Conditions: Asthma
Keywords: QMF149 mometasone furoate indacaterol pediatric asthma PK
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: no

Brief summary:
This clinical study was designed to assess the pharmacokinetics, safety and tolerability of single inhaled doses of mometasone furoate (MF) when administered alone via MF Twisthaler® (TH) or as an indacaterol acetate/MF fixed dose combination (QMF149) via the Concept 1 (C1) device in pediatric asthma patients.

Detailed description:
This study was an open-label, two-period, single-sequence crossover study that consisted of four distinct study periods:

* Screening: Participants underwent a screening period of up to 14 days where were assessed for eligibility.
* First Treatment: On the first treatment visit (Day 1) participants received a single inhaled dose of 100 μg MF administered via the TH device followed by a 4-7-day washout period.
* Second Treatment: On the second treatment visit (Day 6-9) participants received a single inhaled dose of 75/40 μg indacaterol acetate/MF fixed dose combination (FDC) (QMF149) via C1 (Breezhaler®) device. Participants were allowed to use rescue medication (as needed) and potentially their Standard of Care (SoC) asthma therapy (excluding MF and indacaterol acetate).
* Safety Follow-up: Upon completion of the treatment period, participants were followed up for safety assessments for 30 days.

Arms:
arm 1: Single inhaled dose of mometasone furoate on Day 1 delivered via TH inhaler followed by 4-7 days of washout. On Day 6-9, single inhaled dose of QMF149 delivered via C1 inhaler.

Interventions: intervention 1: Mometasone furoate intervention 2: QMF149 intervention 3: Standard of Care (Soc)
Intervention descriptions: intervention 1: Single inhaled dose of 100 µg mometasone furoate (MF) administered via Twisthaler® on Day 1 intervention 2: Single inhaled dose of QMF149 (75/40 µg indacaterol acetate/MF fixed dose combination) administered via Concept 1 device on Day 6-9 intervention 3: Asthma therapy: budesonide and salbutamol being the most frequently used (excluding MF and indacaterol acetate)

Protocol document:
Prot_000.pdf: 


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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.................................................................................................................9
Amendment 1 ....................................................................................................................11
Amendment rationale ........................................................................................................11
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................16
1.1
Background............................................................................................................16
1.2
Purpose ..................................................................................................................18
2
Objectives and endpoints...................................................................................................18
3
Study design ......................................................................................................................18
3.1.1
Study design..........................................................................................19
4
Rationale............................................................................................................................19
4.1
Rationale for study design .....................................................................................19
4.1.1
Rationale for choice of background therapy.........................................20
4.2
Rationale for dose/regimen and duration of treatment ..........................................20
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................21
4.4
Purpose and timing of interim analyses/design adaptations..................................21
4.5
Risks and benefits..................................................................................................21
5
Study Population ...............................................................................................................22
5.1
Inclusion criteria ....................................................................................................22
5.2
Exclusion criteria...................................................................................................23
6
Treatment...........................................................................................................................25
6.1
Study treatment......................................................................................................25
6.1.1
Investigational and control drugs..........................................................25
6.1.2
Additional study treatments ..................................................................26
6.1.3
Supply of study treatment .....................................................................26
6.1.4
Treatment arms/group ...........................................................................26
6.1.5
Treatment duration................................................................................26
6.2
Other treatment(s)..................................................................................................26
6.2.1
Concomitant therapy.............................................................................26
6.2.2
Prohibited medication ...........................................................................27


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6.2.3
Rescue medication ................................................................................28
6.3
Participant numbering, treatment assignment, randomization ..............................28
6.3.1
Participant numbering...........................................................................28
6.3.2
Treatment assignment, randomization ..................................................28
6.4
Treatment blinding.................................................................................................28
6.5
Dose escalation and dose modification..................................................................28
6.5.1
Dose modifications................................................................................28
6.5.2
Follow-up for toxicities.........................................................................29
6.6
Additional treatment guidance...............................................................................30
6.6.1
Treatment compliance...........................................................................30
6.6.2
Recommended treatment of adverse events..........................................30
6.7
Preparation and dispensation.................................................................................30
6.7.1
Handling of study treatment and additional treatment..........................31
6.7.2
Instruction for prescribing and taking study treatment .........................32
7
Informed consent procedures ............................................................................................32
8
Visit schedule and assessments .........................................................................................33
8.1
Screening ...............................................................................................................36
8.1.1
Information to be collected on screening failures.................................36
8.2
Participant demographics/other baseline characteristics .......................................36
8.3
Efficacy..................................................................................................................36
8.4
Safety.....................................................................................................................36
8.4.1
Laboratory evaluations..........................................................................37
8.4.2
Electrocardiogram (ECG) .....................................................................38
8.4.3
Pregnancy and assessments of fertility .................................................39
8.4.4
Appropriateness of safety measurements..............................................39
8.5
Additional assessments..........................................................................................39
8.5.1
Pharmacokinetics ..................................................................................40
9
Study discontinuation and completion ..............................................................................40
9.1
Discontinuation and completion............................................................................40
9.1.1
Study treatment discontinuation and study discontinuation..................41
9.1.2
Withdrawal of informed consent...........................................................42
9.1.3
Lost to follow-up...................................................................................43
9.1.4
Early study termination by the sponsor.................................................43
9.2
Study completion and post-study treatment ..........................................................43
10 Safety monitoring and reporting........................................................................................44
10.1
Definition of adverse events and reporting requirements......................................44


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10.1.1
Adverse events ......................................................................................44
10.1.2
Serious adverse events ..........................................................................45
10.1.3
SAE reporting........................................................................................46
10.1.4
Pregnancy reporting ..............................................................................47
10.1.5
Reporting of study treatment errors including misuse/abuse................47
10.1.6
Concept 1 related adverse event reporting............................................48
10.2
Additional Safety Monitoring................................................................................48
10.2.1
Liver safety monitoring.........................................................................48
11 Data Collection and Database management......................................................................49
11.1
Data collection.......................................................................................................49
11.2
Database management and quality control............................................................50
11.3
Site monitoring ......................................................................................................50
12 Data analysis and statistical methods ................................................................................51
12.1
Analysis sets ..........................................................................................................51
12.2
Participant demographics and other baseline characteristics.................................51
12.3
Treatments .............................................................................................................51
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................51
12.4.1
Definition of primary endpoint(s).........................................................52
12.4.2
Statistical model, hypothesis, and method of analysis..........................52
12.4.3
Handling of missing values not related to intercurrent event ...............52
12.5
Analysis of secondary endpoints/estimands..........................................................52
12.5.1
Safety endpoints....................................................................................52
12.5.2
Pharmacokinetics ..................................................................................53
12.6
Analysis of exploratory endpoints.........................................................................54
12.7
Interim analyses.....................................................................................................54
12.8
Sample size calculation..........................................................................................54
12.8.1
Primary endpoint(s)...............................................................................54
13 Ethical considerations and administrative procedures ......................................................54
13.1
Regulatory and ethical compliance........................................................................54
13.2
Responsibilities of the investigator and IRB/IEC..................................................54
13.3
Publication of study protocol and results...............................................................55
13.4
Quality Control and Quality Assurance.................................................................55
14 Protocol adherence ............................................................................................................55
14.1
Protocol amendments.............................................................................................56
15 References .........................................................................................................................57
16 Appendices ........................................................................................................................58


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16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................58
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements ..........................................................................................................59
16.3
Appendix 3: Blood volumes..................................................................................62
16.4
Appendix 4: Pharmacokinetic/Vital signs/ECG/Lab assessment timed 
schedule on Days 1 and 6 ......................................................................................63
List of tables
Table 2-1
Objectives and related endpoints ..........................................................18
Table 6-1
Investigational and control drug............................................................25
Table 6-2
Prohibited medications..........................................................................27
Table 6-3
Hepatic Disease Assessment.................................................................29
Table 8-1
Assessment Schedule ............................................................................34
Table 8-2
Safety assessments ................................................................................37
Table 8-3
Laboratory evaluations..........................................................................37
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................48
Table 12-1
Non-compartmental pharmacokinetic parameters ................................53
Table 16-1
Liver event and laboratory trigger definitions ......................................59
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms ..............................................................................................59
Table 16-3
Follow up requirements for liver laboratory triggers............................60
Table 16-4
Blood volume........................................................................................62
Table 16-5
PK/VS/ECG/Lab Assessments..............................................................63
List of figures
Figure 3-1
...............................................................................................................19


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List of abbreviations
AAMH
Australian Asthma Management Handbook
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANA
Antinuclear antibody
ASMA
Anti-smooth muscle antibodies
AST
Aspartate Aminotransferase
AV
atrioventricular
b.i.d.
bis in die/twice a day
BUN
Blood Urea Nitrogen
C1
Concept 1 (Breezhaler®)
CD
Carbohydrate-deficient
CDS
Core Data Sheet
CFR
US Code of Federal Regulations
CHF
Congestive heart failure
CK
Creatinine Kinase
CMV
Cytomegalovirus
CO
Country Organization
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTT
Clinical Trial Team
CV
coefficient of variation
CVD
Cardiovascular disease
CYP3A
Cytochrome P450 3A
DILI
Drug-induced liver injury
DNA
Deoxyribonucleic acid
DOB
Date of Birth
DRF
Dose Range Finding
EBV
Epstein-Barr virus
ECG
Electrocardiogram
EDC
Electronic Data Capture
EDD
Expected Delivery Date
EDTA
Ethylenediaminetetraacetic acid
EMA
European Medicines Agency
ERCP
Endoscopic Retrograde Cholangiopancreatography
eSource
Electronic Source
FDC
Fixed dose combinations
FPF
fine particle fraction
FPM
fine particle mass


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GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GINA
Global Initiative for Asthma
GLDH
Glutamate dehydrogenase
h
Hour
HAV
Hepatitis A virus
HBc
Hepatitis B core
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HEV
Hepatitis E virus
HSV
Herpes simplex virus
IA
Interim Analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
ICON
International Consensus On pediatric asthma
ICS
Inhaled corticosteroid
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long Acting ß-Agonist
LAMA
Long Acting Muscarinic Antagonist
LC-MS/MS
Liquid Chromatography-Mass Spectrometry/Mass Spectrometry
LFT
Liver function test 
LLOQ
lower limit of quantification
LTRA
Leukotriene Receptor Antagonist
MCV
Mean Corpuscular Volume
MDDPI
multi-dose dry powder inhaler
MedDRA
Medical dictionary for regulatory activities 
MF
Mometasone furoate
mg
milligram(s)
mL
milliliter(s)
MMWR
Morbidity and Mortality Weekly Report
MRI
Magnetic resonance imaging


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NAEPP
National Asthma Education and Prevention Program
NIH
National Institutes of Health
OTC
Over-the-counter
PK
Pharmacokinetic(s)
PT
prothrombin time
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RBC
red blood cell(s)
RNA
Ribonucleic acid
SABA
short-acting ß-agonist
SAE
Serious Adverse Event
SAMA
Short-acting anti-muscarinic
SARS-CoV-
2 
Severe Acute Respiratory Syndrome Coronavirus 2
SD
standard deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SIGN
Scottish Intercollegiate Guidelines Network
SoC
Standard of care
SUSAR
Suspected Unexpected Serious Adverse Reaction
T3
Triiodothyronine
T4
Thyroxine
TBL
Total bilirubin
TH
Twisthaler®
TSH
Thyroid stimulating hormone
UDDPI
Unit dose dry powder inhaler
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent
γ-GT
Gamma-glutamyl transferase
COVID-19
Coronavirus Disease
IND
Indacaterol


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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same time
Control drug
A study drug (active or placebo) 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
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days)
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 
capture data transcribed from paper source forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which informed consent must 
be obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate
Estimand
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication 
number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)


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Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 
and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Run-in Failure
A participant who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to participant’s intervention or 
other treatment)
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data 


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Amendment 1
Amendment rationale
The protocol is being amended to correct the details regarding the Lab assessments, blood 
sampling and to include the early termination visit assessment details.
Changes to the protocol
The following changes will be implemented in the protocol:

Section 8: The details have been modified to specify the reference to early termination 
visit column in assessment table.

Table 8-1: Additional column for early termination visit included to maintain 
consistency with Section 9.1.1 of protocol which states early termination visit would be 
performed in case of discontinuation.

Table 8-3: Included ‘sodium’ as additional parameter for Chemistry assessment.

Section 8.5.1: Updated EDTA tubes to Lithium Heparin tubes for Blood collection for 
IND analysis.

Table 16-4: Updated the Blood volume.

Table 16-5: Updated the table to include assessment details of early termination visit.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through for deletions and underlining for insertions.
An opportunity was also taken to make smaller changes such as some minor editorial changes 
that include correction of typographical errors and some clarifications in wording and acronyms.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. In addition, if the changes 
herein affect the Informed Consent, sites are required to update and submit for approval a 
revised Informed Consent that takes into account the changes described in this amended
protocol.
Protocol summary
Protocol number
CQMF149G2203


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Full Title
An open-label, two-period, single-sequence, crossover study to compare the 
systemic exposure of a single inhaled dose of mometasone furoate (MF) 
when administered alone via the MF Twisthaler® (TH) to a single inhaled 
dose of QMF149 indacaterol acetate/MF fixed dose combination when 
administered via the Concept 1 (Breezhaler®) device in ≥ 6 to <12 year old 
asthma patients
Brief title
This study in pediatric patients with asthma ages ≥ 6 to < 12 years of age 
compares the pharmacokinetics of mometasone furoate administered alone 
and in fixed dose combination with indacaterol.
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug; Device: Inhaled dose of mometasone furoate (MF) via MF Twisthaler®
(TH), inhaled dose of QMF149 indacaterol acetate/MF fixed dose 
combination via the Concept 1 Breezhaler® (C1) device
Study type
Interventional
Purpose and 
rationale
The measurement of systemic exposure to MF delivered by either TH or C1 
(in combination with indacaterol) is expected to provide an appropriate 
assessment of drug delivery to the lungs to support dose selection of MF as 
part of QMF149. This study will confirm the comparability of mometasone 
exposure between two formulations and support the QMF149 pediatric 
development program.
Primary Objective(s) 
To compare the systemic exposure of MF resulting from single doses of 
MF when administered as MF TH 100 μg versus QMF149 75/40 μg C1.
Secondary 
Objectives
To determine safety and tolerability of QMF149 C1 following its single dose 
administration in pediatric patients with asthma.
To determine the systemic exposure of indacaterol following single dose 
administration as QMF149 C1.
Study design
This is an open-label, two-period, single-sequence crossover study including 
2 single dose treatments of MF TH 100 μg and QMF149 75/40 μg with a 
washout of at least 4 days between the two treatments. The study will enroll 
approximately 32 patients with the aim of having 24 completers.
The study will include the following:

A screening period of up to 14 days

Two single-dose treatments separated by a 4-7 day washout period (4 
days is the minimum washout)

A 30-day investigational drug-free follow-up period
Study population
Approximately 32 male or female children ≥ 6 years and <12 years 
diagnosed with asthma will be screened, 24 study completers are required 
for analysis unless interim analysis determines otherwise.
Inclusion criteria
1.
Male and female children ≥ 6 years and < 12 years at the time of study 
entry.
2.
Written informed consent by parent(s)/legal guardian(s) for the pediatric 
patient and assent by the pediatric patient (depending on local 


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requirements) must be obtained before any study-specific assessment is 
performed.
3.
Confirmed documented diagnosis of asthma, as defined by national or 
international asthma guidelines for at least 6 months prior to study 
enrollment.
4.
Patients using low dose ICS as asthma controller therapy for at least 4 
weeks prior to first treatment.
5.
Patients who are familiar with the use of an inhaler device.
6.
Patients must be able to comply with the Study Visit Assessment 
Schedule which includes approximately 7 hours on two occasions, and 
agree to blood draws as scheduled.
7.
Parents/ legal guardian must be willing and able to attend study visits 
and assist the child with the procedures outlined in the protocol.
Exclusion criteria
1.
Use of other investigational drugs within 5 half-lives of enrollment, or 
[within 30 days (for small molecules) /until the expected 
pharmacodynamic effect has returned to baseline (for biologics)], 
whichever is longer.
2.
Patients with weight < 17kg at screening.
3.
Patients currently taking MF products for any reason at least 7 days prior 
to Day 1. Patients can enroll if MF was discontinued at least 7 days prior 
to Day 1 and MF is substituted with a different steroid during entire study 
duration to avoid its potential impact on PK assessment. These MF 
products include inhalation, topical and/or nasal spray formulations.
4.
Patients on medium- and high- dose ICS or any dose ICS/LABA 
combination.
5.
Patients taking maintenance controller therapy (eg LABAs and 
theophylline) within 4 weeks of screening or during the study as outlined 
in Section 6.2. LTRAs are permitted provided that patients have been on 
a stable dose for 4 weeks prior to screening. Patients using short-acting 
bronchodilators on occasional basis as rescue medication can enroll, 
however, these medications must be withheld at least 8 hours prior to 
study dosing visits and during PK sampling (please refer to Table 6-2).
6.
Contraindicated for treatment with, or having a history of 
reactions/hypersensitivity to any of the following inhaled drugs, drugs of 
a similar class, or any component there of: 

Adrenoreceptor agonist agent

Lactose or any of the other excipients of the study drug (including 
patients with history of galactose intolerance, lactase deficiency or 
glucose-galactose malabsorption)

Corticosteroids

Indacaterol and/or MF
7.
History of chronic lung disease other than asthma within 3 months of first 
treatment visit (Day 1), cystic fibrosis, mycobacterial or other infection 
(including active SARS-CoV-2, tuberculosis or atypical mycobacterial 
disease).
8.
History of active bacterial, viral or fungal infection (including SARS-CoV-
2) within 6 weeks of first treatment visit (Day 1).
9.
Patients who have had an asthma attack/exacerbation requiring 
systemic steroids or hospitalization or emergency room visit within 6 
weeks of first treatment visit (Day 1).


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10. Patients who, in the opinion of the investigator, are not able to comply 
with study treatment or who have any medical or mental disorder, 
situation, or diagnosis, which could interfere with the proper completion 
of the study protocol requirements or pose a safety risk while 
participating in the study.
11. 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.
12. Hemoglobin levels outside normal ranges at screening.
13. Any surgical or medical condition which might significantly alter the 
absorption, distribution, metabolism, or excretion of drugs, or which may 
jeopardize the patient in case of participation in the study.
14. Patients who have a clinically significant ECG abnormality or clinically 
significant abnormal lab values reported at Screening Visit.
15. Patients with a history of long QT syndrome or whose corrected QT 
interval (QTc) measured at Screening Visit (Fridericia method) is 
prolonged (≥ 450 msec for males and females 6 - 12 years old).
16. Use of any prescription drugs, herbal supplements, prescribed medicinal 
use of cannabis/marijuana, within four weeks prior to initial dosing, 
and/or over-the-counter (OTC) medication, dietary supplements within 
two weeks prior to initial dosing. If needed, (i.e. an incidental and limited 
need) paracetamol/acetaminophen is acceptable, but must be 
documented in the Concomitant medications / Significant non-drug 
therapies page of the CRF.
17. History of malignancy of any organ system, treated or untreated, within 
the past 5 years, regardless of whether there is evidence of local 
recurrence or metastases.
18. Patient is an immediate family member of the participating investigator, 
sub-investigator, study coordinator, or employee of the participating 
investigator.
19. Pregnant or nursing (lactating) females.
20. Inability to properly train in the use of the In-Check DIAL® at screening 
(at the investigator's discretion).
21. Inability to properly train in the use of the Twisthaler® or Concept 1 
Breezhaler® prior to dosing (at the investigator's discretion).
22. History of paradoxical bronchospasm in response to inhaled medicines.
23. Patients receiving any medications in the classes specified 
in Table 6-2 unless they undergo the required washout period prior to 
Day 1.
24. Patients who are sexually active.
Study treatment
Treatment A: MF Twisthaler® 100 μg
Treatment B: QMF149 Concept 1 Breezhaler® (indacaterol acetate 75 μg/MF 
40 μg)
Efficacy 
assessments
None
Pharmacodynamic 
assessments 
None


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Pharmacokinetic 
assessments 
The following parameters will be calculated for MF

AUC0-6h

Cmax

Tmax

AUCinf

Lambda_z

T1/2

CL/F

Vz/F
Key safety 
assessments
Adverse event monitoring, physical examinations, monitoring of laboratory 
markers in blood and urine, ECG.
Data analysis
The primary objective is to compare the systemic exposure to MF resulting 
from single doses of MF when administered as MF TH 100 μg versus 
QMF149 75/40 μg C1.
Log-transformed PK parameters Cmax and AUC(0-6h) will be analyzed for 
mometasone furoate by linear fixed effects model with treatment and patient 
as fixed effect. The estimated mean and 90% confidence interval of treatment 
difference of test vs. reference (QMF149 vs. MF) will be back transformed to 
obtain the geometric mean and 90% confidence intervals of the ratio.
Interim analysis
An interim analysis is planned to be performed when 12 patients complete 
both study treatments and there are at least 3 completers in each of the two 
age groups ≥ 6 to < 9 year olds and ≥ 9 to < 12 year olds. The interim 
analysis will be based on preliminary PK and safety data.
Key words
QMF149, pediatric, asthma, PK, Twisthaler®, Concept 1, Breezhaler®


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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 2019). 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 2019). 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 2019). 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 it's 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 stepwise 
intensification of asthma controller medications. Combinations of different controller 
medications are recommended as preferred treatment options by various guidelines (NIH, 
GINA, ICON).


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Fixed dose combinations (FDC) products containing a LABA plus 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 
(Greening et al 1994, Woolcock et al 1996, 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.
QMF149 is a fixed-dose combination (FDC) of indacaterol acetate (inhaled LABA with 24 hour 
duration of action) and mometasone furoate (MF, ICS). QMF149 is approved as maintenance 
treatment of asthma in adults and adolescents 12 years of age and older not adequately 
controlled with inhaled corticosteroids and inhaled short acting beta2 agonists. There are three 
approved dose strengths of QMF in adult and adolescent patients with asthma: 150/80 μg, 
150/160 μg, 150/320 μg. A pediatric dose of QMF149 75/40 μg delivered via Concept 1 device 
is currently being developed as a unit dose dry powder inhaler for children 6 to <12 years of 
age. The individual components of QMF149 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 4-11 year old pediatric patients (Asmanex Twisthaler®).
Studies CQMF149E2203 and CQAB149B2357 evaluated indacaterol acetate and maleate, 
respectively delivered via the Concept 1 (Breezhaler®) inhaler in patients with asthma. These 
two studies support selection of indacaterol dose 150 µg once daily in the adult and adolescent 
population.
Study CQMF149G2202 in children ≥ 6 years and < 12 years showed that indacaterol acetate 
(QAB149) 75 µg and 150 μg o.d. doses delivered via Concept 1 inhaler with background ICS 
therapy demonstrated clinically meaningful improvements in Trough FEV1 after 14 days of 
treatment. Both doses were well tolerated and no new or unexpected safety signals were 
observed in the study. Systemic exposure at the 75 µg dose was lower than that observed at the 
150 µg dose in adults from other studies, while the 150µg dose in 6-11 year olds was higher 
than that observed in adults. Overall, the data supported 75 µg as reasonable dose for further 
evaluation in Phase III.
MF TH 100 µg is a metered dose dry powder inhaler approved as Asmanex Twisthaler®1 for 4-
11 yr old asthma patients.
Fraction of an aerosol containing particles < 5 μm in diameter is termed the fine particle fraction 
(FPF), and is widely used to describe the potential of an aerosol for delivery to the lower 
respiratory tract (Dolovich 2000). The fine particle mass (FPM), is the mass portion of the 
nominal dose (i.e. nominal dose × FPF), which is considered to be delivered to the lungs. MF 
dose for QMF149 75/40 µg is matched in terms of its FPM (in vitro lung dose) at the 
corresponding 100 µg MF TH. Systemic availability of MF following oral inhalation is solely 
due to absorption from lungs since oral bioavailability of MF is low. The FPM of mometasone 
furoate in QMF149 75/40 μg is matched with MF TH 100 μg. Comparisons of QMF149 75/40 
µg delivered via C1 versus MF TH 100 µg in the proposed PK study would compare lung dose 


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of MF between both formulations and build confidence in dose selection of MF in QMF149 
75/40 µg based on data in patient population. Results from the study will provide opportunity 
to re-evaluate doses/formulation if needed before proceeding to a larger Phase III study in 
children.
1 A single dose of the Asmanex Twisthaler® contains 110 μg of mometasone furoate delivering 
100 μg of mometasone furoate from the inhaler mouthpiece following actuation.
1.2
Purpose
The purpose of this study is to assess the dose exposure of MF as part of QMF149 Concept 1 
that provides systemic exposure comparable to that for the approved dose of MF TH 100 µg in 
pediatric asthma patients (≥ 6 to < 12 years of age). The safety and tolerability of single orally 
inhaled doses of QMF149 75/40 µg will also be evaluated when administered via the Concept 1 
in this age group. The selected dose will then be studied in a QMF149 Phase III pediatric study.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary 
objective(s)

To compare the systemic exposure of mometasone 
furoate resulting from single orally inhaled doses of 
QMF149 75/40 µg administered via the Concept 1 unit 
dose dry powder inhaler versus the MF Twisthaler® 100 
µg metered dose dry powder inhaler in pediatric asthma 
patients (≥ 6 to < 12 years of age).

PK parameters (AUC0-6h and 
Cmax) of MF after single dose 
administration of QMF149 
75/40 µg C1 and MF 
Twisthaler® (100 µg).
Secondary objective(s)
Endpoint(s) for secondary 
objective(s)

To evaluate the systemic exposure of indacaterol 
resulting from single orally inhaled doses of QMF149 
75/40 µg.

Systemic exposure of 
indacaterol after single dose 
administration of QMF149 
75/40 µg.

To evaluate the safety and tolerability of QMF149 75/40 
µg after single dose administration in pediatric patients.

Adverse Events, Serious 
Adverse Events and defined 
safety assessments.
3
Study design


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Figure 3-1
3.1.1
Study design
This is an open-label, two-period, single-sequence, crossover study to assess the 
pharmacokinetics, safety and tolerability of single inhaled doses of mometasone furoate (MF) 
when administered alone via MF Twisthaler® (TH) or as an indacaterol acetate/MF fixed dose 
combination (QMF149) via the Concept 1 (C1) device in ≥ 6 to <12 year old asthma patients. 
The study includes two open-label single-dose treatment visits. On the first treatment visit (Day 
1) patients receive a single inhaled dose of 100 µg MF administered via the Twisthaler® device. 
On the second treatment visit (Day 6) patients receive a single inhaled dose of 75/40 µg 
indacaterol acetate/MF fixed dose combination (QMF149). Both treatments are in addition to 
their rescue medication and potentially SoC asthma therapy (excluding MF and indacaterol 
acetate).
Patients currently taking low-dose ICS asthma medications other than MF can enroll in the 
study. However, since the patients will be provided MF or QMF149 as part of study treatment 
on Day 1 and Day 6 respectively, patients should be instructed not to take low-dose ICS 
medication on the 2 treatment days.
The study will include the following:

A screening period of up to 14 days

Two single-dose treatment periods separated by a 4-7 day washout period (4 days is 
minimum washout)

A 30-day investigational drug-free follow-up period
4
Rationale
4.1
Rationale for study design
This is an open-label, two-period, single-sequence, crossover study in 24 asthma patients aged 
≥ 6 to <12 years. The trial is designed to compare the systemic exposure of single inhaled doses 
of mometasone furoate (MF) when administered alone as MF TH 100 µg or as an indacaterol 
acetate/MF fixed dose combination (QMF149 75/40 µg) via the Concept 1 (C1) device.
Blood samples for assessment of MF concentrations will be collected from pre-dose to 6 hours 
after each dose of MF TH or QMF149 C1. Based on data in CQMF149E2101, blood collection 
up to 6 hours is considered adequate since the MF PK parameter AUC0-6h is projected to be 


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approximately 40-50% of AUC0-24h after single inhalation dose of MF TH or QMF149 
Concept 1. This provides reasonable data for comparison of the two formulations.  Since the 
Tmax of MF is approximately 1h post inhalation dose of MF TH or QMF149 C1, the planned 
PK sampling schedule allows reliable assessment of Cmax for comparative assessment of both 
formulations.
Single-dose assessment is preferred as it is a more sensitive marker to measure bioavailability. 
The crossover study design is favored to assess relative bioavailability between two 
formulations as each patient serves as his/her own matched control, thereby requiring fewer 
patients to attain the same level of statistical power or precision as a parallel design. Single-
sequence crossover design including administration of MF TH in the first treatment period 
followed by QMF149 administration in the second treatment period enables a shorter washout 
duration of 4 days based on MF T1/2 (mean: 12-13 hr) following MF administration via TH or 
C1 in adult healthy volunteers.
This study planned in ≥ 6 to < 12 years old pediatric asthma patients will confirm the 
comaparability of mometasome exposure between two formulations and support the QMF149 
pediatric development program. Due to ethical considerations, healthy volunteers in this 
pediatric age group are not being considered. A study in adult healthy volunteers was not 
considered due to the difficulty in extrapolation of PK data of inhaled therapies from adults to 
pediatric patients resulting from differences in inhalation pattern, lung and airway geometry, 
and surface area between both age groups.
4.1.1
Rationale for choice of background therapy
Patients may continue to receive their background asthma therapy (e.g. low dose ICS) 
throughout the study . Since the purpose of the study is to assess PK, safety and tolerability of 
QMF149 there is no need to alter the background medication (with the exception of 
mometasone furoate and those listed on Table 6-2). Background treatments of low dose ICS 
are not anticipated to have potential for drug-drug interaction with either QMF149 or MF TH. 
Strong CYP3A inhibitor or inducer medications should be discontinued at least 7 days prior to 
both study treatments. Further information on prohibited medications are outlined in Table 6-2.
4.2
Rationale for dose/regimen and duration of treatment
QMF149 75/40 μg is a fixed dose combination of indacaterol 75 μg and mometasone furoate 
40 μg intended for children (≥ 6 - < 12 years old) and planned for testing in Phase 3 study. 
While the 75 μg dose level of indacaterol was determined from a DRF study (QMF149G2202), 
the 40 μg dose level for MF is planned based on equivalent lung dose of QMF149 C1 to MF 
TH 100 μg. MF TH 100 μg is used as a comparator to QMF149 C1 for evaluation of systemic 
exposure of mometasone.
A single-dose assessment is preferred as it is a more sensitive marker to measure bioavailability. 
Mouth rinsing is recommended to reduce the potential incidence of oral candidiasis in the 
presence of MF. A washout duration of at least 4 days allows complete washout of MF 
concentrations prior to subsequent QMF149 treatment based on a mean T1/2 of 12-13 hr. 
following MF administration via TH or C1 in adult healthy volunteers (Study QMF149E2101).


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As noted the single-sequence crossover design including administration of MF TH in the first 
treatment period followed by QMF149 administration in the second treatment period enables a 
shorter washout duration of 4 days between treatments.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Placebo control is not required as it does not support the primary pharmacokinetic endpoint.
4.4
Purpose and timing of interim analyses/design adaptations
A planned interim analysis (IA) will be conducted to support decision making when 12 patients 
have completed both treatment visits (MF TH 100 μg and QMF149 75/40 μg) with all planned 
PK and safety data collected. There must be at least 3 patients within each age strata ≥ 6 to < 9 
years and ≥9 to < 12 years for the IA to occur. At interim analysis, PK data and safety data 
will be assessed and a decision will be made to either stop the study or proceed forward to full 
recruitment. This decision will depend on the ability to confirm the MF dose, or if more data is 
needed (possibly due to study performance, e.g., the need for better patient training).
For detailed information, refer to Section 12.7
4.5
Risks and benefits
This is a single-dose study evaluating the phamacokinetics and safety of MF from MF TH and 
QMF149; there are no efficacy evaluations being assessed in this study. Assessing the 
pharmacokinetic profile is an important step in establishing overall benefit/risk for the pediatric 
population.
The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
by close clinical monitoring.
Data from this study will confirm if the MF dose in the QMF149 pediatric formulation is similar 
to the approved MF TH pediatric dose (100 µg daily). The confirmed dose will be used to 
support the QMF149 pediatric development program allowing for the evaluation of efficacy in 
a larger pediatric population.
QMF149 150/80 µg, QMF149 150/160 µg, and QMF149 150/320 µg strengths have been 
approved for use in adult and adolescent asthma patients (QVM149B2301 and QVM149B2303) 
and the risk to pediatric patients exposed to QMF149 75/40 µg in this study is considered low. 
Inhaled doses of 75μg and 150 μg/day of indacaterol administered via the Concept 1 device for 
14 days were well tolerated (CQMF149G2202) in ≥ 6 to <12 year old asthma patients and MF 
TH 100 µg is already approved as a maintenance treatment of asthma in this pediatric patient 
population. In the studies mentioned above, risks associated with indacaterol were consistent 
with what is known in the LABA class.
LABA treatments used alone without ICS in asthma may cause severe asthma exacerbations. 
This safety concern is mitigated in the study as LABA alone will not be allowed to the patients 
and instead it is administered together with ICS MF as a FDC product QMF149.


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Potential safety risk to pediatric patients in the study is minimized by using a single dose 
inhalation of QMF149 75/40 µg for assessment of MF pharmacokinetic profile and by 
adherence to the inclusion/exclusion criteria and close clinical monitoring of vital signs on day 
of dosing and safety follow up. Patients may continue to receive their background asthma 
therapy (with the exception of those listed in Table 6-2) 
For female patients of childbearing potential refer to Section 8.4.3.
The risks of side effects are well characterized in adult and adolescent population with asthma 
from the QMF149 studies mentioned above. 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 9.1.1. 
There is no placebo arm, which mitigates risk of under-treatment.
Pediatric patients participating in the trial may have a small risk of oral and esophageal 
candidiasis (thrush), a known adverse effect of MF. The risk of this will be minimized by rinsing 
of the oral cavity after each dosing. Systemic effects may occur with inhaled corticosteroids, 
particularly at high doses prescribed for prolonged periods while the present study is prescribing 
a single dose of QMF149 and MF. These effects are much less likely to occur than with oral 
corticosteroids and may vary in individual patients and between different corticosteroid 
preparations.
Asthma patients may be at higher risk of complications from the SARS-CoV-2 infection. Since 
this study requires clinic visits there maybe an increased risk for transmission of SARS-CoV-
2. Clinical sites must take all necessary hygienic measures to avoid infection.
5
Study Population
The study population will consist of 24 male or female children ≥ 6 years and < 12 years of age 
with a documented diagnosis of asthma for at least 6 months prior to study enrollment. Patients 
may use rescue medication (e.g., SABA) with or without asthma controller therapy. It is 
intended that approximately 32 patients will need to be enrolled to yield 24 patients who each 
complete the 2 dosing PK collection study visits. Dropouts and non-completers will be replaced 
if needed. Patients will be stratified into two age groups; ≥ 6 to < 9 years and ≥ 9 to < 12 years 
(at least 6 patients in each of the two age groups) to ensure approximate equal enrollment and 
PK assessment across the entire desired age range.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Male and female children ≥ 6 years and < 12 years at the time of study entry.
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.
3. Confirmed documented diagnosis of asthma, as defined by national or international 
asthma guidelines for at least 6 months prior to study enrollment.


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4. Patients using low-dose ICS as asthma controller therapy for at least 4 weeks prior to first 
treatment.
5. Patients who are familiar with the use of inhaler device.
6. Patients must be able to comply with the Study Visit Assessment Schedule which includes 
approximately 7 hours on two occasions, and agree to blood draws as scheduled.
7. Parents/ legal guardian must be willing and able to attend study visits and assist the child 
with the procedures outlined in the protocol.
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Use of other investigational drugs within 5 half-lives of enrollment, or [within 30 days (for 
small molecules) /until the expected pharmacodynamic effect has returned to baseline (for 
biologics)], whichever is longer.
2. Patients with weight < 17kg at screening.
3. Patients currently taking MF products for any reason at least 7 days prior to Day 1. 
Patients can enroll if MF was discontinued at least 7 days prior to Day 1 and MF is 
substituted with a different steroid during entire study duration to avoid its potential 
impact on PK assessment. These MF products include inhalation, topical and/or nasal 
spray formulations.
4. Patients on medium- and high- dose ICS or any dose ICS/LABA combination.
5. Patients taking maintenance controller therapy (eg LABAs and theophylline) within 4 
weeks of screening or during the study as outlined in Section 6.2. LTRAs are permitted 
provided that patients have been on a stable dose for 4 weeks prior to screening. Patients 
using short-acting bronchodilators on occasional basis as rescue medication can enroll, 
however, these medications must be withheld at least 8 hours prior to study dosing visits 
and during PK sampling (please refer to Table 6-2).
6. Contraindicated for treatment with, or having a history of reactions/hypersensitivity to any 
of the following inhaled drugs, drugs of a similar class, or any component there of: 

Adrenoreceptor agonist agent

Lactose or any of the other excipients of the study drug (including patients with 
history of galactose intolerance, lactase deficiency or glucose-galactose 
malabsorption)

Corticosteroids

Indacaterol and/or MF
7. History of chronic lung disease other than asthma within 3 months of first treatment visit 
(Day 1), cystic fibrosis, mycobacterial or other infection (including active SARS-CoV-
2, tuberculosis or atypical mycobacterial disease).
8. History of active bacterial, viral or fungal infection (including SARS-CoV-2) within 6 
weeks of first treatment visit (Day 1).
9. Patients who have had an asthma attack/exacerbation requiring systemic steroids or 
hospitalization or emergency room visit within 6 weeks of first treatment visit (Day 1).


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10. Patients who, in the opinion of the investigator, are not able to comply with study 
treatment or who have any medical or mental disorder, situation, or diagnosis, which 
could interfere with the proper completion of the study protocol requirements or pose a 
safety risk while participating in the study.
11. 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
12. Hemoglobin levels outside normal ranges at screening.
13. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the patient in 
case of participation in the study.
14. Patients who have a clinically significant ECG abnormality or clinically significant 
abnormal lab values reported at Screening Visit.
15. Patients with a history of long QT syndrome or whose corrected QT interval (QTc) 
measured at Screening Visit (Fridericia method) is prolonged (≥ 450 msec for males and 
females 6 - 12 years old).
16. Use of any prescription drugs, herbal supplements, prescribed medicinal use of 
cannabis/marijuana, within four weeks prior to initial dosing, and/or over-the-counter 
(OTC) medication, dietary supplements within two weeks prior to initial dosing. If 
needed, (i.e. an incidental and limited need) paracetamol/acetaminophen is acceptable, but 
must be documented in the Concomitant medications / Significant non-drug therapies page 
of the CRF.
17. History of malignancy of any organ system, treated or untreated, within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases.
18. Patient is an immediate family member of the participating investigator, sub-investigator, 
study coordinator, or employee of the participating investigator.
19. Pregnant or nursing (lactating) females.
20. Inability to properly train in the use of the In-Check DIAL® at screening (at the 
investigator's discretion)
21. Inability to properly train in the use of the Twisthaler® or Concept1 Breezhaler® prior to 
dosing (at the investigator's discretion).
22. History of paradoxical bronchospasm in response to inhaled medicines.
23. Patients receiving any medications in the classes specified in Table 6-2 unless they 
undergo the required washout period prior to Day 1.
24. Patients who are sexually active.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug 
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation
Sponsor (global
or local)
QMF149 75/40 
μg
Capsule for 
Inhalation
Oral inhalation
Open-label blister 
delivered via C1 
device 
(Breezhaler®)
Sponsor (global)
Mometasone 
fuorate
1101 μg
Dry Powder 
Inhalation
Oral inhalation
Open-label 
Twisthaler®
(metered dose 
inhaler)
Sponsor (global)
1 A single dose of the Asmanex Twisthaler® contains 110 μg of mometasone furoate delivering 100 μg 
of mometasone furoate from the inhaler mouthpiece following single actuation.
The Twisthaler® inhaler is a multi-dose dry powder inhaler (MDDPI), with all doses pre-loaded 
in the device. The Concept 1 Breezhaler® device is a unit dose dry powder inhaler (UDDPI), 
which requires loading of the dose prior to each use. The following medication/devices will be 
prepared by Novartis and supplied to the Investigator as open labeled medication:

Treatment A: Mometasone furoate delivered via Twisthaler®inhaler, (MF 100μg TH)

Treatment B: Fixed dose combination of 75 μg indacaterol acetate and 40 μg mometasone
furoate delivered as powder in hard capsules via Concept1 Breezhaler® inhaler (QMF149 
75/40 μg C1)
Under no circumstances is an alternative inhalation device to be used for the administration of 
either study medication during the treatment period. Additionally, the use of spacers is not 
permitted in this study.
Study medication should be administered to patients in the morning between the hours of 07:00 
am and 12:00 noon, on Days 1 and 6. After inhalation of study medication, patients should rinse 
their mouth with water. Water used for mouth rinsing should be spat out and NOT swallowed. 
Patients are encouraged to consume a small snack approximately 1 hour post-dose and a meal 
approximately 4 hours post-dose. Snack and meal times should be recorded on the CRF and 
food content should be recorded in source documents.
On the day of screening (Screening Visit), patients will be instructed to inhale through the In-
Check DIAL® inhalation training device which will simulate inhalation resistance from the 
Asmanex Twisthaler® and C1 Breezhaler® devices. On treatment Day 1, patients will be trained 
in the use of MF Twisthaler® (Asmanex) device with a training Twisthaler® device which does 
not contain inhalation powder. On Treatment Day 6, patients will be trained on the use of C1 
(Breezhaler®) device loaded with an empty capsule which does not contain inhalation powder.


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All inhalation device training should be documented in source. Training with inhalation devices 
at Days 1 and 6 will be followed by actual study drug administration.
The devices containing study medication that will be used for dosing will be IRT assigned. At 
the investigator's discretion, patients who cannot demonstrate an appropriate inhalation 
maneuver at the screening visit should not be enrolled in the study. Patients will be instructed 
by study personnel on the correct inhalation technique and dosing instructions for the device. 
Dosing will be supervised by the site personnel. Study drug supply and dispensation instructions 
are provided in Section 6.1.3. Instructions for inhalation training and use of both the 
Twisthaler® and the Concept 1 devices are provided in the QMF149G2203 Patient Inhalation
Training, Device Training and Study Drug Administration Manual.
6.1.2
Additional study treatments
No other study treatment beyond MF 100 μg Twisthaler® and QMF149 75/40 μg C1 
Breezhaler® are included in this trial.
6.1.3
Supply of study treatment
MF TH 100 will be supplied by Novartis and labeled in accordance to local country 
requirements. QMF149 75/40 μg will be supplied by Novartis and labeled in accordance to local 
country requirements.
Day 6 study medication QMF149 75/40 μg (administered using the C1 device) must be stored 
under refrigeration. This dose must be brought to room temperature at least one hour prior to 
patient dosing.
6.1.4
Treatment arms/group
All patients will receive an inhaled single dose of MF TH 100 μg on Day 1 and an inhaled single 
dose of QMF149 75/40 μg on Day 6 .
6.1.5
Treatment duration
The planned treatment is 1 treatment, single dose each for MF 100 μg TH and QMF149 75/40 
μg. For patients that discontinue from treatment, refer to Section 9.1.1.
6.2
Other treatment(s)
No additional treatment beyond investigational drug is included in this trial. Patients may 
continue to use asthma rescue medication and SoC asthma therapy as outlined in the inclusion 
criteria.
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered within 30-days prior to enrolment and after the patient was 
enrolled into the study must be recorded on the appropriate Case Report Forms.
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 


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assigning the study treatment to patient or allowing a new medication to be started. If the patient 
is already enrolled, contact Novartis to determine if the patient should continue participation in 
the study.
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. 
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Prohibited asthma-related medications, as listed in Table 6-2, must not be taken during the study. 
The specified minimum washout periods are described in Table 6-2. 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 including a 
patient or allowing a new medication to be started.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are either prohibited or allowed only under 
certain conditions.
This table is not considered all-inclusive. Medications listed should be assessed for adherence 
to the indication and other inclusion/exclusion criteria.
Table 6-2
Prohibited medications
Prohibited Medication
Instruction
Fixed combinations of short-acting β2-agonist 
and short-acting anticholinergics
Must be discontinued at least 8 hours prior to 
dosing on treatment day 1.
Medium and high-dose ICS and ICS/LABA 
combinations
Patients taking these treatments are excluded 
per Exclusion 4 (Section 5.2)
Asthma maintenance controller therapies (e.g. 
LABAs and theophylline)
Patients taking these medications within 4 
weeks of screening or during the study are 
excluded per Exclusion 5 (Section 5.2)
Salbutamol/albuterol (SABA) and
Short-acting anti-muscarinic (SAMA)
It should be noted that SABA and SAMA are 
permitted at screening and between dosing 
visits, as required for rescue medication.
SABA/SAMA must be withheld at least 8 
hours prior to study dosing visits and during 
PK sampling. If SABA/SAMA is taken within 8 
hours of a clinic visit, the clinic should be 
notified and the visit rescheduled. 
Inhaled, topical, or nasal steroid therapies 
containing MF (investigator to provide alternative 
medications)
Must be discontinued at least 7 days prior to 
dosing on treatment day 1
Any drug with the potential to prolong QT
Interval
14 days or 5 half-lives, whichever is longer prior 
to dosing visits


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Prohibited Medication
Instruction
Strong inhibitors and inducers of cytochrome 
CYP3A
7 days prior to dosing visits
Noradrenaline reuptake inhibitors
7 days prior to dosing visits
Other investigational drugs
30 days or 5 half-lives, whichever is longer prior 
to dosing visits
6.2.3
Rescue medication
It should be noted that SABA and SAMA are permitted at screening and between dosing visits, 
as required for rescue medication.
SABA/SAMA must be withheld at least 8 hours prior to study dosing visits and during 
PK sampling. If SABA/SAMA is taken within 8 hours of a clinic visit, the clinic should be 
notified and the visit rescheduled.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is enrolled for screening and is retained for the patient throughout his/her 
participation in the trial. A new Patient No. will be assigned at every subsequent enrollment if 
the patient is re-screened. The Patient No. consists of the Center Number (Center No.) (as 
assigned by Novartis to the investigative site) with a sequential Patient Number suffixed to it, 
so that each patient’s participation is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Patient No. 
available.
A new ICF/patient assent will need to be signed if the investigator chooses to re-screen the 
patient after a patient has screen failed, and the patient will be assigned a new Patient No.
6.3.2
Treatment assignment, randomization
Patient randomization will not be performed in this open-label study. The assignment of a 
patient to a particular age strata will be coordinated by the sponsor via IRT.
6.4
Treatment blinding
Treatment will be open to patients, investigator staff, persons performing the assessments, and 
the CTT.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.5.1
Dose modifications
Study drug dose adjustments and/or interruptions are not permitted.


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6.5.2
Follow-up for toxicities
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin increase may be indicative of 
potentially severe DILI, and should be considered as clinically important events and assessed 
appropriately to establish the diagnosis. The required clinical information, as detailed below, 
should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and total 
bilirubin value; patients meeting any of the following criteria will require further follow-up as 
outlined below:

For patients with normal ALT and AST and total bilirubin value at baseline: AST or ALT 
> 3.0 x ULN combined with total bilirubin > 2.0 x ULN

For patients with elevated AST or ALT or total bilirubin value at baseline: [AST or ALT > 
2 x baseline] OR [AST or ALT >300 U/L] whichever occurs first combined with [total 
bilirubin > 2 x baseline AND > 2.0 x ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase. If available, 
testing of Glutamate Dehydrogenase (GLDH) is additionally recommended.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 
may be less specific than ALP as a marker of cholestatic injury, since GGT can also be elevated 
by enzyme induction or by ethanol consumption. It is more sensitive than ALP for detecting 
bile duct injury.
Table 6-3 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities.
Table 6-3
Hepatic Disease Assessment
Disease
Assesment
Hepatitis A, B, C, E

IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV


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Disease
Assesment
Autoimmune hepatitis

Antinuclear Antibodies (ANA) & Anti-Smooth Muscle Antibody 
(ASMA) titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic Congestive heart failure, 
hypotension, hypoxia, hepatic venous occlusion. Ultrasound 
or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)

Ceruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; Cardiovascular Disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis).
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented.
Refer to Section 10.2.1 for further liver safety monitoring.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Treatment in this study will only be given on-site under the supervision of study site staff. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all patients 
treated with both MF 100 μg Twisthaler® and QMF149 75/40 μg C1 Breezhaler®, as detailed 
in Pharmacokinetics Section 8.5.1.
6.6.2
Recommended treatment of adverse events
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
6.7
Preparation and dispensation
Each study site will be supplied with packed study drug as described under investigational and 
control drugs section (Section 6.1.1).


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A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the patient by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the patient, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. QMF149 75/40 μg is stored refrigerated at 5°C+/- 3°C. This medication kit has to 
be taken out of the refrigerator a minimum 1 hour in advance of inhalation to allow medication 
and Concept 1 device to equilibrate to room temperature. Asmanex Twisthaler® 100 mcg is 
stored in accordance to the labeled storage condition, "Do not store above 25°C. Do not 
refrigerate. Do not freeze. Protect from moisture".
Study site staff should refer to QMF149G2203 Patient Inhalation Training and Study Drug 
Administration Manual in preparation for inhalation training and study medication 
administration.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
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 designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels or in the Investigator’s Brochure. QMF149 75/40 μg will be 
delivered refrigerated at 5°C+/- 3°C. The medication kit must be removed from refrigeration at 
least 1 hour in advance of administration allowing the medication and Concept 1 device to 
equilibirate to room temperature. Asmanex Twisthaler® 100 mcg must be stored according to 
the labeled storage condition, "Do not store above 25°C. Do not refrigerate. Do not freeze. 
Protect from moisture." Asmanex Twisthaler® 100 mcg is delivered in a carton box containing 
the inhaler in an aluminum foil pouch. This protective pouch should be opened only on the day 
of dosing.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO 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.
After use both inhalation devices should be stored at the site until the conclusion of the study. 
At the conclusion 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.


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6.7.2
Instruction for prescribing and taking study treatment
Patients will be instructed to come to the study center accounting for an appropriate amount of 
time to complete inhalation training and predosing assessments prior to study drug 
administration. On Day 6 the clinical site needs to ensure QMF149 75/40 μg will be removed 
from refrigeration and brought to room temperature at least one hour prior to patient dosing. 
It should be noted that SABA and SAMA are permitted at screening and between dosing visits, 
as required for rescue medication.
SABA/SAMA must be withheld at least 8 hours prior to study dosing visits and during 
PK sampling. If SABA/SAMA is taken within 8 hours of a clinic visit, the clinic should be 
notified and the visit rescheduled.
Patients currently taking low-dose ICS asthma medications other than MF are permitted to 
enroll in the study however these patients should be instructed not to take low-dose ICS 
medication on the two treatment days since MF or QMF149 will be provided as part of study 
treatment on Day 1 and Day 6 respectively. Patients taking medium and/or high dose ICS are 
excluded from the study.
After inhalation of study drug patients should rinse their mouth with water. Water used for 
mouth rinsing should be spat out and NOT swallowed. If after inhalation of study drug the 
patient sneezes, coughs, vomits or exhibits rejection of inhaled study drug, the event and timing 
relative to dosing must be documented in source. Patients who have not received or retained a 
full dose of study drug cannot be re-dosed during a study visit and should be discontinued. 
All patients will be trained in the use of Concept 1 and Twisthaler® devices per QMF149G2203 
Patient Inhalation Training and Study Drug Administration Manual. Patients must demonstrate 
correct use of both inhalation devices prior to study medication dosing. Inhalation training 
devices  will be supplied by Novartis. On both treatment days, the study drug will be 
administered at the study center, after completion of all pre-dose procedures. The date and time 
of dose administration of study drug at each site visit will be recorded on the Dosage 
Administration Record CRF. 
7
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the patient. 
Patients below the legal age of consent are required to have the Parental Informed Consent 
signed by the patient’s parent(s)/guardian(s); and are required to sign the Assent Form 
(according to locally accepted policy/practice).
In cases where the patient’s representative(s) 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 


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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.
Female patients 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.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) (and/or CDS for marketed drugs). 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 investigational 
drug that is identified between IB updates will be communicated as appropriate, for example, 
via an investigator notification or an aggregate safety finding. New information might require 
an update to the informed 
consent 
and 
then must be discussed 
with the 
patient/parent(s)/guardian(s).
The following informed consents are included in this study:

Main study consent (parental/guardian consent)

Patient assent, which also includes as applicable: 

Pregnancy Outcomes Reporting Consent for female patient
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the patient’s source documentation.
Patients should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. 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 all of the 
assessments listed in the Early Termination visit column of the assessment schedule table will 
be performed. At this final visit all adverse event and concomitant medications should be 
recorded on the CRF.
For patients already started Day 1, the COVID 19 pandemic (or any other reason) may limit or 
prevent an on-site study visit(s). These patients should be discontinued and a phone or virtual 
visit will occur for safety monitoring and discussion of the patient´s health status including 30 
days safety follow up. If the patient can attend the Early Termination visit after Day 1, safety 
monitoring, discussion of the patient´s health status, and urine pregnancy test (dipstick) should 
be performed as the early termination visit, then 30 days safety follow up will be performed.
Refer to Section 9.1.1 for study discontinuation.


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Early Termination
Follow Up
Visit Name
Screening
Day 1
Day 6
Day 361
Days
-14 to -1
1
6
-0 +3
-
36
Obtain parental Informed Consent / patient assent 
(if applicable)
X
Register Patient and Visit in IRT
X
X
X
Demography
X
Inclusion / Exclusion criteria2
X
X
Medical history/current medical conditions
X
Prior/ concomitant medication review
X
X
X
X
AE/SAE
X
X
X
X
X
Device training
X
X
X
Physical Examination
X
X
X
X
Hematology
X
X
X
Clinical Chemistry
X
X
X
Urinalysis
X
X
X
Pregnancy and assessments of fertility3
X
X
X
X
Electrocardiogram (ECG)
X
X
X
Vital Signs
X
X
X
X
Height and Weight
X
Telephone patient/parent/legal guardian in 
advance of study visit4
X
X
Dose administration
X
X
PK blood collection
X
X
Snack/Meal5
X
X
Safety Follow up Call
X


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Period
Screening
Treatment
Early Termination
Follow Up
Visit Name
Screening
Day 1
Day 6
Day 361
Days
-14 to -1
1
6
-0 +3
-
36
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 This would occur 30 days after last study treatment.
2 Inclusion/Exclusion evaluation at screening is recorded in CRF.  Inclusion/Exclusion prior to dosing on Day 1 should be documented in 
source.
3 Serum pregnancy test at screening (approximately 0.5 mL blood volume) and urine pregnancy test during treatment visits
4 Patient/Parent/Legal Guardian should be reminded to withhold controller ICS on Days 1 and 6 study visits AND to withhold rescue 
medication within 8 hours of Days 1 and 6 study visits.
5 Patients should consume a small snack approximately 1 hour post-dose and a meal approximately 4 hours post-dose.  Snack and meal 
times should be recorded on the CRF and food content should be recorded in source documentation.


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8.1
Screening
Screening
It is permissible to re-screen a patient once after 2 weeks (14 days) if s/he fails the initial 
screening; however, each case must be discussed and agreed with the Sponsor on a case-by-
case basis.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent form and are subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure patients. No other data will be entered into the 
clinical database for patients who are screen failures, unless the patient experienced a serious 
adverse event during the screening period (see SAE section for reporting details).
Patients who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition Case Report Form.
8.2
Participant demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected for all patients include age 
(DOB as permitted), sex, race, and ethnicity date of diagnosis of asthma and prior/concomitant 
asthma medication. Country-specific regulations should be considered for the collection of 
demographic and baseline characteristics in alignment with CRF. Relevant medical 
history/current medical conditions present before signing informed consent (diagnosis, not 
symptoms) should also be collected.
8.3
Efficacy
Not applicable.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE Section 10.


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Table 8-2
Safety assessments
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and neurological 
or any other evaluations the investigator considers appropriate based on 
the patients clinical status at the clinic at the time of the visit. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed. Information for all physical 
examinations must be included in the source documentation at the study 
site. Clinically relevant findings that are present prior to signing informed 
consent must be included in the Medical History part of the CRF. Significant 
findings made after the written informed consent/assent is provided which 
meet the definition of an Adverse Event must be recorded on the Adverse 
Event section of the CRF.
Vital signs
Body temperature, 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 visits. Please refer to Section 16.4 for 
time points of vital signs measurements post study treatment on Day1 and 
6.
Clinically notable vital signs are defined in Section 16.1.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram
(kg) in indoor clothing, but without shoes) will be measured
8.4.1
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 and clinical chemistry) will be performed at 
Screening and at 6 hour post QMF149 dose on Day 6.
Clinically notable laboratory findings are defined in Section 16.1.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Table 8-3
Laboratory evaluations
Test Category
Test Name
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.


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Test Category
Test Name
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, sodium, 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.
Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will 
be performed at Screening and Day 6. If the urine dipstick is abnormal, the 
sample will be sent to central laboratory for additional testing, including 
assessment of WBC and RBC sediments.
Macroscopic Panel (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Pregnancy Test
Serum / Urine pregnancy test (refer to Section 8.4.3)
8.4.2
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, and blood 
draws, the ECG should be performed first, followed by vital signs and the blood draws.
Centralized ECG
At screening an ECG will be measured to test for eligibility for trial inclusion. Patients with an 
abnormal ECG at screening, due to technical/mechanical faults, may be rescreened.
ECG will be measured at Screening and on Day 6 at pre-dose and 20-min- post-dose of study 
medication as indicated in Section 16.4. ECGs should include 12 standard leads. ECG will be 
sent electronically for central review directly from the ECG machine. One print-out will be 
generated and kept at the investigator site as source documentation will be dated and signed. 
The patient'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 page as appropriate.


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8.4.3
Pregnancy and assessments of fertility
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric patients who are menarchal or who become 
menarchal during the study and may participate in this study.
Serum pregnancy test will be performed for all females of child-bearing potential according to 
the protocol assessment schedule (Table 8-1).  
All menarchal girls and their parents/caregivers should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. It is important to be sensitive in 
introducing this issue, as understanding and comprehension of puberty, sexual activity, 
pregnancy and contraception is influenced by age, as well as factors such as precocity, 
socio(educational) economic and familial background. These discussions with the patient and 
her parents/caregivers are therefore best performed by investigators familiar with the pediatric 
patient and her family and should be guided by requirements of the local regulatory authorities. 
These discussions should take into account the socio-economic, cultural factors and religious 
beliefs of the patient and her family.
The investigator should also discuss the management of the pregnancy test results with the 
patient and her parents/guardians. The privacy of the patient should be considered in accordance 
with the local law and ethics. Additional pregnancy tests may be performed at the investigator’s 
discretion during the study. Patients becoming pregnant must be discontinued from study drug.
If there is evidence of sexual activity in female patients of child-bearing potential, appropriate 
moral and legal actions should be taken by the investigator to ensure the safety of the child and 
minimize the risk of becoming pregnant.
Abstinence from sexual activity while participating in a clinical trial should be encouraged in 
this category of patients. Sexually active patients are excluded from participation in the study.
Assessments of fertility
Female patients who have reached menarche (and therefore are of child-bearing potential) will 
have a serum pregnancy test at screening and a urine pregnancy test during both dosing visits 
(performed prior to dosing) as noted in the visit schedule of assessments (Table 8-1). If the 
serum pregnancy test performed at the Screening Visit is positive, the patient cannot participate 
in the study (Exclusion 19). If the urine pregnancy test performed prior to dosing (at Days 1 
and 6) is found to be positive, 
study drug must not be administered until serum β-hCG is performed and found to be negative. 
If serum β-hCG test is positive, the patient must be discontinued from the study.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
8.5
Additional assessments
No additional tests will be performed on patients entered into this study.


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8.5.1
Pharmacokinetics
PK samples will be collected at the visits defined in the assessment schedule. Follow 
instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment. Residual samples will be retained for additional PK analysis if 
necessary.
The number of samples/blood draws and total blood volume collected will not exceed those 
stated in the protocol. Pharmacokinetic (PK) samples will be obtained and evaluated in all 
patients at all dose levels.
Mometasone furoate and indacaterol will be determined by a validated LC-MS/MS method; the 
anticipated Lower Limit of Quantification (LLOQ) is 0.25 pg/mL for mometasone and 5.0 
pg/mL for indacaterol. Concentrations will be expressed in mass per volume units and will refer 
to the free base. Concentrations below the LLOQ will be reported as “zero” and missing data 
will be labeled as such in the Bioanalytical Data Report.
Blood collection (Table 16-4):

2 mL blood per sample, EDTA tubes (plasma): Day 1 and Day 6: pre-dose, 0.5, 1, 2, 3, 
and 6h post-dose for MF analysis

1 mL blood per sample, Lithium Heparin tubes (plasma): Day 6 pre-dose, 0.25 and 1 h 
post-dose for IND analysis
Analytes, media and methods: Determination of mometasone furoate in plasma will be 
performed by a validated LC-MS/MS method with an LLOQ at 0.25 pg/mL for mometasone 
furoate and 5 pg/mL for indacaterol.
The following pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.4 or 
higher): Cmax, Tmax, AUC0-6h from the MF plasma concentration-time data.
To maintain the consistency for any potential effect of food on the PK profile of mometasone, 
all patients are encouraged to consume a snack approximately 1 hour post-dosing and a meal 
approximately 4 hours post-dosing.
Due to a drug substance coating effect on inner plastic surfaces of the inhaler, the first delivered 
dose and Fine Particle Mass (FPM) from fresh C1 Breezhaler® device delivered dose and fine 
particle mass is known to be generally slightly lower compared to the average delivered doses.
For comparison purpose of MF delivered in QMF149 through C1 Breezhaler® and MF delivered 
by Twisthaler® the blood exposure values (e.g., Cmax, AUC0-6h) obtained with C1 
Breezhaler® will be multiplied with the factor FPMprimed (MF) / FPMunprimed (MF) to assess 
equivalent MF component doses.
9
Study discontinuation and completion
9.1
Discontinuation and completion
Completion of the study will be when the last patient has completed Day 6 treatment and 
PK sample collection and safety assessments. The investigator must provide follow-up medical 


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care for all patients who are prematurely withdrawn from the study, or must refer them for 
appropriate ongoing care.
9.1.1
Study treatment discontinuation and study discontinuation
If the patient cannot properly and sufficiently inhale the dose of study medication at each 
treatment visit and if the patient does not provide a PK sample at each designated timepoint on 
both treatment days, the patient must be discontinued from the study.
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:

Patients who have not received or retained a full dose of study drug cannot be re-dosed 
during a study visit and should be discontinued

Patient`s or parent/legal guardian’s wish including withdrawal of informed consent

Administration of a prohibited medication

ECGs: 

At predose time on Day 6, if the absolute QTcF ≥ 450 msec or an increase from 
baseline of > 60 msec on 2 adequate ECGs at least a minute apart and the physician 
interprets the data from ECG machine to not initiate study treatment.

2nd or 3rd degree AV block

Atrial or ventricular arrhythmias (as judged clinically significant by the investigator)

Any severe AE or SAE considered possibly related to the study medication

Adverse events for which continuation of the study drug would be detrimental

If a patient develops a medical condition that requires use of prohibited treatment as per 
Section 6.2.2, or if patient exhibits a behavior of non-compliance regarding prohibited 
medications.

Pregnancy (see Section 10.1.4 )

Any situation in which study participation might result in a safety risk to the patient

Clinically significant abnormal laboratory value(s) for children 6 to < 12 years, as per the 
discretion of the physician

Any other protocol deviation that results in a significant risk to the patient’s safety

If the COVID 19 pandemic (or any other reason including any public health emergency) 
limits or prevents an on-site study visit(s), then such patients should be discontinued
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 (End of Treatment will act as an early 
discontinuation visit in this case) and directly move into the 30 day follow-up period. Early 
Termination visit assessments detailed in the Table 8-1 should be completed and recorded in


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the eCRF. The investigator must determine the primary reason for the patient’s premature 
discontinuation of study treatment and record this in the Study Disposition eCRF.
The data which must continue to be collected for all discontinued patients are adverse event and 
serious adverse events for up to 30 days after drug discontinuation until the end of the study 
follow-up visit. Documentation of attempts to contact the patient must be recorded in the source 
documentation.
If the patient fails to return for an end of study visit for unknown reasons, every effort should 
be made to contact them. For patients already started Day 1, the COVID 19 pandemic (or any 
other reason) may limit or prevent an on-site study visit(s). These patients should be 
discontinued and a phone or virtual visit will occur for safety monitoring and discussion of the 
participant´s health status including 30 days safety follow-up. If patients cannot visit the site to 
have a urine pregnancy test done, the urine pregnancy test can be performed at home and the 
result reported to the site. If the patient can attend the early termination visit after Day 1, safety 
monitoring, discussion of the participant´s health status, and urine pregnancy test (dipstick) 
should be performed as the early termination visit, then 30 days safety follow up will be 
performed.
9.1.1.1
Replacement policy
Twenty-four (24) patients must complete the two (2) dosing PK collection study visits which 
includes all PK sampling timepoints. Dropouts and non-completers will be replaced as needed. 
Patients who have received a dose of study treatment and who drop-out or discontinue for any 
reason, may be re-screened after a minimum of 14 days.
9.1.2
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

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 the 
assessment table. Where consent to the use of personal and coded data is not required, patient 


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therefore cannot withdraw consent. They still retain the right to object to the further use of 
personal data.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to patients enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients must be seen as soon as possible. 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 or 
sponsor depending on local regulation will be responsible for informing IRBs/IECs of the early 
termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last patient finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
Patients that completed the study or prematurely discontinued will not be given further access 
to the investigational treatment.
The investigator must provide follow-up medical care for all patients who completed or 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
All treated patients should have a safety follow-up call conducted 30 days after last 
administration of study treatment. All SAEs reported during this time period must be reported 
as described in Section 10.1.3 . Documentation of attempts to contact the patient should be 
recorded in the source documentation.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
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 patient or 
clinical investigation patient after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The investigator has the responsibility for managing the safety of individual patient and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the patient at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the patient during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade. 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single patient.
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
6. Its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving; 
recovered/resolved with sequelae; fatal; or unknown)


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All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Drug interrupted/withdrawn

Concomitant medication or non-drug therapy given

Patient hospitalized/hospitalisation prolonged

No action taken (i.e. further observation only)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
To ensure patient safety, every adverse event, occurring after the patient has provided informed 
consent and until end of the trial for each patient must be reported.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results 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 patients with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 16.1.
Once an adverse event 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).
10.1.2
Serious adverse events
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 
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
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (asthma)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above.
All new 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-E2D Guideline (2003)).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline (2003)).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
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.
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 


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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.
10.1.4
Pregnancy reporting
Pregnancies
Sexually active patients are excluded from the study. 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.
Pregnancy tests are required of female patients partcipating in the study who have reached 
menarche. For details regarding pregnancy testing please refer to Table 8-1 and Section 8.4.3.
Tracking of pregnancy cases occurs until after Expected Delivery Date (EDD) for all 
prospective pregnancy cases received from clinical studies

EDD +1 month (mandatory for all cases). Requesting the pregnancy outcome and othe 
rclinically relevant pregnancy data or changes in data

EDD+2 month (mandatory if no answer is obtained after request at EDD+1 month). A 
reminder letter for the outcome

The follow up at EDD+3 and EDD+12 months is mandatory for all cases of live birth and 
unknown outcome. Information on the status of the baby 3 months after delivery and 
information on any development issue or abnormality that would not be seen at birth must 
be collected
10.1.5
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.


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate 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 within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
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
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.1.6
Concept 1 related adverse event reporting
Any Concept 1 device related adverse events must be reported to Novartis within 24 hours of 
learning of its occurrence. Concept 1 device related adverse events must be recorded on the 
relevant device-related pages of the CRF. Country regulations have to be followed for the 
Concept 1 device related adverse events reporting to Health Authorities and/or Ethics 
Committees.
The investigator has the responsibility for managing the safety of individual patients.
10.2
Additional Safety Monitoring
10.2.1
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 16-1 in Section 16.2 for complete definitions of liver laboratory triggers 
and liver events.
Once a participant is exposed to study treatment, every liver laboratory trigger or liver event as 
defined in Table 16-1 of Section 16.2 should be followed up by the investigator or designated 
personal at the trial site as summarized below. Detailed information is outlined in Table 16-2
in Section 16.2.


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For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats will be performed using the central laboratory . If this is not possible, then 
the repeats can be performed at a local laboratory to monitor the safety of the patient. 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.
If the initial elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Discontinuation of the investigational drug (refer to the Discontinuation of study 
treatment, Section 9.1.1) 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, obtaining more detailed history of symptoms and prior or 
concurrent diseases, history of concomitant drug use, exclusion of underlying liver disease.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the RAVEX 
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.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. After final 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. All data should be recorded, handled, and stored in a way that allows its 
accurate reporting, interpretation, and verification.


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11.2
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.
ECG readings will be processed centrally and the results will be sent electronically to Novartis.
Data about all study drug(s) dispensed to the patient and all dosage changes will be tracked 
using an Interactive Response Technology (IRT). The system will be supplied by a vendor, who 
will also manage the database. The database will be sent electronically to Novartis.
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.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).


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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
12
Data analysis and statistical methods
12.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the assigned treatment if the patient took at least one dose of that treatment or the first 
treatment received if the assigned treatment was never received.
The PK analysis set will include all patients with at least one available valid ( i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact PK data.
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data be listed by patient. Descriptive statistics will be presented 
for all patients  for the Safety set.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical history, current medical conditions, results of laboratory screens and any 
other relevant information will be listed by patient.
12.3
Treatments
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary objective of this study to compare the systemic exposure of mometasone furoate 
resulting from single orally inhaled doses of QMF149 75/40 administered via the Concept 1 
versus the MF Twisthaler® (100 µg) in pediatric asthma patients (≥ 6 to < 12 years of age). All 
patients evaluated for pharmacokinetic (PK) parameter data will be included in the 
pharmacokinetic data analysis.


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12.4.1
Definition of primary endpoint(s)
The primary PK parameters of interest are Cmax, and AUC0-6h of MF after single dose 
administration of QMF149 75/40 μg C 1 and MF TH 100 μg.
12.4.2
Statistical model, hypothesis, and method of analysis
Log-transformed PK paramters Cmax and AUC(0-6h) will be analyzed for mometasone furoate 
by linear fixed effects model with treatment and patient as fixed effect. The estimated mean and 
90% confidence interval of treatment difference of test vs reference ( QMF149 vs MF) will be 
back transformed to obtain the geometric mean and 90% confidence intervals of the ratio.
12.4.3
Handling of missing values not related to intercurrent event
All drug concentrations below the lower limit of quantification (LLOQ) will be reported as 
“zero” and will be treated as zero for the calculation of PK parameters.
Patients with missing PK parameters (e.g. Cmax, AUClast, AUCinf) in one period will be 
excluded from the primary analysis.
In case a certain PK time point is not collected and missing in data, PK parameters may not be 
calculated from this treatment.
12.5
Analysis of secondary endpoints/estimands
For all safety analyses, the safety set will be used.
12.5.1
Safety endpoints
Adverse events
All information obtained on adverse events will be displayed by treatment sequence and patient.
All treatment emergent AEs will be summarized and listed.
AEs starting on or after the time of the first inhalation of study drug and until 30 days after the 
last inhalation will be classified as a treatment emergent AE. Any AEs that started during the 
study after signing informed consent and before the time of the first inhalation of study drug 
will be classified as a prior AE and will not be included in tabulations of the treatment emergent 
AEs.
The following treatment emergent AE summaries will be produced:

by treatment, system organ class and preferred term,

by treatment, 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 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.


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Vital signs
All vital signs data will be listed by treatment sequence, patient, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted centrally. All ECG data will be listed 
by treatment sequence, patientand visit/time, abnormalities will be flagged. Summary statistics 
will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment sequence, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
12.5.2
Pharmacokinetics
Indacaterol and mometasone furoate plasma concentration data will be listed by treatment, 
patient, and visit/sampling time point. Descriptive summary statistics will be provided by 
treatment and visit/sampling time point, including the frequency (n, %) of concentrations below 
the LLOQ and reported as zero.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum.
Indacaterol and mometasone furoate pharmacokinetic parameters will be listed by treatment 
and patient. Descriptive summary statistics will include mean (arithmetic and geometric), SD, 
and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented. PK parameters AUC0-6h and 
Cmax will be used for comparsion of MF exposure after the two treatments. Additional 
parameters such as Tmax and half-life may be calculated for additional qualitative assessments.
Table 12-1
Non-compartmental pharmacokinetic parameters  
AUC0-6h
The AUC from time zero to the last sampling time point 6h (mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for 
terminal elimination rate constant (time-1)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)


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Vz/F
The apparent volume of distribution during terminal phase (associated with λz) 
(volume)
12.6
Analysis of exploratory endpoints
Not applicable.
12.7
Interim analyses
An interim analysis is planned to be performed when 12 patients complete both study treatment 
and there are at least 3 completers in each of the two age groups ≥ 6 to < 9 year olds and ≥ 9 to 
<12 year olds. The interim analysis will be based on preliminary PK and safety data. An 
estimate of the systemic exposure as measured by the PK parameter ratios (QMF149 Concept 
1 Breezhaler® vs MF Twisthaler®) together with corresponding 90% confidence intervals will 
be calculated in order to enable early decision making (e.g., study termination due to having 
achieved the primary objectives). Rationale for study continuation may include measures such 
as a review of training procedure for inhaler use by patients or sample size re-estimation.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Approximately 32 patients will be recruited in order to obtain 24 completers in this study 
considering 25% of drop out rate. The sample size of 24 complete patients is considered to yield 
satisfactory precision in the estimation of the systematic exposure, as measured by the ratio of 
the PK parameter Cmax, AUC(0-6h) of QMF149 Concept 1 Breezhaler® vs MF Twisthaler®.
With 24 complete patients, the 90% confidence intervals of the PK parameter ( AUC (0-6h) and 
Cmax) ratios (QMF149 Concept 1 Breezhaler® vs MF Twisthaler®) are expected to be within 
72% to 138% with 90% coverage probability. The calculation was based on an assumed 2-fold 
increase in variability in pediatric population compared to adults who showed intra-patient CV 
of 30% in the CQMF149E2101 study.
13
Ethical considerations and administrative procedures
13.1
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 with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 


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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.
13.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study patients. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study patients.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented.


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14.1
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 required for patient safety 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, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
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.
Dolovich MA (2000) Influence of inspiratory flow rate, particle size, and airway caliber on 
aerosolized drug delivery to the lung. Respir Care; 45(6):597-608.
Ducharme FM, Ni Chroinin M, Greenstone I, et al (2010) 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;CD005533.
GINA (2019). Global Strategy for Asthma Management and Prevention. Global Initiative for 
Asthma (Internet) Available from: www.ginasthma.org
Greening AP, Ind PW, Northfield M, et al (1994) Added salmeterol versus higher-dose 
corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & 
Hanburys Limited UK Study Group. Lancet; 344:219-224
Masoli M, Fabian D, Holts S, et al (2004) Global burden of asthma. Developed for the Global 
Initiative for Asthma (GINA) (Internet). Available from 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.
Runge P and Hill VL (2009) Practical management of asthma. Pediatrics in Review; 
30(10):375-85.
Woolcock A, Lundback B, Ringdal N, et al (1996) Comparison of addition of salmeterol to 
inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 
153:1481–1488.


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16
Appendices
16.1
Appendix 1: 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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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total 
bilirubin normal at 
baseline:

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

Total bilirubin > 3 × 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 
Total bilirubin > 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*
If ALT or AST abnormal 
at baseline:

ALT or AST > 2x baseline or > 300 U/L (whichever occurs first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms
ALT
TBL
Liver Symptoms
Action
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
Normal
For patients with 
Gilbert’s syndrome: No 
change in baseline 
TBL
None

No change to 
study treatment

Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 
hours.

Follow-up for 
symptoms.
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
If normal at baseline:
ALT > 5 x ULN for 
more than two weeks
Normal
For patients with 
Gilbert’s syndrome: No 
change in baseline 
TBL
None

Interrupt study 
drug

Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, 
albumin, CK, and 
If elevated at 
baseline:
ALT > 3 x baseline


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ALT
TBL
Liver Symptoms
Action
or > 300 U/L 
(whichever occurs 
ﬁrst) for more than two 
weeks
GLDH in 48-72 
hours.

Follow-up for 
symptoms.

Initiate close 
monitoring and 
workup for 
competing 
etiologies.

Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline.
If normal at baseline:
ALT > 8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
TBL > 2 x ULN (or INR 
> 1.5)
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin
None
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
If normal at baseline:
ALT > 3 x ULN
Normal or elevated
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain
If elevated at 
baseline:
ALT > 2 x baseline
or > 300 U/L 
(whichever occurs 
ﬁrst)
Table 16-3
Follow up requirements for liver laboratory triggers
Criteria
Actions required
Follow-up monitoring
Total Biliruin (isolated)
>1.5 – 3.0 ULN

Maintain treatment

Repeat LFTs within 48-72 
hours
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome)

Interrupt treatment

Repeat LFT within 48-72 
hours

Hospitalize if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors (e.g. 
conmeds, med hx, lab) in 
the appropriate CRF
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 10 x ULN

Discontinue the study 
treatment immediately

Hospitalize the patient

Establish causality
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutiona (frequency at 
investigator discretion)


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Criteria
Actions required
Follow-up monitoring

Record the AE and 
contributing factors(e.g. 
conmeds, med hx, lab)in 
the appropriate CRF
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Record the AE and 
contributing factors(e.g., 
conmeds, med hx, lab)in 
the appropriate CRF
Investigator discretion
aResolution 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.
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


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16.3
Appendix 3: Blood volumes
Table 16-4
Blood volume
Study 
Period
Time (h)1
Safety
PK
mL
Dose 
Reference 
ID
Sample no.
(MF 
analysis)
Sample no.
(IND 
analysis)
mL
Screening 
(days -14 to 
-1)
5.5
Day 1 
Treatment
0 (pre-
dose)
MF TH 100 
μg
101
2
0.5
MF TH 100 
μg
102
2
1
MF TH 100 
μg
103
2
2
MF TH 100 
μg
104
2
3
MF TH 100 
μg
105
2
6
MF TH 100 
μg
106
2
Day 6 
Treatment
0 (pre-
dose)
QMF149 
75/40 μg
201
301
3
0.25
-
302
1
0.5
QMF149 
75/40 μg
202
2
1
QMF149 
75/40 μg
203
303
3
2
QMF149 
75/40 μg
204
2
3
QMF149 
75/40 μg
205
2
6
5.5
QMF149 
75/40 μg
206
2
Sub-total 
blood 
volume
11
27
TOTAL 
Blood 
volume 
(mL)
38
1 Time window of ± 5 min for samples up to 3 h and ± 30 min for sample at 6 h. Predose samples 
should be collected within 2 hour window prior to dosing.


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16.4
Appendix 4: Pharmacokinetic/Vital signs/ECG/Lab assessment 
timed schedule on Days 1 and 6
Table 16-5
PK/VS/ECG/Lab Assessments
PK/VS/ECG/Lab 
assessment 
timed schedule
Time point vs. 
0 (dose time, 
hours)*
Vital Signs**
ECG
PK
Hematology/ 
chemistry
Day 
1
Day
6
Early 
Term
Day 
1
Day 
6
Early 
Term
Day 
1
Day 
6
Early 
Term
Day 
1
Day 
6
Early 
Term
Pre-dose
X
X
X
X
X
X*
X*
X
15 minutes
X
X
20 minutes
X
30 minutes
X
X
1 hour
X
X
X
2 hours
X
X
3 hours
X
X
6 hours
X
X
X
Note: For Time points where multiple procedures occur, the following order is recommended: 
e.g. vital signs, PK, and lab. The PK blood draw should be ± 5 min for samples up to 3 h and ± 
30 min for sample at 6 h. Predose samples should be collected within 2 hour window prior to 
dosing.
*If a local anesthetic is used for placing the indwelling catheter, the time for it to take effect has 
to be accounted for prior to any assessment.
** Please refer to Table 8-2 for details.

SAP_001.pdf: 
Clinical Development 
QMF149
CQMF149G2203 / NCT04589663
An open-label, two-period, single-sequence, crossover 
study to compare the systemic exposure of a single 
inhaled dose of mometasone furoate (MF) when 
administered alone via the MF Twisthaler® (TH) to a single 
inhaled dose of QMF149 indacaterol acetate/MF fixed dose 
combination when administered via the Concept 1 
(Breezhaler®) device in ≥ 6 to <12 year old asthma patients
Statistical Analysis Plan (SAP)  
Document type:
SAP Documentation
Document status:
Final Amendment 1
Release date:
19-Apr-2022
Number of pages:
16
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 3.0, Effective from 01-Jul-2020


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SAP Amendment 1
Study No. CQMF149G2203
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
01-
Jun-
2021
Prior 
to 
DB 
Lock
Creation 
of 
final version
N/A-First version
NA
19-
Apr-
2022
Prior 
to 
DB 
Lock
Creation 
of 
Amendment1 
final version
Amendment 1 - First version
Section 2.5 –
Analysis of  the 
primary 
objective. 
Added 
the 
information 
related 
to 
correction
factors.


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................8
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.................................................................................10
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..........................................................................11
2.5.1
Primary endpoint...................................................................................11
2.5.2
Statistical hypothesis, model, and method of analysis..........................11
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 objective(s)........................................................................13
2.7.1
Secondary endpoints .............................................................................13
2.8
Safety analyses.......................................................................................................13
2.8.1
Adverse events (AEs)............................................................................13
2.8.2
Deaths....................................................................................................14
2.8.3
Laboratory data .....................................................................................14
2.8.4
Other safety data ...................................................................................14
2.9
Pharmacokinetic endpoints....................................................................................14
2.10
PD and PK/PD analyses.........................................................................................14
2.11
Patient-reported outcomes .....................................................................................14
2.12
Biomarkers.............................................................................................................15


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2.13
Other Exploratory analyses....................................................................................15
2.14
Interim analysis......................................................................................................15
3
Sample size calculation .....................................................................................................15
4
Change to protocol specified analyses ..............................................................................15
5
Appendix ...........................................................................................................................15
5.1
Imputation rules.....................................................................................................15
5.1.1
Study drug.............................................................................................15
5.1.2
AE date imputation ...............................................................................16
5.1.3
Concomitant medication date imputation .............................................16
5.2
AEs coding/grading ...............................................................................................16
5.3
Laboratory parameters derivations ........................................................................16
5.4
Statistical models...................................................................................................16
5.4.1
Primary analysis....................................................................................16
5.4.2
Key secondary analysis.........................................................................16
5.5
Rule of exclusion criteria of analysis sets..............................................................16
6
Reference...........................................................................................................................16


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List of tables
Table 1-1
Objectives and related endpoints ............................................................8
Table 2-1
Non-compartmental pharmacokinetic parameters ................................12
List of figures
Figure 1-1
Study design............................................................................................7


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List of abbreviations
AE
Adverse Event
AESI
Adverse Events of Special Interest
C1
Concept 1 Breezhaler®
CI
Confidence Interval
CRF
Case Report Form
CRS
Case Retrieval Strategy
CSR
Clinical Study Report
CV
Coefficient of Variation
DMS
Document Management System
ECG 
Electrocardiogram
EXCL
Exclusion
IA
Interim Analyses
ICS
Inhaled corticosteroid
INCL
Inclusion
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MF 
Mometasone furoate
PK
Pharmacokinetics
RAP
Reporting & Analysis Process
SAE
Serious Advere Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Standard Deviation
TFLs
Tables, Figures, Listings
TH 
Twisthaler®


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1
Introduction
This document contains details of the statistical methods that will be used in the phase II clinical 
trial CQMF149G2203.
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 is an open-label, two-period, single-sequence, crossover study to assess the 
pharmacokinetics, safety and tolerability of single inhaled doses of mometasone furoate (MF) 
when administered alone via MF Twisthaler® (TH) or as an indacaterol acetate/MF fixed dose 
combination (QMF149) via the Concept 1 (C1) device in ≥ 6 to <12 year old asthma patients. 
The study includes two open-label single-dose treatment visits. On the first treatment visit (Day 
1) patients receive a single inhaled dose of 100 µg MF administered via the Twisthaler® device. 
On the second treatment visit (Day 6) patients receive a single inhaled dose of 75/40 µg 
indacaterol acetate/MF fixed dose combination (QMF149). Both treatments are in addition to 
their rescue medication and potentially SoC asthma therapy (excluding MF and indacaterol 
acetate).
Patients currently taking low-dose ICS asthma medications other than MF can enroll in the 
study. However, since the patients will be provided MF or QMF149 as part of study treatment 
on Day 1 and Day 6 respectively, patients should be instructed not to take low-dose ICS 
medication on the 2 treatment days.
The study will include the following:

A screening period of up to 14 days

Two single-dose treatment periods separated by a 4-7 day washout period (4 days is 
minimum washout)

A 30-day investigational drug-free follow-up period
Figure 1-1
Study design 


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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To compare the systemic exposure of 
mometasone furoate resulting from single 
orally inhaled doses of QMF149 75/40 µg 
administered via the Concept1 unit dose 
dry powder inhaler versus the MF 
Twisthaler® 100 µg metered dose dry 
powder inhaler in pediatric asthma patients 
(≥ 6 to < 12 years of age)

PK parameters (AUC0-6h and Cmax) 
of MF after single dose administration 
of QMF149 75/40 µg C1 and MF 
Twisthaler® (100 µg)
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the systemic exposure of 
indacaterol resulting from single orally 
inhaled doses of QMF149 75/40 µg.

Systemic exposure of indacaterol after 
single dose administration of QMF149 
75/40 µg 

To evaluate the safety and tolerability of 
QMF149 75/40 µg after single dose 
administration in pediatric patients.

Adverse Events, Serious Adverse 
Events and defined safety assessments 
2
Statistical methods
This section and its subsections follow the CSR template structure of Section 9.7 as of the 
release date of this document for alignment with importing into the CSR template.
2.1
Data analysis general information
The final CSR analysis will be performed by Novartis. SAS version 9.4 or later software will 
be used to perform all data analyses and to generate tables, figures and listings.
2.1.1
General definitions 
Investigational and control drugs

Treatment A: Mometasone furoate delivered via Twisthaler®inhaler, (MF 100μg TH)

Treatment B: Fixed dose combination of 75 μg indacaterol acetate and 40 μg 
mometasone furoate delivered as powder in hard capsules via Concept1 Breezhaler® 
inhaler (QMF149 75/40 μg C1)


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A single dose of the Asmanex Twisthaler® contains 110 μg of mometasone furoate delivering 
100 μg of mometasone furoate from the inhaler mouthpiece following single actuation.
Date of first administration of study drug
The date of first administration of study drug is defined as the first date when a nonzero dose 
of study drug is administered and recorded on the study treatment form. The date of first 
administration of study drug will also be referred as start of study drug.
Date of last administration of study drug
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on study treatment form. The date of last administration 
of study drug will also be referred as end of study drug.
Study day
Study Day 1 for all assessments is taken to be the start date of study treatment.
The study day for all assessments will be calculated as follows:
If date of assessment occurred on or after the start of study treatment, then
Study day = Date of assessment - Start of study treatment + 1.
If date of assessment occurred before the start of study treatment, then
Study day = Date of assessment - Start of study treatment.
The study day will be displayed in the data listings. If an event starts before the reference start
date, the study day displayed on the listing will be negative.
Baseline
For safety evaluations, the last available assessment on or before the date and time of start of 
study drug is taken as ‘‘baseline” assessment. In case time of assessment and time of study drug 
start is captured, the last available assessment before the study drug start date/time is used for 
baseline.
2.2
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The Safety analysis set includes all patients who received at least one dose of study treatment. 
Patients will be analyzed according to the study treatment received, where treatment received 
is defined as the assigned treatment if the patient took at least one dose of that treatment or the 
first treatment received if the assigned treatment was never received.
The PK analysis set will include all patients with at least one available valid ( i.e., not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
2.2.1
Subgroup of interest
Not applicable.


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2.3
Patient disposition, demographics and other baseline 
characteristics
The safety analysis set will be used for all baseline and demographic summaries. Listings will 
be presented for non-screen failed participants.
Demographics and baseline data
Demographic and other baseline data will be listed by patient. Descriptive statistics will be 
provided for all patients for the treatment group.
Summaries will include: 

Age (years)

Age groups:  ≥ 6 to 9 < year and  ≥ 9 to ≤ 12 year 

Gender 

Race

Ethnicity 

Height (cm)

Weight (kg)

Body mass index (BMI) (kg/m2)
Continuous variables will be summarized using descriptive statistics (number of non-missing 
data, mean, median, standard deviation, minimum and maximum) and categorical variables will 
be summarized in terms of the number and percentage of patients in each category including a 
category for missing data if any.
Medical history
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. Relevant medical history and current medical 
conditions will be listed by treatment group and participant.
2.3.1
Patient disposition
Screened participants, including those who completed screening and were treated, and reasons 
for not completing the study will be listed for all patients.
Treated subjects will be included in the safety analysis set will be summarized. The following 
summaries will be provided (with % based on the total number of safety analysis set patients):

Number (%) of patients who were treated.

Number (%) of patients who completed treatment and those who discontinued the study 
treatment phase along with the primary reason for study treatment discontinuation (based 
on the disposition page).
Patient disposition data will be listed by patient. 
Screen failure data will not be presented.


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Protocol deviations
All protocol deviations will be listed by patient.
Analysis sets
The number of patients included in each analysis set (defined in Section 2.2) will be tabulated, 
as well as the reasons for exclusions from analysis set will be listed.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Dose administration data will be listed by patient.
2.4.2
Prior, concomitant and post therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient.
2.5
Analysis of the primary objective
The primary objective of this study is to compare the systemic exposure of mometasone furoate 
resulting from single orally inhaled doses of QMF149 75/40 administered via the Concept 1 
versus the MF Twisthaler® (100 μg) in pediatric asthma patients (≥ 6 to < 12 years of age).
All patients evaluated for pharmacokinetic (PK) parameters data will be included in the 
pharmacokinetic data analysis.
2.5.1
Primary endpoint
The primary PK parameters of interest are Cmax, and AUC0-6h of MF after single dose 
administration of QMF149 75/40 μg C1 and MF TH 100 μg.
2.5.2
Statistical hypothesis, model, and method of analysis 
Log-transformed PK parameters Cmax and AUC(0-6h) will be analyzed for mometasone 
furoate by linear fixed effects model with treatment and patient as fixed effect. The estimated 
mean and 90% confidence interval of treatment difference of test vs reference (QMF149 vs MF) 
will be back transformed to obtain the geometric mean and 90% confidence intervals (CI) of 
the ratio.
Indacaterol and mometasone furoate plasma concentration data will be listed by treatment, 
patient, and visit/sampling time point. Descriptive summary statistics will be provided by 
treatment and visit/sampling time point, including the frequency (n, %) of concentrations below 
the LLOQ and reported as zero.
Summary statistics will include mean (arithmetic and geometric), standard deviation (SD), 
Coefficient of Variation (CV) (arithmetic and geometric), median, minimum, and maximum.


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Indacaterol and mometasone furoate pharmacokinetic parameters will be listed by treatment 
and patient. Descriptive summary statistics will include mean (arithmetic and geometric), SD, 
and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this is 
Tmax where median, minimum, and maximum will be presented. PK parameters AUC0-6h and 
Cmax will be used for comparison of MF exposure after the two treatments.
Arithmetic mean (+/- SD) and overlaying individual plots for plasma concentration data will be 
presented by treatment and also by age group.
For comparison purpose of MF delivered in QMF149 through C1 Breezhaler® and MF 
delivered by Twisthaler® the blood exposure values (e.g., Cmax, AUC0-6h) obtained with C1 
Breezhaler® will be multiplied with the factor FPMprimed (MF) / FPMunprimed (MF) to 
assess equivalent MF component doses. 
For MF Twisthaler, the correction factor is 1.26, for MF Concept 1 device the correction factor 
is 1.62 and for Indacaterol Concept 1 device the correction factor is 2.0.
Similar analysis as mentioned above will be performed using a correction factor for plasma PK 
concentration and PK parameters.
The following pharmacokinetic parameters (Table 2-1) will be determined using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
8.0 or higher):
Table 2-1
Non-compartmental pharmacokinetic parameters  
AUC0-6h
The AUC from time zero to the last sampling time point 6h (mass x time x volume-
1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUClast
The AUC from dosing to the time of the last measured concentration.
Cmax
The maximum (peak) observed plasma drug concentration after single dose 
administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, or other body fluid drug concentration 
after single dose administration (time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for 
terminal elimination rate constant (time-1)
T1/2
The elimination half-life associated with the terminal slope (λz) of a semi 
logarithmic concentration-time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with λz) 
volume.
2.5.3
Handling of missing values/censoring/discontinuations
All drug concentrations below the lower limit of quantification (LLOQ) will be reported as 
“zero” and will be treated as zero for the calculation of PK parameters. 
Patients with missing PK parameters (e.g. Cmax, AUClast, AUCinf) in one period will be 
excluded from the primary analysis.


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In case a certain PK time point is not collected and missing in data, PK parameters may not be 
calculated from this treatment.
2.5.4
Supportive analyses
Not applicable.
2.6
Analysis of the key secondary objective
There is no key secondary objective.
2.7
Analysis of secondary objective(s)
The secondary objectives of this study are:

To evaluate the systemic exposure of indacaterol resulting from single orally inhaled 
doses of QMF149 75/40 µg. 

To evaluate the safety and tolerability of QMF149 75/40 µg after single dose 
administration in pediatric patients.
2.7.1
Secondary endpoints
Pharmacokinetics:
Systemic exposure of indacaterol after single dose administration of QMF149 75/40 µg
Safety parameters: All safety data, including adverse events, laboratory measurements, 
vital signs, 12 Lead ECG
2.8
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. Screen failure data will not be presented in the listings.
2.8.1
Adverse events (AEs)
All information obtained on adverse events will be displayed by treatment sequence and patient.
All treatment emergent AEs will be summarized and listed.
AEs starting on or after the time of the first inhalation of study drug and until 30 days after the 
last inhalation will be classified as a treatment emergent AE. Any AEs that started during the 
study after signing informed consent and before the time of the first inhalation of study drug 
will be classified as a prior AE and will not be included in tabulations of the treatment emergent 
AEs.
The following treatment emergent AE summaries will be produced:

by treatment, system organ class and preferred term,

by treatment, system organ class, preferred term, and maximum severity


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suspected drug-related AEs by system organ class and preferred term, SAEs by system organ 
class and preferred term, and AEs leading to 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.
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
Deaths
All deaths will be listed by patients.
2.8.3
Laboratory data
All laboratory data will be listed by treatment sequence, patient, and visit/time and if normal 
ranges are available abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time.
2.8.4
Other safety data
2.8.4.1
ECG data
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted centrally. All ECG data will be listed 
by treatment sequence, patient and visit/time, abnormalities will be flagged. Summary statistics 
will be provided by treatment and visit/time.
2.8.4.2
Vital signs
All vital signs data will be listed by treatment sequence, patient, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics
will be provided by treatment and visit/time.
2.9
Pharmacokinetic endpoints  
Refer to Section 2.5 and Section 2.7 for primary and secondary objectives related to PK 
endpoints.
2.10
PD and PK/PD analyses
Not applicable. 
2.11
Patient-reported outcomes
Not applicable.


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2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
An iterim analysis is planned to be performed when 12 patients complete both study traetment 
and there are at least 3 completers in each of the two age groups ≥ 6 to 9 < year olds and ≥ 9 to 
≤ 12 year olds. The interim analysis will be based on preliminary PK and safety data. An 
estimate of the systemic exposure as measured by the PK parameter ratios (QMF149 Concept 
1 Breezhaler® vs MF Twisthaler®) together with corresponding 90% confidence intervals will 
be calculated in order to enable early decision making (e.g., study termination due to having 
achieved the primary objectives). Rationale for study continuation may include measures such 
as a review of training procedure for inhaler use by patients or sample size re-estimation.
3
Sample size calculation
Approximately 32 patients will be recruited in order to obtain 24 completers in this study 
considering 25% of drop out rate. The sample size of 24 complete patients is considered to yield 
satisfactory precision in the estimation of the systematic exposure, as measured by the ratio of 
the PK parameter Cmax, AUC(0-6h) of QMF149 Concept 1 Breezhaler® vs MF Twisthaler®. 
With 24 complete patients, the 90% confidence intervals of the PK parameter ( AUC (0-6h) and 
Cmax) ratios (QMF149 Concept 1 Breezhaler® vs MF Twisthaler®) are expected to be within 
72% to 138% with 90% coverage probability. The calculation was based on an assumed 2-fold 
increase in variability in pediatric population compared to adults who showed intra-patient CV 
of 30% in the CQMF149E2101 study.
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
5
Appendix
The sections below contain additional details on statistical methodology that will be included 
in Appendix 16.1.9 (Documentation of Statistical Methods) of the CSR as well as details on 
programming rules that will be followed to implement the analyses described in Section 2.
5.1
Imputation rules
5.1.1
Study drug
Missing/partial start date or end date of treatment will not be imputed.


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5.1.2
AE date imputation
Partial AE start and end dates will be imputed. If there is uncertainty whether an AE occurred 
on-treatment or not, imputation will be performed, such that AE will be considered as on-
treatment. Rules for imputing AE end date or start date will be provided in Programming 
Dataset Specification (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 Programming Dataset 
Specification (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
Laboratory parameters derivations
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.
5.4
Statistical models 
5.4.1
Primary analysis
Refer to Section 2.5.
5.4.2 Key secondary analysis
Refer to Section 2.7.
5.5
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
Informed consent was not obtained before any assessment.
EXCL11
Parent or guardian has a history of psychiatric disease, intellectual 
deficiency, or substance abuse
6
Reference

Clinical Study Protocol, CQMF149G2203 v01 dated 19-Mar-2021.