment 
duration to assess 2 different doses of indacaterol acetate. The primary endpoint, trough FEV1, 
will be evaluated as change from baseline (randomization) after 2 weeks. This is considered 
an adequate duration to demonstrate improvements in the primary endpoint of lung function 
based on the known pharmacodynamic properties of indacaterol. 
In order to preserve the integrity of the study, a randomized, double-blind study design is 
used.  This design enables the study treatments to be given for an appropriate and practical 
length of time to assess the efficacy and safety of the treatments.  The study design does not 
include a placebo control, as this would not be considered ethical in this population of 
pediatric asthma patients with GINA ≥ Steps 2 and 3 (GINA 2015). 
The primary objective of this trial is to evaluate the efficacy of 2 doses of indacaterol in 
patients with persistent asthma in terms of lung function (measured by pre-dose FEV1).  Other 
efficacy endpoints include peak expiratory flow, rescue medication, and FEV1 at 30 minutes 
and 1 hour post-dose.   
Additional secondary endpoints include the evaluation of the systemic exposure to indacaterol 
in plasma according to a sparse PK sampling (≤ 2 hours pre-dose, and 15 minutes and 1 hour 
post-dose).  This will allow comparison of the systemic exposure to indacaterol after single 
dose (Day 1) and at steady state (Day 14) observed in these pediatric patients with that 
collected in adult healthy subjects or patients (historical data).  Safety is also evaluated. 
Double blind treatment Epoch
End of Run-in Visit 199 
Randomization Visit 201 
Day 1 to Day 14 
Indacaterol acetate 150 µg o.d. 
Indacaterol acetate 75 µg o.d. 
Run-in Epoch 
Visit 301
End of 
Treatment 
Visit 299 
Rescue medication 
Visit 1 
Visit 101 
Day -14 
to Day 1 
Screening 
Epoch 
Patients 
switch to 
fluticasone 
propionate 
100 µg b.i.d. 
for trial 
duration 
 
Patients 
it h t
Fluticasone propionate 100 µg b.i.d (or dose equivalent) 
Up to 30 days 
prior to Visit 
101 
 
 
 
Day 44 
Follow-up 
Epoch 


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The lung function data combined with systemic exposure will be used to identify an 
appropriate dose of indacaterol which will be carried forward to the Phase 3 pediatric trials. 
The primary endpoint, change in baseline of pre-dose trough FEV1, will be evaluated 
descriptively as a function of change from baseline between the two indacaterol doses.  Taken 
together with systemic exposure for each dose, which will be compared with historical PK 
data collected in adults, an appropriate dose will be selected.     
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
The dose/regimen, route of administration and duration of treatment are based upon known 
pharmacokinetic/pharmacodynamics effects of indacaterol as well the clinical data from Phase 
II studies in asthma in adults.  
Indacaterol maleate (Onbrez Breezhaler; QAB149) is a LABA approved globally as a once-
daily maintenance bronchodilator treatment of airflow obstruction in adult patients with 
COPD. The recommended dosage for COPD is 150 µg and 300 µg outside of the US and 
Canada; US and Canada is approved at 75 µg.  
A dose-ranging study of indacaterol maleate in asthmatic patients demonstrated that doses of 
75 µg o.d. and 150 µg o.d. were safe and effective with greatest improvements in trough FEV1 
(Study CQAB149B2357).   
The acetate salt of indacaterol was found to result in a lower incidence of the post-inhalation 
cough compared to indacaterol maleate, without impact on efficacy or safety (study 
CQAB149D2301).  For indacaterol, the acetate salt will be used due to lower incidence of 
post-inhalation cough.    
The dose of indacaterol acetate on a mometasone furoate background therapy was 
investigated in Study CQMF149E2203 in adult asthma patients where indacaterol acetate 
150 μg and 75 μg delivered via Concept1 were compared to placebo.  The study demonstrated 
statistically significant improvements compared to placebo for both 150 μg and 75 μg doses.  
Additionally, indacaterol acetate 150 µg showed positive trends in terms of trough FEV1, 
PEF, and rescue medication use compared with indacaterol acetate 75 μg.  QMF149 FDC via 
Twisthaler (indacaterol maleate in a dose equivalent to 150 µg Concept1 with mometasone 
furoate) demonstrated significant improvement in trough FEV1 and significant reduction in 
the risk of exacerbations requiring systemic corticosteroids in adult and adolescent asthma 
patients (study CQMF149A2210).  These data support the evaluation of indacaterol up to 150 
μg daily.   
There is limited information about pharmacokinetics of indacaterol in the pediatric 
population.  In a previous PK and PD study (Study CQAB149C2101), in asthmatic patients 
ranging from 4 to 11 years of age, 24 children were randomized to receive doses of 100, 200 
or 400 μg indacaterol maleate delivered via a multi dose dry powder inhaler 
(MDDPI/Certihaler™).  During the conduct of the study, as a result of a malfunction with a 
commercial Foradil® Certihaler™, this study was terminated after the enrolment of only 12 
children.  Therefore, the pharmacokinetic information was incomplete and firm conclusions 
could not be drawn.  In general; however, the systemic exposure appeared to increase with 
increasing dose and the data suggested that after 7 days of once-daily dosing systemic 
exposure was close to steady-state.   


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On the basis of dose-normalized AUCs the exposure seemed to be similar to that of adults.  
The limited data set showed no correlations to age or body weight.  In the adult COPD 
population, covariate analysis on age, body weight, and body mass index did not indicate a 
need for change in dosage regimen.  Therefore the selected doses of indacaterol acetate are 
anticipated to result in systemic exposure in 6-11-year-old children that is similar to the 
systemic exposure of indacaterol maleate in adults. 
Based on the totality of the available data in adults as well as limited PK information in 
children, the 75 and 150 ug doses of indacaterol are considered appropriate for evaluation to 
establish appropriate dose for confirmatory Phase III studies.   
3.4 
Rationale for choice of comparator 
It was considered appropriate to explore two doses of indacaterol acetate, 75 µg o.d. and 150 
µg o.d. in 6-11-year-olds and to compare the systemic exposure obtained in this trial with that 
obtained in adults (historical data). Relative differences in lung function between 2 doses will 
be evaluated descriptively.  
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable 
3.6 
Risks and benefits  
The risk to patients in this trial will be minimized by compliance with the eligibility criteria 
and by close clinical monitoring.  Although altering current asthma medication regimens 
during the trial carries an inherent risk of a decline in lung function and/or a worsening of 
symptoms, providing patients with rescue medication (salbutamol/ albuterol) and requiring 
them to take background ICS (fluticasone propionate 100 µg b.i.d.) throughout the trial 
mitigates this risk. 
Patients will be required to perform repetitive lung function measurement maneuvers during 
the study, and these can lead to cough, shortness of breath, dizziness, or exhaustion.  PEF 
measurements are part of the usual care of most pediatric asthma patient and are not 
considered an additional burden to patients.  Considering the 2-week treatment duration, the 
number of assessments is relatively small and these are part of the regular medical 
assessments of this patient population.  Other procedural risks are related to blood sampling 
for safety or PK laboratory analyses: puncturing of the veins can cause discomfort, pain, 
hematoma, or in rare cases lead to an infection. 
The risk to the patients in participating in the study is that QMF149 is under development and 
there is limited safety data in children 6-11 years old for indacaterol. Data to support the 
efficacy and safety of indacaterol in adolescents was demonstrated in one large Phase II event 
driven trial with a duration up to 68 weeks in over 1500 moderate to severe asthma patients 
including 66 adolescents (12-17 years old). Patients treated with QMF149 
(indacaterol/mometasone delivered by Concept1) compared with patients treated with MF 
delivered by Twisthaler showed a favorable efficacy and safety profile over MF (Beasley et al 
2015). 
It is possible that unexpected safety issues may be identified; this will be minimized by 
compliance with the eligibility criteria and close clinical monitoring. The risks of side effects 
are well characterized in adult population in COPD as well from the early QMF149 asthma 


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development in the Twisthaler® device (see Section 1.1 Background and QMF149 
Investigator Brochure (IB)).    
There are concerns that LABA treatment used alone in asthma might cause severe asthma 
exacerbations. To address this safety concern, all patients are treated with background ICS in 
this study so LABA alone will not be allowed. 
During the trial, additional treatment options for the patients are limited as the protocol does 
not allow administration of other asthma medications except ICS, previously initiated 
Leukotriene Receptor Antagonist (LTRA), and short acting β2-adrenergic receptor agonist 
(SABA) for rescue use. Furthermore, patients will have to discontinue their pre-study ICS 
controller medication and begin taking fluticasone propionate.  Change of the device and 
controller medication may introduce a risk for worsening of asthma symptoms and lung 
function for these patients due to reduced adherence.  ICS therapy as controller treatment for 
asthma is aligned with GINA guidelines at all times.  In order to minimize the risk to patients, 
extensive safety monitoring (e.g. electronic daily patient dairy assessment of rescue 
medication use, PEF measurements, and adverse event monitoring) will be carried out 
throughout the study. E-Diary data will be transmitted electronically from the device to the 
investigator regularly. 
Investigators should withdraw a patient if they feel, based on their medical judgment, that this 
would be best for the patient, or after occurrence of any of the discontinuation criteria listed in 
Section 5.6.2.  Parents/legal guardians are also instructed that their child can withdraw from 
the trial at any time, and for whatever reason. 
The potential individual benefit for the patient lies in a thorough medical evaluation of the 
patient’s disease and close clinical monitoring for the duration of the study.  The potential 
benefit also includes an improvement in lung function, and symptoms (during treatment 
periods).  All patients in the study will be receiving active treatment with indacaterol acetate 
on ICS background, which is consistent with GINA treatment guidelines. There is no placebo 
arm, which mitigates risk of under-treatment. 
4 
Population 
The study population will consist of approximately 80 male and female children ≥ 6 years and 
< 12 years with persistent asthma for at least 1 year and on stable ICS dose (with or without 
additional controller medication, GINA step 2 & 3) for at least 4 weeks prior to study start.  It 
is anticipated that approximately 200 patients will need to be screened in order to randomize 
80 patients into the treatment epoch. 
It is intended that approximately 72 patients will complete the study. Dropouts may be 
replaced if dropout rate is higher than expected (>10%).    
4.1 
Inclusion criteria 
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. Male and female children ≥ 6 years and <12 years. 
2. Written informed consent by parent(s)/legal guardian(s) for the pediatric patient and assent 
by the pediatric patient (depending on local requirements) must be obtained before any 
study-specific assessment is performed.  


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3. Confirmed diagnosis of asthma, as defined by national and international asthma guidelines 
(GINA 2015) for at least 1 year prior to study enrollment. 
4. Patients receiving daily treatment with a stable low dose ICS (with or without additional 
controller), or patients receiving daily treatment with a stable mid-dose ICS (monotherapy 
or together with LTRA) for at least 4 weeks prior to Screening, and able to tolerate 
fluticasone propionate 100 µg b.i.d. inhaler starting at Visit 1 (or soon after).  
5. Patients with a pre-bronchodilator FEV1 ≥50% and ≤ 90% of the predicted normal value 
for the patient at the start and end of Run-in (Visits 101 and 199) (performed according to 
ATS/ERS guidelines). 
• Withholding period of bronchodilators prior to spirometry at Visit 101: SABA for ≥ 6 
hours and FDC or free combinations of ICS/LABA for ≥ 48 hours, o.d. LABA for at 
≥ 14 days,  SAMA for ≥ 8 hours, LAMA for ≥ 7 days, xanthines ≥ 7 days 
• A one-time re-testing of pre-bronchodilator FEV1 is allowed only at Visit 101. Re-
assessment 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.* 
6. Patients who demonstrate an increase in FEV1 of ≥ 12% within 30 minutes after 
administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose) at Visit 101 
(performed according to ATS/ERS guidelines, use of spacer mandatory). All patients must 
perform a reversibility test at Visit 101. If reversibility is not demonstrated at Visit 101, it 
may be repeated once. If reversibility is still not demonstrated at Visit 101 (or after 
repeated assessment) patients must be screen failed.* 
*If patients do not meet FEV1, reversibility or ATS/ERS criteria after re-testing, patients 
may be re-screened once. 
7. A single parent/legal guardian must be designated to complete all e-Diary entries and 
attend all clinic visits with the patient. 
8. Parents/ legal guardian must be willing and able to assist the child with the procedures 
outlined in the protocol, e.g. compliance with study medication, completion of electronic 
patient diary.  
9. Patient must be able to use Concept1 dry powder inhaler and also be proficient in use of 
other study devices (including those used during Run-in), and complete spirometry 
procedures. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study.  No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Patients taking a mid-dose ICS (per GINA guidelines) in combination with LABA or any 
patient taking high-dose ICS.  
2. Evidence of unstable disease within 4 weeks prior to Screening (Visit 1) that in the 
opinion of the investigator would put the safety of the subject at risk through study 
participation or would confound the interpretation of the results if the condition/disease 
exacerbated during the study. 


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3. Patients who have had an asthma attack/exacerbation requiring SCS or hospitalization or 
emergency room visit within 3 months prior to Visit 1 (Screening) or more than 3 separate 
exacerbations in the 12 months preceding Visit 1. If patients experience an asthma 
attack/exacerbation requiring SCS or hospitalization between Visit 1 and Visit 199 they 
may be re-screened 3 months after recovery from the exacerbation. 
4. Suspected or documented bacterial or viral infection of the upper or lower respiratory 
tract, sinus or middle ear that is not resolved within 4 weeks of Screening (Visit 1). 
5. Prior intubation for asthma  
6. Patients who, in the opinion of the investigator, are not able to be compliant with study 
treatments, properly use study drug devices (e.g. Dry powder inhaler (DPI), MDI, 
Concept1, peak flow meter), or who have any medical or mental disorder, situation, or 
diagnosis which could interfere with the proper completion of the protocol requirements. 
7. History of hypersensitivity to any ingredients of the study drugs including indacaterol, 
rescue medication, or fluticasone.  This includes any known hypersensitivity or 
intolerance to the excipients, including lactose. 
8. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption or diagnosed intolerance to lactose or milk 
products. 
9. Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance 
abuse, or other condition (e.g. inability to read, comprehend and write) which will limit 
the validity of consent for their child to participate in this study. 
10. Patients with a history of long QT syndrome or whose corrected QT interval (QTc) 
measured at Visit 101 and 199 (Fridericia method) is prolonged (≥ 450 msec for boys and 
girls) and confirmed by a central assessor (these patients should not be rescreened). 
11. Patients who have a clinically significant ECG abnormality at Visit 101 (start of Run-in) 
and prior to randomization (Visit 199). 
12. Patient who is a ward of the state or government. 
13. Patient is an immediate family member of the participating investigator, sub-investigator, 
study coordinator, or employee of the participating investigator 
14. History of malignancy of any organ, treated or untreated within the past 5 years, whether 
or not there is evidence of local recurrence of metastases 
15. Any chronic condition of the respiratory tract which in the opinion of the investigator may 
interfere with study evaluation or optimal participation in the study 
16. History of chronic lung disease other than asthma within 3 months of Visit 101, 
sarcoidosis interstitial lung disease, cystic fibrosis, and known active bacterial, viral, 
fungal, mycobacterial or other infection (including active tuberculosis or atypical 
mycobacterial disease). 
17. Patients with Type I diabetes or uncontrolled Type II diabetes. 
18. Patients who have any clinically significant abnormal lab values reported at Visit 101.  
19. History or presence of impaired renal function as indicated by clinically significantly 
abnormal creatinine or blood urea nitrogen (BUN) and/or urea values, or abnormal urinary 
constituents (e.g., albuminuria).  


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20. History of immunodeficiency diseases, including a positive HIV (ELISA and Western 
blot) test result. 
21. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in 
case of participation in the study. 
22. Patients receiving any asthma-related medications in the classes specified in Table 5-1 
unless they undergo the required washout period prior to Visit 101 and follow the 
adjustment to treatment program. 
23. Patients receiving medications in the classes listed in Table 5-2 should be excluded unless 
the medication has been stabilized for the specified period and the stated conditions have 
been met. 
24. Patients receiving any of the prohibited medications in the classes listed in Table 5-3 
should be excluded.   
25. Immunotherapy or desensitization for allergies started within 3 months prior to Visit 101, 
or where the maintenance dose is expected to change during the study. 
26. Parent or legal guardian unable or unwilling to complete an electronic patient diary. 
27. Treatment with any investigational agent within 30 days of Screening. 
28. Pregnant or nursing (lactating) females 
5 
Treatment 
5.1 
 Study treatment 
5.1.1 
Investigational and control drugs 
The Investigational treatments are as follows: 
• Indacaterol acetate 75 µg capsules for inhalation, delivered via Concept1 
• Indacaterol acetate 150 µg capsules for inhalation, delivered via Concept1 
Indacaterol acetate will be provided as powder filled capsules with a Concept1 inhalation 
device.  
Under no circumstances is an alternative inhalation device to be used for the 
administration of indacaterol acetate capsules during the treatment period.  
Both doses of indacaterol acetate will be supplied by Novartis Drug Supply Management in 
blister packs, providing sufficient quantity of medication to last each patient between visits. 
Patients will be instructed by study personnel on the correct technique and dosing instructions 
for the device.  Dosing will be supervised by the site personnel.  Dispensation instructions are 
provided in Sections 5.5.2, 5.5.3, and 5.5.4. Instructions for use of the Concept1 device are 
provided in Appendix 1.  
5.1.2 
Additional treatment 
At Visit 1 (Screening visit), patients will be provided with a salbutamol/albuterol inhaler to 
use as rescue medication on an “as needed” basis throughout the study (Section 5.5.6). 
Additionally, patients will be supplied with a fluticasone propionate inhaler (Diskus®/ 
Accuhaler®) and will be instructed to take 100 µg b.i.d for the trial duration (if not available in 


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a specific country, MDI dosed 125 µg should be used; in case these formulations are not 
available, then the closest equivalent to fluticasone propionate 100 µg b.i.d. should be given; 
MDI can be used with spacer). Patients taking another ICS (with our without controller 
medication) must be discontinued from that medication and begin the fluticasone propionate 
provided. Patients taking background LTRA may continue this throughout the study, if all 
other entry criteria are met. 
5.2 
Treatment arms 
Patients/subjects will be randomized at Visit 201 to one of the following two treatment arms 
in a ratio of 1:1 
• Indacaterol acetate 75 µg o.d. delivered via Concept1 inhaler (in the morning) 
• Indacaterol acetate 150 µg o.d. delivered via Concept1 inhaler (in the morning) 
5.3 
Treatment assignment and randomization  
At Visit 201, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms above. The investigator or his/her delegate will contact the 
IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the patient, which will be used to link the patient to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. 
A patient randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).  
Randomization will be stratified by region. 
The randomization scheme for patients will be reviewed and approved by a member of the 
COAR Randomization Group. 
5.4 
Treatment blinding 
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods: 
• Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone involved in the study 
• The identity of the treatment will be concealed by the use of study drugs that are all 
identical in packaging, labeling, and schedule of administration, appearance, taste, and 
odor. 
The randomization codes associated with patients/subjects from whom PK samples are taken 
will be disclosed to PK bioanalysts who will keep PK results confidential until data base lock. 


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Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study.  
5.5 
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems. 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused. 
Upon signing the informed consent form, the patient is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site must 
select the Case Report/Record Form (CRF) book with a matching Subject Number from the 
electronic data capture (EDC) system to enter data.  
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the CRF. 
5.5.2 
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance. 
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the investigational drugs. Investigator staff will 
identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the 
patient, investigator staff will detach the outer part of the label from the packaging and affix it 
to the source document (Drug Label Form) for that patient’s unique subject number. 
5.5.3 
Handling of study and additional treatment  
5.5.3.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis Country 
Pharma Organization (CPO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number. 
 The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients/subjects will 
be asked to return all unused study treatment and packaging at the end of the study or at the 
time of discontinuation of study treatment.  


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At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
5.5.3.2 
Handling of additional treatment 
The following non-study drug will be monitored as follows: 
The non-study drug must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Clinical supplies are to be dispensed only in accordance with the 
protocol. 
The investigator must maintain an accurate record of the shipment and dispensing of the non-
study drug in a drug accountability log. Monitoring of drug accountability will be performed 
by monitors during site visits or remotely and at the completion of the trial. Patients will be 
asked to return all unused non-study drug and packaging at the end of the Run-in for the Run-
in medication and at the end of the study or at the time of discontinuation of study drug for the 
rescue medication.  
These medications are: 
• Salbutamol (100 µg) or albuterol (90 µg) used as rescue medication from Visit 1 to Visit 
299 
• Fluticasone propionate (100 µg b.i.d. or acceptable dose equivalent as outlined in Section 
3.1 used as Background medication from Visit 1 to Visit 299 
5.5.4 
Instructions for prescribing and taking study treatment 
Patients will be provided with medication as described in Section 5.1. 
Study medication prescribed and dispensed to the patient and all dose changes during the 
study must be recorded on the Dosage Administration Record CRF (e-CRF).   
At Visit 1 all patients (and parent/legal guardian) will be instructed how to use the inhalers to 
administer rescue salbutamol/albuterol and the fluticasone propionate correctly. Patients and 
parent/legal guardian will be trained to use the peak flow meter and e-Diary as well.  
Beginning at Visit 101, patients will be fully trained in the correct use of the Concept1 inhaler 
device used to administer study medication. Patients/parents who are unable to use the device 
correctly will not be eligible to enter the treatment epoch. Additional training devices will be 
supplied for demonstration purposes.  At clinic visits the investigator should check the 
patient’s use of the inhalational device to ensure that the child is using the device correctly. 
Additional device training may be provided if required. 
At randomization, the patient will take a single inhalation, from the Concept1 device, while at 
the site.   
Patients, along with their parent/ legal guardian will be instructed to take one inhalation 
from the Concept1 device once daily, at approximately the same time each day during 
the two-week timeframe.  Dosing should be done in the morning, following the patient’s 
morning dose of fluticasone propionate.  Parents/legal guardian should be instructed to 
rinse the child’s mouth after inhalation of study drug. Water used for mouth rinsing should be 


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spat out and should NOT be swallowed.  Patients should take their 2nd dose of fluticasone 
propionate in the evenings. 
The time of study medication taken on morning of Day 13 (or one day prior to Day 
14/Visit 299/End of Treatment) should be recorded by the parent and brought to the 
clinic at Visit 299.  The child should not take study medication at home on the morning 
of Visit 299 (end of treatment visit). Study medication will be taken at the site on this 
day, under staff supervision. 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. All 
used and unused study medication/packaging must be returned at each study visit and/or at the 
time of discontinuation. 
The investigator must promote compliance by instructing the parent/legal guardian that their 
child needs to take the study treatment exactly as prescribed and by stating that compliance is 
necessary for the child’s safety and the validity of the study. The parent/legal guardian must 
also be instructed to contact the investigator if their child is unable for any reason to take the 
study treatment as prescribed. 
Instructions for use of the Concept1 device are provided in Appendix 1. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Investigational treatment dose adjustments and/or interruptions are not permitted unless the 
investigator considers an interruption is necessary for the treatment of an adverse event. 
These changes must be recorded on the Dosage Administration Record CRF. 
In case of blind broken, the study medication is to be permanently discontinued. 
5.5.6 
Rescue medication 
At Visit 1 (Screening), all patients will be provided with a short acting β2-agonist (100 µg 
salbutamol/90 µg albuterol via inhaler) which they will be instructed to use throughout the 
study as rescue medication.  Nebulized salbutamol is not allowed as rescue medication 
throughout the entire trial.  No other rescue treatment is permitted.  
In order to standardize measurements, patients will be instructed to abstain from taking rescue 
medication (salbutamol) within 6 hours of the start of each visit where spirometry is being 
performed unless absolutely necessary.  If rescue medication is taken within 6 hours prior to 
spirometry assessments, then the visit should be rescheduled to the next day if possible and 
the number of puffs of rescue medication taken recorded in the patient e-Diary. 
Additionally, patients will be provided with fluticasone propionate 100 µg (or dose equivalent 
see Section 5.1.2) via an inhaler, which should be taken b.i.d. beginning at Visit 1, or the next 
day if patient already took their daily ICS, and continue through the duration of the trial.  If 
the patient is currently taking an ICS (with or without additional controller medication) the 
patient must switch to fluticasone provided at this visit.  Fluticasone should be taken in the 
morning, prior to study drug, and in the evening.  On days of study visits, patients should 
bring their fluticasone inhaler with them and take the dose at the site under supervision of 
study staff. Fluticasone use should also be captured in the eCRF. 
The rescue salbutamol/albuterol and fluticasone will be provided to the patients by the study 
center and reimbursed locally by Novartis. 


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5.5.7 
Concomitant medication 
The investigator must instruct the patient to notify the study staff about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies e-CRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. 
5.5.8 
Prohibited medication 
Prohibited asthma-related medications, as listed in Table 5-1, must not be taken during the 
study. The specified minimum washout periods are described in Table 5-1. The classes of 
medication listed in Table 5-3 are not permitted to be taken during the study. The medications 
in Table 5-2 are only permitted under the circumstances given. Each concomitant drug must 
be individually assessed against all exclusion criteria and the tables below to see if it is 
allowed. If in doubt, the investigator should contact the medical monitor before randomizing a 
patient or allowing a new medication to be started. 
Table 5-1 
Prohibited asthma-related medications 
Class of medication 
Minimum washout period starting at Visit 1011,2 
Long-acting β2 agonists (LABA)  
LABAs used b.i.d. must be discontinued 48 hours 
prior to Visit 101. LABAs used o.d. must be 
discontinued at least 14 days prior to Visit 101).  
Long Acting Muscarinic Antagonist (LAMA) 
Must be discontinued 7 days prior to Visit 101.  
Short acting anticholinergics (SAMA)  
Must be discontinued 8 hours prior to Visit 101.  
Fixed combinations of short-acting β2-agonist 
and short-acting anticholinergics 
Must be discontinued 8 hours prior to Visit 101.   
Salbutamol/albuterol (SABA) provided at Visit 1 
and throughout study as required for rescue 
medication  
Must be withheld 6 hours prior to study visits 
beginning at Visit 101. 
Short acting β2-agonists (SABAs) (other than 
Salbutamol/albuterol provided at Visit 1 for 
rescue medication) 
Must be discontinued at Visit 1 and are not 
permitted during the study 3 
Intra-muscular depot corticosteroids 
Must be discontinued 3 months prior to Run-in 
(Visit 101) 
Systemic corticosteroids (Parenteral or oral) 
Must be discontinued 3 months prior to Run-in 
(Visit 101) 
Immunoglobin E inhibitors (e.g. omalizumab) 
Must be discontinued 6 months prior to Run-in 
(Visit 101) 
Xanthines 
Must be discontinued 7 days prior to Run-in 
(Visit 101) 
Systemic mast cell stabilizers (e.g. 
cromoglycate, nedocromil, ketotifen) 
Must be discontinued 7 days prior to Run-in (Visit 
101) 
1 This table is not considered all-inclusive. Medications should be assessed for adherence to the 
indication and other inclusion/exclusion criteria. 
2 These medications are also prohibited if administered for other indications. 


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3 SABA (salbutamol/albuterol rescue medication) should be withheld for at least 6 hours prior to 
spirometry measurements at clinic visits if possible. Clinic visits may be rescheduled if rescue 
medication were taken less than 6 hours prior to the spirometry assessments. 
 
Table 5-2 
Medications allowed under certain conditions 
Class of medication 
Condition under which medication is permitted 
Topical Corticosteroids for treatment of eczema 
Recommended doses and dosage regimens 
Leukotriene antagonists and leukotriene 
synthesis inhibitors 
Stable dose for at least 4 weeks prior to Visit 101. 
Maintenance Immunotherapy for allergies 
Stable dose for at least 3 months prior to Visit 101 
and must continue unchanged for the duration of the 
study 
Mucolytic agents not containing bronchodilators 
If stabilized for at least 4 weeks prior to Visit 101 and 
throughout the trial. 
Inactivated influenza vaccination, pneumococcal 
vaccination or any other inactivated vaccine 
Not administered within 48 hours prior to a study visit  
Intra-nasal corticosteroids 
If an established pattern of use has been 
documented prior to Visit 101. 
Table 5-3 
Other prohibited medications 
Class of medication 
Minimum cessation period prior to Run-in 
(Visit 101) 
Any drug with the potential to prolong QT 
interval 
14 days or 5 half-lives, whichever is longer 
Non-potassium sparing diuretics (unless 
administered as a fixed-dose combination with a 
potassium conserving drug 
7 days 
Strong inhibitors of cytochrome P4503A 
7 days 
Other investigational drugs 
30 days or 5 half-lives, whichever is longer 
Noradrenaline reuptake inhibitors 
7 days 
Live attenuated vaccines 
30 days 
 
5.5.9 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation (TD) and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IRT. When the investigator contacts the system to break a treatment code for a patient, 
he/she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Global Trial Leader (GTL) that the code has been broken. 


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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name (if available) 
• patient number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time.  
5.6 
Study completion and discontinuation  
5.6.1 
Study completion and post-study treatment 
Completion of the study will be when the last patient has completed Visit 301 and as close as 
possible to serious adverse event (SAE) Follow-up at Day 44. 
The investigator must provide Follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.6.2 
 Discontinuation of study treatment  
Discontinuation of study treatment for a patient occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by the patient, patient’s parent/ legal 
guardian, or the investigator.  
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances:  
• Patient`s or parent/ legal guardian’s wish  
• Administration of a prohibited medication (Table 5-1 and Table 5-3) 
• Worsening asthma as defined in Section 6.5.6, as well as the following.  
• Excessive use of rescue medication (more than 200 µg salbutamol/ 180 µg albuterol 
four times per day for three consecutive days) 
• Abnormal test procedure results indicating risk for the patient on continued inhalation 
of the study drug including:  
• Decline in PEF from the baseline PEF of ≥ 20% for one day or ≥ 15% for 3 consecutive 
days. The baseline PEF for the Run-in epoch would be the PEF taken at Visit 101. The 
baseline PEF (morning and evening) for the treatment epoch is calculated at visit 199 and 
is the mean of the best of the three daily PEF measurements over the past 14 days. 
• Patients who experience moderate or severe asthma exacerbations (Section 6.5.7) 
• ECGs: 
• If the absolute QTcF ≥450 msec or an increase from baseline of > 60 msec on 2 
adequate ECGs at least a minute apart 
• 2nd or 3rd degree AV block 
• Atrial or ventricular arrhythmias (as judged clinically significant by the investigator) 


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• Any severe or serious adverse event considered possibly related to the study medication 
• Patients who experience paradoxical bronchospasm: dyspnea and wheezing significantly 
increasing shortly after the administration of bronchodilator (see Investigator’s Brochure 
for more details) 
• 
Adverse events for which continued inhalation of the study drug would be detrimental 
• If a patient develops a medical condition that requires use of prohibited treatment as per 
Section 5.5.8, or if patient exhibits a behavior of non-compliance regarding prohibited 
medications. 
• Pregnancy (see Section 7.5) 
• Any situation in which study participation might result in a safety risk to the patient 
• Clinically significant abnormal laboratory value(s) (e.g., potassium below 3.0 mmol/L, 
LFT >3 x ULN) 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
If discontinuation of study treatment occurs, the patient should NOT be considered withdrawn 
from the study. The patient should return to the clinic as soon as possible, after 
discontinuation of study drug, for a study treatment discontinuation visit (Visit 299 will act as 
an early discontinuation visit in this case) and directly move into the Follow-up epoch.  
Treatment discontinuation visit assessments detailed in the Table 6-1 should be completed and 
recorded in the eCRF. The investigator must determine the primary reason for the patient’s 
premature discontinuation of study treatment and record this in the End of treatment 
disposition page in the eCRF.  
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
The data which must continue to be collected for all patients (including the patients 
discontinuing study treatment) are adverse event and serious adverse events for up to 30 days 
after drug discontinuation until the end of the study Follow-up visit (Visit 301). 
Documentation of attempts to contact the patient should be recorded in the source 
documentation. 
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9. 
If the patient fails to return for an end of study visit for unknown reasons, every effort should 
be made to contact them as specified in Section 5.6.4. 
5.6.3 
Withdrawal of informed consent 
Patients themselves or parents/ legal guardians may voluntarily withdraw consent for their 
child to participate in the study for any reason at any time. Withdrawal of consent from the 
study is defined as when a patient does not want to or the patient’s parent/ legal guardian does 
not want their child to: 
• Participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 


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• Does not want any further study related contacts 
and 
• Does not allow analysis of already obtained biologic material  
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient`s or parent’s/ legal guardian’s decision to 
withdraw their 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 parent/legal guardian are not allowed unless safety findings 
require communicating or Follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in  
Table 6-1. 
5.6.4 
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. If contact has not been re-established, all efforts should 
still be made to locate the patient and obtain information regarding concomitant medications, 
serious adverse events, and survival status at the end of the 2 weeks intended treatment epoch 
(Visit 299). This information should also be obtained at the safety Follow-up visit (Visit 301). 
A patient cannot be considered as lost to Follow-up until the time point of his/her scheduled 
end of study visit has passed. 
5.6.5 
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, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
The study will consist of a Screening epoch, a Run-in epoch, a 2-week blinded treatment 
epoch and a Follow-up epoch of 30 days after the last treatment. 
Table 6-1 lists all the assessments to be performed for the study and indicates with an “X” the 
visits at which they will be performed. Patients should be seen for all visits on the designated 
day or as close as possible to that date. All data obtained for these assessments must be 
supported in the patients’ source documentation. 


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Study assessments should be performed in a manner that the spirometry measurements occur 
at the scheduled time point (See Table 6-2 and 6-3 for Timed Assessments).  
Whenever other assessments are scheduled at the same time-point, spirometry should occur at 
the scheduled time point or as near as possible.  
Patients must be seen for all visits on the designated day, or as close to it as possible. Visit 
199/201 (Randomization) and 299 (End of treatment) must occur in the morning, since 
patients will be taking their study medication in the morning.  Missed or rescheduled visits 
should not lead to automatic discontinuation. Patients who prematurely discontinue the study 
for any reason should be scheduled for a visit as soon as possible, at which time assessments 
listed for early discontinuation will be performed.  
Since the first spirometry measurement is 45 minutes prior to inhalation of study 
medication, and study medication is adminstered in the morning, it is important to 
schedule study visits early enough so the patient will have enough time to take their 
fluticasone on site, have other study assessments done (questionnaire, vital signs, ECG, 
labs), have the first spirometry 45 minutes prior to study medication, and be dosed with 
study medication in the morning. 
Patients who discontinue early are not required to undergo the spirometry measurements. 
However, at least one spirometry measurement should be measured if the patient can tolerate 
it. Study drug is not administered following early discontinuations. 
If a patient’s parent/legal guardian refuses to bring their child to the clinic for a 
discontinuation visit, or is unable to do so, every effort should be made to contact the 
parent/legal guardian, by telephone, to determine the reason for their child’s study 
discontinuation. 
Study medication should be reconciled and the adverse event and concomitant medications 
reconciled on the CRF. Patients must return the indacaterol at the end of the study. 
Thirty days after the End of treatment epoch (Visit 299), the patient’s parent/ legal guardian 
will be contacted for safety evaluations following the last administration of study treatment. 
This information should be captured in the patient’s source documents and SAEs/ AEs will be 
captured in the eCRF (Visit 301). 
 


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Table 6-1 
Assessment schedule 
Epoch 
Screening* 
Run-in 
Treatment 
Follow-up 
 
 
End of study 
treatment/ Early 
termination** 
 
Visit 
1 
101 
199 
201 
299 
3016 
Day 
Note: V199 and 201 will occur 
on the same day if the patient 
is randomized. 
Up to 30 days 
prior to Visit 101 
-14 
1 
1 
14 
44 
Obtain parental Informed 
Consent / patient assent (if 
applicable) 
X 
 
 
 
 
 
Current medication review/ 
adjust 
X 
 
 
 
 
 
Contact IRT 
S 
S 
S 
S 
S** 
S** 
Randomization via IRT 
 
 
 
S 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
Demographics, Medical 
History 
X 
 
 
 
 
 
Pulmonary history: -
protocol solicited events 
for asthma 
X 
 
 
 
 
 
Asthma exacerbation 
history 
X 
 
 
 
 
 
Smoking exposure 
X 
 
 
 
 
 
Prior/ concomitant 
medication review  
X 
X 
X 
X 
X** 
 
Urine pregnancy test1 (if 
applicable) 
X 
X 
X 
 
X** 
 


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Epoch 
Screening* 
Run-in 
Treatment 
Follow-up 
 
 
End of study 
treatment/ Early 
termination** 
 
Visit 
1 
101 
199 
201 
299 
3016 
Day 
Note: V199 and 201 will occur 
on the same day if the patient 
is randomized. 
Up to 30 days 
prior to Visit 101 
-14 
1 
1 
14 
44 
Evaluation of sexual 
development status8 
X 
 
 
 
 
 
Device training4 
S 
S 
S 
 
 
 
Height and weight 
 
X 
X 
 
X** 
 
Physical examination 
complete 
 
S 
 
 
 
 
Physical examination short 
 
 
S 
 
S** 
 
Oropharyngeal 
examination 
 
S 
S 
 
S** 
 
ECG3  
 
X 
X 
X 
X** 
 
Vital signs3 
 
X 
X 
X 
X** 
 
Issue rescue medication 
as necessary 
S 
S 
S 
S 
 
 
Review rescue medication 
use 
 
X 
X 
X 
X** 
 
Issue fluticasone 
propionate  
X 
 
 
 
 
 
Review daily fluticasone 
use 
 
X 
X 
X 
X** 
 
Spirometry Practice 
S 
 
 
 
 
 


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Epoch 
Screening* 
Run-in 
Treatment 
Follow-up 
 
 
End of study 
treatment/ Early 
termination** 
 
Visit 
1 
101 
199 
201 
299 
3016 
Day 
Note: V199 and 201 will occur 
on the same day if the patient 
is randomized. 
Up to 30 days 
prior to Visit 101 
-14 
1 
1 
14 
44 
(Optional) 
Screening spirometry 
(FEV1)7 
 
X 
X 
 
 
 
Screening reversibility 
(SABA)7 
 
X 
 
 
 
 
Spirometry3 
 
 
X 
X 
X** 
 
Issue e-Diary 
S 
 
 
 
 
 
Issue Peak Flow meter 
S 
 
 
 
 
 
Review and upload e-Diary 
recordings 
 
S 
S 
S 
S** 
 
Dispense study medication 
via IRT 
 
 
 
S 
 
 
Administer study drug at 
visit 
 
 
 
X 
X 
 
Provide parent/ legal 
guardian and patient with 
instructions to record time 
of last dose of study 
medication taken on Day 
13 (or one day prior to Visit 
299/Day 14). 
 
 
 
S 
 
 


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Epoch 
Screening* 
Run-in 
Treatment 
Follow-up 
 
 
End of study 
treatment/ Early 
termination** 
 
Visit 
1 
101 
199 
201 
299 
3016 
Day 
Note: V199 and 201 will occur 
on the same day if the patient 
is randomized. 
Up to 30 days 
prior to Visit 101 
-14 
1 
1 
14 
44 
Record time of study drug 
taken one day prior (Day 
13) to Visit 299/Day 14 
 
 
 
 
X** 
 
Collect unused study 
medication 
 
 
 
 
 S** 
 
Record interruption/ 
changes in study drug 
administration to assess 
compliance 
 
 
 
X 
X** 
 
AE recording 
 
X 
X 
X 
X** 
X 
SAE recording 
X 
X 
X 
X 
X** 
X 
Review and record 
surgeries and procedures 
 
X 
X 
X 
X** 
X 
Study disposition 
(Screening) 
X 
 
 
 
 
 
Study disposition (Run-in) 
 
 
X 
 
 
 
Study disposition (End of 
Treatment)  
 
 
 
 
X** 
 
Study disposition (Follow-
up) 
 
 
 
 
 
X 
Safety Lab assessments1 
 
X 
X 
 
X** 
 


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Epoch 
Screening* 
Run-in 
Treatment 
Follow-up 
 
 
End of study 
treatment/ Early 
termination** 
 
Visit 
1 
101 
199 
201 
299 
3016 
Day 
Note: V199 and 201 will occur 
on the same day if the patient 
is randomized. 
Up to 30 days 
prior to Visit 101 
-14 
1 
1 
14 
44 
(hematology, chemistry, 
urine dipstick)  
PK sampling3 
 
 
X 
X 
X** 
 
ACQ-IA5  
 
X 
X 
 
X** 
 
Telephone parent/ legal 
guardian in advance of 
study visit, with reminder to 
not take rescue medication 
within 6 hours of study 
visit, and bring in all study 
medication and e-Diary 
 
S 
S 
S 
S 
 
*Screening Visit 1 and Run-in Visit 101 can occur on the same day if patient did not take any salbutamol/albuterol within 6 hours of the study visit. 
**These assessments should be conducted for patients who discontinue. 
S These assessments are source documentation only and will not be entered into the CRF. 
X Assessment to be reported in the clinical database. 
1For females of child-bearing potential only.  
2Labs and urine dipstick are done pre-dose. 
3Details of timed assessments are provided in Table 6-2 and 6-3. 
4Device training at Visit 1 is for e-diary/peak flow meter, salbutamol/albuterol and fluticasone propionate inhaler. Device training at Visits 101 and 199 is for Concept1.  
5The ACQ-IA is completed at the clinic, before any other assessment. 
6Information about any AEs/ SAEs occurring within 30 days of the patients’ last study treatment will be obtained by a telephone call 30 days after the patient’s last dose 
of study drug for completed patients. For patients who withdraw early, please refer to discontinuation of study treatment and premature patient withdrawal Section. 


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Epoch 
Screening* 
Run-in 
Treatment 
Follow-up 
 
 
End of study 
treatment/ Early 
termination** 
 
Visit 
1 
101 
199 
201 
299 
3016 
Day 
Note: V199 and 201 will occur 
on the same day if the patient 
is randomized. 
Up to 30 days 
prior to Visit 101 
-14 
1 
1 
14 
44 
7If reversibility fails on the first attempt, it can be repeated once. 
8For girls the sexual development status has to be evaluated to identify females who have reached menarche, and thus, with child bearing potential. 
 


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Table 6-2 
Timed assessment schedule (Visit 199) 
 
Time point 
vs. 0 (dose 
time)*** 
ACQ-IA 
ECG  
Vitals (Systolic/ 
diastolic BP 
/radial pulse) 
PK 
Hematology/ 
chemistry/ 
urine dipstick 
Spiro-
metry 
Call 
IRT** 
 
≤ - 2 hr 
Administer fluticasone dose and ancillary study assessments 
 
Visit 199 
≤ - 2 hr 
X 
X 
X 
X 
X 
 
 
 
-45 min 
 
 
 
 
 
X* 
X 
 
-15 min 
 
 
 
 
 
X 
 
*At Visit 199, patients are required to meet FEV1 criteria of ≥50% and ≤ 90% of the predicted normal value for the 
patient. If criteria are met at this visit, the patient will be immediately randomized. 
**IRT can be called for randomization information after the -45 minute spirometry assessment, assuming the 
patient meets the FEV1 criteria at -45 min. Study medication should not be dispensed until appropriate time in Visit 
201. 
***All time points are approximate time points, and fluctuations are allowed. 
Table 6-3 
Timing of key visit procedures during treatment 
 
Time 
point vs. 
0 (dosing 
time)*** 
ACQ-IA 
Vitals 
(Systolic/ 
diastolic 
BP and 
radial 
pulse) 
PK 
Hematology/ 
chemistry/ 
urine dipstick 
ECG 
Spirometry 
Visit 201 
 0 min 
Morning dose of study medication 
 
15 min 
 
X 
X 
 
 
 
 
20 min 
 
 
 
 
X 
 
 
30 min 
 
 
 
 
 
X 
 
50 min 
 
 
 
 
X 
 
 
1 hour 
 
X** 
X 
 
 
X 
 
≤ - 2 hr 
Administer fluticasone dose and ancillary study assessments 
 
≤ - 2 hr 
X* 
X 
X 
X 
X** 
 
Visit 299 
-45 min 
 
 
 
 
 
X 
 
-15 min 
 
 
 
 
 
X 
 
0 min 
Morning dose of study medication 
 
15 min 
 
X 
X 
 
 
 
 
20 min 
 
 
 
 
X 
 
 
30 min 
 
 
 
 
 
X 
 
50 min 
 
 
 
 
X** 
 
 
1 hour 
 
X** 
X 
 
 
X 
*ACQ-IA should be given prior to any other assessment. 
** Vitals done 1 hour post-dose should be taken before the 1-hour post-dose spirometry measurement. 
*** All time points are approximate time points, and fluctuations are allowed. 
 
 
 


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6.1 
Information to be collected on screening failures 
All patients/subjects who have signed informed consent but not entered into the next epoch 
will have the study completion page for the Screening epoch, demographics, 
inclusion/exclusion, and serious adverse event (SAE) data collected. Adverse events that are 
not SAEs will be followed by the investigator and collected only in the source data. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristic data to be collected on all patients include: 
• Year of birth 
• Age (calculated) 
• Gender 
• Race & Ethnicity 
• Height & Weight 
• Body Mass Index (BMI) (calculated) 
• Baseline physical examination (not databased other than in the context of relevant medical 
history) 
• Vital signs 
• ECG 
• Date of diagnosis of asthma 
• Relevant medical history/current medical condition present before signing the informed 
consent 
• Smoking exposure 
• Health status 
• Prior/ concomitant medication (asthma and non-asthma related) 
• Pre and post-bronchodilator spirometry (Screening spirometry and reversibility testing). 
 
6.3 
Treatment exposure and compliance 
The time of study treatment dosing, at Visit 201 and 299/End of treatment, will be collected 
on the e-CRF as well as any dosing interruptions.  For assessments where spirometry is 
performed, the time of dosing is to be taken from the spirometer.   
Study treatment compliance should be assessed by the investigator and/or center personnel at 
all visits.  Where necessary, the Investigator will discuss compliance/documentation issues 
with the patient’s parent/legal guardian.  The Investigator or designee will collect, from the 
patient’s parent/legal guardian, the used/unused investigational medication and packaging 
(unused capsules/blister strips SDDPIs) at Visits 299/End of Treatment/ Early Treatment 
Discontinuation. Study treatment compliance will be assessed from the capsule count from 
previously dispensed blister strips for the Concept1®. 
The number of puffs of rescue medication (salbutamol/albuterol) between study visits will be 
recorded by the patient’s parent/ legal guardian in the e-Diary. 


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Fluticasone use should be assessed by the investigator and/or center personnel at all visits.  
The investigator or designee should ask the patient and parent about their daily fluticasone use 
and should document this in the patient’s source document as well as in the eCRF. 
6.4 
Efficacy 
The following assessments of efficacy will be performed: 
• Spirometry  
• Pediatric ACQ-IA 
• Asthma symptoms recorded in e-Diary 
• Peak Expiratory Flow 
• Rescue Medication Use 
6.4.1 
Spirometry assessments 
The following spirometry assessments will be made: 
• Forced expiratory volume in 1 second (FEV1) 
• Forced Vital Capacity (FVC) 
• Spirometric assessments will be measured at Visits 199, 201 and 299/EOT as indicated in 
Table 6-1 through Table 6-3.  
• Pre-dose FEV1 is defined as the mean of the two FEV1 values measures at -45 min and -15 
min prior to morning dose. 
Please refer to the Spirometry Guidance in Appendix 3 and Table 6-2 and Table 6-3 for full 
details on scheduling and performing spirometry. 
6.4.2 
Patient reported outcomes (PRO) 
Asthma Control Questionnaire-Interviewer administered, for children 
In this study, the Asthma Control Questionnaire Interviewer - Administered (ACQ-IA) will be 
used to assess improvements in asthma symptom control.  The ACQ-IA is a seven-item 
disease-specific instrument developed and validated to assess asthma control in patients in 
clinical trials as well as in individuals in clinical practice.  The ACQ is valid for use in 
children 6-16 years old, and has strong measurement properties in this age group.  Initial 
cognitive debriefing studies provided evidence that children 11 years and older could 
understand the instructions, questions and response options of the self-administered version of 
the adult ACQ accurately and unaided; however, children 10 years and younger needed help.  
Therefore, the interviewer-administered version of the adult ACQ was developed for children 
6-10 years old, and must be administered by a trained interviewer (Juniper et al 2010).  Given 
the fact that this trial includes 11-year-old, and to make it consistent, all patients will have the 
ACQ given to them by a trained interviewer.   
The ACQ-IA will be provided to the site.  All seven items are then scored on a 7-point Likert 
scale, with 0 indicating total control and 6 indicating no control.  The questions are equally 
weighted and the total score is the mean of the seven items.  
The interviewer must ask the child the first 6 questions of the ACQ-IA and the child should be 
encouraged to respond directly (parent/ legal guardians should only help if the child is having 


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difficulties responding).  The investigator should complete the last question (for the last ACQ 
question – airway caliber FEV1% predicted based on the masterscope at site) at the 
investigator’s site at Visits 101, 199, and 299/End of treatment (EOT). 
The ACQ-IA will be asked in the language most familiar to the patient, at the scheduled study 
visit prior to the patient seeing the investigator for any clinical assessment or evaluation.  The 
patient’s parent/ legal guardian can be present during the interview.  The interviewer should 
make the child comfortable and should reassure the child that there are no right or wrong 
answers.  The interviewer can have the child read aloud each of the questions and responses, 
if the child is able to read.  The interviewer will complete the questionnaire with the patient’s 
responses.  All questionnaires should be complete. 
For paper CRFs the original questionnaire will be kept with the patient’s file as the source 
document. 
Completed questionnaires will be reviewed and examined by the investigator, before the 
clinical examination, for responses that may indicate potential adverse events (AEs) or serious 
adverse events (SAEs). The investigator should review not only the responses to the questions 
in the questionnaires but also for any unsolicited comments written by the patient. If AEs or 
SAEs are confirmed, then the physician must record the events as per instructions given in 
Section 7.1 and Section 7.2 of the protocol. 
6.4.3 
Electronic Diary 
At Visit 1, parents/ legal guardians will be provided with an e-Diary to record their child’s 
rescue medication (salbutamol/albuterol) use. From Visit 101 on, they will record their child’s 
clinical symptoms and PEF in the e-diary. The patient’s parent/ legal guardian will be 
instructed to routinely complete the e-Diary twice daily – at the same time each morning and 
again approximately 12 hours later in the evening.  The e-Diary is to be reviewed at each 
clinic visit until study completion. Sites and the patient’s parent/ legal guardian will receive 
appropriate training and guidance on the use of the e-Diary device. A list of the Patient 
asthma control e-Diary questions is provided in Appendix 4. 
6.4.4 
Peak expiratory flow 
An electronic Peak Flow Meter part of the e-Diary device will be provided to the patient’s 
parent/ guardian at Visit 1 for the measurement of morning and evening PEF during the study 
(Appendix 4).  
PEF will be measured at consistent times for a patient, in the morning and evening each day 
during the study from Visit 1 to 299/End of study. PEF will be measured twice a day; in the 
morning just prior to taking study medication and again 12 hours later. Patients should be 
encouraged to perform morning and evening PEF measurements BEFORE taking study 
medication. At each time point, the parent/guardian should instruct their child to perform 3 
consecutive maneuvers within 10 minutes. These PEF values are captured in the e-PEF/diary. 
The best of 3 values will be used. The PEF/ e-Diary is to be reviewed at each clinic visit until 
study completion.  
6.4.5 
Rescue medication usage 
The use of rescue salbutamol/albuterol should be recorded by the patient’s parent/ legal 
guardian in the e-Diary twice each day in the morning and evening. In the morning the 


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number of puffs of rescue medication their child has taken during the night and since the last 
diary entry, and in the evening the number of puffs of rescue medication the child has taken 
during the day since the morning diary entry should be recorded. 
6.4.6 
Appropriateness of efficacy assessments  
The efficacy assessments selected are standard for this indication/patient population. 
6.5 
Safety  
The following safety assessments will be performed: 
• Medical history and physical examination including oropharyngeal examination 
• Vital signs 
• Hematology, blood chemistry, urine dipsticks 
• ECG 
• Adverse events including asthma exacerbations, worsening asthma, and serious adverse 
events 
ECG and Laboratory assessments, excluding urine dipsticks, will be centralized.  
6.5.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, vascular and neurological. An oropharyngeal examination will be performed 
at each clinic visit. A short physical examination will include the examination of vital signs, 
heart, lungs, abdomen, extremities and any other evaluation the Investigator considers 
appropriate based on the patient’s clinical status at the time of the visit. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to informed consent being granted must 
be included in the Relevant Medical History/Current Medical Conditions screen on the 
patient’s e-CRF. Significant findings made after informed consent (Visit 1) is given which 
meet the definition of an Adverse Event must be recorded on the Adverse Event screen of the 
patient’s e-CRF. 
6.5.2 
Vital signs  
Systolic and diastolic blood pressure and radial pulse rate (over a 30 sec interval), performed 
in the sitting position, will be recorded at each scheduled clinic visit as detailed in Table 6-1 
through Table 6-3.  Vitals are taken pre-dose and 15 minutes and 1 hour post-dose.  The vitals 
taken 1-hour post-dose should be done before the 1-hour post-dose spirometry measurement. 
6.5.3 
Height and weight  
Height in centimeters (cm) and weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but 
without shoes) will be measured at Visit 101, 199, and 299. BMI will be calculated based on 
height and weight. 


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6.5.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected.  Details on the 
collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. 
All patients with laboratory tests containing clinically significant abnormalities should be 
followed regularly until the values return to within the normal ranges or until a valid reason 
other than drug-related adverse experiences is identified, even after the medication has 
discontinued. 
Safety Laboratory assessments (hematology, clinical chemistry, blood eosinophil counts) will 
be performed at Visits 101, 199 and 299/EOT if applicable. 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured. 
Peripheral blood eosinophil counts will be captured with a unit of cells/ mcL.  
6.5.4.2 
Clinical chemistry 
Albumin, alkaline phosphatase, aspartate aminotransferase (AST) or Serum Glutamic-
Oxaloacetic Transaminase (SGOT), alanine aminotransferase (ALT) or Serum Glutamic 
Pyruvic Transaminase (SGPT), bilirubin, creatinine, γ-GT, glucose, potassium, magnesium, 
BUN and uric acid will be measured. 
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal 
range, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. 
6.5.4.3 
Urinalysis 
In this trial, urine dipsticks will be collected at Visits 101, 199, and 299/EOT. 
 
6.5.4.4 
Hepatotoxicity 
Any liver event which meets the criteria for “medically significant” event as outlined in 
Table 13-1 of Appendix 7 should follow the standard procedures for SAE reporting as 
described in Section 7.2. 
6.5.5 
Electrocardiogram (ECG)  
ECGs must be recorded after the patient rests (10 minutes if possible) in the supine position to 
ensure a stable baseline. 
When the ECG recording time coincides with vital signs, spirometry, and blood draws, the 
ECG should be performed first, followed by vital signs and the blood draws but with enough 
time planned to ensure the spirometry is performed at the planned time point outlined in Table 
6-2 and 6-3. Spirometry must be performed as close to the scheduled time point as possible. 
Centralized ECG equipment 
At Visit 101, a screening ECG will be measured to test for eligibility for trial inclusion.  
Patients with an abnormal ECG at Visit 101, due to technical/mechanical faults, may be 
rescreened. 


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At Visits 199/201 and 299/End of study, ECGs will be measured at pre-dose (prior to 
spirometry) and 20 minutes and 50 minutes post-dose of study medication as indicated in 
Table 6-2 and 6-3.  All ECGs should include 12 standard leads.  An ECG tracing should be 
taken for those patients who prematurely discontinue from the study treatment. 
For each ECG performed original traces and identical duplicate traces should be printed.  
Each ECG will be sent electronically for central review directly from the ECG machine.  Two 
‘identical’ duplicate print-outs will be generated and kept at the investigator site as source 
documentation and as back-up for submission to the central laboratory in case of problems 
with the electronic transmission.  Each print out will be kept at the investigator site and will 
be dated and signed.  The subject's number, the date, actual time of the tracing, and Study 
Code must appear on each page of the tracing. 
Full details of all procedures relating to the ECG collection and reporting will be contained in 
an investigator manual to be provided by the central ECG group to each investigator site.  In 
the event that the central cardiologist reports that an ECG is abnormal, the investigator must 
assess whether the ECG abnormality is clinically significant or not.  A clinically significant 
abnormality should be reported as an AE.  If necessary a pediatric cardiologist may be 
consulted. 
Clinically significant ECG findings at baseline must be discussed with the sponsor before 
administration with investigational treatment. 
If a patient experiences a clinically significant change in cardiac rhythm or other clinically 
significant cardiovascular abnormality, the investigator should consider withdrawing the 
patient from the study. 
Clinically significant abnormalities should be recorded on the relevant Section of the medical 
history/Current medical conditions/AE CRF/e-CRF page as appropriate. 
6.5.6 
Worsening of asthma 
Investigators and patients will be instructed how to deal with worsening of asthma symptoms. 
The data captured in the patient diary will also be used to alert the patient and/or investigator 
to possible signs of worsening asthma.  Worsening asthma should be recorded as an Adverse 
Event. The investigator must provide the patient’s parent/ legal guardian with written 
instructions to contact the investigator if at any time during the trial from the Run-in onwards 
one or more of the following criteria of worsening asthma develops: 
Asthma Worsening Criteria 
• Excessive use of rescue medication (more than 200 µg salbutamol/ 180 µg albuterol four 
times per day for three consecutive days) 
• Decline in PEF from the baseline PEF of ≥ 20% for one day or ≥ 15% for 3 consecutive 
days. 
• 20% decrease in FEV1 from baseline value (this criterion applies to Investigator review at 
the time of a study visit and an alert setting in the Masterscope) 
• < 60% of PEF compared to baseline 
• Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive nights 
(patients may be continued in the study based on their general pattern of night time 
symptoms as per investigators judgement) 


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• Urgent unscheduled clinic visit due to asthma related deterioration 
Note: The baseline FEV1 and PEF for the Run-in epoch would be the FEV1 and PEF taken at 
Visit 101. The baseline FEV1 for the treatment epoch is the mean of the 45 min and 15 min 
pre-dose FEV1 measurements at Day 1. The baseline PEF (morning and evening) for the 
treatment epoch is calculated at visit 199 and is the mean of the best of the three daily PEF 
measurements over the past 14 days.  
If patients develop any of the above criteria, the patient should notify the investigator and be 
evaluated by the investigator and treated as clinically appropriate.  
If any of the above criteria are met while a patient is in the Run-in epoch of the study, they 
may be withdrawn if, in the opinion the investigator, it is appropriate to do so. 
Patients should also be withdrawn for safety reasons if, in the opinion of the investigators, it is 
appropriate to do so. 
Worsening of asthma symptoms may require unscheduled evaluation between visits. Study 
site personnel must be available to monitor and document patient’s progress until asthma 
control is regained. 
6.5.7 
Asthma Exacerbation 
In this trial, any patient who suffers from a moderate or severe asthma exacerbation will 
be discontinued from this trial. 
Asthma exacerbations will be recorded as Adverse Events. 
A severe asthma exacerbation (Draft note for guidance on clinical investigation of medicinal 
products for treatment of asthma CHMP/EWP/2922/01 Rev.1) is defined as an aggravation of 
asthma symptoms (like shortness of breath, cough, wheezing, or chest tightness) that requires 
systemic corticosteroids (SCS) for at least three consecutive days and/or a need for an ER 
visit (or local equivalent structure), or hospitalization due to asthma or death due to asthma.  
• Start date and end date: 
• In case of the use of SCSs for at least three days, the first day of treatment will determine 
the onset date of the event while the last day of treatment will define the stop date. 
• In the event that an ER visit and/or hospitalization due to asthma exacerbation were not 
associated with a course of SCSs as described above, start and end dates would be defined 
by the corresponding dates entered by the Investigator in the CRF. 
A moderate asthma exacerbation in this protocol is defined as the occurrence of two or more 
of the following:  
1. Progressive increase of at least one of the asthma symptoms like shortness of breath, 
cough, wheezing, or chest tightness. The symptoms should be outside the patient’s usual 
range of day-to-day asthma and should last at least two consecutive days 
2. Increased use of “rescue” inhaled bronchodilators defined by: 
a. 50% increase in SABA use and >8 puffs on 2 out of any 3 consecutive days compared 
to baseline captured  
OR 
b. Night time awakenings requiring SABA use on at least 2 out of any 3 consecutive 
nights 


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3. Deterioration in lung function, which last for two days or more but usually not severe 
enough to warrant SCSs for more than 2 days or hospitalization. This deterioration would be 
defined by: 
a. 20% decrease in FEV1 from baseline value 
OR 
b. ≥ 20% decrease in am or pm PEF from baseline on 2 out of any 3 consecutive days 
compared to baseline 
OR 
c. < 60% of PEF compared to baseline 
At no time may patients self-medicate (other than rescue medication use) for treatment of 
asthma exacerbation or worsening of symptoms. 
6.5.8 
Pregnancy and assessments of fertility 
Girls who begin menstruating (reached menarche) will have urine pregnancy tests at study 
visits 1, 101, 199, and 299/EOT. A positive pregnancy test will result in study 
discontinuation.  Refer to Sections 5.6.2 and 7.5 for more details. 
6.5.9 
Appropriateness of safety measurements  
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 
6.6.1 
Pharmacokinetics  
Blood samples for PK analysis will be collected in all patients at the following time points 
below, with the aim to collect indacaterol exposure data in asthma patients. 
Visit 199/201 (End of Run-in/Randomization) 
• Pre-dose: ≤ 2 hours Post-dose: 15 minutes and 1 hour 
Visit 299/End of treatment 
• Pre-dose: ≤ 2 hours 
• Post-dose: 15 minutes and 1 hour 
All blood samples will be taken by either direct venipuncture or indwelling cannula inserted 
in a forearm or vein at time points specified in Table 6-2 and Table 6-3. 
All time points listed are relative to the time of dose administration.  The time of the dosing, 
as well as actual sample collection date and time will be entered on the PK blood collection 
summary page of the e-CRF.  Sampling problems will be noted in the Notes field of the e-
CRF.  Details of the blood collection methods and the analytical methods will be provided in 
the Laboratory Manual. 
7 
Safety monitoring 
7.1 
Adverse events (AEs) 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or 


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clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
AE irrespective if a clinical event has occurred. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying AEs. Alert ranges for laboratory and other test abnormalities are 
included in Appendix 1. 
AEs must be recorded in the AEs CRF under the signs, symptoms or diagnosis associated 
with them, accompanied by the following information. 
• The severity grade -  
Mild: usually transient in nature and generally not interfering with normal activities 
Moderate: sufficiently discomforting to interfere with normal activities 
Severe: prevents normal activities 
• its relationship to the study treatment (Yes or No): 
“No Relationship to study treatment or other investigational treatment” or 
“Relationship to study treatment” or 
“Relationship to other investigational treatment or  
“Relationship to both study treatment and other investigational treatment or 
indistinguishable”.  
• Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved should be reported. 
• Whether it constitutes a SAE, as defined in Section 7.2 and which seriousness criteria 
have been met. 
• Action taken regarding the study treatment  
All AEs should be treated appropriately. Treatment may include one or more of the 
following:  
• no action taken (e.g. further observation only)  
• study treatment dosage increased/reduced 


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• study treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given  
• patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product 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 has then to be discussed with the patient. Investigators should be 
familiar with known potential AEs outlined in the IB as well as local labelling. If patients 
experience such AEs (or any AE), they should be treated as considered clinically appropriate. 
This may include discontinuation from treatment medication. 
The investigator must also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events (SAEs) 
7.2.1 
Definition of SAE 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  


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• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E12D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E12D 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 eCRF. SAEs are also required for 
individual reporting to Drug Safety & Epidemiology (DS&E) as per Section 7.2.2. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the patient has stopped study participation 
(defined as time of last dose of study drug taken or last visit whichever is later) must be 
reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 30 day period following the last administration of study treatment 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. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a Follow-
up to that event regardless of when it occurs.  The Follow-up information should describe 


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whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries. 
7.2.3 
Pneumonia reporting 
Pneumonia will be defined as an event characterized by increased respiratory symptoms (e.g. 
increased cough, dyspnea, wheezing, purulent sputum), fever (i.e. body temperature greater 
than 38 °C) or pleuritic chest pain or leukocytosis or other clinical signs consistent with 
pneumonia considered relevant in the opinion of the investigator and confirmed by X-ray. 
Any reported pneumonia will have to be confirmed by either X-ray or radiologist reading 
report of the X-ray (to be kept in the source documents). If not confirmed by X-ray, it should 
be reported as lower respiratory tract infection. 
7.3 
Liver safety monitoring  
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, Follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Table 13-1 in Appendix 7 for complete definitions of liver laboratory triggers 
and liver events.  
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 7 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 in Appendix 7. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages. 


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• If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the patient if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All Follow-up information, and 
the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 
7.4 
Reporting of study treatment errors including misuse/abuse  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient 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. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) e-CRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE. 
 
Treatment error 
type 
Document in Dose 
Administration (DAR) 
e-CRF (Yes/No) 
Document in AE e-
CRF 
Complete SAE form 
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 
7.5 
Pregnancy reporting  
Given the age of this patient population, there may be female patients who have reached 
menarche (and therefore of child-bearing potential).  Female patients who fall in this category 
will have routine urine pregnancy tests as noted in Table 6-1.  
If there is evidence of sexual activity in female patients of child-bearing potential, appropriate 
moral and legal actions for reporting should be taken by the investigator to ensure the safety 
of the child and minimize the risk of becoming pregnant.  


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Abstinence from sexual activity while participating in a clinical trial should be encouraged in 
this category of patients. Otherwise, contraceptive methods should be discussed and may be 
provided as appropriate to sexually active pediatric patients after careful consideration of any 
medical conditions, the individual situation, and cultural and legal aspects. 
The basic contraception methods are (if allowed by local regulations): 
• Barrier method: Condom or Occlusive cap (diaphragm or cervical/vault caps).  
• 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 local regulations deviate from the methods listed, local regulations apply and will be 
described in the ICF. 
In the event the patient become pregnant, and to ensure patient safety, each pregnancy 
occurring after signing the informed consent must be reported to Novartis within 24 hours of 
learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
Follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment.  
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of patient records, the accuracy of entries on the (e)CRFs, the 
adherence to the protocol and to GCP, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization.   
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 


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information on CRFs must be traceable to these source documents in the patient's file. The 
investigator must also keep the original informed consent form signed by the patient/parent or 
guardian (a signed copy is given to the patient/parent or guardian). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients/subjects will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff (or a designated Contract Research Organization (CRO) will 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. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Spirometry readings will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Diary data will be entered into an electronic diary by the patient`s parent/legal guardian. The 
system will be supplied by a vendor(s), who will also manage the database. The database will 
be sent electronically to Novartis. 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 


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supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO). 
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 relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management. 
8.4 
Data Monitoring Committee  
Not required. 
8.5 
Adjudication Committee 
Not required. 
9 
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. 
9.1 
Analysis sets  
The following analysis sets are defined for data analysis. 
• The Randomized Set (RAN) will consist of all patients who were assigned a 
randomization number; regardless they actually received study medication. Several tables 
will summarize all screened subjects (e.g. “Screening Phase subject disposition, All 
screened subjects” and “Analysis sets by treatment, All subjects”). In consistency with the 
master analysis plan (MAP), there will not be a definition of a screened set.  
• The Full Analysis Set (FAS) will consist of all patients in the RAN who received at least 
one dose of study medication. Following the intent-to-treat principle, patients in the FAS 
will be analyzed according to the treatment they were randomized to in the assigned 
treatment sequence. The FAS will be used in the analysis of all efficacy variables. 
• The Per Protocol Set (PPS) will include all patients in the FAS who did not have any 
major protocol deviations. Rules for exclusion of subjects from the PPS will be defined in 
the Statistical Analysis Plan (SAP) prior to database lock and the un-blinding of the study. 
Patients in the PPS will be analyzed according to the treatment they actually received. The 
PPS will be used for supportive analysis of the primary analysis. 
• The Safety Set will consist of all patients who received at least one dose of study 
medication. Patients in the Safety Set will be analyzed according to treatment received. 
The Safety Set will be used in the analysis of all safety variables. 


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9.2 
Patient demographics and other baseline characteristics  
Demographic and baseline characteristics measured before randomization age, gender, race, 
ethnicity, height, weight, body mass index (BMI), relevant medical history, screening 
spirometric parameters (FEV1, FVC, FEV1/FVC), FEV1 reversibility, predicted and 
percentage of predicted FEV1, duration of asthma, history of asthma exacerbations, smoking 
exposure, prior concurrent medications (non-asthma and asthma-related), vital signs (systolic 
and diastolic blood pressure, pulse rate), peripheral blood eosinophil counts, QTc using 
Fridericia’s correction and baseline ACQ-IA will be summarized by treatment group.  
Continuous variables will be summarized using descriptive statistics (n, mean, 25th percentile, 
median, 75th percentile, standard deviation, minimum and maximum) and categorical variables 
will be summarized in terms of the number and percentage of patients in each category. 
Baseline is defined as the last measurement before first dose of study drug. 
No statistical analyses will be provided for baseline comparability among the treatment 
groups. 
9.3 
Treatments 
Study drug administration and concomitant medication data will be listed and summarized 
using the Safety set. The duration of exposure, the number of patients randomized who 
completed the treatment period, and who discontinued from study medication will be 
summarized.  
Medications started and stopped prior to study drug and taken concomitantly, will be 
summarized by treatment group in separate tables in the Safety Set.  
Concomitant therapies will be recorded, listed and summarized separately for asthma related 
medications / non-drug therapies and other medications. Concomitant asthma related 
medications will be summarized by pharmacological (ATC) class and preferred term. 
Concomitant medications not related to asthma will be summarized by ATC class. More than 
one ATC class per medication is possible and the medication will be reported under all 
applicable classes. 
SABA usage (number of puffs) during the Screening epoch will be summarized.  
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations. 
Treatment compliance with study medication over the study period will be summarized. 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Variable(s) 
The primary endpoint is change from baseline in pre-dose trough FEV1 (mL) after 2 weeks of 
treatment. The pre-dose trough FEV1 (mL) is defined as the mean of the two FEV1 (mL), 
values measured at -45 min and -15 min pre-dose. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The dose selection will be based on the totality of clinical, physiological and PK data in 
pediatric patients ≥ 6 years and < 12 years years old. Summary statistics (n, mean, 25th 
percentile, median, 75th percentile, standard deviation, minimum and maximum) by treatment 


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group will be provided for change from baseline in pre-dose trough FEV1 as well as pre-dose 
trough FEV1 after 2 weeks of treatment. Inferential testing statistics will not be performed 
since the sample size is small and power is limited. 
9.4.3 
Handling of missing values/censoring/discontinuations 
If any of the -45 min and -15 min values contributing to the pre-dose trough FEV1 are 
collected within 7 days of systemic corticosteroid use, 6 hours of rescue medication, or actual 
measurement times are outside the 22 - 25 hour from last dose of the previous day (Day 13) 
then the individual FEV1 value will be set to missing. 
If one of the two values is missing (or set to missing) then the remaining non-missing value 
will be taken as pre-dose trough FEV1. If both values are missing, or if the patient withdrew 
from the study, regardless of the reason for discontinuation, then pre-dose trough FEV1 will 
be regarded as missing in which case the missing value(s) of the patient at the particular 
visit(s) would not contribute to the summary statistics. 
9.4.4 
Sensitivity analyses 
As a supportive analysis, summary statistics will be provided for the PPS. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
9.5.1.1 
Spirometry 
All spirometric efficacy variables will be analyzed for the FAS, unless otherwise specified. 
Spirometry measurements taken within 7 days of systemic corticosteroid use and/or within 
6 hours of rescue medication use will be set to missing and not be imputed, unless specified 
otherwise. 
Summary statistics will be provided for pre-dose trough FEV1 and post-dose FEV1 (30 min, 1 
hr) by visit and by treatment. Similar analyses will be performed for pre- and post-dose FVC 
and change from baseline in the spirometry values. 
9.5.1.2 
ACQ-IA 
ACQ-IA score at each visit will be summarized by treatment groups. The proportion of 
patients who achieve an improvement of at least 0.5 in ACQ-IA (i.e. decrease of ACQ-IA 
score of at least 0.5 from baseline) at visit 299 will be summarized by treatment groups. 
9.5.1.3 
Exposure to indacaterol in plasma following sparse pharmacokinetic 
(PK)  
Blood samples for PK analysis will be collected in all patients. 
9.5.1.4 
Rescue medication 
The number of puffs of the rescue medication use in the last 12-hour is recorded twice daily 
(morning/evening) by the patient`s parent/legal guardian in the e-Diary. The mean daily 
number of puffs (morning + evening) of rescue medication use over the 2 weeks of treatment 
will be summarized by treatment. The mean change from baseline in the daily number of 


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puffs of rescue medication use will be summarized by treatment. No imputation will be done 
for missing data. This analysis will be repeated for morning (nighttime) and evening 
(daytime) rescue medication use. 
In addition, the percentage of ‘rescue medication free days’ (defined from diary data as any 
day where the patient did not use any puffs of rescue medication) will be summarized by 
treatment. 
9.5.1.5 
Peak expiratory flow rate 
All the patients are instructed to record PEF twice daily using an electronic Peak Flow Meter 
device, once in the morning and once approximately 12 hours later in the evening, from 
Run-in visit 101 and throughout the study. 
PEF (liters/min) will be analyzed separately for morning and evening values. Mean values 
will be calculated over the 2 weeks Treatment Phase. Morning and evening PEF data 
averaged over the days of Run-in period will be used as baseline values. 
Mean morning/evening PEF will be summarized by treatment. In addition, change from 
baseline in mean morning/evening PEF during the 2 weeks treatment will be summarized. 
9.5.1.6 
Asthma symptoms based on e-Diary 
The e-Diary data on asthma symptoms will be summarized for: 
• the mean daytime asthma symptom score 
• the total daily symptom score 
• percentage of days with no daytime symptoms 
• percentage of nights with no nighttime awakenings 
• percentage of mornings with no symptoms on rising 
• percentage of asthma symptoms free days, i.e., days with no daytime symptoms and no 
nighttime awakenings and no mornings with symptoms on rising 
Daily scores will be averaged for each patient over the days of the Run-in period (which will 
be used as the baseline value) and the 2 weeks treatment period. Days with no daytime 
symptoms, nights with no night-time awakenings, mornings with no symptoms on awakening, 
and days with no asthma symptoms will be expressed in percentage of days with data during 
the respective periods. The same periods as for average scores will be analyzed for percentage 
of days. For post-baseline periods only the days on double-blind treatment will be considered. 
In addition, summary statistics will be provided for changes from baseline. 
9.5.2 
Safety variables 
All safety parameters will be summarized on the safety set. 
Adverse events 
All treatment emergent AEs including asthma exacerbations will be summarized and listed. 
AEs starting on or after the time of the first inhalation of study drug but not later than 7 days 
(30 days in the case of a SAE) after the last inhalation will be classified as a treatment 
emergent AE. Any AEs that started during the study before the time of the first inhalation of 
study drug will be classified as a prior AE. 


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The following treatment emergent AE 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 AEs by system organ class and preferred term, SAEs by system organ 
class and preferred term, and AEs leading to permanent discontinuation of study-drug by 
system organ class and preferred term. 
The number and percentage of patients with the most frequent AEs will be summarized by 
treatment. 
In addition, AEs will be summarized by standardized MedDRA query (SMQ) level. The 
Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify AEs of special interest which will be summarized too. 
Electrocardiogram (ECG) and vital signs 
Data from the electrocardiogram will be summarized by treatment and visit. 
Vital signs (blood pressure and radial pulse rate) data will be summarized by treatment and 
visit. 
The maximum (QTc, systolic blood pressure, pulse rate and heart rate) or minimum (diastolic 
blood pressure) post first dosing (i.e. post baseline) value will also be summarized. Changes 
from baseline will also be summarized by treatment. 
Weight will be summarized by visit and treatment group. Changes from baseline will also be 
summarized by treatment. The baseline measurement will be the measurement at Visit 101. 
All data will be included in the analysis regardless of rescue medication usage. 
The number (%) of patients with treatment emergent pulse rate, systolic blood pressure and 
diastolic blood pressure outside the ranges of below defined notable values will be 
summarized by treatment group. 
Notable values for vital signs and change from baseline will be summarized. A notable value 
is defined per age group as follows: 
Systolic blood pressure: 
“Low” criterion: ≤ 80 mmHg (6-8 years) or ≤ 85 mmHg (9-11 years) and decrease from 
baseline ≥ 20 mmHg (Haque et al 2007) 
“High” criterion: ≥ 115 mmHg (6-8 years) or ≥ 120 mmHg (9-11 years) and increase from 
baseline ≥ 20 mmHg (Fourth Report 2004) 
Diastolic blood pressure: 
“Low” criterion: ≤ 40 mmHg (6-8 years) or ≤ 45 mmHg (9-11 years) and decrease from 
baseline ≥ 20 mmHg (Horan et al 1987 
“High” criterion: ≥ 75 mmHg (6-8 years) or ≥ 80 mmHg (9-11 years) and increase from 
baseline ≥ 20 mmHg (Fourth Report 2004) 
Pulse rate: 
”Low” criterion: decrease from baseline ≥ 25% to a value < 70 bpm (6-8 years) or < 60 bpm 
(9-11 years) 


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“High” criterion: increase from baseline ≥ 25% to a value > 115 bpm (6-8 years) or > 110 
bpm (9-11 years) (according to internal draft ECQ_QT Guidelines) 
Categorical QTc values and changes from baseline will be summarized as the number (%) of 
patients with new (treatment-emergent) QTc >450, >480 and >500 ms. 
QTc change from baseline will be presented as QTc changes, both positive and negative, or 0-
30 ms, >30ms, and >60 ms. 
Notable QT values are defined as QTc increases of >30 and >60 ms, and QTc >500 ms. 
QTc will be calculated from the QT interval and RR (in seconds) using the Fridericia formula 
or dependent on the age Bazett formula, respectively. 
Vital signs and ECG data measured more than 7 days after last inhalation of study drug is 
regarded as post-treatment data and will not be summarized, only listed. 
Laboratory data 
The laboratory parameters (hematology, blood chemistry including glucose and potassium, 
urinalysis and evening plasma cortisol, eosinophil counts) will be summarized by treatment, 
visit and time point, including changes from baseline.  
All laboratory data will be listed with abnormal values flagged. The laboratory values and the 
change from baseline for continuous laboratory parameters will be summarized at each visit. 
A frequency table of results for categorical laboratory parameters will be produced by visit. 
Shift tables relative to the normal reference ranges will be used to summarize the change from 
baseline to post-baseline by visit for each laboratory parameter. 
The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria will be summarized by laboratory 
parameter, scheduled post-baseline visit and time point and additionally at any time on 
treatment considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits. Similar analysis will be done for newly occurring or worsening 
abnormalities in liver function tests (LFT). 
Laboratory data measured more than 7 days after last inhalation of study drug is regarded as 
post-treatment data and will not be summarized, only listed. 
9.5.3 
Pharmacokinetics 
For PK concentration data, listings and descriptive statistics will be provided. The descriptive 
statistics will comprise arithmetic and geometric means, SD, median, minimum and maximum 
for plasma indacaterol concentrations at pre-dose (<2 hours) and at 15 min and 1 hour post-
dose at Visit 199/201 and 299. Plasma concentrations will be expressed in pg/mL units. All 
concentrations below the lower limit of quantification or missing data will be labeled as such 
in the concentration data listings. Concentrations below the lower limit of quantification will 
be treated as zero in summary statistics of concentration data. In addition, the plasma 
concentration data from this study may be combined with data from other studies to perform a 
population PK analysis, which will follow the principles outlined in the FDA Guidance for 
Industry 1999. 
9.5.4 
PK/PD 
Not applicable. 


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9.6 
Interim analyses 
No interim analyses are planned for this study.  
9.7 
Sample size calculation 
The sample size of 72 patients evaluable for the primary endpoint in the study is based on 
pragmatic considerations and per agreement with EU Pediatric Committee (PDCO), not based 
on statistical considerations. It is assumed that approximately 10% of patients will not 
complete the trial so that 80 patients need to be randomized to ensure 72 patients will be 
evaluable for the primary endpoint.  
10 
Ethical considerations 
10.1 
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 CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki. 
Participation of patients in this study will be based on the local regulations and ethics 
committee requirements in various participating countries. 
10.2 
Informed consent procedures 
Eligible patients/subjects may only be included in the study after providing written 
(witnessed, where required by law or regulation), IRB/IEC-approved informed consent, or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative(s) of the patient. Patients below the legal age of consent are required to have 
the Parental Informed Consent signed by the patient’s parent/guardian; children are required 
to sign the Assent Form (according to locally accepted policy/practice). 
In cases where the patient’s representative gives consent, the patient must be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she must indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting 
any study-specific procedures (e.g. all of the procedures described in the protocol). The 
process of obtaining informed consent must be documented in the patient source documents.  
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Girls of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the patient will not reliably comply, they must not be 
entered in the study. 


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10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, written assent form (according to local 
policy/practice), consent form updates, subject recruitment procedures (e.g., advertisements) 
and any other written information to be provided to patients/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. 
10.4 
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. 
10.5 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/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. All significant protocol deviations will be recorded and reported in the clinical 
study report (CSR). 


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11.1 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/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 patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed. 
12 
References 
References are available upon request 
Annex IV, ICH-E2D Guideline (2003) Available from www.ich.org. 
Bastain TM, Islam T, Berhane KT, et al (2011) Exhaled nitric oxide, susceptibility and new-
onset asthma in the Children’s Health Study. Eur Respir J; 37(3):523-531. 
Beasley R, Donohue JF, Mehta R et al (2015) Effect of once-daily indacaterol 
maleate/mometasone furoate on exacerbation risk in adolescent and adult asthma: a double-
blind randomized controlled trial; BMJ Open 2015;5:e006131. doi:10.1136/bmjopen-2014-
006131.  
Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-
agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with 
persistent asthma. Cochrane Database Syst Rev 2010:CD005533. 
Global Initiative for Asthma (GINA) (2015). Global Strategy for Asthma Management and 
Prevention. Available from http://ginasthma.org 
Global Initiative for Asthma (GINA) (2014). Global Strategy for Asthma Management and 
Prevention. Available from http://ginasthma.org 
Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose 
corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & 
Hanburys Limited UK Study Group. Lancet 1994;344:219–224. 
Haque IU, Zaritsky AL. Analysis of the evidence for the lower limit of systolic and mean 
arterial pressure in children. Pediatr Crit Care Med 2007 Vol. 8, No. 2: 138-144. 
Horan MJ, Sinaiko AR. Synopsis of the Report of the Second Task Force on Blood Pressure 
Control in Children. Hypertension. 1987;10:115-121. doi: 10.1161/01.HYP.10.1.115. 
Juniper EF, Gruffydd-Jones K, Ward S et al (2010) Asthma Control Questionnaire in 
children: validation, measurement properties, interpretation. Eur Respir J; 36(6):1410-1416. 
Masoli M, Fabian D, Holts S, et al (2004) Global burden of asthma. Developed for the Global 
Initiative for Asthma (GINA). Available from http://ginasthma.org 
Moorman JE, Rudd RA, Johnson CA, et al (2007) National surveillance for asthma—United 
States, 1980-2004. MMWR Surveill Summ; 56(8):1-54. 


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Runge P and Hill VL (2009) Practical management of asthma. Pediatrics in Review; 
30(10):375.  
The Fourth Report on the Diagnosis, Evaluation, and Treatment of  High Blood Pressure in 
Children and Adolescents. National High Blood Pressure Education Program Working Group 
on High Blood Pressure in Children and Adolescents. Pediatrics 2004;114;555-576. DOI: 
10.1542/peds.114.2.S2.555. 
Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to 
inhaled steroids with doubling of the dose of inhaled steroids. Am J RespirCrit Care Med 
1996;153:1481–1488. 


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13 
Appendices 
Appendix 1: Instruction for Use of Concept1 
Instructions for using inhaler and capsules. 
Do not swallow capsules. 
Follow the instructions below for using your inhaler. You will take the study drug contained 
within the capsules by inhalation using the inhaler. If you have any questions, please ask the 
doctor or nurse at the study center. 
Your inhaler and capsules 
The study drug package consists of both the inhaler and one or more blister-packaged 
capsules. 
• Capsules are supplied in blisters. 
• Inhaler consists of a cap, mouthpiece and a base. 
 
Your inhaler is designed to deliver the medicine contained within the capsules. 
Do not use the study medication capsules with any other capsule inhaler, and do not use the 
inhaler to take any other capsule medicine. 
How to use your inhaler 
Pull off cap. 


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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. 
Close the inhaler: 
You should hear a “click” as the mouthpiece closes onto the 
inhaler base. 


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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. 
 
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 


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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. 
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. 


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• 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.  
• Do not store the capsules in the inhaler. 
• Always keep the inhaler and capsules in a dry place, and avoid very hot or cold 
temperatures. 
How to clean your inhaler 
• Clean your inhaler once a week. 
• Wipe the mouthpiece inside and outside to remove any powder with a clean, dry lint-free 
cloth. 
• Do not wash your inhaler with water. Keep it dry. 
• Do not take the inhaler apart. 
 


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Appendix 2: How to Use an Accuhaler®/ Diskus®  
Instructions for use 
Follow the instructions below for using your Diskus® inhalation device. You will breathe in 
(inhale) the medicine from the Diskus. Do not use the Diskus unless your healthcare provider 
has taught you, and you understand everything. If you have any questions, ask the doctor, 
nurse or pharmacist personnel at the study site. 
Figure 1 
Parts of the Diskus 
  
Take the Diskus out of the medication pack given to you. The Diskus will be in the closed 
position. The dose indicator on the top of the Diskus tells you how many doses are left. The 
dose indicator number will decrease each time you use the Diskus. After you have used 55 
doses from the Diskus, the numbers 5 to 0 will appear in red to warn you that there are only a 
few doses left (see Figure 2). 
Figure 2 
Dose Indicator for the Diskus®  
 
Taking a dose from the Diskus® requires the following 3 steps: Open, Click, Inhale. 
1. OPEN 
Hold the Diskus® in one hand and put the thumb of your other hand on the thumbgrip.  Push 
your thumb away from you as far as it will go until the mouthpiece appears and snaps into 
position (see Figure 3). 


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Figure 3 
Opening the Mouthpiece Cover 
 
2. CLICK 
Hold the Diskus® in a level, flat position with the mouthpiece towards you. Slide the lever 
away from you as far as it will go until it clicks (see Figure 4). The Diskus® is now ready to 
use.  
Figure 4 
Sliding the Lever Until It Clicks 
 
Every time the lever is pushed back, a dose is ready to be inhaled. This is shown by a 
decrease in numbers on the dose counter. To avoid releasing or wasting doses once the 
Diskus® is ready: 
• Do not close the Diskus. 
• Do not tilt the Diskus. 
• Do not play with the lever. 
• Do not move the lever more than once. 
3. INHALE 
Before inhaling your dose from the Diskus®, breathe out (exhale) fully while holding the 
Diskus® level and away from your mouth (see Figure 5). Remember, never breathe out into 
the Diskus® mouthpiece. 


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Figure 5 
Exhaling 
 
Put the mouthpiece to your lips (see Figure 6). Breathe in quickly and deeply through the 
Diskus®. Do not breathe in through your nose. 
Figure 6 
Inhaling 
 
Remove the Diskus® from your mouth. Hold your breath for about 10 seconds, or for as long 
as is comfortable. Breathe out slowly. The Diskus® delivers your dose of medicine as a very 
fine powder. Most patients can taste or feel the powder. Do not use another dose from the 
Diskus® if you do not feel or taste the medicine. 
4. CLOSE 
Close the Diskus® when you are finished taking a dose so that the Diskus® will be ready 
for you to take your next dose. Put your thumb on the thumbgrip and slide the thumbgrip 
back towards you as far as it will go (see Figure 7). The Diskus® will click shut. The lever 
will automatically return to its original position. The Diskus® is now ready for you to take 
your next scheduled dose, due in about 12 hours. (Repeat steps 1 to 4 at that time). 


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Figure 7 
Closing the Mouthpiece Cover 
 
Remember: 
• Never breathe into the Diskus®. 
• Never take the Diskus® apart. 
• Always ready and use the Diskus® in a level, flat position. 
• Do not use the Diskus® with a spacer device. 
• Never wash the mouthpiece or any part of the Diskus®. Keep it dry. 
• Always keep the Diskus® in a dry place. 
Never take an extra dose, even if you did not taste or feel the medicine 


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


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• No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, or no volume change for at least 1 second) or the subject cannot continue 
to exhale further 
Repeatability 
The 2 largest FVC and FEV1 values from 3 acceptable maneuvers should not vary by more 
than 0.150 L. 
Recording of data 
The highest FEV1 and FVC from any of the acceptable curves are recorded. (The highest 
FEV1 and FVC may not necessarily result from the same acceptable curve). 
Predicted normal 
This study will utilize the spirometric predication equation standards for the European 
Community for Coal and Steel2, Nhanes3, ERS Global Lung Function Initiative (GLI)2 or 
Japanese Respiratory Society3.  
Reversibility 
All reversibility evaluations should follow the recommendations of the ATS/ERS Task force: 
Standardization of Lung Function Testing 
Administer 400 µg of salbutamol/albuterol following the completion of the baseline 
assessment. A second spirometry assessment is then performed within 30 minutes after 
administration of the salbutamol/albuterol.  
 
Reversibility is calculated as:  
100 x        FEV1 (post β2-agonists) – FEV1 (baseline) 
                                     FEV1 (baseline) 
Subjects will be considered reversible if an increase of at least 12% is demonstrated after 
administration of the bronchodilator.  
Predicted normal values will be calculated according to ECSC 
For height measured in meters 
Males: FEV1 predicted (L)=4.30x(height(meters))-0.029xage(years)-2.49 
Females: FEV1 predicted (L)=3.95x(height(meters))-0.025xage(years)-2.60 
 
References 
1 Miller MR et al, Standardization of Lung Function Testing. Eur Resp J 2005;26:153-161. 
2 Quanjer PH, et al.  ERS Global Lung Function Initiative, Multi ethnic reference values for 
spirometry for the 3-95 year age range: the global lung function 2012 equations. Report of the 
Global Lung Function Initiative (GLI). ERS Task Force to establish improved Lung Function 
Reference Values. 
3 Kubota, Kobayashi, Quanjer PH, et al. Reference values for spirometry, including vital 
capacity, in Japanese adults calculated with the LMS method and compared with previous 
values.  Clinical Pulmonary Functions Committee of the Japanese Respiratory Society.   
Respiratory Investigations 2014, 242-250.    
 


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Appendix 4: Patient Asthma Control e-Diary 
For illustrative purposes only 
The patient’s parent/ legal guardian should assist the patient in completing the e-Diary. 
The following information will be captured: 
In the Morning 
In the Evening 
Peak expiratory flow rate 
 
How often were you woken up by your asthma 
during the night? 
 
Did you have asthma symptoms upon awakening 
in the morning? 
 
Number of puffs of rescue medication during the 
past 12 hours 
 
 
Peak expiratory flow rate 
 
Did your symptoms stop you from performing 
your usual daily activities? 
 
How severe was your shortness of breath today? 
 
How much did you wheeze today? 
 
How was your cough today? 
 
Did you have chest tightness today? 
 
Number of puffs of rescue medication during the 
past 12 hours. 


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Appendix 5: ACQ-IA 
For illustrative purposes only 
 
 
 
 


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Appendix 6: Clinically notable laboratory values and vital signs 
There are no specific criteria for this study; however, the Central Laboratory will flag 
laboratory values falling outside of the normal range on the Central Laboratory Report (which 
the investigator should sign off) and the investigator will report any values considered 
clinically significant in the eCRF. 


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Appendix 7: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements 
Table 13-1 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
• 
3 x ULN < ALT / AST ≤ 5 x ULN 
• 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
• 
ALT or AST > 5 × ULN 
 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
 
• 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
• 
ALT or AST > 3 × ULN and INR > 1.5  
 
• 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
 
• 
Any clinical event of jaundice (or equivalent term) 
 
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
• 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms 
TBL: total bilirubin; ULN: upper limit of normal  
Table 13-2 
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
ALT or AST 
> 8 × ULN 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 3 × ULN and INR > 
1.5 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, continue Follow-up 
monitoring 
• 
If elevation persists for more than 2 
weeks, discontinue the study drug 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 


Novartis 
Confidential 
Page 86 
Clinical Trial Protocol (Version 00) 
 
Protocol No. CQMF149G2202 
 
Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN 
accompanied by 
symptomsb 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, establish causality 
• 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, discontinue the study 
drug immediately 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g., reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic) 
• 
Repeat LFT within the next week 
• 
If elevation is confirmed, initiate close 
observation of the patient  
Investigator discretion 
Monitor LFT within 1 to 4 weeks or at 
next visit 
Jaundice 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the patient 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP and 
γGT until resolutionc (frequency at 
investigator discretion) 
Any AE potentially 
indicative of a liver 
toxicity* 
• 
Consider study treatment interruption or 
discontinuation  
• 
Hospitalization if clinically appropriate 
• 
Establish causality 
• 
Complete liver CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death. 
 

SAP_000.pdf: 
Clinical Development 
QMF149/Indacaterol acetate 
CQMF149G2202 / NCT02892019
A multicenter, randomized, double-blind, active-controlled, 
2 week treatment, parallel-group study to assess the 
efficacy and safety of indacaterol acetate delivered via the 
Concept1 inhalation device in children greater or equal to 6 
and less than 12 years of age with asthma 
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician: 
  
Trial Statistician (CRO): 
 
Document type: 
SAP Documentation 
Document status: 
Amendment 1 
Release date: 
27-Aug-2019
Number of pages: 
27 
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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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Correction of definition of 
study day, it is defined as day 
relative to first dose of study 
drug. 
Section 2.1.1 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Replaced 
analysis 
of 
disposition epochs by region 
and treatment by a summary of 
number of patients by region, 
country and treatment group. 
Section 2.3.1 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Major PDs completed 
Section 5.4 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Removed analysis of medical 
histories by ongoing status. 
Section 2,3 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Replaced analysis of prior and 
concomitant medications by 
ATC class by analysis by 
prespecified category, route 
and preferred term/ingredient. 
Section 
2.4 
and Section 4 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Added analysis of pre-dose 
trough 
FEV1 
applying 
a 
different 
time 
window, 
excluding 
measurements 
outside of the 22 – 30 hour from 
last dose of the previous day 
(Day 13). 
Section 2.5.4 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Added exclusion of implausible 
spirometry values.  
Removed 
exclusion 
of 
spirometry values based on 
unacceptable flag. 
Sections 
2.5.4, 
2.7.3 
and 5.5 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Replaced 
AEs 
of 
special 
interest terms by reference to 
Case Retrieval Sheet 
Section 
2.8.1.1 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Added details for baseline and 
post baseline derivations for 
Section 
2.7 
and 5.5 


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SAP Amendment 1 
 
CQMF149G2202 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
diary parameter PEF, rescue 
medication use and symptoms. 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Replaced 
details 
for 
date 
imputations 
by 
referencing 
PDS. 
Section 5.1 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Update of notable laboratory 
ranges to SI units. Added 
Magnesium. 
Section 5.6 
27.3.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Minor 
corrections 
and 
modifications 
All Sections 
3.6.2019 
Before DB 
lock 
Creation 
of 
Amendment 1 
Time window of for trough 
measurement exceeded to 22-
30h. 22-25h window will be 
kept as supportive analysis. 
Sections 2.5 
and 2.7 
3.6.2019 
Before DB 
lock 
Creation 
of 
Amendment 1  
Remove analysis for rescue use 
at screening. 
Section 2.4 
3.6.2019 
Before DB 
lock 
Creation 
of 
Amendment 1 
Removed BMI categorization. 
Section 2.3 
13.8.2019 Before DB 
lock 
Creation 
of 
Amendment 1 
Added 
categorical 
ECG 
summaries for QTcF 
Section 2.8.3 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 8 
2.1 
Data analysis general information ........................................................................... 8 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets ............................................................................................................ 9 
2.2.1 
Subgroup of interest ................................................................................ 9 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 10 
2.3.1 
Patient disposition ................................................................................. 11 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 11 
2.4.1 
Study treatment / compliance ................................................................ 11 
2.4.2 
Prior, concomitant and post therapies ................................................... 11 
2.5 
Analysis of the primary objective .......................................................................... 12 
2.5.1 
Primary endpoint ................................................................................... 12 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 12 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 12 
2.5.4 
Supportive analyses ............................................................................... 13 
2.6 
Analysis of the key secondary objective ............................................................... 13 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 13 
2.7.1 
Secondary endpoints ............................................................................. 13 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 13 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 15 
2.8 
Safety analyses ....................................................................................................... 16 
2.8.1 
Adverse events (AEs) ............................................................................ 16 
2.8.2 
Laboratory data ..................................................................................... 17 
2.8.3 
Other safety data ................................................................................... 19 
2.9 
Pharmacokinetic endpoints .................................................................................... 20 
2.10 
PD and PK/PD analyses......................................................................................... 21 
2.11 
Interim analysis ...................................................................................................... 21 
3 
Sample size calculation ..................................................................................................... 21 
4 
Change to protocol specified analyses .............................................................................. 21 
5 
Appendix ........................................................................................................................... 22 


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5.1 
Imputation rules ..................................................................................................... 22 
5.1.1 
Study drug ............................................................................................. 22 
5.1.2 
AE date imputation ............................................................................... 22 
5.1.3 
Concomitant medication date imputation ............................................. 22 
5.2 
AEs coding/grading ............................................................................................... 22 
5.3 
Statistical models ................................................................................................... 22 
5.4 
Rule of exclusion criteria of analysis sets.............................................................. 22 
5.5 
Baseline definitions ............................................................................................... 24 
5.6 
Laboratory parameters – definition of clinically notable values ........................... 26 
5.7 
Vital signs and ECG – definition of clinically notable values ............................... 27 
6 
Reference ........................................................................................................................... 27 
 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
CSR 
Clinical Study report 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
o.d. 
Once Daily 
PD 
Protocol Deviation 
PDS 
Programming Dataset Specification 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This document contains details of the statistical methods that will be used in the phase IIb 
clinical trial CQMF149G2202. 
Data will be analyzed according to Section 9 of the study protocol. Important information is 
given in the following sections and details are provided, as applicable, in Appendix 5. 
1.1 
Study design 
 
This study uses a randomized, multicenter, double-blind, active-controlled study design. The 
primary endpoint is change from baseline in pre-dose trough FEV1 (mL) after 2 weeks of 
treatment with indacaterol acetate in children with GINA step 2&3. Study treatment will be 
administered on top of background asthma ICS controller therapy (fluticasone propionate 100 
µg b.i.d. or dose equivalent). This study will consist of 4 epochs: Screening, Run-in, Treatment, 
and Follow-up (telephone contact for safety). 
The study population will consist of approximately 80 male and female children ≥6 years and 
< 12 years with persistent asthma for at least 1 year and on stable ICS dose (with or without 
additional controller medication) for at least 4 weeks prior to study start. It is anticipated that 
approximately 200 patients will need to be screened in order to randomize 80 patients into the 
treatment epoch. It is intended that approximately 72 patients will complete the study. 
At Visit 201, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study drug to be dispensed 
to the patient. The randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients/subjects and investigator staff. A 
patient randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of patient numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s).  
The randomization scheme for patients/subjects will be reviewed and approved by a member 
of the Randomization Group. 
Randomization will be stratified by region (EU, LA, and other) 
No interim analysis is planned for this study. 
1.2 
Study objectives and endpoints 
The study objectives and corresponding endpoints are summarized by the following table 
from the protocol. 
 


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Primary Objectives(s) 
To evaluate indacaterol acetate 75 µg o.d 
and 150 µg o.d. in terms of change from 
baseline in pre-dose trough FEV1 after 2 
weeks of treatment. 
Secondary Objectives 
• To evaluate the systemic exposure to 
indacaterol in plasma following sparse 
pharmacokinetic (PK) sampling on Day 
1 and Day 14 after oral inhalation of 
indacaterol acetate 75 µg and 150 µg. 
• To evaluate the clinical effects and 
pharmacodynamics of indacaterol acetate 
(75 μg and 150 μg o.d.) after 2 weeks of 
treatment in terms of: 
• Pediatric interviewer-administered 
Asthma Control Questionnaire 
(ACQ-IA) score at Week 2  
• FEV1 and forced vital capacity 
(FVC) rate at 30 minutes and 1-hour 
post dose at Week 2 
• Rescue medication usage over 2 
weeks of treatment as determined by 
patient diary data 
• Symptoms as recorded by patient e-
diary  
• Pre-dose morning and evening peak 
expiratory flow (PEF) over 2 weeks 
of treatment as determined by 
electronic peak flow meter data. 
• To evaluate the safety (including labs, 
vital signs, ECG, adverse events), and 
tolerability of indacaterol acetate (75 and 
150 μg o.d.) over 2 weeks of treatment. 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The statistical analysis will be performed by 
 (CRO) using SAS Version 9.4.. 
Since the sample size is limited, no inferential analysis will be performed and all analyses will 
be descriptive. The stratification is used in randomization mainly to minimize imbalance 
between treatment groups and will not be used in analysis.  


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2.1.1 
General definitions  
Study treatment/drug is indacaterol acetate. There are two treatment groups defined: 
• Indacaterol acetate 75 µg capsules for inhalation, delivered via Concept1 
• Indaceterol acetate 150 µg capsules for inhalation, delivered via Concept1 
Indacaterol acetate will be provided as powder filled capsules with a Concept1 inhalation 
device. 
Study day will be defined as the number of days since the date of first dose of study treatment. 
The date of first dose of study treatment will be defined as Day 1 and the day before the first 
dose of study treatment will be defined as Day -1.In general, baseline is defined as the last 
measurement before or at the randomization visit or prior to first administration of study drug 
on Day 1. Detailed baseline definitions for certain variable are described in Appendix 5.6. 
2.2 
Analysis sets 
The following analysis sets are defined for data analysis. 
• The Randomized Set (RAN) will consist of all patients who were assigned a 
randomization number; regardless of whether they actually received study medication. 
Patients in RAN will be analyzed according to the treatment they were randomized to. 
The RAN will be used for summaries of patient disposition, demographics, and baseline 
characteristics. 
• The Full Analysis Set (FAS) will consist of all patients in the RAN who received at least 
one dose of study medication. Following the intent-to-treat principle, patients in the FAS 
will be analyzed according to the treatment they were randomized to.. The FAS will be 
used in the analysis of all efficacy variables. 
• The Per Protocol Set (PPS) will include all patients in the FAS who did not have any 
major protocol deviations. Rules for complete exclusion of subjects from the PPS will 
be defined in Appendix 5.4 prior to database lock and the un-blinding of the study. 
Patients in the PPS will be analyzed according to the treatment they actually received. 
The PPS will be used for supportive analysis of the primary efficacy analysis. 
• The Safety Set (SAF) will consist of all patients who received at least one dose of study 
medication. Patients in the Safety Set will be analyzed according to treatment received. 
The Safety Set will be used in the analysis of all safety and pharmacokinetic variables. 
Note that the safety set allows the inclusion of non-randomized subjects who receive 
study drug in error.  
2.2.1 
Subgroup of interest 
No subgroup analysis is planned for this study. 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and baseline characteristics will be summarized by treatment group using the 
RAN set. Summaries will include:  
• age  
• gender  
• race 
• ethnicity  
• height  
• weight  
• body mass index (BMI)  
• relevant medical history  
• screening spirometric parameters (FEV1, FVC, FEV1/FVC) 
• FEV1 reversibility  
• predicted and % of predicted FEV1  
• duration of asthma  
• history of asthma exacerbations  
• prior concurrent medications (non-asthma and asthma-related)  
• vital signs (systolic and diastolic blood pressure, pulse rate)  
• peripheral blood eosinophil counts  
• QTc using Fridericia’s correction  
• ACQ-IA.   
Continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, 25th percentile, median, 75th percentile, standard deviation, minimum and 
maximum) and categorical variables will be summarized in terms of the number and percentage 
of patients in each category including a category for missing data if any. 
In addition, the following categorizations of continuous variables will be done:  
• Duration of asthma into < 1 year, 1 - 5 years, and > 5 - 10 years;  
• Number of asthma exacerbations in the 12 months prior to the start of the study that 
required treatment into 0, 1 ,  >= 2 
• pre-bronchodilator FEV1 into 50 - < 70%, 70% - <= 90% of predicted FEV1 
• Eosinophils counts into <300/mcl and >=300/mcl.   
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 


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History/conditions will be summarized for the RAN set by primary system organ class and 
preferred term. Verbatim recorded history/conditions will be listed together with the coded 
terms, date of diagnosis/surgery and whether the problem was ongoing at start of the study.  
2.3.1 
Patient disposition 
RAN will be used for the summaries and listings of patient disposition.  
 The number of patients will be summarized by region, country and treatment group. 
Further, for each study epoch (i.e., screening, run-in, treatment phase, post treatment follow-
up), the overall number of patients who entered, completed, and discontinued that phase will be 
summarized including the reasons for discontinuation. 
The number of subjects with protocol deviations will be tabulated by category and deviation.  
The number of patients included in each analysis set will be tabulated, as well as the reasons 
for exclusions from analysis set. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Compliance will be calculated by counting the days where study drug was administered "As 
per protocol" according to the records on the Dosage Administration Record (DAR) Summary 
eCRF. The percentage of days divided by the days of exposure will be analyzed.  Compliance 
will be calculated by study treatment. 
Compliance will be categorized into < 80 % and 80 % - 100 % and summarized by treatment 
for the safety set. 
The above compliance analysis will be repeated for Fluticasone propionate.  
The SAF set will be used to summarize duration of exposure. The extent of exposure will be 
examined to determine the degree to which safety can be assessed for the study drug. The extent 
of exposure to study drug will be characterized according to the duration of exposure and the 
number of subjects exposed. Duration of exposure to study treatment will be calculated as the 
number of days starting from the first dose date up to and inclusive of the last dose date. The 
duration of exposure will be summarized by treatment for the safety set as a continuous variable 
with the standard descriptive statistics. 
2.4.2 
Prior, concomitant and post therapies 
All summaries will be by treatment group in the SAF Set. 
Prior medications are defined as drugs taken and stopped prior to first dose of study medication. 
Any medication given at least once between the day of first dose of randomized study 
medication and last day of study visit will be a concomitant medication, including those which 
were started pre-baseline and continued into the treatment period. 
Each medication, either an asthma or non-asthma medication, will have the start and end dates 
recorded on the eCRF. Separate tables will be provided for medications which were started and 


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stopped prior to the first dose of study drug and medications which were taken concomitantly 
to the study drug (regardless of whether they were continued or started after the first dose of 
study drug). 
Asthma medications will be summarized by the route of administration, the recorded pre-
specified drug subcategories (including types of combination) and the coded preferred terms. 
The summary will be repeated by showing ingredients instead of preferred terms. Non-asthma 
medications will be summarized by route of administration and preferred term.  
Surgical and medical procedures (non-drug therapies) will be coded using MedDRA and 
presentations will be done by MedDRA primary system organ class and preferred term, 
separately for prior procedures and those after start of study drug. 
Patients taking prohibited concomitant medications will be noted in the summary of protocol 
deviations. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is change from baseline in pre-dose trough FEV1 after 2 weeks of 
treatment. The pre-dose trough FEV1 is defined as the mean of the two FEV1 values measured 
at -45 min and -15 min pre-dose. 
The primary efficacy analysis will be based on the FAS. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Summary statistics (n, mean, 25th percentile, median, 75th percentile, standard deviation, 
minimum, and maximum) by treatment will be provided for change from baseline in pre-dose 
trough FEV1 as well as pre-dose trough FEV1 after 2 weeks of treatment. Inferential testing 
statistics will not be performed since the sample size is small and power is limited. The data 
will be presented graphically as well.  
2.5.3 
Handling of missing values/censoring/discontinuations 
If any of the -45 min and -15 min values contributing to the pre-dose trough FEV1 are collected 
within 7 days of systemic corticosteroid use, 6 h of rescue medication,  or actual measurement 
times are outside the 22 - 30 hour from last dose of the previous day (Day 13) then the individual 
FEV1 value will be set to missing. 
If one of the two values is missing (or set to missing) then the remaining non-missing value will 
be taken as pre-dose trough FEV1. If both values are missing, or if the patient withdrew from 
the study, regardless of the reason for discontinuation, then pre-dose trough FEV1 will be 
regarded as missing in which case the missing value(s) of the patient at the particular visit(s) 
would not contribute to the summary statistics. 
For all spirometry measurements, implausible values will be excluded. If a patient has 
implausible FEV1 value (defined as > 7 L) at an assessment, all spirometry measurements 
related to that assessment will be excluded. The threshold of 7 L was chosen because according 


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to Polgar child predicted values, the maximum normal predicted FEV1 is 5.42 L, we set 7 L as 
the implausible cutoff to allow for some fluctuation around the maximum mean. 
2.5.4 
Supportive analyses 
As a supportive analysis, summary statistics will be also performed on the PPS. 
In addition, the same summary analysis on the FAS will be performed including all spirometric 
measures irrespective of systemic corticosteroid or rescue medication use but those measures 
taken outside of the 22 – 30 hour from last dose of the previous day (Day 13) will not be 
included. 
In addition, the same summary analysis on pre-dose trough FEV1 will be performed applying 
a different time window, excluding measurements outside of the 22 – 25 hour from last dose of 
the previous day (Day 13). 
No subgroup analysis is planned for the primary endpoint.  
2.6 
Analysis of the key secondary objective 
There is no key secondary objective in this study. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
All secondary endpoints are listed as below. 
• Pediatric interviewer-administered Asthma Control Questionnaire (ACQ-IA) score at 
Week 2  
• FEV1 and forced vital capacity (FVC) rate at 30 minutes and 1-hour post dose at 
Week 2 
• Rescue medication usage over 2 weeks of treatment as determined by patient diary 
data 
• Symptoms as recorded by patient e-diary  
• Pre-dose morning and evening peak expiratory flow (PEF) over 2 weeks of treatment 
as determined by electronic peak flow meter data.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
Spirometry 
All spirometric efficacy variables will be analyzed for the FAS, unless otherwise specified. 
Summary statistics will be provided for post-dose FEV1 (30 min, 1 hr) by treatment. Similar 
analyses will be performed for pre-dose trough FVC and post-dose FVC and change from 
baseline in the spirometry values. 
Pediatric ACQ-IA 
ACQ-IA score at Visit 299 as well as change from baseline will be summarized by treatment 
using summary statistics. In addition, the proportion of patients who achieve an improvement 


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of at least 0.5 in ACQ-IA (i.e., a decrease of ACQ-IA score of at least 0.5 from baseline) at 
Visit 299 will be summarized by treatment. 
Rescue medication 
The number of puffs of the rescue medication use in the last 12-hour is recorded twice daily 
(morning/evening) by the patient’s parent/caregiver in the e-Diary. The mean daily (morning + 
evening) number of puffs of rescue medication use over the 2 weeks of treatment will be 
summarized by treatment. The mean change from Baseline in the daily number of puffs of 
rescue medication use will be analyzed using summary statistics. No imputation will be done 
for missing data. This analysis will be performed for morning (night time) and evening 
(daytime) rescue medication use. Any values > 30 for the number of puffs of rescue medication 
in a 12 hour period will be set to missing. These high numbers are not realistic and could impact 
the analyses. 
In addition, the percentage of ‘rescue medication free days’ (defined from diary data as any day 
where the patient did not use any puffs of rescue medication during daytime and nighttime) will 
be summarized by treatment.  
Peak Expiratory Flow (PEF) Rate 
All the patients are instructed to record PEF twice daily using an electronic Peak Flow Meter 
device, once in the morning and once approximately 12 hours later in the evening, from Run in 
visit 101 and throughout the study. PEF (liters/min) will be analyzed separately for morning 
and evening values. Mean values will be calculated over the 2 weeks treatment phase. Morning 
and evening PEF data averaged over the days of run-in period will be used as baseline values. 
Mean morning/evening PEF will be summarized by treatment. In addition, change from 
baseline in mean morning/evening PEF during the 2 weeks treatment will be summarized. 
Asthma symptoms based on e-Diary 
Daily e-Diary recordings will be used to derive 
• the mean daytime asthma symptom score i.e., the mean score over the 5 evening 
questions with respect to shortness of breath, wheeze, cough, chest tightness, and 'Did 
your respiratory symptoms stop you from performing your usual daily activities?', each 
with scores from 0 (no problems) to 4 (very severe problems) 
• the total daily symptom score, defined as the sum of the nighttime score ('How often 
were you woken up by your asthma during the night?' with scores from 0 - 4), the 
morning awakening score ('Did you have asthma symptoms upon awakening in the 
morning?' with scores from 0 - 4) and the mean daytime asthma symptom score. The 
sum will be in the range of 0 – 12. 
• day with no daytime symptoms, i.e., all 5 evening questions must have a score = 0. 
However, a patient will not be considered symptom free if they have used rescue 
medication that day even if his/her total daytime symptoms score is zero. 
• night with no night-time awakenings, i.e., the question How often were you woken up 
by your asthma during the night?' must be answered with 'I did not wake up because of 
any breathing problems'  


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• morning with no symptoms on awakening, i.e., the question 'Did you have asthma 
symptoms upon awakening in the morning?' to be answered with 'None' 
• asthma symptoms free days, i.e., days with no daytime symptoms and no night-time 
awakenings and no symptoms on awakening 
Daily scores will be averaged for each patient over the days of the run-in period (which will be 
used as the baseline value) and the 2 weeks double-blind period. Specifically, the average score 
is defined as the sum of daily scores divided by the number of days where e-Diary records have 
been made on night time/morning/daytime score for the time period of interest. Days with no 
daytime symptoms, nights with no night-time awakenings, mornings with no symptoms on 
awakening, and days with no asthma symptoms will be expressed in percentage of days with 
data during the respective periods where diary recordings have been made. The same periods 
as for average scores will be analyzed for percentage of days. For post-baseline periods only 
the days on double-blind treatment will be considered. In addition, changes from baseline will 
be summarized as well. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Spirometry 
Spirometry measurements taken within 7 days of systemic corticosteroid use, within 6 hours of 
rescue medication use or if the actual measurement times are outside the 22-30 hour post 
morning dose time window, then the individual FEV1 value will be set to missing and not be 
imputed, unless specified otherwise. For all spirometry measurements, implausible values will 
be excluded. If a patient has implausible FEV1 value (defined as > 7 L) at an assessment, all 
spirometry measurements related to that assessment will be excluded. The threshold of 7 L was 
chosen because according to Polgar child predicted values, the maximum normal predicted 
FEV1 is 5.42 L, we set 7 L as the implausible cutoff to allow for some fluctuation around the 
maximum mean. 
Rescue Medication 
No explicit imputation will be done for missing data. 
Each night time use will be based on the data recorded in the 12h prior to the morning 
assessment and each daytime use will be based on the data recorded the 12h prior to the evening 
assessment. Where the number of puffs of rescue medication is missing but the rest of the e-
Diary has non-missing data, the number of puffs will be assumed to be zero. 
The daily total number of puffs of rescue medication will be divided by the total number of 
days with non-missing rescue data to derive the mean daily number of puffs of rescue 
medication taken for the patient for each given time interval.  If the number of puffs is missing 
for part of the day (either morning or evening) then a half day will be used in the denominator. 
The non-missing data within the time period of interest will be used to calculate the mean value, 
as long as there are at least 7 days with non-missing data within a the time period. 
Asthma symptoms based on e-Diary 
Unless otherwise specified, no daily value for diary symptom score will be explicitly imputed. 


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The non-missing data within the time period of interest will be used to calculate the mean value, 
as long as there are at least 7 days with non-missing e-diary data within the time period. 
E-Diary data recorded during the run-in period (visits 101-199) will be used to calculate the 
baseline values, as long as there is at least 7 days (e.g. 7 days) of non-missing data available. 
Otherwise, the baseline will be set as missing.  
Peak Expiratory Flow (PEF) Rate 
No explicit imputation will be done for missing data. The non-missing data within the time 
period of interest will be used to calculate the mean value, as long as there are at least 7 days 
with non-missing data within a the time period. 
2.8 
Safety analyses 
All safety parameters will be summarized on the safety set. 
2.8.1 
Adverse events (AEs) 
All adverse events including asthma exacerbations, coded with MedDRA using the most actual 
version at the time of database lock, will be summarized and listed. In general, summaries will 
include treatment-emergent adverse events only, i.e., those starting on or after the time of the 
first administration of study drug but not later than 7 days (30 days in the case of a SAE) after 
the last study drug administration. Any adverse events that started during the study before the 
time of the first inhalation of study drug of the first period will be classified as a prior adverse 
event.  
The number and percentage of patients who reported treatment-emergent adverse events will 
be summarized by primary system organ class, preferred term, and treatment for 
• all adverse events 
• all adverse events by maximum severity 
• adverse events suspected to be related to study drug 
• adverse events leading to permanent study drug discontinuation 
• serious adverse events 
• fatal adverse events 
• adverse events of special interest 
Unless otherwise specified, primary system organ classes will be sorted alphabetically and, 
within each primary system organ class, the preferred terms will be sorted in descending order 
of frequency in the indacaterol acetate 75 μg treatment group. If a patient reported more than 
one adverse event with the same preferred term, the adverse event with the greatest severity 
will be presented. If a patient reported more than one adverse event within the same primary 
system organ class, the patient will be counted only once at the system organ class level, where 
applicable. 
In addition, the number and percentage of patients with the most frequent AEs will be 
summarized by treatment, in descending order of frequency in the indacaterol acetate 75 μg 
treatment group. 


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For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
x% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.  
2.8.1.1 
Adverse events of special interest  
 
The Compound Case Retrieval Strategy (CRS) will be used to determine the MedDRA search 
criteria to be used to identify events of special interest. The most recent list of adverse events 
of special interest at the time of database lock will be used. 
2.8.2 
Laboratory data 
All laboratory samples will be processed through the central laboratory. Laboratory data consist 
of hematology, biochemistry and urinalysis measurements. All data will be listed with abnormal 
values being flagged. 
Laboratory data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
The following analyses will be performed by treatment: 
• absolute values and change from baseline summarized for continuous laboratory 
parameters by visit 
• frequency table of results for categorical laboratory parameters by visit 
• shift tables relative to the normal reference ranges summarizing the change from 
baseline to post-baseline by visit for each continuous laboratory parameter 
• shift tables from baseline to post-baseline by visit for categorical laboratory parameters 
• the number and percentage of patients with newly occurring or worsening laboratory 
abnormalities meeting the clinically notable criteria (see Appendix 5.7 for definition of 
notable values) summarized by laboratory parameter, scheduled post-baseline visit and 


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additionally at any time on treatment considering all post-baseline data from scheduled, 
unscheduled and premature discontinuation visits 
 Serum potassium and blood glucose at all visits will be summarized. All data will be included 
in the analysis regardless of rescue medication usage. 
For a patient to meet the criterion of a newly occurring clinically notable value, the patient 
needs to have a baseline value that is not clinically notable for that parameter. For a patient to 
meet the criterion of a worsening clinically notable value, the patient needs to have a baseline 
value that is clinically notable and also have a worse post-baseline value. For patients with 
missing baseline value, any post-baseline notable value will be considered as newly occurring. 
A listing of all patients with notable laboratory values will be provided. 
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) at any time post-baseline will be summarized by 
treatment based on the following criteria: 
Notable liver function test values  
Criterion 
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin > 1 x ULN 
Total bilirubin > 1.5 x ULN 
Total bilirubin > 2 x ULN 
Total bilirubin > 3 x ULN 
ALP > 1.5 x ULN 
ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 


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ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP  < 2 x ULN (Hy's law) 
ALT or AST > 3 x ULN and (nausea or vomiting or fatigue or general malaise or abdominal pain or (rash and eosinophilia))* 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
* Based on the signs/symptoms information as recorded on the liver events eCRF, not the adverse events eCRF. 
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur at the same time (i.e., within the same sample). A 
case where all criteria are met at a post-baseline time point will be considered as newly 
occurring if the criteria are not met at baseline and will be considered as worsening if the criteria 
are met at baseline and at least one component is worsening from baseline irrespective of 
whether the other(s) are better. 
Listings of patients with clinically notable LFT values will be provided. 
2.8.3 
Other safety data 
2.8.3.1 
ECG and cardiac imaging data 
ECG measurements include heart rate, QT interval, RR interval, PR interval, QRS duration, and 
QTc (calculated using Fridericia’s formula as QTcF = QT / 3√ RR (in seconds), where 3√ 
denotes the cube root). Furthermore, an overall interpretation of the central cardiologist will be 
provided as well as a specification of abnormal findings. 
ECG data measured more than 7 days after last inhalation of study drug are regarded as 
posttreatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
The following analyses will be performed by treatment: 
• absolute values and change from baseline summarized by parameter, visit and time 
point. The by-visit/time point summaries will include the maximum QTcF and 
maximum heart rate (even if from post-baseline unscheduled and premature 
discontinuation visits, if not measured more than 7 days after last dose). 
• the number and percentage of patients with newly occurring or worsening notable QTcF 
values (see Appendix 5.8 for definition of notable values) summarized by scheduled 
post-baseline visit and time point and additionally at any time on treatment considering 
all post-baseline data from scheduled, unscheduled and premature discontinuation visits 
• In addition to notable QTcF values, the number and percentage of patients with newly 
occurring or worsening QTcF values > 450 msec and >480 msec and change from 
baseline 0-30, >30 msec will be summarized by scheduled post-baseline visit and time 
point and additionally at any time on treatment considering all post-baseline data from 
scheduled, unscheduled and premature discontinuation visits. 
• frequency table of results for overall ECG interpretation (normal, abnormal) by visit and 
time point and with shift tables from baseline to the worst interpretation during treatment 


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• the number and percentage of patients with ECG abnormalities summarized by 
evaluation type, abnormality finding, visit and time point. In addition, the number and 
percentage of patients with newly occurring or persistent/recurrent ECG abnormalities 
at any time point over the treatment period (considering all post-baseline data from 
scheduled, unscheduled and premature discontinuation visits) will be summarized by 
evaluation type and abnormality finding 
The same approach as for notable laboratory values will be used to define a newly occurring 
notable QTc value and a worsening notable QTc value.  
A listing of all patients with notable QTc values and changes will be provided. 
2.8.3.2 
Vital signs 
Vital signs measurements include systolic and diastolic blood pressure (SBP and DBP), radical 
pulse rate, and body weight. 
Vital signs data measured more than 7 days after last inhalation of study drug are regarded as 
post-treatment data and will not be summarized, only listed. All data will be included in the 
analyses regardless of rescue medication use. 
Weight will be summarized by visit and treatment group. Changes from baseline will also be 
summarized by treatment. The baseline measurement will be the measurement at Visit 101. 
The following analyses will be performed by treatment: 
• absolute values and change from baseline summarized by parameter, visit and time 
point. The by-visit/time point summaries will include the maximum and minimum post-
baseline SBP, DBP, and pulse rate values (even if from post-baseline unscheduled and 
premature discontinuation visits, if not measured more than 7 days after last dose). 
• the number and percentage of patients by parameter, visit and time point with 
• pulse rate < 40 bpm, 40 – 90 bpm, and > 90 bpm 
• SBP < 90 mm Hg, 90 – 140 mm Hg, and > 140 mm Hg 
• DBP < 50 mm Hg, 50 – 90 mm Hg, and > 90 mm Hg 
• the number and percentage of patients with newly occurring or worsening notable vital 
signs values (see Appendix 5.8 for definition of notable values) summarized by 
parameter, scheduled post-baseline visit and time point and additionally at any time on 
treatment considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits 
The same approach as for notable laboratory values will be used to define a newly occurring 
notable vital sign value and a worsening notable vital sign value. 
A listing of all patients with notable vital sign values and changes will be provided. 
2.9 
Pharmacokinetic endpoints   
For PK concentration data, listings and descriptive statistics will be provided. The descriptive 
statistics will comprise arithmetic and geometric means, SD, geometric CV, median, minimum 


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and maximum for plasma indacaterol concentrations at pre-dose (<2 hours) and at 15 min and 
1 hour post-dose at Visit 199/201 and 299. Plasma concentrations will be expressed in pg/mL 
units. All concentrations below the lower limit of quantification or missing data will be labeled 
as such in the concentration data listings. Concentrations below the lower limit of quantification 
will be treated as zero in summary statistics of concentration data.. 
2.10 
PD and PK/PD analyses 
Not applicable. 
2.11 
Interim analysis 
No interim analyses are planned for this study. 
3 
Sample size calculation 
The sample size of 72 patients evaluable for the primary endpoint in the study is based on 
pragmatic considerations and per agreement with EU Pediatric Committee (PDCO), not based 
on statistical considerations. It is assumed that approximately 10% of patients will not complete 
the trial so that 80 patients need to be randomized to ensure 72 patients will be evaluable for 
the primary endpoint.   
4 
Change to protocol specified analyses 
The study protocol planned a summary analysis on plasma cortisol and smoking exposure. As 
plasma cortisol and smoking exposure data will not be collected, this analysis will not be 
conducted.  
The study protocol planned to summarize concomitant asthma related medications by 
pharmacological (ATC) class and preferred term and concomitant medications not related to 
asthma by ATC class. To be consistent with other studies under QVM program, which the study 
CQMF149G2202 is part of, asthma medications will be summarized by the route of 
administration, the recorded pre-specified drug subcategories (including types of combination) 
and the coded preferred terms. The summary will be repeated by showing ingredients instead 
of preferred terms. Non-asthma medications will be summarized by route of administration and 
preferred term.  
For primary endpoint it is described in the protocol that trough measurements outside the 22 - 
25 hour window will not be considered for the analysis. This time window will be extended to 
a time window of 22 - 30 hours. A broader time window is considered appropriate given the 
known half-life of Indacaterol, which ranges from 40-56 hours and supports once daily 
administration. This also provides a reasonable time window for parents of school age children 
to schedule visits in which spirometry is assessed. A supportive analysis will be performed 
using the initial time window of 22 - 25 hours.  
For consistency with QVM pivotal trials QTc time will be analyzed using Fridericia's formula 
and not Bazett. 


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5 
Appendix 
5.1 
Imputation rules 
The general approach to handling missing dates is shown below for dates of AEs, medical 
history diagnosis, and concomitant treatment. The imputation of missing dates for surgery or 
procedures will use the same rules as for concomitant treatment. 
The detailed algorithms will appear in Programming Dataset Specifications (PDS).  
5.1.1 
Study drug 
Missing date and time of study treatment will not be imputed for this study.  
5.1.2 
AE date imputation 
Rules for imputing AE end date or start date will be provided in PDS document in details. 
5.1.3 
Concomitant medication date imputation 
Rules for imputing the CM end date or start date will be provided in PDS document in details. 
5.2 
AEs coding/grading 
The MedDRA version which will be available at the time of database lock, will be used for the 
coding purpose of the adverse events. 
5.3 
Statistical models 
Not applicable as no inferential analyses will be conducted.  
5.4 
Rule of exclusion criteria of analysis sets  
The following table provides the protocol deviations (PD) and other criteria leading to partial 
or complete exclusion from analyses sets 
 
Deviation 
ID 
Description of Deviation 
Deviations leading to exclusion from all analyses sets 
INCL02 
Patient entered the study without signing the informed consent. 
EXCL09 
Parent/guardian has a history of psychiatric disease/intellectual deficiency, substance 
abuse, or other condition which limits the validity of consent for their child to participate. 
Deviations leading to exclusion from RAN, FAS and PPS 
OTH05 
Patient received study drug before or without randomization. 
Deviations leading to exclusion from FAS, PPS and Safety 
OTH04 
Patient randomized but did not receive study drug. 
Deviations leading to exclusion from FAS and PPS 


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Deviation 
ID 
Description of Deviation 
OTH03 
Patient randomized in error, randomized more than once in this study, randomized in 
another study, randomized in wrong study. 
Deviations leading to exclusion from PPS 
INCL01 
Age < 6 years or greater than equal to 12 years or missing 
INCL03 
No documented diagnosis of Asthma for at least 1 year prior to study enrollment 
INCL04 
Patient not receiving daily treatment with ICS or ICS/LABA according to study 
requirements. 
INCL05 
Patient with a pre-bronchodilator FEV1 < 50% or > 90% of the predicted normal value, 
or spirometry not performed as per protocol or missing at the start and/or end of Run-
in (Visits 101 and 199). 
INCL06 
Reversibility test is negative or missing or not performed as per protocol. 
INCL08 
Parents/ legal guardian not willing or able to assist the child with the procedures 
outlined in the protocol, eg. completion of electronic patient diary. 
INCL09 
Patient not able to use Concept1 dry powder inhaler or be proficient in use of other 
study devices (including those used during Run-in), or complete spirometry 
procedures. 
EXCL01 
Patient taking a mid-dose ICS (per GINA guidelines) in combination with LABA or high 
dose ICS. 
EXCL03a 
Patient who had more than 3 separate asthma attack/exacerbation in the 12 months 
prior to visit 1 or 1 asthma attack/exacerbation within 3 months prior to Visit 1 
EXCL03b 
Patient had an exacerbation requiring SCS/hospitalization or emergency room visit 
within 3 months prior to Visit 1 or > than 3 separate exacerbations in the 12 months 
prior to Visit 1. 
EXCL04 
Patient who had suspected or documented bacterial or viral infection of the upper or 
lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 
1. 
EXCL05 
Patients who has prior intubation for asthma. 
EXCL06 
Patient not able to be compliant with study requirements or has any medical or mental 
disorder, situation, or diagnosis which could interfere with the proper completion of the 
study. 
EXCL13 
Patient is an immediate family member of the participating investigator, sub-
investigator, study coordinator or employee of the participating investigator. 
EXCL15 
Any chronic condition of the respiratory tract which in the opinion of the investigator 
may interfere with study evaluation or optimal participation in the study. 
EXCL16 
History of chronic lung disease other than asthma within 3 months of V101 or other 
infection listed on. 
EXCL25 
Patients that receive immunotherapy or desensitization for allergies that started within 
3 months prior to Visit 101 or where the maintenance dose is expected to change 
during the study. 


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Deviation 
ID 
Description of Deviation 
EXCL27 
Patients that received treatment with any investigational agent within 30 days of 
Screening. 
COMD01 
LABA b.i.d taken within 48 hours prior to visit 101 
COMD02 
LABA o.d continuing at visit 1 
COMD03 
LAMA taken less than 7 days prior to Visit 101 
COMD04 
SAMA taken less than 8 hours prior to visit 101 
COMD05 
Fixed combinations of short-acting β2-agonist and short-acting anticholinergic taken 
within 8 hours prior to Visit 101. 
COMD07 
Short Acting B2 Agonist, other than Salbutamol / Albuterol is not discontinued after 
visit 1. 
COMD08 
Intra-muscular depot corticosteroids taken within 3 months prior to Run in 101 
COMD09 
Systemic (Parenteral or oral) corticosteroids taken within 3 months prior to run in 101 
COMD10 
Immunoglobin E inhibitors taken 6 months prior to visit 101 
COMD11 
Xanthines taken within 7 days prior to Run In 101 
COMD12 
Systemic mast cell stabilizers taken within 7 days prior to Run in visit 101 
OTH01 
Patient not having correct run in medication (i.e. 100mcg accuhaler or 125 mcg via 
MDI inhaler). 
OTH02 
Patient 
not 
taking 
run 
in 
medication 
as 
per 
protocol. 
(At least one dose less or more is missed by the subject)  
OTH07 
Patient took study drug not as per protocol. 
OTH08 
Patient received wrong treatment or expired drug. 
WTH01 
Patient remains on study treatment even after discontinuation and/or withdrawal on 
patient's or parent/legal guardian's wish. 
WTH05 
Patient experienced moderate or severe exacerbation according to Section 6.5.7 of 
study protocol, and not discontinued from study 
WTH15 
Blind broken and study treatment not permanently discontinued. 
Deviations leading to exclusion of data collected after occurence of that event, from all 
analyses set 
WTH16 
Study procedures performed after withdrawing of informed consent. 
 
5.5 
Baseline definitions 
In general, baseline is defined as the last measurement before the first dose of study drug at Day 
1. Detailed baseline definitions for diary data, vital signs, height and weight, ECG, laboratory 
data,  ACQ-IA, FEV1, and FVC are provided below. 


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• For patient diary data (PEF, symptoms, and rescue medication use), the baseline 
values are defined as the average from all non-missing records taken in the run-in period 
over 14 days from Visit 101 up to the morning assessment at date of first dose of study 
drug (i.e., from Day -14 to Day 1 morning assessment inclusively). Missing diary data 
will not be imputed. If a patient has less than 7 days with non-missing data, then the 
respective baseline value will be set to missing. 
• Vital signs include pulse rate (measured as radial pulse for 60 seconds) and systolic and 
diastolic blood pressures. Baseline vital signs are defined as the last scheduled 
assessment taken pre-dose on Day 1. Checks may be performed to ensure the 
assessments were indeed taken prior to the first dose of study drug on Day 1.  If this 
assessment is missing or not confirmed to be pre-dose, the last value prior to the first 
dose will be used for baseline. Otherwise, the vital sign baseline will be set to missing 
without imputation. 
• Height and weight are defined as the measurements taken at Visit 199. If the value is 
missing, then the value from Visit 101 will be used.  
• ECG is defined as the last scheduled assessment (≤ -2 hr) taken prior to the first dose 
of study drug on Day 1. Checks will be performed to ensure the ECG was indeed 
assessed prior to the first dose of study drug. If the value on Day 1 is missing (or not 
confirmed to be pre-dose) then the last value prior to the first dose will be used for 
baseline. Otherwise, the ECG baseline will be set to missing without imputation. For 
baseline ECG interpretation there will only be one assessment at each time-point, and 
hence this will be used as the baseline ECG interpretation (pre-dose Day 1 value if 
present and confirmed to be pre-dose, otherwise the last value prior to the first dose). 
• Laboratory data include hematology, clinical chemistry, urinalysis and 
hepatotoxicity. Baseline is defined as the last scheduled assessment taken prior to first 
dose of study drug on Day 1. Checks will be performed to ensure baseline laboratory 
values were indeed assessed pre-dose. If the pre-dose measurement on Day 1 is 
missing (or was not confirmed to be pre-dose), then the last value prior to the first 
dose may be used. Otherwise, the baseline laboratory data will be set to missing.  
• ACQ-IA score is defined as ACQ-IA scores obtained on Day 1 (Visit 199). If the 
ACQ-IA score on Day 1 is missing then the last available ACQ-IA score prior to Day 
1 will be used. 
• FEV1 is defined as average of the last FEV1 assessments taken at 45 minutes and 15 
minutes prior to the first dose of study drug (Day 1, Visit 201). If any one of these 
assessments is missing (or is not confirmed to be pre-dose), then the remaining non-
missing observation will be considered as baseline. If both assessments are missing (or 
are not confirmed to be pre-dose) then the last available average of the FEV1 
assessments prior to Day 1 will be used for baseline. If the FEV1 measurements are 
missing on Day 1 and at the run-in visit, the respective baseline values will be set to 
missing. Measurements taken within 6 hours of rescue use or within 7 days of systemic 
corticosteroid use will be set to missing. For all spirometry measurements, implausible 
values will be excluded. If a patient has implausible FEV1 value (defined as > 7 L) at 
an assessment, all spirometry measurements related to that assessment will be excluded. 


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The threshold of 7 L was chosen because according to Polgar child predicted values, the 
maximum normal predicted FEV1 is 5.42 L, we set 7 L as the implausible cutoff to 
allow for some fluctuation around the maximum mean. 
• FVC is derived in a similar way as baseline FEV1.  
5.6 
Laboratory parameters – definition of clinically notable values 
 
The following table shows the criteria for clinically notable laboratory values. Not all 
parameters have notable criteria defined. 
Clinical notable criteria for selected laboratory tests  
Laboratory parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of clinically 
notable range 
Hematology 
 
 
Hematocrit (v/v)) 
     Male 
     Female 
 
0.34 
0.31 
 
 
Hemoglobin (g/L) 
    Male 
    Female 
 
108 
90 
 
 
Thrombocytes (x10E9/L 
75  
700 
WBC’s (x10E9/L) 
2.4 
16.0 
Chemistry 
 
 
Alkaline Phosphatase (U/L) 
- 
2xULN 
Total Bilirubin (umol/L) 
- 
35.9 
Creatinine (umol/L) 
 
132.6 
Potassium (mmol/L) 
3 
6 
Glucose (mmol/L) 
2.78 
11.10 
SGOT (U/L) 
- 
3 x ULN 
SGPT (U/L) 
- 
3 x ULN 
BUN/Serum Urea (mmol/L) 
 
10.71 
Albumin (g/L) 
 
 
10 
70 
Gamma GT (U/L) 
 
3 x ULN 
Magnesium (mmol/L) 
0.51 
1.07 
v = volume, ULN = upper limit of normal  


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5.7 
Vital signs and ECG – definition of clinically notable values 
The following table shows the clinical notable criteria for vital signs. 
Clinical notable criteria for vital signs 
Vital sign parameter (unit) 
Lower bound of clinically 
notable range 
Upper bound of clinically 
notable range 
Notable Value 
Systolic blood pressure (mmHg) 
≤ 80 mmHg (6-8 years) or ≤ 
85 mmHg (9-11 years) and 
decrease from baseline ≥ 20 
mmHg  
≥ 115 mmHg (6-8 years) 
or ≥ 120 mmHg (9-11 
years) and increase from 
baseline ≥ 20 mmHg 
Diastolic blood pressure (mmHg) 
≤ 40 mmHg (6-8 years) or ≤ 
45 mmHg (9-11 years) and 
decrease from baseline ≥ 20 
mmHg 
≥ 75 mmHg (6-8 years) or 
≥ 80 mmHg (9-11 years) 
and increase from 
baseline ≥ 20 mmHg 
Pulse rate (bpm) 
Low” criterion: decrease 
from baseline ≥ 25% to a 
value < 70 bpm (6-8 years) 
or < 60 bpm (9-11 years) 
increase from baseline 
≥ 25% to a value > 115 bpm 
(6-8 years) or > 110 bpm (9-
11 years) (according to 
internal draft ECQ_QT 
Guidelines) 
 
 
Notable QT values are defined as QTc increases of 30-60 and >60 ms, and QTc >500 ms. 
6 
Reference 
Polgar child predicted values for FEV1 (https://vitalograph.com/resources/ers-normal-values)