Clinical trial NCT04848662
Conditions: Asthma
Sponsor: Bond Avillion 2 Development LP
Start date: 2021-05-06; Completion date: 2021-07-08
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To compare the pharmacokinetics of budesonide delivered by BDA MDI to budesonide delivered by Pulmicort Respules in children with Asthma aged 4 to 8 years.

Detailed description:

Arms: arm 1: Subjects randomized to receive a single dose of budesonide/albuterol by metered-dose inhaler, BDA MDI, (PT027) 160/180 μg at Visit 2, and a single dose of budesonide by nebulization (Pulmicort Respules) 1mg at Visit 3. arm 2: Subjects randomized to receive a single dose of budesonide by nebulization (Pulmicort Respules) 1mg at Visit 2, and a single dose of budesonide/albuterol by metered-dose inhaler, BDA MDI, (PT027) 160/180 μg at Visit 3.
Interventions: intervention 1: BDA MDI (PT027) 160/180 μg intervention 2: Pulmicort Respules 0.5 MG/ML Inhalation Suspension
Intervention descriptions: intervention 1: Combination Product: Budesonide/albuterol sulfate metered-dose inhaler 80/90 μg per puff. Two puffs to administer 160/180 μg dose. intervention 2: Budesonide 0.5 mg/ml. Each 2 ml Respule contains 1 mg budesonide.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
CONFIDENTIAL AND PROPRIETARY 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
A Phase I, Randomized, Open-label, Single-dose, 2-way Crossover 
Study to Compare the Pharmacokinetics of Budesonide Delivered 
by PT027 to Pulmicort Respules® in Children with Asthma Aged 4 
to 8 Years (BLANC) 
Study centers and number of children planned 
It is planned to randomize a sufficient number of children with asthma to obtain evaluable 
pharmacokinetic (PK) samples from 10 children aged 4 to 8 years, with at least 4 children 
aged 4 to 5 years. Children who do not complete both treatments (Treatment A and 
Treatment B) may be replaced. Approximately 3 study centers in Bulgaria and the United 
States (US) are anticipated to be included. 
Phase of development 
Phase I Pediatric 
Study design 
This will be a randomized, multicenter, open-label, single-dose, 2-way crossover study. The 
purpose of this study is to compare the systemic exposure of budesonide delivered by the 
combination inhaler (budesonide/albuterol sulfate [BDA] metered-dose inhaler [MDI]) to 
Pulmicort Respules®. 
To be eligible for the treatment period of the study, children with asthma will be required to 
meet all of the inclusion and none of the exclusion criteria. 
At Visit 2, the children will be randomly assigned to a treatment sequence: 
A/B: BDA MDI at Visit 2 and Pulmicort Respules at Visit 3 
OR 
B/A: Pulmicort Respules at Visit 2 and BDA MDI at Visit 3 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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The study will comprise: 
•
Screening (Visit 1): within 14 days prior to randomization.
•
Two treatment days:
•
Visit 2/Randomization visit: children will be dosed with a single dose of BDA MDI
or Pulmicort Respules (A/B or B/A) and blood will be drawn for PK sampling for up
to 12 hours after dosing in alignment with the sampling schedule.
•
Visit 3 will occur not less than 2 and no greater than 14 days after dosing on Visit 2
(ie, washout of 2 to 14 days) during which children will be dosed with a single dose
of BDA MDI or Pulmicort Respules (A/B or B/A) and blood will be drawn for PK
sampling for up to 12 hours after dosing in alignment with the sampling schedule.
•
A follow-up telephone call (TC) will occur 2 to 5 days after the last dose (Visit 3) for
safety follow-up (or early withdrawal, if applicable).
Safety will be monitored by spontaneously reported adverse events (AEs)/serious AEs (SAEs) 
and physical examination findings. Vital signs (heart rate and blood pressure) will be assessed 
at the beginning (pre-dose) and the end (post-last PK sample) of each clinic visit to ensure the 
well-being of the children. 
Objectives 
Primary objective 
Primary endpoints 
To determine and compare the systemic 
exposure of budesonide after single-dose 
administrations of BDA MDI and 
Pulmicort Respules. 
AUC0-t and Cmax 
Secondary objective: 
Secondary endpoints: 
To determine and compare other PK 
parameters for budesonide delivered by 
BDA MDI and Pulmicort Respules 
tmax, tlast, t½λz, λz, Clast, and AUC0-inf (if 
feasible) 
Safety objective: 
Safety endpoints: 
To assess the safety and tolerability of 
BDA MDI and Pulmicort Respules 
AEs/SAEs 
AE: adverse event; AUC0-inf: area under the plasma concentration-time curve from time zero to infinity; AUC0-t: area under 
the plasma concentration-time curve from time zero to time of last quantifiable concentration; BDA MDI: 
budesonide/albuterol sulfate metered-dose inhaler; Clast: drug concentration at last observed timepoint; Cmax: maximum 
observed plasma concentration; PK: pharmacokinetic; SAE: serious adverse event. tlast: time of last quantifiable plasma 
concentration; tmax: time to reach maximum observed plasma concentration; t½λz: half-life associated with terminal slope 
(λz) of a semi-logarithmic concentration-time curve. 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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Target subject population 
This study will be conducted in male and female children with asthma, 4 to 8 years of age, with 
at least 4 children aged 4 and 5 years. It is planned to randomize enough children with asthma 
to obtain evaluable PK samples from 10 children. 
Duration of treatment 
The randomized treatment period will start after a screening period of up to 14 days. The 
open-label treatment will occur with single dosing of either the test (Treatment A) or reference 
product (Treatment B) at Visits 2 and 3, which will be approximately 1 week apart. Visit 3 
will occur not less than 2 and no greater than 14 days after dosing on Visit 2 (ie, washout of 2 
to 14 days). The overall study duration for the children will take approximately 3 to 4 weeks. 
Investigational Medicinal Products 
Treatment A (test product) a 
Treatment B (reference product) b 
Formulation: 
BDA MDI 
Pulmicort Respules 
Supplier: 
Strength: 
80/90 µg (budesonide/albuterol) 
1 mg budesonide  
Dose: 
2 inhalations 
1 ampoule 
Route of 
administration: 
Oral inhalation 
Oral inhalation 
Regimen: 
Single dose – 2 inhalations 
Single nebulization dose 
Special handling 
requirements: 
Prime per instructions. 
Contamination avoidance 
procedures. 
Nebulization until sputtering with 
nebulization cup as empty as possible 
Contamination avoidance procedures. 
BDA MDI: budesonide/albuterol sulfate metered-dose inhaler 
Note: The IMPs (test product and the reference product) will be manufactured by 
The placebo MDI for the test product will be used for training purposes only during screening (Visit 1) and will 
be taken home for training as well. 
A saline ampoule for the reference product will be used for training purposes only during screening (Visit 1). 
Pharmacokinetic assessments 
A total of 10 samples (~4 mL each) will be taken for determination of budesonide in plasma 
per treatment visit at pre-dose and at 10, 20, 40, 60, 120, 240, 360, 480 and 720 minutes after 
dosing. 
Statistical methods 
Presentation and analysis of pharmacokinetic data: 
The PK analysis set will consist of all randomized children for whom at least 1 of the primary 
PK parameters can be calculated and who have no major protocol deviations impacting PK. 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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A listing of PK blood sample collection times, and all reportable budesonide concentrations 
will be provided for all children. Budesonide concentrations will be summarized by treatment 
using descriptive statistics. 
Plasma samples will be analyzed using non-compartmental analysis (NCA) to determine the 
pharmacokinetics (AUC0-t, Clast, Cmax, tmax, tlast, λz, t½λz, and AUC0-inf [if feasible)]) of 
budesonide in plasma. 
This study is descriptive. There are no predefined statistical hypotheses and/or decision rules. 
The relative exposure of budesonide between BDA MDI versus Pulmicort Respules will be 
based on estimates of the AUC0-t and Cmax. 
The AUC0-t and Cmax for budesonide will be compared between treatments using a 
multiplicative (ie, log-transformation) analysis of variance (ANOVA) model with treatment, 
sequence, period, and subject within sequence as fixed factors. Geometric mean treatment 
ratios and 90% confidence limits will be calculated from the model. Half-life and tmax will be 
compared by means of descriptive statistics. 
Presentation and analysis of safety and eligibility data: 
The safety analysis set will include all children who received any amount of either IMP (BDA 
MDI or Pulmicort Respules, respectively). Safety data will be presented in data listings. 
Continuous safety variables will be summarized using descriptive statistics (n, mean, standard 
deviation, minimum, median, maximum) by treatment. Categorical variables will be 
summarized in frequency tables (frequency and proportion) by treatment. The analysis of the 
safety variables will be based on the safety analysis set. 
Determination of sample size 
For this study, no prospective calculations of statistical power have been made. Complete data 
from 10 children is considered sufficient to provide information on the PK in this population 
without exposing more children than necessary to the IMP. 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
VERSION HISTORY ................................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.........................................................................3 
TABLE OF CONTENTS ...........................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................11 
1 
INTRODUCTION ................................................................................................13 
1.1 
Background ...........................................................................................................13 
1.2 
Rationale for study design, doses and control groups ...........................................13 
1.3 
Benefit/risk and ethical assessment .......................................................................14 
1.4 
Study design ..........................................................................................................15 
2 
STUDY OBJECTIVES .........................................................................................17 
2.1 
Primary objective ..................................................................................................17 
2.2 
Secondary objectives.............................................................................................17 
2.3 
Safety objective .....................................................................................................17 
3 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL .....................18 
3.1 
Inclusion criteria ...................................................................................................18 
3.2 
Exclusion criteria ..................................................................................................18 
3.3 
Subject enrollment and randomization .................................................................20 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects ..................20 
3.5 
Methods for assigning treatment groups ...............................................................21 
3.6 
Methods to minimize bias: randomization and blinding .......................................21 
3.7 
Restrictions............................................................................................................22 
3.8 
Criteria for study withdrawal ................................................................................22 
3.8.1 
Screen failures .......................................................................................................23 
3.9 
Discontinuation of the study .................................................................................23 
4 
TREATMENTS ....................................................................................................24 
4.1 
Identity of the test and reference products ............................................................24 
4.2 
Nebulization inhalation and metered-dose inhaler device technique ....................24 
4.2.1 
Nebulization inhalation technique ........................................................................25 
4.2.2 
Metered-dose inhalation technique .......................................................................25 
4.3 
Supply of test and reference products ...................................................................27 
4.4 
Dose and treatment regimens ................................................................................27 
4.5 
Labelling ...............................................................................................................27 
4.6 
Drug accountability, dispensing, and destruction .................................................28 
4.7 
Storage ..................................................................................................................29 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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4.8 
Compliance ...........................................................................................................29 
4.9 
Accountability .......................................................................................................29 
4.10 
Metered-dose inhaler handling..............................................................................29 
4.11 
Concomitant and other treatments ........................................................................30 
4.11.1 
Investigational medicinal product .........................................................................30 
4.11.2 
Permitted asthma therapies ...................................................................................30 
4.11.3 
Prohibited medications ..........................................................................................30 
4.11.4 
Food and beverage restrictions .............................................................................31 
5 
STUDY PLAN AND TIMING OF PROCEDURES ............................................31 
5.1 
Screening period ...................................................................................................34 
5.1.1 
Visit 1 ....................................................................................................................34 
5.2 
Randomization/treatment period ...........................................................................34 
5.2.1 
Visit 2 and 3 ..........................................................................................................34 
5.3 
Follow-up period or early withdrawal ..................................................................35 
6 
MEASUREMENTS AND METHODS OF ASSESSMENTS .............................36 
6.1 
Appropriateness of Measurements ........................................................................36 
6.2 
Pharmacokinetic Assessments ..............................................................................36 
6.3 
Safety assessments ................................................................................................36 
6.3.1 
Laboratory assessments.........................................................................................36 
6.3.2 
Physical examination ............................................................................................38 
6.3.3 
Vital signs .............................................................................................................38 
6.3.4 
Adverse event assessments ...................................................................................38 
6.4 
Other assessments .................................................................................................38 
6.4.1 
Concomitant medications ......................................................................................38 
7 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................39 
7.1 
Definition of adverse event ...................................................................................39 
7.2 
Definition of serious adverse event .......................................................................39 
7.3 
Recording of adverse events .................................................................................40 
7.3.1 
Period for collection of adverse events .................................................................40 
7.3.2 
Follow-up of unresolved adverse events ...............................................................40 
7.3.3 
Variables ...............................................................................................................40 
7.3.4 
Causality collection ...............................................................................................41 
7.3.5 
Adverse events based on signs and symptoms ......................................................41 
7.3.6 
Adverse events based on examinations and tests ..................................................41 
7.4 
Reporting of serious adverse events ......................................................................42 
7.5 
Follow-up of adverse events .................................................................................43 
7.6 
Overdose ...............................................................................................................43 
7.7 
Medication error ....................................................................................................44 
7.8 
Management of test product-related toxicities ......................................................45 
8 
STATISTICAL METHODS .................................................................................46 
8.1 
Statistical considerations .......................................................................................46 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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8.2 
Sample size estimate .............................................................................................46 
8.3 
Definitions of analysis sets ...................................................................................46 
8.3.1 
Pharmacokinetic analysis set ................................................................................46 
8.3.2 
Safety analysis set .................................................................................................46 
8.3.3 
All subjects enrolled analysis set ..........................................................................46 
8.3.4 
All subjects randomized analysis set ....................................................................47 
8.4 
Violations and deviations ......................................................................................47 
8.5 
Subject disposition ................................................................................................47 
8.6 
Demographic and baseline characteristics ............................................................47 
8.7 
Prior and concomitant medication ........................................................................48 
8.8 
Pharmacokinetic analysis methods and parameters ..............................................48 
8.9 
Safety analysis.......................................................................................................48 
8.9.1 
Laboratory assessments.........................................................................................49 
8.9.2 
Physical examination ............................................................................................49 
8.9.3 
Vital signs .............................................................................................................49 
8.9.4 
Adverse events ......................................................................................................49 
9 
STUDY AND DATA MANAGEMENT ..............................................................50 
9.1 
Training of study center staff ................................................................................50 
9.2 
Monitoring of the study.........................................................................................50 
9.2.1 
Source data ............................................................................................................51 
9.2.2 
Study agreements ..................................................................................................51 
9.2.3 
Archiving of study documents ..............................................................................51 
9.3 
Study timetable and end of study ..........................................................................51 
9.4 
Data management ..................................................................................................51 
10 
ETHICAL AND REGULATORY REQUIREMENTS ........................................53 
10.1 
Ethical conduct of the study ..................................................................................53 
10.2 
Subject data protection ..........................................................................................53 
10.3 
Ethics and regulatory review .................................................................................53 
10.4 
Informed consent/assent ........................................................................................54 
10.5 
Changes to the clinical study protocol and informed consent/assent ....................54 
10.6 
Audits and inspections ..........................................................................................55 
11 
LIST OF REFERENCES ......................................................................................56 
12 
LIST OF APPENDICES .......................................................................................57 
APPENDIX A AVILLION PROTOCOL SIGNATURE PAGE.............................................58 
APPENDIX B PRIMARY INVESTIGATOR SIGNATURE PAGE .....................................59 
APPENDIX C ADDITIONAL SAFETY INFORMATION ...................................................60 
APPENDIX D COVID-19 EMERGENCY MEASURES PERMITTED TO ENSURE 
SUBJECT SAFETY ..............................................................................................62 
 
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Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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LIST OF TABLES 
Table 1:  
Investigational medicinal product strength and dosage form ......................24 
Table 2: 
Schedule of assessments ..............................................................................32 
Table 3: 
Treatment sequence .....................................................................................35 
Table 4: 
Laboratory variables ....................................................................................37 
Table 5:  
Total blood volume ......................................................................................38 
 
LIST OF FIGURES 
Figure 1: Study Flow Chart......................................................................................................16 
Figure 2: How to Hold the Metered-dose Inhaler ....................................................................25 
Figure 3: How to Use the Metered-dose Inhaler ......................................................................26 
 
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Clinical Study Protocol  
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Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC0-inf 
Area under the plasma concentration-time curve from time zero to infinity 
AUC0-t 
Area under the plasma concentration-time curve from time zero to time of last 
quantifiable concentration 
BDA 
Budesonide/albuterol sulfate 
BDA MDI (PT027) 
Budesonide/albuterol sulfate metered-dose inhaler 
BMI 
Body mass index 
Clast 
Drug concentration at last observed (quantifiable) concentration 
Cmax 
Maximum observed plasma concentration 
CRF 
Case report form 
CRO 
Clinical research organization 
CSP 
Clinical study protocol 
CYP 
Cytochrome P450 
DDI 
Drug-drug interaction 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EU 
European Union 
FEV1 
Forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GMP 
Good Manufacturing Practice 
HFA 
Hydrofluoroalkane 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICS 
Inhaled corticosteroid 
IMP 
Investigational medicinal product 
λz 
Terminal elimination rate constant 
LABA 
Long-acting β2-agonist 
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Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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Abbreviation or special 
term 
Explanation 
LAMA 
Long-acting muscarinic antagonist 
LAR 
Legally authorized representative 
LTRA 
Leukotriene receptor antagonist 
MDI 
Metered-dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCA 
Non-compartmental analysis 
PK 
Pharmacokinetic(s) 
PRN 
As-needed  
QID 
Four times a day 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event  
SAMA 
Short-acting muscarinic antagonist 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
SULT1A3 
Sulfotransferase 1A3 
TEAE 
Treatment-emergent adverse event 
t½λz 
Half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve 
tlast 
Time of last quantifiable plasma concentration 
tmax 
Time to reach maximum observed plasma concentration 
TC 
Telephone call 
US 
United States 
 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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1 
INTRODUCTION 
1.1 
Background 
Bond Avillion 2 Development LP (Sponsor) is developing budesonide/albuterol sulfate 
(PT027, a fixed-dose combination product; hereafter referred to as budesonide and albuterol 
sulfate metered-dose inhaler [BDA MDI]) pressurized inhalation suspension product in adults 
and children (≥4 years of age) with asthma. Please refer to the current Investigator’s Brochure 
(IB) for additional information (1). 
Albuterol is a short/rapid-acting β2-agonist (SABA), inducing airway smooth muscle 
relaxation and reducing or preventing bronchoconstriction. Albuterol is approved in many 
countries in multiple formulations for treatment or prevention of bronchoconstriction, and is 
also known under the generic name of salbutamol. In clinical practice, albuterol is used as 
reliever therapy on an as-needed (PRN) basis (2). 
Budesonide is a well-established anti-inflammatory corticosteroid that exhibits potent 
glucocorticoid and weak mineralocorticoid activity and is approved worldwide in inhaled 
formulations for the treatment of asthma and chronic obstructive pulmonary disease both as a 
mono-product and in combination with a long-acting β2-agonist (LABA), (ie, formoterol). 
Research studies have demonstrated that inhaled corticosteroid (ICS) agents potentiate the 
effects of SABAs in reducing airway smooth muscle tone (3) and can reverse adrenergic 
receptor tolerance and desensitization (4). Clinically, similar functional potentiation with 
combined ICSs and albuterol has been observed in patients with asthma for functional 
measures of airway smooth muscle and airway blood flow (5). 
Combining albuterol with budesonide in the BDA MDI combination product should not only 
provide rapid bronchodilation, but also treat worsening airway inflammation by the addition 
of the budesonide component. Current treatment guidelines (2) recommend addition of low-
dose ICS to SABA used as reliever medication as early as in Global Initiative for Asthma 
(GINA) step 1 asthma (previously treated with SABA PRN alone), broadening the range of 
asthma severity grades that would be treated by both ICS and β2-agonist. Anti-inflammatory 
and bronchodilation components used PRN in a fixed-dose combination are expected to result 
in overall better asthma control and decreased risk of experiencing asthma symptoms than 
bronchodilation alone. 
1.2 
Rationale for study design, doses and control groups 
The BLANC study is a Phase I, randomized, multicenter, open-label, single-dose, 2-way 
crossover study to compare the pharmacokinetics (PK) of budesonide delivered by BDA MDI 
to Pulmicort Respules® in children with asthma aged 4 to 8 years. Avillion is obtaining safety 
and efficacy information for the intended PRN use of BDA MDI in patients with asthma aged 
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Budesonide/Albuterol Sulfate (BDA), AV006 
Version 2.0, 19 March 2021 
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4 years and older in 2 ongoing Phase III pivotal studies: the MANDALA study, which 
investigates time to first severe exacerbation, and the DENALI study, which investigates 
change from baseline in forced expiratory volume in 1 second (FEV1) AUC0-6 hours over 12 
weeks and change from baseline in trough FEV1 at 12 weeks. 
For BDA MDI, a single dose of 160/180 µg (given as 2 inhalations of 80/90 µg 
[budenoside/albuterol respectively]) will be administered. The selection of dose is limited by 
the albuterol component to be given as a single dose and is chosen to be as high as possible for 
the budesonide component to ensure adequate PK measurements. A dose of 160/180 µg is 
considered relevant for budesonide PK measurements and safe for albuterol based on dosing 
recommendations for Proventil in children (6). 
For Pulmicort Respules, a single dose of the highest recommended dose of 1 mg will be 
studied (7). This dose is known to be safe in this study’s age group and is adequate to measure 
PK parameters of budesonide after a single dose. 
Based on the known metabolic routes of budesonide and albuterol, the potential for a 
drug-drug interaction (DDI) between these 2 drugs is low. Budesonide is known to be a 
substrate of cytochrome P450 (CYP) 3A, and the effects of inhibitors of CYP3A on 
budesonide PK are well documented. Information available in the published literature 
indicates that the primary enzyme responsible for the metabolism of albuterol in humans is 
sulfotransferase 1A3 (SULT1A3); labelling for albuterol does not suggest any potential for 
metabolic DDI. The lack of a DDI between budesonide and albuterol was confirmed in Study 
D6930C00003, which was designed to demonstrate comparable systemic exposure between 
BDA MDI and the mono-components in healthy volunteers. This study also confirmed 
comparability of the formulation of the combination product BDA MDI versus the 
mono-products. 
In the United States (US) development program for BDA MDI, Pulmicort Respules will be 
used as a reference product for the BDA MDI marketing application for children ages 4 and 
5 years. It is therefore required that a scientific bridge be established between the test and 
reference products which can be obtained by determining the comparability of systemic 
budesonide exposure of both products. Avillion is proposing to enroll children 4 to 8 years of 
age with asthma in this study to facilitate the collection of sufficient PK data to adequately 
bridge BDA MDI to Pulmicort Respules. 
1.3 
Benefit/risk and ethical assessment 
To mitigate any potential risks, all children will be closely monitored to ensure child safety. 
At study visits, children will only be discharged from the study center based on the 
Investigator’s clinical judgment. 
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The study will be conducted in accordance with International Council for Harmonisation 
(ICH) guidelines. Permission from the research ethics committee (EC) will be sought and the 
study will start only after authorization. In the study, single-dose treatment and single-dose 
comparison with Pulmicort Respules is necessary to compare the systemic exposure in 
children between the ages of 4 to 8 years. When considering and assessing all non-clinical and 
clinical data available for the investigational medicinal products (IMPs), the Sponsor 
considers the risk and benefit profiles of the BLANC study to be acceptable. 
1.4 
Study design 
This will be a randomized, multicenter, open-label, single-dose, 2-way crossover study. The 
Study Flow Chart is presented in Figure 1. The purpose of this study is to compare the 
systemic exposure of budesonide delivered by the combination inhaler (BDA MDI) to 
Pulmicort Respules. 
To be eligible for the treatment period of the study, children with asthma will be required to 
meet all of the inclusion criteria and none of the exclusion criteria. 
At Visit 2, the children will be randomly assigned to a treatment sequence: 
A/B: BDA MDI at Visit 2 and Pulmicort Respules at Visit 3 
OR 
B/A: Pulmicort Respules at Visit 2 and BDA MDI at Visit 3 
 
The study will comprise: 
• Screening (Visit 1): within 14 days prior to randomization. 
• Two treatment days: 
• 
Visit 2/Randomization visit: children will be dosed with a single dose of BDA MDI 
or Pulmicort Respules (A/B or B/A) and blood will be drawn for PK sampling for up 
to 12 hours after dosing in alignment with the sampling schedule. 
• 
Visit 3 will occur not less than 2 and no greater than 14 days after dosing on Visit 2 
(ie, washout of 2 to 14 days) during which children will be dosed with a single dose 
of BDA MDI or Pulmicort Respules (A/B or B/A) and blood will be drawn for PK 
sampling for up to 12 hours after dosing in alignment with the sampling schedule. 
• A follow-up telephone call (TC) will occur 2 to 5 days after the last dose (Visit 3) for 
safety follow-up (or early withdrawal, if applicable). 
 
The overall study duration for the children will take approximately 3 to 4 weeks. 
Safety will be monitored by spontaneously reported adverse events (AEs)/serious AEs (SAEs) 
and physical examination findings. Vital signs (heart rate and blood pressure) will be assessed 
at the beginning and the end of each clinic visit to ensure the well-being of the children. 
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Figure 1: Study Flow Chart 
 
AE: adverse event; BDA MDI: budesonide/albuterol sulfate metered-dose inhaler; PK: pharmacokinetic; SAE: 
serious adverse event; TC: telephone call
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2 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary objective: 
Primary endpoints: 
To determine and compare the systemic 
exposure of budesonide after single-dose 
administrations of BDA MDI and 
Pulmicort Respules. 
AUC0-t and Cmax 
2.2 
Secondary objectives 
Secondary objective: 
Secondary endpoints: 
To determine and compare other PK 
parameters for budesonide delivered by 
BDA MDI and Pulmicort Respules 
tmax, tlast, t½λz, λz, Clast, and AUC0-inf (if 
feasible) 
2.3 
Safety objective 
Safety objective: 
Safety endpoints: 
To assess the safety and tolerability of 
BDA MDI and Pulmicort Respules 
AEs/SAEs 
AE: adverse event; AUC0-inf: area under the plasma concentration-time curve from time zero to infinity; 
AUC0-t: area under the plasma concentration-time curve from time zero to time of last quantifiable 
concentration; BDA MDI: budesonide/albuterol sulfate metered-dose inhaler; Clast: drug concentration at last 
observed timepoint; Cmax: maximum observed plasma concentration; PK: pharmacokinetic; SAE: serious 
adverse event. tlast: time of last quantifiable plasma concentration; tmax: time to reach maximum observed 
plasma concentration; t½λz: half-life associated with terminal slope (λz) of a semi-logarithmic 
concentration-time curve. 
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3 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL  
Each child must meet all of the inclusion criteria and none of the exclusion criteria for this 
study. There can be no exceptions to this rule. 
3.1 
Inclusion criteria 
For inclusion in the study, children should fulfill the following criteria: 
1. Provision of informed consent prior to any study specific procedures. Children should 
provide assent to join the study, as applicable. The child’s parent(s) or legally authorized 
representative (LAR) must sign the informed consent form (ICF). The LAR must be aged 
≥18 years old. 
2. Male or female aged between 4 and 8 years inclusive (not having reached his/her 9th 
birthday by the time of screening ([Visit 1]). 
3. Weigh at least 14 kg or higher. 
4. Clinician-diagnosed asthma of at least 3 months 
5. Stable on treatment with albuterol PRN and/or ICS and/or leukotriene receptor antagonists 
(LTRAs) for 2 weeks prior to screening; children taking budesonide in any form at Visit 1 
will be switched to another corticosteroid with a washout of budesonide of 3 to 7 days. 
6. Demonstrate ability to correctly use the nebulizer and metered-dose inhaler (MDI) device 
without a spacer (according to the instructions in Section 4.2). 
7. Willingness and ability of the child and parent(s)/LAR to comply with the demands of the 
study as described in the informed consent/assent. 
3.2 
Exclusion criteria 
Children should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Inability to change from any budesonide therapy to another suitable corticosteroid. 
2. History of life-threatening asthma defined as any asthma episode associated with loss of 
consciousness, intubation or admission to an intensive care unit. 
3. Unstable asthma as judged by the Investigator (eg, any change in asthma therapy within 
2 weeks prior to screening or use of more than 2 occasions of rescue medication 
(albuterol) per day within 1 week prior to screening (potential for rescreen). 
4. Children receiving regular maintenance treatment with prohibited anti-inflammatory or 
long-acting bronchodilator asthma medication (inhaled, nebulized, oral, or systemic) 
within 1 month prior to Visit 1. Note: During the treatment period, children are not 
allowed to use any asthma treatments/medications (of any class) other than the IMPs and 
their background treatment (ie, SABA PRN alone and/or ICS and/or LTRAs) that was 
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started before screening. No child can be on other asthma maintenance therapies. See 
Section 4.11.2 for details. 
5. More than 1 short course of oral/rectal/systemic corticosteroids within 6 months preceding 
screening (Visit 1), or any oral/rectal/systemic corticosteroids within 30 days prior to 
Visit 1. 
6. Evidence of active concomitant pulmonary disease other than asthma (children with stable 
allergic rhinitis will be permitted, as long as, there are no changes in the treatment and the 
medications do not interfere with the analytical assay methods). 
7. Upper respiratory infection involving antibiotic treatment not resolved within 14 days 
prior to Visit 1. 
8. Children with a known or suspected hypersensitivity to albuterol/salbutamol, budesonide 
or any of the excipients used in the IMPs. 
9. Having received any marketed (eg, omalizumab, mepolizumab, reslizumab, benralizumab, 
dupilumab) or investigational biologic within 3 months or 5 half-lives before Visit 1, 
whichever is longer. 
10. Systemic treatment with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, and 
ritonavir). 
11. Receipt of any other prohibited medication as detailed in Section 4.11.3. 
12. Treatment with any investigational product within the last 30 days (or 5 half-lives, 
whichever is longer) of Visit 1. 
13. Historical or current evidence of a clinically significant disease or congenital abnormality 
including, but not limited to the areas of cardiovascular, hepatic, renal, hematological, 
neuropsychological, endocrine, or gastrointestinal. Significant is defined as any disease or 
condition that, in the opinion of the Investigator, would put the safety of the child at risk 
through study participation, or that could affect the PK or safety analysis if the 
disease/condition exacerbated during the study. 
14. Cancer not in complete remission for at least 5 years before Visit 1. 
15. Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1. 
16. History of psychiatric disease, intellectual deficiency, or other conditions if their 
magnitude limits the child’s capacity to assent to the study. 
17. Having a scheduled/planned hospitalization during the study. 
18. Inability (and/or unwillingness) to abstain from protocol-defined prohibited medications 
during the study. 
19. Use of drugs with enzyme-inducing properties such as St. John’s Wort within 3 weeks 
prior to the first administration of the IMP. 
20. Use of any herbal products by inhalation or nebulizer within 2 weeks of Visit 1 and/or the 
unwillingness to stop during the study duration. 
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21. Consumption of grapefruit or grapefruit juice, Seville oranges, quinine (e.g., tonic water) 
from 7 days prior to screening (Visit 1) until after the follow-up TC. 
22. Current participation in any interventional study. 
23. Previous enrollment in the present study or randomization in any other BDA MDI clinical 
study. 
24. Immediate family member of the Sponsor or study center staff. 
For procedures for withdrawal of incorrectly enrolled children, see Section 3.4. 
3.3 
Subject enrollment and randomization 
Approximately 3 study centers in Bulgaria and the US are anticipated to be included. 
Approximately 28 children (4 to 8 years of age) will need to be screened, assuming an 
estimated screen failure rate of 50% prior to randomization in order for 14 to be randomized 
and 10 to complete. At least 4 children should be randomized in the age range of 4-5 years. 
Children who do not complete both treatments (Treatment A and Treatment B) may be 
replaced. 
Investigator(s) should keep a record, ie, the subject screening log, of children who entered 
pre-study screening. 
Randomization codes will be assigned separately for the treatment sequence and entered by 
the Investigator or designee into the electronic case report form (eCRF). If a subject 
withdraws from participation in the study, then his/her enrollment/randomization code cannot 
be reused. 
3.4 
Procedures for handling incorrectly enrolled or randomized 
subjects 
Children who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled, randomized, or receive the IMP. There can be no exceptions to this rule. There can 
be no waivers granted from the Sponsor for any child not meeting all of the inclusion criteria 
and none of the exclusion criteria. 
Where a child does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the medical monitor immediately, and a 
discussion should occur between the medical monitor and the Investigator regarding whether 
to continue or withdraw the child in the study. The medical monitor must ensure all decisions 
are appropriately documented. 
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3.5 
Methods for assigning treatment groups 
A randomization schedule will be generated by a designated statistical representative 
performing statistical support for the study. This schedule will assign children to a treatment 
sequence (A/B [BDA MDI at Visit 2 and Pulmicort Respules at Visit 3] or B/A [Pulmicort 
Respules at Visit 2 and BDA MDI at Visit 3]). This will be prepared before the first child is 
screened. The designated statistical representative will follow their established standard 
operating procedures regarding generation, security, and distribution of the randomization 
schedule. 
Upon screening, each child will receive a screening number starting with the first child and 
continuing sequentially as required. This will be specific for each study center. Children who 
drop out of the clinical study before randomization will retain their screening number. 
Randomization will occur at Visit 2 after all pre-dose procedures have been performed and 
eligibility for randomization has been re-checked. Children will be assigned a unique 
randomization number in accordance with the randomization list generated for the study. 
Randomization numbers will encode the child’s treatment assignment (A/B or B/A). 
Randomized children who withdraw or are withdrawn from clinical study participation for any 
reason, regardless of whether IMP was administered or not, will retain their randomization 
number and the child will not be allowed to re-enter the study. 
The Investigator or study center staff designee will enter the randomization number into the 
electronic data capture system (EDC). Once it has been determined that a child meets all 
eligibility criteria, the child’s information will be entered into the EDC system. 
3.6 
Methods to minimize bias: randomization and blinding 
This is an open-label study and not blinded. At Visit 2, the children will be randomly assigned 
to a treatment sequence (A/B or B/A). 
The Investigator(s) will: 
1. Obtain signed informed assent from the child and informed consent from the child’s 
parent(s) or LAR before any study-specific procedures are performed. 
2. Assign potential subject a screening number. 
3. Determine subject eligibility (see Sections 3.1 and 3.2). 
4. Re-check eligibility and subsequently randomize the child at Visit 2. 
 
Children will not have a direct access to data recorded or reported by the children. 
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3.7 
Restrictions 
Study restrictions are detailed in Section 4.11. 
3.8 
Criteria for study withdrawal 
At any time, children may withdraw from the study (ie, study procedures/visits) at their own 
request or their parent/LAR’s request for any reason, without prejudice. Children may also be 
withdrawn from the study upon request of the Investigator, or by the Sponsor at any time or 
for any reason. Some reasons for study withdrawal include: 
An AE or other unacceptable toxicity considered to jeopardize the safety of a child 
participating in the study. 
Children who suffer 1 severe exacerbation or worsening of asthma that in the Investigator’s 
opinion could affect short-term disease course or the study assessments will be discontinued if 
the Sponsor and the Investigator decide that it is in the best interest of the child to withdraw 
from the study. 
General or specific change(s) in the child’s condition that render(s) him/her ineligible for 
further participation according to the inclusion/exclusion criteria. 
• 
Non-compliance: in the opinion of the Investigator, the child is non-compliant with the 
requirements of the Clinical Study Protocol (CSP) (eg, post-enrollment eligibility 
violation). 
• 
Lost to Follow-up: the child is lost to follow-up and no alternative contact information is 
available (this implies that at least 2 documented attempts have been made to contact the 
child). 
• 
Intercurrent illness: a condition, injury, or disease unrelated to the primary diagnosis that 
becomes apparent during treatment and necessitates the child’s termination from the 
study, eg, a symptomatic lower respiratory tract infection that puts the child at potential 
risk and interferes with the child’s ability to carry out the required procedures. 
If a child is withdrawn from the study for any reason, the study center must immediately 
notify the medical monitor. The date and the reason for study withdrawal must be recorded on 
the eCRF. The child will be asked to complete the safety follow-up (or early withdrawal) TC. 
The TC will occur 2 to 5 days after the last study dose, as indicated in the Schedule of 
Assessments (Table 2). 
Children who complete both visits will have a follow-up TC and children who withdraw 
between Visit 2 and Visit 3 will have a withdrawal TC. 
In the event that a child withdraws prematurely from the study because of an AE or SAE, the 
AE/SAE will be followed up until it resolves (returns to normal or baseline values) or 
stabilizes, or until it is judged by the Investigator to no longer be clinically significant. 
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Once a child is withdrawn from the study, the child may not re-enter the study. If a child 
withdraws from participation in the study, then his/her enrollment/randomization code cannot 
be reused. Withdrawn children will be replaced if there are not enough evaluable PK samples. 
3.8.1 
Screen failures 
Screening failures are children who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomized. These children should have the reason for study withdrawal 
recorded as “Screen failure” (the potential child who does not meet 1 or more criteria required 
for participation in a study, this reason for study withdrawal is only valid for non-randomized 
children). 
Children who are screen failures may be rescreened once if temporary reasons for the original 
screen failure (eg, respiratory infections, asthma exacerbations, episodes of unstable asthma) 
have resolved. These should be at the Investigator’s discretion and in discussion with the 
medical monitor. 
3.9 
Discontinuation of the study 
The study may be stopped if, in the judgment of the Sponsor, children in the study are placed 
at undue risk because of clinically significant findings that: 
• meet individual stopping criteria or are otherwise considered significant 
• are assessed as causally related to IMP 
• are not considered to be consistent with continuation of the study. 
 
Regardless of the reason for termination, all data available for the child at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the children’s interests. 
 
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4 
TREATMENTS 
4.1 
Identity of the test and reference products 
The BDA MDI is formulated as both micronized budesonide and micronized albuterol 
co-suspended with spray-dried porous particles in a hydrofluoroalkane (HFA) propellant 
(Table 1). The co-suspension formulation ensures that children receive a consistent delivery of 
the drug from each actuation of the MDI. 
Pulmicort Respules is a sterile suspension for inhalation via jet nebulizer and contains the 
active ingredient budesonide (micronized) and the inactive ingredients disodium edetate, 
sodium chloride, sodium citrate, citric acid, polysorbate 80, and water for injection. Pulmicort 
Respules should be administered from jet nebulizers at adequate flow rates via mouthpieces 
(instructions for Pulmicort Respules will be provided separately). 
Table 1:  
Investigational medicinal product strength and dosage form 
 
Investigational Medicinal Products 
 
Treatment A (test product) a 
Treatment B (reference product) b 
Formulation: 
BDA MDI 
Pulmicort Respules 
Supplier: 
 
  
Strength: 
80/90 µg (budesonide/albuterol) 
1 mg budesonide 
Dose: 
2 inhalations 
1 ampoule 
Route of 
administration: 
Oral inhalation 
Oral inhalation 
Regimen: 
Single dose – 2 inhalations 
Single nebulization dose 
Special handling 
requirements: 
Prime per instructions. 
Contamination avoidance 
procedures. 
Nebulization until sputtering with 
nebulization cup as empty as possible. 
Contamination avoidance procedures. 
BDA MDI: budesonide/albuterol sulfate metered-dose inhaler 
Note: The IMPs (test product and the reference product) will be manufactured by 
 
a 
The placebo MDI for the test product will be used for training purposes only during screening (Visit 1) and 
will be taken home for training as well. 
A saline ampoule for the reference product will be used for training purposes only during screening (Visit 1). 
 
4.2 
Nebulization inhalation and metered-dose inhaler device 
technique 
A jet nebulizer (with mouthpiece for adequate flow rates) will be connected to a compressor 
and will be used to deliver Pulmicort Respules to each child. The brand of jet nebulizer will be 
standard across all study sites. Further details will be provided in the Site Manual. 
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The children will be provided with detailed instructions on the use of the placebo MDI device 
and Pulmicort Respules nebulization. All children must demonstrate adequate MDI and 
nebulizer administration techniques in order to be randomized as determined by the 
Investigator. 
4.2.1 
Nebulization inhalation technique 
Correct nebulization inhalation technique will be defined as follows: 
As determined by the Investigator: 
• 
No pauses during nebulization 
• 
No leakage around the mouthpiece 
• 
No breathing through the nose (a nose clip will be used if the child will accept it) 
• 
Calm and even breathing (tidal breathing) 
 
Nebulizer device and inhalation training will be conducted at screening (Visit 1). The children 
will receive placebo MDI for additional training at home. 
4.2.2 
Metered-dose inhalation technique 
Using the MDI 
1. The MDI should be held upright with the mouthpiece at the bottom and the actuation 
counter at the top as pictured in Figure 2. 
Note: The patient can be supported by an adult for performing correct inhalation (examples: 
shaking the MDI, actuating the MDI, etc). 
Figure 2: How to Hold the Metered-dose Inhaler 
 
2. Shake the MDI for 5 to 10 seconds. 
 
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3. Breathe out fully through your mouth, expelling as much air from your lungs as possible. 
Tilt your head back slightly, placing the mouthpiece into your mouth, holding the MDI 
with the mouthpiece down, and closing your lips around it, as presented in Figure 3. To 
allow the medication to enter your lungs, keep your tongue flat on the bottom of your 
mouth. 
Figure 3: How to Use the Metered-dose Inhaler 
 
 
4. While breathing in deeply and slowly through your mouth, fully depress the top of the 
actuation counter with your index finger. Immediately after the spray is delivered, release 
your finger from the canister. When you have breathed in fully, remove the MDI from 
your mouth and close your mouth. 
NOTE: an audible “click” may be heard which is advancement of the actuation counter and 
considered normal. 
 
5. Hold your breath as long as possible, up to 10 seconds, and then breathe normally. 
6. Repeat steps #2 to #5 for the second inhalation to complete the full dose. 
7. After you finish taking 2 inhalations, rinse your mouth with water. Spit out the water. Do 
not swallow it.  
8. Place the dust cap back onto the device. 
 
Training with the placebo MDI (Children) 
Placebo MDI and inhalation training will be conducted at screening (Visit 1). 
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After demonstrating correct inhalation technique, the child will receive placebo MDI for 
training at home. Children should use the placebo MDI with an adult’s help, as instructed by 
study center staff. Children should practice with the placebo MDI as appropriate, with 2 
actuations per training inhalation, to be able to demonstrate adequate MDI inhalation 
technique at the randomization visit. 
4.3 
Supply of test and reference products 
The test product (BDA MDI) will be supplied by 
 The reference product 
(Pulmicort Respules) will be supplied by 
 Both products will be labelled with a 
study-specific label. 
Dispensing and retention of reserve samples of the test and reference products will be 
performed in accordance with the Compliance Policy for the Quantity of Bioavailability and 
Bioequivalence Samples Retained Under 21 CFR 320.38(c) Guidance for Industry. 
4.4 
Dose and treatment regimens 
At screening (Visit 1), assenting children and consenting parents (or LAR) will be assessed to 
ensure that the child meets eligibility criteria. At this visit, nebulizer device and inhalation 
training will be conducted. 
At Visit 2, eligible children will be randomized to either the A/B or B/A treatment sequence. 
Handling instructions for the BDA MDI and Pulmicort Respules will be available for each 
study center throughout the study (Sections 4.2 and 4.10). 
4.5 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. 
The labels will fulfill GMP Annex 13 requirements for labelling. Label text will be translated 
into local language. 
The address and telephone number of the main contact for information on the product, clinical 
study and emergency contact will be provided to the child in the form of a leaflet or card 
which provides these details. The child must be informed to keep this in their possession at all 
times. 
Test Product (BDA MDI) labelling: 
Each kit will contain an MDI device, wrapped in a foil bag held within a carton. 
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All unused supplies of IMP will either be destroyed or returned at the end of the study in 
accordance with instruction by the Sponsor. 
4.7 
Storage 
All test and reference products should be kept in a secure place under appropriate storage 
conditions. 
Due to regional differences in regulatory requirements and standards, each countries’ 
permitted storage conditions are detailed in the local language of the carton label. 
Test Product (BDA MDI 80/90 μg) should be stored as below: 
For US: Store between 20° to 25°C, excursions permitted up to 30°C (86°F) 
For European Union (EU): Store between 15° to 25°C 
Reference Product (Pulmicort Respules) should be stored as below: 
For US: Store at controlled room temperature 20° to 25°C (68° to 77°F [see USP]) 
For EU: Do not store above 30°C 
Temperature readings of the storage area (minimum/maximum) should be recorded on every 
working day at a minimum. 
4.8 
Compliance 
The administration of all test and reference products will be captured and recorded in the 
appropriate sections of the eCRF, as applicable. The IMP accountability will be recorded in 
the eCRF. Compliance will be assured by direct supervision and witnessing of IMP 
administration. Device and nebulization inhalation training is discussed in Section 4.2. 
4.9 
Accountability 
All test and reference products will be returned to the approved study returns vendor for 
destruction after accountability and reconciliation is complete. 
4.10 
Metered-dose inhaler handling 
Detailed handling instructions will be provided to the study center in the form of a “Site 
Manual” document, which will cover all aspects of the study with regards to the test product. 
The importance of the device priming requirements should be emphasized. Priming of the test 
product MDI must occur. 
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4.11 
Concomitant and other treatments 
4.11.1 
Investigational medicinal product 
During the study, subjects are not allowed to use any asthma medication other than the IMPs 
and their background treatment (ie, SABA PRN alone and/or ICS and/or LTRA) that was 
started before screening (with the exception of budesonide) and continued as part of their 
asthma treatment (see Section 3.1). Non-asthma medications which are necessary for the 
subject’s wellbeing and which do not affect the participation or results of the study are 
allowed at the investigator’s discretion. All such medication should be recorded in the 
appropriate sections of the subject’s eCRF. 
4.11.2 
Permitted asthma therapies 
Short-acting beta agonists taken PRN and/or low-to-medium dose ICS and/or LTRAs are the 
only permitted therapies to be used as asthma therapy on-study as specified in Section 3.2. No 
child can be on any other asthma maintenance therapies. 
During the study, children should maintain stable dosing of their maintenance and/or PRN 
therapy as presented at screening. Dose changes to maintenance therapy are discouraged 
unless clinically indicated. Investigators should notify the study medical monitors of any 
change to maintenance therapy for study subjects; considerations should be made to subject 
treatment compliance and other factors in advance of making changes to maintenance therapy. 
4.11.3 
Prohibited medications 
Prohibited concomitant medications during and at least 1 month prior to the study include the 
following, with specified timeframes where needed: 
• Oral, parenteral, or rectal corticosteroids (except if required to treat severe asthma 
exacerbation) during and at least 30 days prior to Visit 1. 
• Any other asthma medication except Sponsor-provided test product or Pulmicort 
Respules during Visits 2 and/or 3 and the permitted SABA PRN alone and/or ICS 
and/or LTRA treatment that was started before screening and continued as part of 
maintenance treatment (see Section 3.1), regular SABA use (eg, four times a day 
[QID]) is not permitted. 
• Inhaled disodium cromoglycate or inhaled nedocromil sodium 
• 5-lipoxygenase inhibitors (ie, zileuton) 
• Inhaled short-acting anticholinergics (or short-acting muscarinic antagonists [SAMA], 
ie, ipratropium) 
• Inhaled long-acting muscarinic antagonists (LAMA) 
• Inhaled LABA 
• Phosphodiesterase-4 inhibitors (ie, roflumilast) 
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• Xanthine and theophylline 
• Omalizumab, benralizumab, mepolizumab, reslizumab, dupilumab, or any other 
monoclonal or polyclonal therapy for any reason during the study or within 3 months 
or 5 half-lives before Visit 1, whichever is longer; (locally administered biologics, eg, 
intra-ocular, are allowed) 
• Beta-2-adrenergic blockers, including eye-drops; (For the purpose of this study, 
metoprolol is considered to have beta-2-adrenergic receptor blocking ability.) 
• Drugs with enzyme-inducing properties such as St. John’s Wort within 3 weeks prior 
to the first administration of the IMP. 
• Systemic treatment with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, 
and ritonavir). 
4.11.4 
Food and beverage restrictions 
Children should abstain from consumption of grapefruit or grapefruit juice, Seville oranges, 
quinine (eg, tonic water) from 7 days prior to screening on Day 1 until after the follow-up TC. 
Children may eat a light breakfast at home prior to the clinic visits. 
5 
STUDY PLAN AND TIMING OF PROCEDURES 
Table 2 presents study assessments and procedures. 
General Considerations 
To ensure standardization, it is recommended that study centers review and remind/discuss the 
following with the child on at least the day before a scheduled visit, as applicable: 
• Site personnel will remind/instruct children not to take any prohibited asthma 
medications during the study. Non-asthma medications which are necessary for the 
child’s well-being and which do not affect the participation in or results of the study, 
are allowed. All such medication should be recorded in the child’s eCRF. 
• Children must not ingest/consume xanthine and/or xanthine analogue 
(caffeine)-containing foods and beverages for at least 6 hours prior to each study visit 
and for the duration of each study visit. Examples of such products include coffee, tea, 
chocolate, and cola. Decaffeinated beverages are acceptable. 
• To minimize diurnal variance, study centers should make every effort to assess 
children at the same time throughout the study. 
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Table 2: 
Schedule of assessments 
Screening 
Period 
Open-label Treatment 
Period 
Follow-up or early 
withdrawal 
Visit 
1 
2 
3 
4 - TC 
Day 
Starting from 
Day -14 
0 
2 to 14 days 
after V2 
2 to 5 days after V3 
Informed consent/assent 
X 
Eligibility criteria 
X 
Re-check eligibility criteria 
X 
Randomization 
 
X 
 
 
Routine clinical procedures 
Medical/surgical history 
X 
Demography 
X 
Physical examination 
X 
Height, weight, and BMI 
X 
Routine safety measurements 
Laboratory assessments (including local laboratory clinical chemistry, 
hematology, and urinalysis) a 
X 
AEs and concomitant medications 
X 
X 
X 
X 
Seated vital signs (blood pressure and heart rate) b 
X 
X 
X 
Placebo MDI training c 
X 
 
 
 
Nebulization training 
X 
 
 
 
Randomized IMP 
X 
X 
Blood sampling for PK - Timepoints 
A total of 10 samples 
will be taken per 
treatment visit at 
pre-dose and at 10, 20, 
40, 60, 120, 240, 360, 
480 and 720 min after 
dosing.  
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AE: adverse event; BMI: body mass index; IMP: investigational medicinal product; MDI: metered-dose inhaler; min: minute; PK: pharmacokinetic; 
TC: telephone call; V: Visit. 
a Laboratory assessments (clinical chemistry, hematology and urinalysis) will be performed according to Section 6.3.1. 
b Vital signs will be assessed at the beginning (pre-dose) and the end (post-last PK sample) of each study visit. 
c Training for placebo MDI will occur at Visit 1 and the placebo MDI will go home with the child for additional training prior to randomization. 
 
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5.1 
Screening period 
Screening (Visit 1) will take place within 14 days prior to Randomization. During screening, 
assenting children and consenting parent(s) (or LAR) are assessed to ensure that the child 
meets eligibility criteria. Procedures will be performed according to study assessments and 
procedures presented in Table 2. Children who do not meet all of the inclusion criteria and 
none of the exclusion criteria must not be randomized into the study. 
5.1.1 
Visit 1 
Standard demographic data and other characteristics will be recorded and will include age, 
gender, race, and ethnicity according to local regulations. 
If a child has COVID-19 at Visit 1, the child should not attend the visit. The study center 
should take adequate measures (See Appendix D COVID-19 Emergency Measures Permitted 
to Ensure Subject Safety). 
A standard medical, disease, and surgical history will be obtained with review of the inclusion 
and exclusion criteria with the child. Other study procedures carried out during this period will 
include physical examination (with height, weight, and body mass index [BMI]), concomitant 
medications review, seated vital signs (blood pressure and heart rate), training with placebo 
MDI and nebulization, AEs assessment/review, blood samples for hematology and clinical 
chemistry, and urine samples for urinalysis. See Sections 4.2, 6.3 and 6.4 for details on 
assessments. 
5.2 
Randomization/treatment period 
Procedures will be performed according to study visit assessments presented in Table 2. The 
Open-label Treatment Period consists of 2 visits (Visit 2 and Visit 3). Children meeting all of 
the inclusion criteria and none of the exclusion criteria will be randomized at Visit 2. 
5.2.1 
Visit 2 and 3 
At Visit 2, eligibility criteria will be re-checked. Eligible children will then be randomized 
(1:1) to treatment sequence A/B or treatment sequence B/A at Visit 2. Pharmacokinetic 
samples will be taken up to 12 hours after dosing in alignment with the sampling schedule. 
Other study procedures carried out during this period will include seated vital signs (blood 
pressure and heart rate), AEs assessment/review, and concomitant medications review. 
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Table 3: 
Treatment sequence 
Treatment 
sequence 
Visit 2 
Visit 3 
A/B 
BDA MDI 160/180 μg (given as 2 
actuations of BDA MDI 80/90 μg) 
1 mg Pulmicort Respules 
B/A 
1 mg Pulmicort Respules  
BDA MDI 160/180 μg (given as 2 actuations of BDA MDI 
80/90 μg [budesonide/albuterol])  
BDA MDI: budesonide/albuterol sulfate metered-dose inhaler 
 
For the test product, after the BDA MDI is primed and ready for use, the Investigator will 
provide the test product to the child (written instructions will be provided in the study 
manual). The test product will be administered in the study center. 
For the reference product, one dose is removed from the foil envelope and added to the jet 
nebulizer to be ready for use. The reference treatment will then be provided to the child in the 
study center. A manual with instructions on delivering the Pulmicort Respules will be 
provided. 
The exact date and start time of BDA MDI and Pulmicort Respules will be recorded in the 
eCRF in addition to the exact date and time of PK sampling. 
In order to reduce the possibility of contamination of blood samples via hands, clothes, 
furniture, etc., precautions must be taken to avoid the possibility of contamination. BDA MDI 
activation and Pulmicort Respules nebulization must take place in a separate room from all 
other activities. The persons entering the room must wear appropriate protective gear (coats, 
gloves, caps, and shoes). Protective clothing must be discarded prior to leaving the room. 
Children must be instructed to wash their hands (soap and water) and faces (with at least two 
wet tissues (discard after washing), prior to leaving the room. The staff and parent(s) must 
remove/discard the face mask worn to protect the face and then wash their hands with soap 
and water. Cross contamination between multiple children being dosed must be considered as 
well for study center staff and additional precautions taken per the study center’s normal 
practice. 
All handling of the nebulizers must be done in the nebulization room. 
Additionally, children must rinse their mouths twice with tap water directly after taking the 
BDA MDI or receiving nebulization. 
5.3 
Follow-up period or early withdrawal 
The planned end of study will occur upon completion of Visit 4. The follow-up TC will occur 
2 to 5 days after Visit 3. 
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Procedures will be performed according to study visits and procedures presented in Table 2. 
The study procedures carried out during the follow-up period will include recording of 
concomitant medications and AEs. 
Children who complete both visits will have a follow-up TC and children who withdraw 
between Visit 2 and Visit 3 will have a withdrawal TC. 
See Sections 3.8 and 3.9 for details on study withdrawal procedures. 
6 
MEASUREMENTS AND METHODS OF ASSESSMENTS 
6.1 
Appropriateness of Measurements 
Standard measures to assess PK and safety apply during the study. For the single doses of 
BDA MDI and Pulmicort Respules, no safety issues are expected. 
For timing of assessments, refer to Table 2. 
6.2 
Pharmacokinetic Assessments 
Venous blood samples (~4 mL each) to determine plasma budesonide concentration will be 
collected at Visit 2 and Visit 3. A total of 10 samples will be collected at each visit, the pre-
dose sample within 30 minutes prior to dose administration and then at 10, 20, 40, 60, 120, 
240, 360, 480 and 720 minutes after dosing of the BDA MDI (Treatment A) and after the start 
of inhalation of the Pulmicort Respules (Treatment B). 
The blood samples will be collected, labeled, processed, stored, and shipped as detailed in the 
Laboratory Manual. The date and actual sampling times will be recorded on the appropriate 
eCRF. 
The reference time for blood sampling will be at the start of inhalation as captured in the 
eCRF. In total, 40 mL of blood will be collected from each child at each visit for analysis of 
budesonide in plasma. 
6.3 
Safety assessments 
6.3.1 
Laboratory assessments 
Samples for determination of clinical chemistry, hematology, and urinalysis will be taken at 
Visit 1 as indicated in Table 2. Total blood volume, including PK sampling, is summarized in 
Table 5. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. 
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The clinical chemistry, hematology, and urinalysis assessments will be performed using a 
local laboratory. Sample tubes and sample sizes may vary depending on laboratory method 
used and routine practice at each study center. 
The following laboratory variables in Table 4 will be measured: 
Table 4: 
Laboratory variables 
Hematology/Hemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
Basophils (%) 
Albumin 
Basophils Abs 
Alanine transaminase  
Eosinophils (%) 
Alkaline phosphatase  
Eosinophils Abs 
Aspartate transaminase  
Hemoglobin  
Bilirubin, total 
Hematocrit 
Calcium, total 
Mean Corpuscular Hemoglobin 
Chloride 
Mean Corpuscular Hemoglobin Concentration 
Cholesterol, total 
Mean Corpuscular Volume 
Creatinine 
Monocytes (%) 
Creatine kinase 
Monocytes Abs 
Gamma-glutamyl transpeptidase  
Neutrophils (%) 
Glucose (random) 
Neutrophils Abs 
Magnesium 
Red blood cells (erythrocytes) 
Phosphate  
White blood cells (leukocytes)  
Potassium  
Platelet count 
Protein, total 
Lymphocytes Abs 
Sodium 
Lymphocytes (%) 
Triglycerides 
 
 
Urine* 
 
Urine blood 
 
Leukocyte esterase 
 
Urine protein 
 
Urine glucose 
 
Nitrite 
 
Abs: absolute 
*If leukocyte esterase is detected, the site should send the sample for culture. If abnormal levels of blood or 
protein are detected, the sample should be sent for microscopic examination. 
 
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Table 5:  
Total blood volume 
 
Volume per 
Sample 
Number of 
Samples 
Total 
Clinical chemistry 
~0.5 mL 
1 
0.5 
Hematology 
~0.5 mL 
1 
0.5 
Pharmacokinetics 
~4 mL 
20 
80 mL 
TOTAL 
 
81 mL 
 
Approximately 20-30 mL urine per sample will be taken for urinalysis. 
6.3.2 
Physical examination 
A complete physical examination will be performed at Visit 1 (if applicable) as indicated in 
Table 2. This will include an assessment of the following items: height in centimeters and 
weight (kilograms) and BMI (kg/m2) (at Visit 1 only), general appearance, respiratory system, 
cardiovascular system, abdomen, skin, head and neck (including ears, eyes, nose, and throat), 
lymph nodes, thyroid, musculoskeletal system (including spine and extremities), and 
neurological system. 
6.3.3 
Vital signs 
Vital signs will include measurements of blood pressure (mmHg) and heart rate (beats/min), 
while the child is seated. 
Blood pressure measurements (systolic blood pressure and diastolic blood pressure) should be 
taken in the sitting position after at least 10 minutes of rest. 
Any clinically significant values in vital signs should be recorded as an AE if applicable. 
6.3.4 
Adverse event assessments 
Adverse events will be collected from time of signature of ICF/assent form through to the 
follow-up timepoint, as described in Section 7.3. 
6.4 
Other assessments 
6.4.1 
Concomitant medications 
The collection and recording of all concomitant medications, including all pre-enrollment 
asthma therapies will be performed as indicated in Table 2. Permitted and restricted 
concomitant medications are further described in Section 4.11. 
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All prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications 
taken within 3 months before screening will be recorded as prior medications. All medications 
taken after screening and through the follow-up TC will be recorded as concomitant therapy. 
For restrictions relating to prior and concomitant medications, see Sections 3.1 and 3.2. 
7 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section. 
Serious AEs will be reported as per standard reporting guidance. Associated symptoms of 
asthma are considered as symptoms of disease under study and will not be recorded as AEs 
unless considered an SAE. 
7.1 
Definition of adverse event 
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
the screening period, even if no IMP has been administered. 
7.2 
Definition of serious adverse event 
An SAE is an AE occurring during any study period (ie, after the signing of the ICF/assent 
form through to the safety follow-up TC), that fulfills 1 or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability or incapacity  
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent 1 of the outcomes listed above 
For further guidance on the definition of an SAE, see Appendix C. 
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7.3 
Recording of adverse events 
7.3.1 
Period for collection of adverse events 
Adverse events (including SAEs) will be collected from the time of signature of the 
ICF/assent form through the safety follow-up TC. 
7.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the child’s last assessment visit in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. 
 and the Pharmacovigilance Department representative retains the right to 
request additional information for any child with ongoing AE(s)/SAE(s) at the end of the 
study (after the child’s follow-up TC) and capture that information in the eCRF, if judged 
necessary. 
7.3.3 
Variables 
The following variables will be collected for each AE: 
• Adverse event (verbatim) 
• Dates when the AE started and stopped 
• Maximum severity 
• Seriousness 
• Investigator causality rating against the IMP (yes or no) 
• Action taken with regard to the IMP 
• Outcome 
In addition, the following variables will be collected for SAEs, when applicable: 
• Date AE met criteria for SAE 
• Date the Investigator became aware of SAE 
• Reason why the AE is considered serious 
• Treatment given for the SAE 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Whether an autopsy is performed 
• Causality assessment in relation to study procedure(s) 
• Causality assessment to other medication 
• Description of AE 
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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 7.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Section 7.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Section 7.2. 
The severity of the event should be assessed as mild, moderate, or severe. 
7.3.4 
Causality collection 
The Investigator and the Sponsor will assess causal relationship between the IMP and each 
AE, and answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?” 
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as “yes”. 
A guide to the interpretation of the causality question is found in Appendix C. 
7.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the child or care provider or reported in response to the 
open question from the study center staff: “Have you/your child had any health problems 
since the previous visit/you (or your child) were last asked?”, or revealed by observation will 
be collected and recorded in the eCRF. When collecting AEs, recording a diagnosis is 
preferred (when possible) to the recording of a list of signs and symptoms. However, if a 
diagnosis is known and there are other signs or symptoms that are not generally part of the 
diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
Asthma symptoms or signs, such as wheeze, cough, chest tightness, dyspnea, breathlessness, 
and phlegm, will be recorded as AEs only when: 
• The sign or symptom is serious 
• The child discontinues the study because of the sign or symptom 
• The sign or symptom is new to the child or not consistent with the child’s pre-existing 
asthma history (defined as within 1 year of Visit 1) as judged by the Investigator. 
7.3.6 
Adverse events based on examinations and tests 
The results from the CSP mandated and repeat/unscheduled measurements for laboratory 
tests, vital signs (ie, blood pressure and heart rate) and other assessments will be summarized 
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in the Clinical Study Report. Deterioration from baseline in these parameters should therefore 
only be reported as AEs if they fulfill any of the AE criteria or are the reason for 
discontinuation from the study or are considered “clinically significant.” 
The criteria for determining whether the mandated laboratory tests, vital signs, and other 
assessments are clinically significant and should be reported as AEs are generally: 
• 
Test result is associated with accompanying symptoms or signs, and/or  
• 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or  
• 
Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or  
• 
Test result is considered to be an AE by the Investigator or Sponsor. 
 
If deterioration in a laboratory value, vital sign, or other assessment is associated with clinical 
signs and symptoms, the sign or symptom will be reported as an AE and the associated 
parameter will be considered as additional information. Wherever possible the reporting 
Investigator uses the clinical, rather than the laboratory term (eg, anemia versus low 
hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
7.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs during the course of the study, then investigators or other study center 
personnel should inform the Clinical Research Organization (CRO) within 1 day ie, 
immediately but no later than 24 hours of when he/she becomes aware of it. 
The Principal Investigator will review each SAE and evaluate the intensity and the causal 
relationship of the event to IMP. All SAEs will be recorded from signing of the ICF/assent 
until the End-of-study Visit. Serious AEs occurring after the End-of-study Visit and coming to 
the attention of the Principal Investigator must be reported only if there is (in the opinion of 
the Principal Investigator) reasonable causal relationship with the IMP. 
The Principal Investigator is responsible for providing notification to the CRO/Sponsor of any 
SAE, whether deemed IMP-related or not, that a child experiences during their participation in 
study within 24 hours of becoming aware of the event. 
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As a minimum requirement, the initial notification should provide the following information: 
• 
Study number 
• 
Subject number 
• 
Sex 
• 
Date of birth 
• 
Name of Principal Investigator and full study center address 
• 
Details of SAE 
• 
Criterion for classification as ‘serious’ 
• 
The IMP name, or code if unblinded, and treatment start date 
• 
Date of SAE onset 
• 
Causality assessment (if sufficient information is available to make this classification). 
 
The CRO/Sponsor will request clarification of omitted or discrepant information from the 
initial notification. The Principal Investigator or an authorized delegate is responsible for 
emailing or faxing the requested information to the CRO/Sponsor within 24 hours of the 
request. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear 
photocopies of other documents as necessary (eg, hospital reports, consultant reports, autopsy 
reports), with the child’s personal identifiers removed. All relevant information obtained by 
the Principal Investigator through review of these documents will be recorded and faxed to the 
Sponsor within 24 hours of receipt of the information. If a new SAE Report Form is faxed, 
then the Principal Investigator must sign and date the form. The CRO/Sponsor may also 
request additional information on the SAE, which the Principal Investigator or an authorized 
delegate must fax to the Sponsor within 24 hours of the request. Contact information for the 
appropriate safety reporting service will be provided in the Site Manual. 
7.5 
Follow-up of adverse events 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored 
until the event has resolved, until any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Principal Investigator and Medical Monitor, until there is 
a satisfactory explanation for the changes observed or until the subject is lost to follow-up. 
7.6 
Overdose 
Acute overdosage with inhaled budesonide, even in excessive doses, is not expected to be a 
clinical problem. 
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For the purpose of this study, an accidental or deliberate intake of treatment of more than 2 
actuations of the BDA MDI or more than 1 Respule of Pulmicort during Visits 2 and 3 is 
defined as an overdose and must be reported as such as described below. 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose/Medication Error eCRF module. An overdose 
without associated symptoms is only reported on the Overdose/Medication Error eCRF 
module. 
The maximum daily dosage of IMP should not exceed 2 actuations per visit. If an overdose of 
IMP occurs in the course of the study which has an associated SAE, then the Investigator or 
other study center personnel will inform the CRO immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
In the event of a suspected overdose, the Investigator should: 
1. Contact the 
 Medical Monitor immediately. 
2. Closely monitor the child for AE/SAE and laboratory abnormalities until the IMP can no 
longer be detected systemically (at least 6 weeks). 
3. Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
IMP if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with 
the Medical Monitor based on the clinical evaluation of the child. 
For overdoses associated with an SAE, the standard SAE reporting timelines apply, see 
Section 7.4. 
7.7 
Medication error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for the Sponsor’s test product or the reference product that either causes 
harm to the child or has the potential to cause harm to the child. 
A medication error is not lack of efficacy of the drug, but rather a human or process-related 
failure while the drug is in control of the study center staff or child. 
A medication error includes situations where an error:  
• occurred 
• was identified and intercepted before the child received the drug 
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• did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
• Drug name confusion 
• Preparation error, eg, medication prepared incorrectly, even if it was not actually given 
to the child 
• Drug not administered as indicated, eg, wrong route or wrong site of administration 
• Drug not taken as indicated 
• Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature 
• Wrong child received the medication (excluding data system errors) 
• Wrong drug administered to child (excluding data system errors) 
• Child received the medication in the wrong order (excluding data system errors) 
Examples of events that do not require reporting as medication errors in clinical studies: 
Errors related to or resulting from the data system - including those which lead to 1 of the 
above listed events that would otherwise have been a medication error  
Accidental overdose (will be captured as an overdose) 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error. 
All medication errors must be recorded in the Overdose/Medication Error eCRF. Any 
associated AEs should also be recorded as the AE diagnosis/symptoms on the relevant 
AE/SAE modules in the eCRF. 
If a medication error occurs during the course of the study which has an associated SAE, then 
the Investigator or other study center personnel will inform the CRO immediately, or no 
later than 24 hours of when he or she becomes aware of the medication error. 
The CRO will work with the Investigator to ensure that all relevant information is provided to 
CRO representative. For medication errors associated with an SAE, the standard SAE 
reporting timelines apply, (see Section 7.4). 
7.8 
Management of test product-related toxicities 
In the absence of a specific antidote, management of toxicities can be dealt with on the basis 
of the symptoms. 
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8 
STATISTICAL METHODS 
8.1 
Statistical considerations 
Analyses will be performed by the Sponsor or its representatives. Comprehensive analysis 
plans will be written for PK and statistical analyses separately, and any subsequent 
amendments will be documented, with final amendments completed before the database lock. 
8.2 
Sample size estimate 
No prospective calculations of statistical power have been made. Complete data (evaluable data 
from both Treatment A and Treatment B) from 10 children is considered sufficient to provide 
information on the PK in this population without exposing more children than necessary to the 
IMP. Considering potential dropouts, approximately 14 children will be randomized. Results 
will be interpreted in the perspective of the explorative nature of the study. 
8.3 
Definitions of analysis sets 
8.3.1 
Pharmacokinetic analysis set 
The PK analysis set will consist of all randomized children for whom at least 1 of the primary 
PK parameters can be calculated and who have no major protocol deviations impacting PK. 
Children who do not provide evaluable data for both treatments (Treatment A and 
Treatment B) will be excluded from the statistical analysis, which is the analysis of variance 
(ANOVA). 
Any excluded cases will be documented together with the reason for exclusion. 
8.3.2 
Safety analysis set 
The safety analysis set is defined as all children receiving any amount of either the test or 
reference product. Children will be classified on the basis of treatment they actually received 
within the treatment period. Occurrences of safety events (ie, AEs and use of concomitant 
medication) will be summarized under the actual treatment corresponding to the treatment 
period of which the event occurred. All safety summaries will be based on the safety analysis 
set. 
8.3.3 
All subjects enrolled analysis set 
The all subjects enrolled analysis set will be defined as all children who provide informed 
assent and whose parent(s) or LAR(s) have provided informed consent. This analysis set will 
be used for descriptive summaries of disposition. 
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8.3.4 
All subjects randomized analysis set 
The all subjects randomized analysis set will be defined as all children who have been 
randomized to a treatment sequence. This analysis set will be used for listings of demographic 
variables and listings and descriptive summaries of prior and concomitant medications. 
8.4 
Violations and deviations 
Important protocol deviations will be listed and summarized by randomized treatment group. 
All children who failed any inclusion/exclusion criteria will be listed along with details of the 
failed criteria. This information will also be summarized in terms of the number and 
percentage of children failing any of the inclusion/exclusion criteria and will be based on the 
full analysis set. 
8.5 
Subject disposition 
Summaries of subject disposition will include the following information: Number of children 
enrolled, screen failed, randomized, number and percentage of randomized children treated, 
not treated, who completed the study, and the number and percentage of randomized children 
who were withdrawn (including reasons for withdrawal). Disposition data will be presented by 
planned treatment sequence and overall based on the all subjects enrolled analysis set. 
Randomized children who are excluded from the analysis sets (as defined in Section 8.3) will 
be listed and will include the planned treatment sequence and reason for exclusion. 
8.6 
Demographic and baseline characteristics 
Demographic variables (age, gender, race, ethnicity, height, weight, and BMI) will be listed 
by child, for all randomized children. 
Demographic characteristics (age, gender, race, and ethnicity) and subject characteristics 
(height, weight, and BMI) will be summarized by treatment sequence and overall based on the 
children in the safety analysis set. The denominator for percentages will be the number of 
children in the safety analysis set. 
Medical history data will be listed by child including planned treatment sequence, visit, 
description of the disease/procedure, Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class (SOC), MedDRA Preferred Term, start date and stop date (or ongoing if 
applicable). 
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8.7 
Prior and concomitant medication 
Prior medications are those that started and stopped prior to the first dose of randomized 
treatment; all medications taken after first dose of randomized treatment are considered as 
concomitant (including medications that started prior to dosing and continued after). 
Prior and concomitant medication will be summarized separately by coded preferred term 
(according to the WHODrug dictionary) and planned treatment sequence. Prior and 
concomitant medication will be listed by child and will include the following information: 
planned treatment sequence, reported name, coded preferred term, the route of administration, 
dose, frequency, start date/time and indication. Descriptive summaries and listings of prior 
and concomitant medication will be based on the all subjects randomized analysis set. 
8.8 
Pharmacokinetic analysis methods and parameters 
A listing of PK blood sample collection times, and all reportable budesonide concentrations 
will be provided for all children. Budesonide concentrations will be summarized by treatment 
using descriptive statistics. 
Plasma samples will be analyzed using non-compartmental analysis (NCA) to determine the 
PK (AUC0-t, Clast, Cmax, tmax, tlast, λz, t½λz, and AUC0-inf [if feasible]) of budesonide in 
plasma. 
This study is descriptive. There are no predefined statistical hypotheses and no predetermined 
tests or decision rules. The relative exposure of budesonide between BDA MDI versus 
Pulmicort Respules will be based on estimates of the AUC0-t and Cmax. 
The AUC0-t and Cmax for budesonide will be compared between treatments using a 
multiplicative (ie, log-transformation) ANOVA model with treatment sequence, period, and 
subject within sequence as fixed effects. Geometric mean ratios between test (BDA MDI) and 
reference (Pulmicort Respules) treatments and 90% confidence limits will be calculated from 
the model. Half-life and tmax will be compared by means of descriptive statistics. 
A detailed PK analysis plan will be prepared prior to database lock. 
8.9 
Safety analysis 
Continuous safety variables will be summarized using descriptive statistics (n, mean, standard 
deviation, minimum, median, maximum) by treatment. Categorical variables will be 
summarized in frequency tables (frequency and proportion) by treatment. The analysis of the 
safety variables will be based on the safety analysis set and will be reported using the actual 
treatment associated with the observed data. 
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8.9.1 
Laboratory assessments 
The clinical chemistry, hematology, and urinalysis assessments will be listed by treatment 
sequence and visit including repeat/unscheduled measurements. 
The listings will include the following information: test name, date of measurement, reference 
range, result and clinical significance, as determined by the Investigator. 
8.9.2 
Physical examination 
The results of the physical examination conducted at Visit 1 will be documented in medical 
history for each child. 
Any new or aggravated clinically relevant abnormal medical physical examination finding 
compared to the baseline assessment will be reported as an AE. 
Results of height, weight, and BMI will be listed by child, treatment sequence and visit, and 
summarized with other demographics and baseline characteristics data. 
8.9.3 
Vital signs 
Vital signs of heart rate (beats/min), systolic blood pressure (mmHg) and diastolic blood 
pressure (mmHg) will be listed by treatment sequence and visit including the date/time of the 
assessment, and repeat/unscheduled measurements. 
Descriptive statistics of heart rate, systolic blood pressure and diastolic blood pressure 
collected at Visit 2 and 3 will be summarized by treatment group and timepoint (pre-dose and 
post-last PK assessment). 
8.9.4 
Adverse events 
All AEs will be coded using the MedDRA dictionary and will be listed for each child by 
treatment sequence assigned. A treatment-emergent adverse event (TEAE) is defined as an AE 
with onset (start date/time) on or after the first dose of randomized IMP at Visit 2. Any AEs 
occurring in the washout between successive treatment periods will also be regarded as 
treatment-emergent and assigned to the treatment administered in the period prior to the 
washout. Additional details on assigning an AE to a treatment period based on AE start and 
end dates will be further detailed in the statistical analysis plan (SAP). 
Adverse events will be summarized by Preferred Term and SOC using MedDRA dictionary. 
Furthermore, children with SAEs, AEs that led to death, and AEs that led to withdrawal will 
be summarized and listed separately. 
Adverse events that occur before dosing will be reported separately. 
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9 
STUDY AND DATA MANAGEMENT 
9.1 
Training of study center staff 
An EDC system will be used for data collection and query handling. The Investigator will 
ensure that data are recorded on the eCRFs as specified in the CSP and in accordance with the 
instructions provided. 
Before the first child is entered into the study, a designated representative will review and 
discuss the requirements of the CSP and related documents with the investigational staff and 
also train them in any study specific procedures and the EDC DataLabs system(s) utilized. 
The Investigator(s) will ensure that appropriate training relevant to the study is given to all of 
these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Investigator(s) will maintain a record of all individuals involved in the study (medical, 
nursing, and other staff). 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Trial Agreement. The 
Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study center. 
Hematology, chemistry, and urinalysis will be done by the study center’s local laboratory and 
PK assessments will be done by a central laboratory. 
9.2 
Monitoring of the study 
During the study, the Sponsor or a designated representative will have regular contacts with 
the study center, including visits to: 
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the CSP, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that IMP accountability checks are being 
performed. 
• Perform source data verification (a comparison of the data in the eCRFs with the 
child’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent/assent of participating children. This 
will require direct access to all original records for each child (eg, clinic charts). 
• Ensure all SAEs and AEs have been captured and reported correctly, providing 
oversight of child safety while on-study. 
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• Verify the correct storage, handling, administration, and return of all test and reference 
products. 
The designated representative will be available between visits if the Investigator(s) or other 
staff at the center needs information and advice about the study conduct. 
9.2.1 
Source data 
Source documents provide evidence for the existence of the child and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s study center. 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records. Also, current medical records must be 
available. 
Definition of what constitutes source data can be found in the Source Data Agreement, agreed 
with each Investigator before site initiation. 
9.2.2 
Study agreements 
The Investigator(s)/the participating center(s) should comply with all the terms, conditions, 
and obligations of the CSP for this study. 
Clinical Trial Agreements with the Investigator(s)/the participating center(s) should be in 
place before any study-related procedures can take place, or children are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Trial Agreement. 
9.3 
Study timetable and end of study 
The end of the study is defined as “the last visit of the last child undergoing the study”. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow. The Sponsor may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with either the test or reference product. 
9.4 
Data management 
All subject data relating to the study will be recorded in eCRFs unless transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
case report form (CRF). 
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Guidance on completion of eCRFs will be provided in the CRF Completion Instructions 
document. 
The Investigator must permit study-related monitoring, audits, EC review, and Regulatory 
Agency inspections and provide direct access to source data documents. 
Monitoring details describing strategies, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
Records and documents, including signed ICF/assent, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No records 
may be transferred to another location or party without written notification to the Sponsor. 
All data generated by the study center personnel will be captured electronically at each study 
center using eCRFs. Data from external sources (such as laboratory data) may be imported 
into the database. Once the eCRF clinical data have been submitted to the central server at the 
independent data center, corrections to the data fields will be captured in an audit trail. The 
reason for change, the name of the person who performed the change, together with the time 
and date will be logged to provide an audit trail. 
If additional corrections are needed, the responsible monitor or data manager will raise a 
query in the EDC application. The appropriate staff at the study center will answer queries 
sent to the Investigator. The name of the staff member responding to the query, and time and 
date stamp will be captured to provide an audit trail. Once all source data verification is 
complete and all queries are closed, the eCRF pages will be frozen. 
The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study centers in a training manual. In addition, study center 
personnel will receive training on the EDC system/eCRF. 
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Serious adverse event reconciliation 
The SAE reconciliation reports are produced and reconciled in accordance with the safety and 
medical management plans for the study. 
Management of external data 
 Data Management will set up import agreements with third party data sources, to 
ensure external data is integrated in line with data standards, if applicable. 
Final database lock 
Database lock will occur once “the last visit of the last child participating in the study has 
been completed” and all data have been coded, validated, signed, and locked, and clean file 
has been declared. 
10 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements. 
10.2 
Subject data protection 
The ICF/assent will incorporate (or, in some cases, be accompanied by a separate document) 
incorporating wording that complies with relevant data protection and privacy legislation. 
Children will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the child identifiable will not be transferred. Children must be 
informed that his/her personal study-related data will be used by the Sponsor in accordance 
with local data protection law(s). The level of disclosure must also be explained to the child. 
Children must also be informed that his/her medical records may be examined by study 
monitors, clinical quality assurance auditors, or other authorized personnel appointed by the 
Sponsor, by appropriate EC members, and by inspectors from regulatory authorities. 
10.3 
Ethics and regulatory review 
An EC should approve the final CSP, including the final version of the ICF/assent and any 
other written information and/or materials to be provided to the children. The Investigator will 
ensure the distribution of these documents to the applicable EC, and to the study center staff. 
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to the Sponsor or designee before enrollment of any child into the study. 
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The EC should approve all advertising used to recruit children for the study. 
The Sponsor or designee should approve any modifications to the ICF/assent that are needed 
to meet local requirements. 
If required by local regulations, the CSP should be re-approved by the EC annually. 
Before enrollment of any child into the study, the final CSP, including the final version of the 
ICF/assent, is approved by the national regulatory authority or a notification to the national 
regulatory authority is done, according to local regulations. 
The Sponsor or designee will handle the distribution of any of these documents to the national 
regulatory authorities. 
The Sponsor or designee will provide regulatory authorities, ECs and Investigator(s) with 
safety updates/reports according to local requirements. 
10.4 
Informed consent/assent 
The Investigator(s) at each center will: 
• Ensure each child (and/or parent/LAR as applicable) is given full and adequate oral 
and written (or pictoral) information about the nature, purpose, possible risk(s) and 
benefit(s) of the study. 
• Ensure each child (and/or parent/LAR, as applicable) is notified that they are free to 
discontinue from the study at any time. 
• Ensure that each child (and/or parent/LAR, as applicable) is given the opportunity to 
ask questions and allowed time to consider the information provided. 
• Ensure each child (and/or parent/LAR, as applicable) provides signed and dated 
informed consent/assent before conducting any procedure specifically for the study. 
• Ensure the original, signed ICF/assent(s) is/are stored in the Investigator’s Study File. 
• Ensure a copy of the signed ICF/assent is given to the child (and/or parent/LAR as 
applicable). 
• Ensure that any incentives for children who participate in the study as well as any 
provisions for children harmed as a consequence of study participation are described in 
the ICF/assent that is approved by an EC. 
10.5 
Changes to the clinical study protocol and informed consent/assent 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and the Sponsor. 
If there are any substantial changes to the CSP, then these changes will be documented in a 
new version of the CSP. 
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The new version of the CSP is to be approved by the relevant EC and if applicable, also the 
national regulatory authority, before implementation. Local requirements are to be followed 
for new versions of CSPs. 
The Sponsor will distribute any new versions of the CSP to each investigator for distribution 
to the EC, see Section 10.3. 
If a change to a CSP requires a change to a center’s ICF/assent, the Sponsor and the center’s 
EC are to approve (or submit a notification to the national regulatory authority, where 
applicable for) the revised ICF/assent before the revised form is used. 
10.6 
Audits and inspections 
Authorized representatives of the Sponsor, a regulatory authority, or an EC may perform 
audits or inspections at the center, including source data verification. The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, data were recorded, 
analyzed, and accurately reported according to the CSP, GCP, guidelines of the ICH, and any 
applicable regulatory requirements. The Investigator will contact the Sponsor immediately if 
contacted by a regulatory agency about an inspection at the center.
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11 
LIST OF REFERENCES 
1. Investigator Brochure Edition 2.0. Budesonide/Albuterol Sulfate Pressurized Inhalation 
Suspension (BDA MDI, PT027); Budesonide Pressurized Inhalation Suspension (BD 
MDI, PT008); Albuterol Sulfate Pressurized Inhalation Suspension (AS MDI, PT007), 
20 September 2019. 
2. Global Initiative for Asthma. Global strategy for asthma management and prevention. 
2020. Available from: https://ginasthma.org/gina-reports/. 
3. Mendes ES, Horvath G, Campos M, Wanner A. Rapid corticosteroid effect on 
β(2)-adrenergic airway and airway vascular reactivity in patients with mild asthma. 
J Allergy Clin Immunol. 2008;121(3):700-704. 
4. Cooper PR, Panettieri RA. Steroids completely reverse albuterol-induced β2-adrenergic 
receptor tolerance in human small airways. J Allergy Clin Immunol. 2008;122(4):734-
740. 
5. Mendes ES, Cadet L, Arana J, Wanner A. Acute effect of an inhaled glucocorticosteroid 
on albuterol-induced bronchodilation in patients with moderately severe asthma. Chest. 
2015;147(4):1037-1042. 
6. 
 Prescribing Information for Proventil HFA. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020503s046lbl.pdf 
7. 
 Prescribing Information for Pulmicort Respules. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020929s052lbl.pdf 
 
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12 
LIST OF APPENDICES
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APPENDIX B PRIMARY INVESTIGATOR SIGNATURE PAGE 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please keep the signed original form in your study files and return a copy to your local study 
monitor. 
 
 
 
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APPENDIX C ADDITIONAL SAFETY INFORMATION 
Further guidance on the definition of a Serious Adverse Event (SAE) 
Life-threatening 
“Life-threatening” means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. “Life-threatening” does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalization 
Out-patient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. Examples of important medical events include but are not limited to: 
Angioedema not severe enough to require intubation but requiring intravenous hydrocortisone 
treatment 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with N-
acetylcysteine 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or convulsions 
that do not result in hospitalization 
Development of drug dependency or drug abuse 
 
A guide to interpreting the causality question 
When making an assessment of causality, consider the following factors when deciding if 
there is a “reasonable possibility” that an AE may have been caused by the drug. 
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Time Course. Exposure to suspect drug. Has the subject actually received the suspect drug? 
Did the AE occur in a reasonable temporal relationship to the administration of the suspect 
drug? 
Consistency with known drug profile. Was the AE consistent with the previous knowledge of 
the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological class? 
Or could the AE be anticipated from its pharmacological properties? 
No alternative cause. The AE cannot be reasonably explained by another cause/etiology such 
as, the underlying disease, other drugs, and other host or environmental factors. 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
Is this a recognized feature of overdose of the drug? 
Is there a known mechanism? 
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed on the basis of the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is highly encouraged for the reporting investigator to express his/her clinical opinion. 
If (despite all efforts) the causality assessment cannot be made, these SAEs will be considered 
to be “related.” 
Causal relationship in cases where the disease under study has deteriorated because of lack of 
effect should be classified as “no reasonable possibility.” 
REDACTED COPY 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
2.0, 19 March 2021 
CONFIDENTIAL AND PROPRIETARY 
 62 of 63 
APPENDIX D COVID-19 EMERGENCY MEASURES PERMITTED TO 
ENSURE SUBJECT SAFETY 
The following activities are implemented in order to ensure subject safety during the global 
lockdown due to the COVID-19 pandemic. While global lockdown restrictions are currently 
being released, the pandemic continues and in certain territories cases remain on the rise. 
Therefore, necessary emergency measures accepted during the initial global lockdown will be 
permitted to protect subject safety in the event that infection rates return to levels requiring the 
return of government or local restrictions on movement of people and goods. 
COVID-19 tests for subjects or caregiver/ parent may be conducted proactively prior to 
inclusion or site visits at any point throughout the study in accordance with local and national 
guidance. This will be documented as an unscheduled procedure with a positive result 
recorded as an AE. Any patients that undergo COVID-19 tests as part of an adverse event 
investigation will have the results recorded via the AE process. 
Any procedure performed outside the protocol specified requirements will be documented as a 
protocol deviation. 
Visit Management: 
Delayed Visits 
•
Out of window visits should be considered if it is necessary to
safeguard the health of the subject and study center staff or
enables an on-site subject visit.
•
If a return to lockdown is announced or the study center is on
lockdown and cannot process a visit, if possible, visits should
be rescheduled to earlier/later as required to safeguard subjects
and study center staff.
•
Randomization: If a subject is in screening and cannot
complete the randomization visit within 14 days due to local
COVID-19 lockdown restrictions, the screening period may be
extended to a maximum of 6 weeks. In the event of an
extension to the screening period >14 days due to COVID-19,
the following safety measurements should be repeated in
advance of randomization: safety laboratory assessments, vital
signs, concomitant medications, and medical/surgical history.
Subject 
Discontinuation 
•
Refer to Section 3.9.
REDACTED COPY 
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Clinical Study Protocol  
Bond Avillion 2 Development LP 
Budesonide/Albuterol Sulfate (BDA), AV006 
2.0, 19 March 2021 
CONFIDENTIAL AND PROPRIETARY 
 63 of 63 
Subjects with 
Confirmed 
COVID-19 Infection 
•
If a subject has confirmed COVID-19 this is to be reported as
an AE/SAE. It should be discussed with the medical monitor
prior to determining if/when to withdraw the subject.
•
The Investigator should continue to reassess the benefit-risk of
continued study involvement for a study subject infected with
COVID-19. In-clinic visits for this subject should only
re-commence 14 days after a negative test.
•
For new subjects previously identified as COVID-19 positive,
a re-test must be performed after resolution of symptoms (if
present). The subject can only be considered for enrollment
2 weeks after having a negative result.
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SAP_001.pdf: 
Statisti cal A nal ysis Pl a n 
A villi o n 
A V 0 0 6 1. 0   
1 8/ 0 5/ 2 0 2 1 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 of 3 0
St atistic al A n al ysis Pl a n
St u d y C o d e
A V 0 0 6
E diti o n N u m ber
1. 0
Date
1 8/ 0 5/ 2 0 2 1
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 of 3 0
St u d y St atistici a n
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 of 3 0
 
1.  
S T U D Y D E T AI L S.................................................................................................. 8  
1. 1  
St u d y o bj ecti v es...................................................................................................... 8  
1. 1. 1  
Pri mar y o bjecti ve.................................................................................................... 8  
1. 1. 2  
Sec o n dar y o bjecti ve................................................................................................ 8  
1. 1. 3  
Safet y o bj ecti v e....................................................................................................... 8  
1. 1. 4  
E x pl orat or y o bjecti ve.............................................................................................. 8  
1. 2  
St u d y d esi g n............................................................................................................ 8  
1. 3  
N u m ber of s u bj ects ............................................................................................... 1 1  
1. 3. 1  
Ra n d o mi zati o n ...................................................................................................... 1 1  
1. 3. 2  
Sa m pl e Siz e Calc ulati o n....................................................................................... 1 1  
2.  
A N A L Y SI S S E T S A N D P R O T O C O L D E VI A TI O N S........................................ 1 1  
2. 1  
Defi niti o n of a nal ysis sets..................................................................................... 1 1  
2. 1. 1  
P h ar mac o ki netic ( P K) a n al ysis s et........................................................................ 1 1  
2. 1. 2  
Safet y a nal ysis set................................................................................................. 1 1  
2. 1. 3  
All s u bjects e nr oll e d a nal ysis s et.......................................................................... 1 2  
2. 1. 4  
All s u bjects ra n d o mi ze d a nal ysis set .................................................................... 1 2  
2. 2  
Pr ot o c ol de viati o ns................................................................................................ 1 2  
3.  
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S.................................................. 1 2  
3. 1  
Ge neral D efi niti o ns............................................................................................... 1 2  
3. 1. 1  
Scree ni n g peri o d ................................................................................................... 1 2  
3. 1. 2  
Cr oss o ver p eri o ds.................................................................................................. 1 3  
3. 1. 3  
Deri v ati o n of P K p ara meters................................................................................. 1 3  
3. 1. 4  
Relati ve ti m e fr o m first d ose of ra n d o mize d treat me nt ........................................ 1 3  
3. 1. 5  
Visit wi n d o wi n g.................................................................................................... 1 4  
3. 1. 6  
I m p utati o n r ules .................................................................................................... 1 4 
3. 2  
Pri mar y e n d p oi nts................................................................................................. 1 6  
3. 3  
Sec o n dar y e n d p oi nts............................................................................................. 1 6  
3. 4  
Safet y v aria bl es..................................................................................................... 1 6  
3. 4. 1  
Vital si g ns ............................................................................................................. 1 6  
3. 4. 2  
A d verse e ve nts (i ncl u di n g Seri o us A d v erse E ve nts)............................................ 1 7  
3. 4. 3  
La b orat or y Safet y Varia bles ................................................................................. 1 9  
3. 5  
Ot h er v aria bles...................................................................................................... 2 0  
3. 5. 1  
Pri or a n d C o nc o mita nt me di cati o ns...................................................................... 2 0  
3. 5. 2  
Wit h dra wal fr o m st u d y ......................................................................................... 2 0  
3. 5. 3  
Scree n Fail ures...................................................................................................... 2 1  
4.  
A N A L Y SI S M E T H O D S....................................................................................... 2 2  
4. 1  
Statistical C o nsi derati o ns...................................................................................... 2 2  
4. 1. 1  
Treat m e nt gr o u ps .................................................................................................. 2 2  
4. 2  
A nal ysis met h o ds.................................................................................................. 2 2  
4. 2. 1  
S u bject Dis p ositi o n............................................................................................... 2 3  
4. 2. 2  
De m o gra p hic a n d Baseli ne C haracteristics........................................................... 2 3  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 of 3 0
4. 2. 3  
Treat m e nt E x p os ure.............................................................................................. 2 4  
4. 2. 4  
Pr ot o c ol de viati o ns ................................................................................................ 2 4  
4. 2. 5  
P h ar mac o ki neti cs ( P K) ......................................................................................... 2 5  
4. 2. 6  
A nal ysis of safet y v aria bles .................................................................................. 2 7  
4. 2. 7  
C O VI D- 1 9 i m pacts............................................................................................... 2 9  
5.  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L .............................................. 3 0  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 of 3 0
A M E N D M E N T HI S T O R Y 
D ate
Brief descri pti o n of c h a n g e
N/ A
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 8 of 3 0
1. 
S T U D Y D E T AI L S 
1. 1 
St u d y o bjecti ves 
1. 1. 1 
Pri m ar y o bjecti ve 
Pri m ar y O bjecti ve:
Pri m a r y e n d p oi nt:
T o d eter mi ne a n d c o m pare t he s yste mic 
e x p os ure of b u des o ni d e after si n gl e- d ose 
a d mi nistrati o ns of B D A M DI a n d 
P ul mic ort Res p ules.
A U C 0-t a n d C m a x
1. 1. 2 
Sec o n d a r y o bjecti v e 
Sec o n d a r y O bjecti v e:
Sec o n d a r y e n d p oi nt:
T o d eter mi ne a n d c o m pare ot h er P K 
p ara meters f or b u des o ni de deli vere d b y 
B D A M DI a n d P ul mic ort Res p ules
-i nf (if
feasi bl e)
1. 1. 3 
S afet y o bjecti ve 
S afet y o bjecti v e: 
S afet y e n d p oi nts:
T o assess t h e safet y a n d t olera bilit y of
B D A M DI a n d P ul mic ort Res p ules
A Es/ S A Es
A E: a d verse e ve nt; A U C 0-i nf: area u n d er t he plas ma c o nce ntr ati o n-ti me c ur ve fr o m ti me zer o t o i nfi nit y; A U C 0-t:
area u n d er t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o ti me of last q ua ntifia ble c o nce ntrati o n; B D A 
M DI: b u des o ni de/al b uter ol s ulfate meter e d- d ose i n haler; Clast: dr u g c o nce ntrati o n at last o bser ve d ( q ua ntifi a bl e) 
ti me p oi nt; C ma x: ma xi m u m o bser ve d plas ma c o nce ntrati o n; P K: p har mac o ki netic; S A E: seri o us a d verse e ve nt. 
tl ast: ti me of last q ua ntifia bl e plas ma c o nce ntrati o n; t ma x: ti me t o reac h ma xi m u m o bser ve d plas ma c o nce ntrati o n; 
-
-l o garit h mic c o nce ntrati o n-ti me c ur ve. 
1. 1. 4 
E x pl o r at or y o bjecti ve 
E x pl orat or y o bjecti ves are n ot pla n ne d f or t his st u d y. 
1. 2 
St u d y d esi g n 
T his is a ra n d o miz e d, m ulti ce nter, o pe n-la b el, si n gl e- d ose, 2- wa y cr oss o ver st u d y t o c o m pare t he 
s yste mic e x p os ure of b u d es o ni de deli vere d b y t he c o m bi nati o n i n haler ( B D A M DI 1 6 0/ 1 8 0 u g)
wit h P ul mic ort Res p ules 1 m g. T h e st u d y c o nsists of a scree ni n g visit ( Visit 1) a n d 2 treat me nt 
visits ( Visit 2 a n d Visit 3). Ra n d o mi zati o n ta k es pl ace at Visit 2. A f oll o w- u p ( or earl y 
wit h dra wal, if a p plic a ble) tele p h o ne c all ( T C) will occ ur 2 t o 5 da ys after t h e last d ose. 
See Fi g ure 1 f or a gra p hi cal pres e ntati o n of t he st u d y desi g n a n d Ta ble 1 f or a list of st u d y 
assess me nts, as per pr ot oc ol. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 of 3 0
 
Fi g u re 1: St u d y sc he m a 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 1 of 3 0
1. 3  
N u m ber of s u bjects 
T he tar get p o p ul ati o n will be male a n d fe male c hil dre n wit h ast h m a, 4 t o 8 years of a ge. 
A p pr o xi matel y 2 8 c hil dre n will nee d t o b e s cree n e d, ass u mi n g a n esti mate d s cree n fail ure rate 
of 5 0 % pri or t o ra n d o mizati o n i n or der f or 1 4 c hil dre n t o be ra n d o mize d a n d 1 0 t o c o m plete. 
At least 4 c hil dre n s h o ul d b e ra n d o miz e d i n t h e a ge ra n ge of 4- 5 years. C hil dre n w h o d o n ot 
c o m plete b ot h treat m e nts ( B D A M DI a n d P ul mic ort Res p ules) m a y be re pla ce d. 
1. 3. 1  
R a n d o miz ati o n 
At Visit 2, eli gi ble s u bje cts are ra n d o mize d ( 1: 1) t o recei v e 1 of 2 treat m e nt se q u e nces ( B D A 
M DI 1 6 0/ 1 8 0 / P ul mic ort Res p ules or P ul mic ort Res p ules / B D A M DI 1 6 0/ 1 8 0). 
Ra n d o mi zati o n is stratifie d b y st u d y ce nter, s o t hat all s u bjects ca n b e recr uite d at a si n gl e
st u d y ce nt er if n ee de d.
1. 3. 2 
S a m ple Size C alc ul ati o n 
N o pr os p ecti ve calc ulati o ns of statistical p o w er ha ve bee n ma de. As t h e st u d y is descri pti v e 
wit h n o f or mal h y p ot h esis tests, c o m plete d ata (e val u a ble data fr o m b ot h B D A M DI a n d 
P ul mic ort Res p ules) fr o m 1 0 c hil dre n is c o nsi dere d s ufficie nt t o pr o vi de esti mates of t he P K 
p ara meters i n t his p o p ulati o n wit h o ut e x p osi n g m ore c hil dre n t h a n necessar y t o t he I M P. 
Res ults will be i nt er prete d i n t he p ers pecti ve of t h e e x pl orati ve n at ure of t h e st u d y. 
2.  
A N A L Y SI S S E T S A N D P R O T O C O L D E VI A TI O N S 
2. 1  
Defi niti o n of a n al ysis sets 
2. 1. 1 
P h ar m a c o ki netic ( P K) a n al ysis set 
T he P K a nal ysis s et will c o nsist of all ra n d o miz e d c hil dre n f or w h o m at l east 1 of t he pri mar y 
P K p ara meters ( A U C 0-t a n d C ma x) ca n be calc ul ate d a n d w h o h a ve n o i m p orta nt pr ot o c ol 
d e viati o ns i m pacti n g t h e i nt er pretati o n of t he P K d ata. 
C hil dre n w h o d o n ot pr o vi de e val ua ble d ata f or b ot h treat me nts ( B D A M DI a n d P ul mic ort 
Res p ules) will b e e xcl u de d fr o m t he a n al ysis of varia nce ( A N O V A). 
A n y e x cl u de d cases will b e d oc u m e nte d t o get her wit h t he reas o n f or e xcl usi o n.  
Pr ofil es b el o n gi n g t o t h e P K a n al ysis s et will be s u m marize d a n d a nal yze d acc or di n g t o t he 
treat m e nt t h at was a d mi nistere d at t h e s pecific visit. A n y treat me nt err ors will b e d oc u me nte d 
as pr ot oc ol d e viati o ns. All P K s u m m aries will be b ase d o n t h e P K a n al ysis set. 
2. 1. 2 
S afet y a n al ysis set 
T he safet y a nal ysis set is defi n e d as all c hil dre n re cei vi n g a n y a m o u nt of ra n d o mi ze d 
treat m e nt.  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 2 of 3 0
Occ urre nces of safet y e ve nts (ie, A Es a n d use of c o nc o mita nt me di cati o n) will b e s u m marize d 
u n d er t h e a ct ual treat me nt c orres p o n di n g t o t h e treat me nt peri o d of w hic h t he e ve nt occ urre d. 
All safet y s u m maries will be base d o n t he safet y a nal ysis set.  
2. 1. 3  
All s u bjects e nr olle d a n al ysis set
T he all s u bjects e nr olle d a nal ysis s et will be d efi n e d as all c hil dre n w h o pr o vi de i nf or me d 
asse nt a n d w h ose p are nt(s) or le gall y a ut h orize d re pr ese nt ati ve(s) ( L A R) ha ve pr o vi de d 
i nf or me d c o nse nt. T his a nal ysis s et will be use d f or descri pti ve s u m maries of dis p ositi o n. 
2. 1. 4  
All s u bjects r a n d o miz e d a n al ysis set
T he all s u bjects ra n d o mi ze d a nal ysis set will be d efi n e d as all c hil dre n w h o ha ve bee n 
ra n d o mi ze d t o a treat me nt se q ue nce. T his a n al ysis set will be use d f or listi n gs a n d d escri pti v e 
s u m m aries of de m o gra p hic varia bles.  
S u bjects will be liste d a n d s u m marize d acc or di n g t o t h eir ra n d o miz e d treat me nt se q ue nce.
2. 2 
Pr ot oc ol de vi ati o ns 
A pr ot oc ol de viati o n is a n y c ha n ge, di v er ge nce, or de part ure fr o m t he st u d y desi g n or 
pr oce d ures defi n e d i n t h e pr ot oc ol. Maj or pr ot oc ol d e viati o ns are d efi n e d as a s u bset of 
pr ot oc ol de viati o ns t h at ma y si g nifica ntl y affect t h e c o m plete ness, acc urac y, a n d/ or reli a bilit y 
of t h e st u d y d ata or t h at ma y si g nific a ntl y affect a s u bject's ri g hts, safet y, or well- bei n g. 
I m p orta nt pr ot o c ol d e viati o ns (I P Ds) are a s u bset of m aj or P Ds d ee me d t o i m pact t he 
p har mac o ki n etics or t h e safet y pr ofile of t he st u d y. Mi n or P Ds are t h e pr ot o c ol de viati o ns 
w hic h are n eit h er m aj or n or i m p orta nt. 
S u bjects m ust m eet t he eli gi bilit y criteria, ass ess e d d uri n g scree ni n g, t o be ra n d o miz e d t o 
treat m e nt. T he list of i ncl usi o n a n d e xcl usi o n criteria are pr o vi d e d i n t h e pr ot o c ol. Eli gi bilit y 
criteria n ot met are c olle cte d o n t h e electr o ni c cas e re p ort f or m (e C R F). A n y c hil dre n w h o d o 
n ot f ulfil all t he eli gi bilit y criteria, b ut t he y are s u bs e q ue ntl y ra n d o mi ze d i n err or a n d c hil dr e n 
w h o are err o n e o usl y ra n d o miz e d will be i d e ntifie d as I P Ds. Ot her I P Ds ma y be i d e ntifie d b y 
t h e s p o ns or pri or t o t h e pri mar y data base l o c k.  
A per pr ot oc ol a nal ysis e x cl u di n g s u bjects wit h I P Ds is n ot pla n ne d. 
3. 
P RI M A R Y A N D S E C O N D A R Y V A RI A B L E S  
3. 1  
Ge ner al Defi niti o ns 
3. 1. 1 
Scree ni n g peri o d 
Scree ni n g ass ess me nts are c oll ecte d at Visit 1 (see Ta ble 1). A n y re-s cree ni n g ass ess m e nts 
t h at ma y o cc ur (see 3. 5. 3) will b e c ollecte d at R e- Scree ni n g visit. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 3 of 3 0
3. 1. 2  
Cr oss o v er peri o ds
S u bjects will be ra n d o miz e d t o a partic ular se q u e nce a n d will recei ve t h e first tr eat me nt i n 
t h eir se q ue nce at Visit 2 a n d sec o n d treat me nt at Visit 3. P eri o d 1 c orres p o n ds t o t h e res ults 
c oll ecte d at Visit 2 a n d P eri o d 2 c orres p o n ds t o res ults c oll ecte d at Visit 3. T he bel o w ta ble 
re pres e nts pl a n ne d treat me nt gr o u p assi g n me nt b ase d o n ra n d o miz e d se q u e n ce a n d cr oss o ver 
p eri o d. 
R a n d o mize d T re at me nt 
Se q ue nce
Pl a n ne d tre at me nt gr o u p
Peri o d 1 ( Visit 2)
Pe ri o d 2 ( Visit 3)
B D A M DI 1 6 0/ 1 8 0; 
P ul mic ort Res p ules
B D A M DI 1 6 0/ 1 8 0
P ul mic ort Res p ules
P ul mic ort Res p ules;
B D A M DI 1 6 0/ 1 8 0
P ul mic ort Res p ules
B D A M DI 1 6 0/ 1 8 0
P ul mic ort Res p ules is a d mi nistere d as a si n gl e d os e of 1 m g. 
3. 1. 3  
Deri v ati o n of P K p ar a meters
Plas ma s a m pl es will be a nal yz e d usi n g n o n-c o m p art me ntal a nal ysis ( N C A) t o deter mi n e t he 
P K p ara meters ( A U C 0-
-i nf [if feasi ble]) of 
b u d es o ni de i n pl as m a.  
A se parate P K a nal ysis pla n, a ut h or e d b y t he P K s pecialists, will c o ntai n t he deri vati o n 
s pecificati o ns of t h e P K para meters t o b e deli vere d t o 
T he d eri v e d P K para met ers recei ve d fr o m t h e P K s p ecialists will b e ma p pe d t o S D T M. P P, 
w hic h will s u bse q u e ntl y b e m a p pe d t o A D A M. A D P P. T h e latter a nal ysis dataset will b e use d 
f or pr o gra m mi n g d at a listi n gs a n d des cri pti v e s u m m aries of t h e P K p ara met ers.
3. 1. 4  
Rel ati ve ti me fr o m first d ose of r a n d o mize d tre at me nt
Plas ma c o nce ntrati o ns of b u d es o ni de will be m eas ure d i n bl o o d s a m pl es ta k e n at pla n n e d 
ti me p oi nts ( See Ta ble 1). T h e act ual ti me p oi nts wit h refere nce t o t he ti me of first d ose of 
ra n d o mi ze d treat m e nt will b e calc ulate d s e paratel y f or eac h visit ( Visit 2 a n d Visit 3) as:
[ Relati ve ti m e fr o m first d ose ( mi n utes)] = [ act u al ti m e of bl o o d sa m ple ( h h: m m)]  [ti me of 
first d ose ( h h: m m)]. 
Ti mes of bl o o d s a m ples a n d ti me of first d os e at t h e sc he d ule d visits will b e rec or de d o n t he 
e C R F at site. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 4 of 3 0
3. 1. 5  
Visit wi n d o wi n g 
D ue t o t h e desi g n of t his trial, t here will be n o visit wi n d o wi n g a p plie d. A n y u nsc he d ule d 
visits w hic h ma y o cc ur will n ot b e use d i n a nal ys es, h o w e ver all data will be liste d w here 
a p pr o priate. 
Dela ye d visits d ue t o C O VI D- 1 9 s h o ul d b e c o nsi dere d i n t he a n al yses if it is necessar y t o 
safe g uar d t he h ealt h of t h e s u bject a n d st u d y ce nter staff or e n a bles a n o n-site s u bject visit. 
If a ret ur n t o l oc k d o w n is a n n o u nce d or t h e st u d y ce nter is o n l oc k d o w n a n d ca n n ot pr ocess a 
visit, if p ossi ble, visits s h o ul d be resc he d ule d t o earlier/lat er as re q uire d t o s afe g u ar d s u bjects 
a n d st u d y ce nter staff. 
3. 1. 6 
I m p ut ati o n r ules
T he f oll o wi n g i m p utati o n r ules will be a p plie d t o t he ra w d at a i n or der t o e na ble t he P K a n d 
Safet y a nal yses. 
3. 1. 6. 1
Missi n g d ate/ti me i m p ut ati o ns 
W he n deter mi ni n g w h et h er c o n c o mit a nt me dicati o n or a d verse e ve nt e mer ge nce is pre- or
p ost-ra n d o miz e d treat m e nt, t he f oll o wi n g i m p utati o n met h o ds will b e a p plie d. 
P arti al e n d d ate
1. If missi n g da y [--/ m m/ y y y y] t h e n i m p ute as mi ni m u m {t h e e n d of t h e m o nt h, e n d of 
st u d y partici p ati o n }. 
2. If missi n g m o nt h [--/--/ y y y y] t h e n i m p ute as mi ni m u m {[ 3 1/ 1 2/ y y y y], e n d of st u d y 
p artici pati o n }. 
3. If c o m pletel y missi n g, t h e n set t o e n d of st u d y partici pati o n. 
P arti al st art d ate
1. If missi n g da y [--/ m m/ y y y y] t h e n i m p ute as t he mi ni m u m of: 
If m m/ y y y y is t he s a me as t he d os e d ate of B D A M DI t h e n set t o d ose dat e of 
B D A M DI; else if m m/ y y y y is t h e sa me as t he d os e d ate of P ul mic ort Res p ules 
t h e n set t o d os e d ate of P ul mic ort Res p ules; else set t o 0 1/ m m/ y y y y 
E n d date of me dicati o n/ e ve nt (after partial date h a n dli n g has b ee n a p plie d). 
2. If missi n g m o nt h [--/--/ y y y y] t h e n i m p ute as t he mi ni m u m of: 
If y y y y s a me year as B D A M DI t h e n set t o d ate of B D A M DI d ose; els e if 
y y y y sa m e year as P ul mi c ort Res p ules d ose date set t o d ose date of P ul mic ort 
Res p ules; Else set t o start of t he ye ar [ 0 1/ 0 1/ y y y y]. 
E n d date of me dicati o n/ e ve nt (after partial date h a n dli n g has b ee n a p plie d). 
3. If c o m pletel y missi n g, t h e n i m p ute as t he mi ni m u m of: 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 5 of 3 0
Date of first d ose of B D A M DI, u nless missi n g t he n date of first d ose of 
P ul mic ort Res p ules. 
E n d date of me dicati o n/ e ve nt (after partial date h a n dli n g has b ee n a p plie d). 
T he e n d of st u d y partici p ati o n is defi n e d as t he dat e of t he f oll o w- u p T C. 
A d diti o nall y, A Es will h a ve t he start a n d e n d ti me c ollecte d. T h e f oll o wi n g i m p utati o n r ul e 
will be a p plie d t o missi n g or p artiall y missi n g ti mes.
P arti al e n d ti me 
1. If missi n g mi n ute [ h h:--] t h e n i m p ute as h h: 5 9. 
2. If c o m pletel y missi n g, t h e n i m p ute as 2 3: 5 9. 
P arti al st art ti me 
1. If missi n g mi n ute [ h h:--], t he n: 
-
If start date a n d h o ur are t he sa me as t he d ose date a n d h o ur of t h e ra n d o mi ze d 
treat m e nt, t he n set t o t h e ti m e of d osi n g. 
-
Els e set t o h h: 0 0. 
2. If c o m pletel y missi n g, t h e n: 
-
If start date is t h e s a me as t he d os e date of t he ra n d o miz e d treat m e nt, t he n set t o 
t h e ti m e of d osi n g. 
-
Els e set t o 0 0: 0 0. 
C ollecti o n of t he start a n d e n d ti m e is n ot pla n ne d f or c o n c o mita nt me dicati o ns. T his 
i m p utati o n m et h o d is defi ne d t o e na ble t h e classificati o n of a d v erse e v e nts a n d c o n c o mit a nt 
me di cati o ns as pre- or p ost-treat me nt f or re p orti n g i n s u m m ar y ta bles. T h e a b o ve i m p utati o n 
pr ocess will a d diti o n all y assi g n t he o cc urre nce t o t he B D A M DI treat m e nt gr o u p, u nl ess it ca n 
b e u n e q ui v oc all y d eter mi ne d ot h er wise, b ase d o n t he parti al i nf or mati o n c ollecte d. T h e ra w, 
ori gi nal dat es will b e prese nte d i n a n y listi n gs pr o d uce d. 
3. 1. 6. 2
I m p ut ati o n of pl as m a c o nce ntr ati o ns 
Pl as ma c o nce ntrati o ns b el o w t he l o w er li mit of q ua ntificati o n ( L L o Q) t h at are re p orte d as 
 ha n dle d as f oll o ws; 
If t he y occ ur after t he first q ua ntifia ble c o n ce ntrati o n wit hi n eac h visit-s pecific c o nce ntrati o n 
pr ofil e, t h e n t he y will b e set as missi n g f or t he cal c ulati o n of t h e d escri pti v e s u m mar y 
statisti cs. Else if t he y oc c ur pri or t o a q ua ntifia ble val u e, or n o q ua ntifia bl e v al ue is pr o vi de d 
wit hi n a visit-s pecific c o nce ntrati o n pr ofil e, t h e n t he y will be set t o 0 f or t h e calc ul ati o n of t he 
d escri pti v e s u m mar y statistics. T h e ori gi nal v al ue will b e liste d. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 6 of 3 0
3. 2 
Pri m ar y e n d p oi nts 
T he f oll o wi n g P K p ara meters are of k e y i nt erest f or e val uati n g t he s yste mi c e x p os ure of 
b u d es o ni de after si n gl e- d os e a d mi nistrati o ns of B D A M DI a n d P ul mic ort Res p ules. 
A U C 0-t: Area u n der t h e plas ma c o n ce ntrati o n-ti me c ur ve fr o m ti m e zer o t o ti me of 
last q ua ntifia ble c o n ce ntrati o n  
C m a x: Ma xi m u m o bser ve d plas ma c o nc e ntrati o n 
3. 3 
Sec o n d ar y e n d p oi nts 
I n a d diti o n t o t h e a b o ve, t h e f oll o wi n g para meters will be calc ulate d t o f urt her assess t h e 
p har mac o ki n etics of B D A M DI c o m pare d t o P ul mic ort Res p ules: 
t ma x: ti me t o reac h ma xi m u m o bser ve d plas ma c o nce ntrati o n  
tlast: ti m e of last q u a ntifia ble plas ma c o n ce ntrati o n  
-
-l o garit h mic 
c o n ce ntrati o n-ti me c ur ve 1
Cl ast: dr u g c o nce ntrati o n at t h e last o bser ve d ( q ua ntifia ble) ti m e p oi nt 
A U C 0-i nf: area u n der t he plas ma c o n ce ntrati o n-ti me c ur ve fr o m ti m e z er o t o i nfi nit y 1
1 Feasi bilit y of e n d p oi nt pr o visi o n will be deter mi n e d b y t h e P K s pecialist ve n d or. 
3. 4 
S afet y v ari a bles 
3. 4. 1  
Vit al si g ns
T he f oll o wi n g vit al si g ns meas ure me nts will b e c ollecte d at scree ni n g Visit 1 a n d b ef ore d ose 
a n d after t h e last bl o o d sa m ple is ta ke n at Visit 2 a n d Visit 3 as per Ta bl e 1.
P uls e rate ( beats/ mi n) 
S yst olic bl o o d press ure ( m m H g) 
Diast olic bl o o d press ure ( m m H g) 
A n y cli nicall y si g nifica nt c ha n ges i n vital si g ns are rec or de d as a n A E if a p pli ca ble. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 7 of 3 0
3. 4. 2  
A d v erse e ve nts (i ncl u di n g Seri o us A d v erse E ve nts)
3. 4. 2. 1
D efi niti o n of a d verse e ve nt 
A n A E is t he d e v el o p m e nt of a n y u nt o war d me dical occ urre n ce i n a s u bje ct or cli nical st u d y 
s u bject a d mi nistere d a me dici n al pr o d uct a n d w hic h d o es n ot necessaril y ha v e a ca us al 
relati o ns hi p wit h t his treat me nt. A n A E ca n t h eref ore be a n y u nfa v ora ble a n d u ni nte n d e d si g n 
(e. g., a n a b n or mal la b orat or y fi n di n g), s y m pt o m (e. g., n a usea, c hest p ai n), or disease 
te m p orall y ass ociate d wit h t he use of a me di ci nal pr o d uct, w h et h er or n ot c o nsi dere d rel ate d 
t o t h e me dici n al pr o d uct.  
T he ter m A E is use d t o i n cl u de b ot h seri o us a n d n o n-seri o us A Es a n d ca n i ncl u de a 
d eteri orati o n of a pre-e xisti n g me dical o cc urre nce. A n A E m a y occ ur at a n y ti me, i n cl u di n g 
t h e scree ni n g peri o d, e ve n if n o ra n d o mize d treat me nt h as bee n a d mi nistere d. 
A treat me nt-e mer ge nt a d verse e v e nt ( T E A E) is defi n e d as a n A E wit h o nset (st art date/ti me)
o n or after t h e first d ose of ra n d o mi ze d I M P at Visit 2. A n y A Es occ urri n g i n t he was h o ut 
b et w ee n s u ccessi v e treat me nt p eri o ds will als o be re gar d e d as treat me nt-e mer ge nt a n d 
assi g ne d t o t h e treat m e nt a d mi nistere d i n t he peri o d pri or t o t he was h o ut. 
3. 4. 2. 2
D efi niti o n of seri o us a d v erse e v e nt 
A n S A E is a n A E o cc urri n g d uri n g a n y st u d y p has e (i. e., after t he si g ni n g of t he i nf or me d 
c o nse nt/ asse nt t hr o u g h t o t h e safet y f oll o w- u p T C), t h at f ulfills 1 or m ore of t he f oll o wi n g 
criteria: 
Res ults i n deat h 
Is i m m e diatel y life-t hreate ni n g 
Re q uires i n- patie nt h os pitali zati o n or pr ol o n gati o n of e xisti n g h os pit aliz ati o n  
Res ults i n persiste nt or si g nific a nt disa bilit y or i nca pacit y  
Is a c o n ge nit al a b n or malit y or birt h defect 
Is a n i m p orta nt me dical e ve nt t hat ma y j e o p ar dize t he s u bject or ma y re q uir e me dical 
i nter ve nti o n t o pre ve nt 1 of t h e o utc o m es liste d a b o ve 
will be s
3. 4. 2. 3
C ollecti o n of A Es a n d S A Es 
A Es a n d S A Es will be c ollecte d fr o m ti m e of si g nat ure of i nf or me d c o nse nt/asse nt, t hr o u g h 
t h e safet y f oll o w- u p T C. 
T he f oll o wi n g varia bles will be c ollecte d o n t he e C R F f or eac h A E: 
A E ter m ( ver bati m) 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 8 of 3 0
Date/ti me w he n t he A E starte d a n d st o p pe d  
D D/ M M M/ Y Y Y Y 
H H: M M 
Ma xi m u m s e verit y  
Mil d 
M o d erat e 
Se v ere 
Seri o us ness  
Yes or n o 
I n v esti g at or ca us alit y rati n g a gai nst t h e ra n d o miz e d treat me nt  
Yes or n o 
Acti o n ta ke n wit h re gar d t o t h e ra n d o miz e d treat m e nt 
D os e n ot c ha n g e d 
D os e i ncrease d 
D os e re d u ce d 
Dr u g i nt err u pte d 
Dr u g per ma n e ntl y dis c o nti n ue d 
N ot a p pli ca ble 
O utc o m e 
Rec o v ere d/res ol ve d  
Rec o v eri n g/res ol vi n g 
Rec o v ere d/res ol ve d wit h se q u elae 
N ot rec o vere d/ n ot res ol ve d 
Fatal 
3. 4. 2. 4
A d v erse e ve nts d at a h a n dli n g 
A d verse e ve nts will b e r e p orte d as st arti n g d uri n g scree ni n g if t h e A E start date/ti me is pri or 
t o t h e first d ose of ra n d o mi ze d treat me nt ta ke n at Visit 2. 
A d verse e ve nts will b e c o nsi d ere d as tr eat m e nt e mer ge nt if t he o nset dat e/ti m e is o n or after 
t h e first d ose of ra n d o mi ze d treat m e nt at Visit 2. A n y A Es o cc urri n g i n t h e was h o ut b et w ee n 
s uccessi v e treat me nt p eri o ds will als o be re gar d e d as treat me nt e mer ge nt a n d assi g ne d t o t he 
act ual treat me nt a d mi nistere d i n t h e peri o d pri or t o t h e was h o ut. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 1 of 3 0
S u bject decisi o n 
A d verse e ve nt 
Se v ere n o n-c o m plia nce t o pr ot oc ol 
C o n diti o n u n der i n vesti gati o n w orse ne d 
S u bject l ost t o f oll o w- u p
I n v esti g at or d ecisi o n 
St u d y t er mi nate d b y s p o ns or 
Deat h 
C o nse nt wit h dra wal 
Ot h er 
Ra n d o mi ze d s u bjects w h o wit h dra w pri or t o Visit 3 are as ke d t o c o m plete a n earl y wit h dra wal 
T C (see Ta ble 1).
S u bjects w h o wit h dra w pri or t o ra n d o miz ati o n, or are l ost t o f oll o w- u p f oll o wi n g Visit 3 (i. e. 
t h e safet y f oll o w- u p call) will ha ve t h eir e n d of st u d y stat us c olle cte d i n t h e e C R F u n der t he 
f oll o wi n g fiel ds: 
A d verse e ve nt  
Deat h 
L ost t o f oll o w- u p 
P h ysicia n d ecisi o n 
Pr ot o c ol de viati o n 
Scree n fail ure 
Sit e ter mi n ate d b y s p o ns or 
St u d y t er mi nate d b y s p o ns or 
Wit h dra wal b y s u bject 
Wit h dra wal b y pare nt/ g u ar dia n 
N o n-c o m plia nce wit h st u d y dr u g 
Ot h er (s p ecif y) 
3. 5. 3 
Scree n F ail ures 
Scree n fail ures are s u bjects w h o d o n ot f ulfill t he eli gi bilit y criteria f or t he st u d y, a n d 
t h e dis p ositi o n e C R F pa g e. S u bjects w h o are scree n fail ures ma y b e re-s cree ne d o nce if 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 2 of 3 0
te m p orar y reas o ns f or t h e ori gi n al scree n fail ure (e g, res pirat or y i nfecti o ns, ast h ma 
e xacer bati o ns, e pis o d es of u nsta ble ast h m a) ha ve res ol v e d.  
If a s u bject is i n scree ni n g a n d ca n n ot c o m plete t he ra n d o miz ati o n visit wit hi n 1 4 da ys d ue t o 
l o cal C O VI D- 1 9 l o c k d o w n restricti o ns, t he s cree ni n g p eri o d ma y be e xte n de d t o a ma xi m u m 
of 6 wee ks. I n t he e v e nt of a n e xte nsi o n t o t h e scree ni n g p eri o d > 1 4 d a ys d ue t o C O VI D- 1 9, 
t h e f oll o wi n g safet y m eas ure me nts s h o ul d be re p eate d i n a d va n ce of r a n d o mizati o n: safet y 
la b orat or y assess m e nts, vital si g ns, c o nc o mita nt me dicati o ns, a n d me dical/s ur gic al hist or y. 
W here a s u bject d o es n ot meet all t h e eli gi bilit y criteria b ut is ra n d o miz e d i n err or, or 
i n c orrectl y starte d o n treat me nt, t h e i n vesti gat or s h o ul d i nf or m t h e me dical m o nit or 
i m m e di atel y, a n d a disc ussi o n s h o ul d occ ur bet wee n t he m e dical m o nit or a n d t h e i n vesti gat or 
re gar di n g w h et h er t o c o nti n ue or wit h dra w t he s u bject i n t h e st u d y. T h e m e dical m o nit or m ust 
e ns ure all de cisi o ns are a p pr o priatel y d oc u me nt e d. All s u bjects ra n d o mize d err o ne o usl y will 
b e mar k e d as maj or P Ds, c o nsi dere d as I P Ds a n d will be a nal yz e d i n acc or da nce wit h t he P K 
a n d Safet y a n al ysis set defi niti o ns ( Secti o n 2. 1).
4.  
A N A L Y SI S M E T H O D S 
4. 1 
St atistic al C o nsi der ati o ns 
A nal ys es descri be d wit hi n t his St atistical A nal ysis Pl a n will be p erf or me d b y  
  
T he st u d y is des cri pti v e. T here are n o pre defi ne d statistical h y p ot h eses a n d/ or decisi o n r ules. 
4. 1. 1 
Tre at me nt gr o u ps 
Descri pti ve s u m maries a n d a nal ys es of e n d p oi nts liste d bel o w will be gr o u pe d b y treat m e nt. 
As s u bje cts will recei v e b ot h B D A M DI 1 6 0/ 1 8 0 a n d P ul mic ort Res p ules, t h e y will be 
re pres e nte d b y t h e treat m e nt t h e y recei v e at eac h visit. T heref ore, p ost-ra n d o miz ati o n a nal ys es 
of e n d p oi nts will n ot b e br o k e n d o w n b y visits, si n ce visits will be m ut u all y e x cl usi v e p er 
s u bject a n d t heir d ose d treat me nt c o m bi nati o ns. 
U nless st ate d ot her wis e, listi n gs will be gr o u pe d b y ra n d o mi ze d treat m e nt s e q u e nc e a n d visit. 
4. 2  
A n al ysis met h o ds 
All s u bjects w h o are p art of t h e P K a nal ysis set will be a nal yze d acc or di n g t o t h e act ual 
treat m e nt t h e y recei ve d. A n y s u bjects w h o are err o ne o usl y ra n d o miz e d will be i d e ntifie d as 
maj or P Ds, c o nsi d ere d as I P Ds a n d liste d i n t he C S R.  
U nless ot her wis e state d, descri pti ve s u m m aries of c o nti n u o us e n d p oi nts will i ncl u d e: T h e 
n u m b er of s u bjects i ncl u de d i n t h e a nal ysis ( n); Mea n; Sta n dar d De viati o n; Me dia n; 
Mi ni m u m; M a xi m u m. S u m maries of cate g oric al e n d p oi nts will i ncl u de t he a bs ol ute c o u nts 
a n d perce nta ge, wit h t h e d e n o mi nat or use d i n t h e perce nt a ge c alc ulati o n clearl y defi n e d i n t h e 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 3 of 3 0
f o ot n ote of t he ta ble. U nl ess state d ot her wise, t h e de n o mi nat or will b e t h e n u m ber of s u bjects 
i n t h e a nal ysis s et us e d f or t h e descri pti v e s u m mar y. 
4. 2. 1 
S u bject Dis p ositi o n 
S u bject dis p ositi o n will be s u m m ariz e d f or all s u bjects w h o ha v e bee n e nr olle d a n d ha v e 
pr o vi d e d i nf or me d c o ns e nt/asse nt. T he n u m b er of s u bj ects w h o were e nr olle d, scree ne d a n d 
scree n faile d will b e s u m mariz e d.  T he n u m ber a n d p erce nt a ge of s u bje cts will be prese nte d 
b y t he f oll o wi n g cate g ories; ra n d o mi ze d, i ncl u de d i n P K a nal ysis set, i n cl u de d i n Safet y 
a nal ysis s et, n ot ra n d o mize d (a n d reas o ns), ra n d o miz e d w h o recei ve d st u d y treat m e nt, 
ra n d o mi ze d w h o di d n ot recei v e st u d y treat me nt (a n d reas o ns), c o m pl ete d, a n d disc o nti n ue d 
t h e st u d y (a n d reas o ns). F or cate g ories t h at are p ost-ra n d o mi zati o n, s u m maries will be f urt her 
s plit b y ra n d o mi ze d treat m e nt se q u e nce a n d o v erall. 
All ra n d o mi ze d s u bjects w h o were dis c o nti n ue d pre mat urel y will be liste d b y ra n d o mi ze d 
treat m e nt se q u e nce i ncl u di n g d ate of, a n d reas o n f or st u d y dis c o nti n uati o n.  
A se parate listi n g will dis pla y t he pl a n n e d treat m e nt se q ue nce a n d t he act ual treat me nt 
recei v e d f or all ra n d o mize d s u bjects. 
A d diti o nall y, s u bjects i n t h e safet y a n al ysis set w h o w ere e x cl u de d fr o m t he P K a nal ysis set 
will be liste d a n d will i ncl u de t he act u al treat m e nt se q u e nce a n d reas o n f or e x cl usi o n.  
M ore o ver, d ata e x cl u d e d fr o m t he P K a nal ysis set will b e liste d se paratel y f or all s u bjects i n 
t h e P K a nal ysis s et, i ncl u di n g act u al treat me nt a n d reas o n f or e x cl usi o n. 
4. 2. 2
De m o gr a p hic a n d B aseli ne C h a r acteristi cs
T he f oll o wi n g de m o gra p hics a n d s u bject c haracteristics will b e c oll ecte d at Visit 1 a n d Re-
Scree ni n g visit, if a p plica ble. 
A ge ( years) 
Se x: Male, Fe m ale 
Race 
Et h nicit y 
Wei g ht ( k g) 
Hei g ht (c m) 
B MI ( k g/ m 2) 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 4 of 3 0
T hese varia bles will be s u m marize d b y ra n d o miz e d treat m e nt se q u e nce a n d o verall f or all 
ra n d o mi ze d s u bjects. T his s u m m ar y will b e re- pr o d uce d f or s u bj ects i n t h e P K a n al ysis set. 
A d diti o nall y, t he varia bles a b o ve, al o n g wit h ra n d o miz e d tr eat me nt se q ue nce a n d c o u ntr y, 
will be liste d f or all ra n d o miz e d s u bjects.  
4. 2. 2. 1
Me di c al hist o r y 
A sta n d ar d me dic al, dise ase, a n d s ur gical hist or y will be rec or d e d o n t he e C R F at Visit 1. T he 
res ults of t h e p h ysical e x a mi n ati o n at Visit 1 a n d at u nsc he d ule d visits, if a p pli ca ble, will b e 
d oc u me nte d i n m e dical hist or y f or eac h s u bj ect. A n y n e w or a g gra v ate d cli nicall y rele va nt 
a b n or mal m e di cal p h ysic al e xa mi nati o n fi n di n g c o m p are d t o t h e bas eli n e assess m e nt will b e 
re p orte d as a n A E. 
Ge neral m e dical hist or y will be cate g orize d i nt o past a n d c urre nt me dic al hist or y. C urre nt 
me di cal hist or y will be defi ne d as a c o n diti o n t hat is eit h er cl assifie d as o n- g oi n g or e n di n g 
after t he s cree ni n g Visit 1.
Me dical, dis ease a n d s ur gical hist or y d ata will be liste d b y s u bject i ncl u di n g ra n d o mi ze d 
treat m e nt se q u e nce, M e dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) S yste m Or ga n 
Class ( S O C), Me d D R A Preferre d Ter m, start d at e a n d st o p date ( or o n g oi n g if a p pli ca ble) a n d 
cate g or y ( past, c urre nt).  
Partial dates f or t he a b o ve calc ul ati o ns will be h a n dle d as per s ecti o n 3. 1. 6.
4. 2. 2. 2
Ast h m a hist or y 
Ast h ma hist or y will b e liste d se paratel y b y s u bj ect a n d will i n cl u de ra n d o mi ze d treat me nt 
se q u e nce, d ate of ast h m a dia g n osis, ast h ma dia g n ose d b y cli nici a n f or at l east 3 m o nt hs pri or 
t o Visit 1 ( Yes, N o), a n y life t hreate ni n g ast h ma e pis o des pri or t o Visit 1 ( Yes, N o), u p per 
res pirat or y i nfecti o n i n v ol vi n g a nti bi otic treat me nt w hic h was n ot res ol v e d wit hi n t he 1 4 d a ys 
pri or t o Visit 1 ( Yes, N o) a n d ass o ciate d c o n diti o ns / tri g gers / aller gies. 
4. 2. 3 
Tre at me nt E x p os ure
Treat m e nt e x p os ure a n d d osi n g i nf or mati o n will be c ollecte d o n t he e C R F a n d will be liste d 
f or all s u bjects i n t h e safet y a nal ysis set, i n cl u di n g d osi n g d ate/ti m e, treat m e nt, t otal d os e, 
o ver d ose ( Yes, N o). 
4. 2. 4 
Pr ot o c ol de vi ati o ns
All ra n d o mi ze d s u bjects wit h pr ot oc ol de viati o ns will b e liste d b y ra n d o mi ze d treat m e nt 
se q u e nce, d ate, visit (if a p plica ble) a n d re p orte d d e viati o n ter m a n d will be s orte d b y m aj or 
a n d mi n or, wit h a n i n dicati o n o n w het her or n ot t he d e viati o n was c o nsi dere d i m p orta nt ( Yes, 
N o).  
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 5 of 3 0
A se parate listi n g i ncl u di n g o nl y t he C O VI D- 1 9 relate d P Ds will b e pr o d u ce d. 
4. 2. 5 
P h ar m a c o ki netics ( P K) 
T he c o m plete P K a n al ysis, deri v ati o n a n d pres e ntati o n of t he ass ociate d P K p ara meters will 
b e descri b e d i n t he P K a nal ysis pla n a n d will b e perf or me d b y t h e P K s p eci alists. 
T he P K listi n gs a n d s u m maries descri b e d bel o w will be rec o n cil e d a n d c o m pare d wit h t he 
fi n di n gs fr o m t h e P K re p ort. 
Plas ma c o nce ntrati o n a n d P K p ara m eter s u m mari es will be b ase d o n t h e P K a nal ysis set. 
I n di vi d ual pl as ma c o nce ntrati o n a n d p h ar mac o ki netic p ara meter listi n gs will b e b ase d o n t h e 
safet y a n al ysis set. 
4. 2. 5. 1
A n al ysis of t he pl as m a c o nce ntr ati o ns 
A listi n g of t he act u al P K bl o o d sa m ple c ollecti o n ti mes, a n d all re p orta ble b u des o ni de 
c o n ce ntrati o ns will be pr o vi de d f or all c hil dre n i n t h e safet y a n al ysis set. Pl as ma 
c o n ce ntrati o ns o utsi d e of t h e q ua ntificati o n ra n ge will b e prese nte d as N Q ( N ot Q u a ntifia ble). 
C o nce ntrati o n data will b e prese nte d t o 3 si g nifi ca nt fi g ures, as recei v e d fr o m t h e 
bi oa nal ytical la b orat or y. 
Plas ma c o nce ntrati o ns of b u d es o ni de will be s u m marize d b y treat me nt a n d n o mi n al 
ti me p oi nts usi n g t he f oll o wi n g d es cri pti ve statistics: 
n: N u m ber of e v al ua ble o bs er v ati o ns i n t he a nal ysis 
n-: N u m ber of o bser vati o ns b el o w t he l o wer li mit of q ua ntificati o n ( L L O Q) 
Mea n: Arit h metic mea n calc ulate d usi n g u ntra nsf or me d data 
S D: Sta n d ar d De viati o n cal c ulate d usi n g u ntra nsf or me d data 
g Me a n: Ge o m etri c mea n, calc ul ate d as e x p[ m], w here m = mea n(l o g-tra nsf or me d 
d ata) 
- 1], w here s 
is t he sta n d ar d de viati o n of t he data o n t h e l o g scale 
Me dia n: M e dia n c alc ulate d usi n g u ntra nsf or me d data 
Mi n: Mi ni m u m v al u e of t he u ntra nsf or m e d data 
Ma x: M a xi m u m v al ue of t he u ntra nsf or me d d ata 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 6 of 3 0
N Q o bser vati o ns at a n y ti me p oi nt will be h a n dle d as per t h e r ul es defi ne d i n Secti o n 3. 1. 6. 2.
A n y N Q o bser vati o ns i m p ute d as 0 will be e xcl u de d fr o m t h e calc ulati o n of t h e ge o metric 
mea n a n d t he ge o metric c oeffi cie nt of variati o n. 
As per t h e P K a nal ysis pl a n, at least 6 6 % of o bs er vati o ns wit hi n t h e q ua ntificati o n ra n ge are 
re q uire d at eac h ti m e p oi nt f or t h e descri pti ve statistics t o be cal c ulate d. Ot her wise t he 
statisti cs will be s et as N C ( N ot Calc ula bl e) a n d o nl y t he mi ni m u m a n d m a xi m u m will be 
prese nte d.  
4. 2. 5. 2
A n al ysis of t he pri m ar y P K e n d p oi nts 
T he pri m ar y e n d p oi nts; A U C 0-t a n d C ma x ( Secti o n 3. 2) f or b u des o ni de will be c o m pare d 
se parat el y b et w ee n treat m e nts wit h a n A N O V A m o d el usi n g t h e n at ural l o garit h m of A U C 0-t
a n d C ma x as t he res p o nse a n d treat me nt, treat me nt se q u e nce, p eri o d, a n d s u bject wit hi n 
se q u e nce as fi x e d effects. Please see e xa m ple S A S ® c o d e b el o w. 
p r o c  m i x e d  d a t a = m a x f a l l  m e t h o d = R E M L ;   
 
b y  p a r a m c d ;  
 
c l a s s  t r t a n  t r t s e q a n  a p e r i o d  u s u b j i d ( t r t s e q a n ) ;  
 
m o d e l  l o g
a v a l  =  t r t a n  t r t s e q a n  a p e r i o d  u s u b j i d ( t r t s e q a n ) ;  
 
L S m e a n s  t r t a n  /  C L  a l p h a = 0 . 0 5 ;  *  T r e a t m e n t  L S m e a n  e s t i m a t e s  w i t h  9 5 %  C I ;  
 
L S m e a n s  t r t a n  /  d i f f  C L  a l p h a = 0 . 1 ;  * *  L S m e a n  d i f f e r e n c e s  w i t h  9 0 %  C I ;  
r u n ;  
Least s q uares mea n esti mat es fr o m t he m o dels will be bac k-tra nsf or me d t o pr o vi d e t h e 
ge o m etric m ea ns t o g et her wit h 2-si d e d 9 5 % c o nfi d e nce i nter vals f or eac h treat me nt gr o u p. 
Als o, ge o m etri c me a n rati os bet wee n test ( B D A M DI) a n d refere nce ( P ul mi c ort Res p ules) 
treat m e nts, al o n g wit h t he ass ociate d 9 0 % c o nfi d e nce li mits will b e calc ulat e d fr o m t he 
m o d els. M ore o ver, t h e i ntra-s u bject c o effi cie nt v ariati o n ( C V %) will be calc ulate d as 
, w here 
is t he m ea n s q uare d err or fr o m t h e m o del. 
T he pri m ar y treat m e nt c o m paris o n of B D A M DI v ers us P ul mic ort R es p ul es f or t he relati v e 
e x p os ure of b u des o ni d e will b e c o n d u cte d o n t he P K a n al ysis set. O nl y s u bjects wit h 
e val ua ble P K m eas ures fr o m b ot h treat m e nt ar ms will be i n cl u d e d i n t h e A N O V A.  
A d diti o nall y, t he pri m ar y P K e n d p oi nts will be s u m mariz e d descri pti vel y as per ( 4. 2. 5. 3, P K 
p ara meters).
As t his st u d y is pri m aril y descri pti ve i n nat ure, t h ere are n o pre defi n e d statistical h y p ot hes es 
a n d n o pre det er mi ne d tests or decisi o n r ules f or t h e af ore me nti o n e d a n al yses. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 7 of 3 0
4. 2. 5. 3
P K p a r a meters 
A listi n g of t he deri v e d P K para meters will be pr o vi d e d f or all c hil dre n i n t he safet y a n al ysis 
set, i ncl u di n g treat me nt a n d visit, w here: C m a x will be prese nte d t o t h e sa me n u m ber of 
A U C 0-t a n d A U C 0-i nf 
; t ma x, tlast a n d 
will be 
prese nte d i n h o urs wit h 2 deci mal places. 
A d diti o nall y, t he P K p ara meters ( See 3. 2 a n d 3. 3) will b e s u m marize d b y treat m e nt usi n g t h e 
f oll o wi n g des cri pti v e statistics: 
n: N u m ber of s u bjects i n treat m e nt gr o u p 
Mea n: Arit h metic mea n cal c ulate d usi n g u ntra nsf or me d data 
S D: Sta n d ar d De viati o n cal c ulate d usi n g u ntra nsf or me d data 
g Me a n: Ge o m etri c mea n, calc ul ate d as e x p[ m], w here m = mea n(l o g-tra nsf or me d 
d ata) 
- 1], w here s 
is t he sta n d ar d de viati o n of t he data o n a l o g s cale  
Me dia n: M e dia n c alc ulate d usi n g u ntra nsf or me d data 
Mi n: Mi ni m u m v al u e of t h e u ntr a nsf or me d d ata 
Ma x: M a xi m u m v al ue of t he u ntra nsf or me d d ata 
Descri pti ve statistics f or s u bjects i n t h e P K a nal ysis set will be prese nte d t o 4 si g nifica nt 
s
O nl y me dia n, mi ni m u m a n d ma xi m u m will be re p orte d 
f or t m a x a n d tlast. 
As per t h e P K a nal ysis pl a n, at least 6 6 % of o bs er vati o ns p er P K para meter are re q uire d f or 
t h e d escri pti v e statisti cs t o b e calc ul ate d. Ot h er wise t h e statisti cs will b e s et as N C ( N ot 
Calc ula ble) a n d o nl y t he mi ni m u m a n d m a xi m u m will be prese nte d.  
4. 2. 6  
A n al ysis of s afet y v a ri a bles 
T he a nal ysis of t he safet y varia bles will be base d o n t he safet y a nal ysis set a n d will be 
re p orte d usi n g t h e act ual treat m e nt ass o ciat e d wit h t he o bser ve d d ata. All data c ollecte d pri or 
t o st u d y wit h dra wal will b e i n cl u d e d i n t h e a nal ys es. Safet y d at a c ollecte d d uri n g scree ni n g 
will be liste d se paratel y. 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 8 of 3 0
4. 2. 6. 1
A d v erse e ve nts 
All A Es will be c o d e d usi n g t h e m ost rece nt v ersi o n of Me d D R A dicti o nar y at t he ti me of 
d ata base l o c k. 
A Es d uri n g s cr ee ni n g will b e liste d b y act ual treat m e nt se q ue nce, M e d D R A ter m, re p ort e d 
ter m, st u d y da y of start of A E, d urati o n of A E, ma xi m u m i nte nsit y, seri o us ness a n d o utc o me. 
Treat m e nt e mer ge nt A Es ( T E A Es) will be liste d b y act u al treat me nt recei v e d, Me d D R A ter m, 
re p orte d ter m, st u d y d a y of start of A E, d urati o n of A E, ma xi m u m i nte nsit y, seri o us ness, 
acti o n ta ke n wit h I M P, ca usalit y a n d o ut c o me. 
A d diti o nall y, a ke y s u bje ct i nf or mati o n listi n g of all S A Es d uri n g t h e e ntire st u d y will b e 
creat e d, i ncl u di n g, act u al treat me nt recei ve d (if a p plica ble), c orres p o n di n g visit, re p orte d 
ter m, preferre d ter m, ti m e fr o m start of treat m e nt t o o nset of A E ( da ys), ti m e fr o m start of 
treat m e nt t o b ec o mi n g seri o us ( da ys), o utc o m e, acti o n ta ke n wit h I M P a n d ca us alit y. Ti me 
refere nces are peri o d s pecific. 
F urt her m ore, s u bjects wit h T E A Es, s eri o us T E A Es, T E A Es t h at l e d t o deat h, a n d T E A Es t hat 
le d t o st u d y wit h dra w al will be se paratel y liste d a n d s u m marize d b y S O C a n d P T. 
A hi g h-le vel descri pti ve s u m mar y will als o be pr o d uce d f or s u bjects wit h a n y T E A E i n a n y of 
t h e f oll o wi n g cate g ories: 
o
A n y T E A E 
o
A n y T E A E wit h o ut c o m e of d eat h 
o
A n y treat me nt relate d T E A E 
o
A n y seri o us T E A E 
o
A n y T E A E lea di n g t o wit h dra wal fr o m st u d y 
4. 2. 6. 2
Vit al si g ns 
Vital si g ns varia bl es ( Secti o n 3. 4. 1) will be liste d b y s u bject, i ncl u di n g act ual treat m e nt 
se q u e nce, visit (re peat/ u nsc he d ule d ass ess me nts i n cl usi ve), a n d date/ti m e of t he assess me nts 
a n d cli nical si g nifica nce ( Yes, N o). 
Vital si g ns varia bl es will be d escri pti vel y s u m mari ze d b y act u al treat me nt gr o u p a n d 
ti me p oi nt ( pre- d ose a n d p ost-last P K assess me nt). 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 9 of 3 0
4. 2. 6. 3
L a b o r at or y assess me nts 
T he cli nical c h e mistr y, h e mat ol o g y, a n d uri nal ysis assess m e nts will be liste d b y act ual 
treat m e nt se q u e nce a n d visit i ncl u di n g re p eat/ u nsc he d ule d meas ure me nts. T he listi n gs will 
i n cl u de t h e f oll o wi n g i nf or mati o n: test n a me, date/ti me of m eas ure me nt, res ult, res ult u nits, 
cli nical si g nifica nce ( Yes, N o) as deter mi ne d b y t he I n vesti gat or, a n d a n i n dicat or v ari a ble 
relati ve t o t he n or mal ra n ges ( L o w, N or m al, Hi g h). 
4. 2. 6. 4
Pri o r a n d C o nc o mit a nt me di c ati o n 
T he n u m ber a n d p erce nta ge of s u bjects w h o t a k e all o w e d c o nc o mita nt m e dicati o ns, a n d t h os e 
w h o ta ke pr o hi bite d c o n c o mit a nt me dicati o ns d uri n g t he st u d y, will b e prese nte d se paratel y b y 
sta n dar dize d me dicati o n na me, wit hi n g e neric class ( W H O Dr u g dicti o nar y t e xt) f or eac h 
act ual treat me nt se q u e n ce. Si mil arl y, a s u m mar y of pri or m e dicati o ns will be pr o d uce d.  
Pri or a n d c o nc o mita nt me dicati o n will be liste d se paratel y b y s u bj ect a n d will i ncl u de t h e 
f oll o wi n g i nf or mati o n: act ual treat me nt se q u e n ce, re p orte d n a me, c o d e d preferre d ter m, t he 
r o ute of a d mi nistrati o n, d ose ( u nit), fre q u e nc y, start a n d st o p date, i n di cati o n, o n g oi n g stat us 
( Yes, N o) a n d t hera p y reas o n. A n y i de ntifie d pr o hi bite d me dic ati o n will be clearl y i n dicate d 
i n t h e listi n gs. 
Descri pti ve s u m maries a n d listi n gs of pri or a n d c o n c o mita nt me dicati o n will b e base d o n t he 
safet y a n al ysis set.
4. 2. 7  
C O VI D- 1 9 i m p a cts 
Bla nc is a n o n- g oi n g trial t hr o u g h o ut t he c or o na vir us dis ease 2 0 1 9 ( C O VI D- 1 9) o ut brea k. 
D ue t o t h e desi g n a n d s h ort st u d y d urati o n, it is n ot e x pecte d t h at trial data or t he a n al yses will 
b e greatl y i m p act e d b y t h e p a n de mic. Alt h o u g h, it is i m p orta nt t o be a ble t o i d e ntif y a n y 
p ote ntial i nt erc urre nt e ve nts d ue t o C O VI D- 1 9 a n d t o be a ble t o q u a ntif y t heir i m p act o n t he 
st u d y. 
4. 2. 7. 1
Pr e m at ure disc o nti n u ati o n d u e t o C O VI D- 1 9
If a s u bject ca n n ot c o nti n ue wit h pr oce d ures a n d sc h e d ule d ass ess m e nts d ue t o C O VI D- 1 9
p ost-ra n d o miz ati o n, t h e y will b e wit h dra w n fr o m t he trial a n d will be as k e d t o c o m plete t he 
earl y- wit h dra wal T C. A s e parate listi n g of s u bjects w h o pre mat urel y wit h dra w d ue t o 
C O VI D- 1 9 will be pr o vi de d. T he listi n g will detail t he reas o n f or wit h dra wal a n d rel ati o ns hi p 
t o C O VI D- 1 9. T he listi n g of pre m at ure wit h dra w als d ue t o C O VI D- 1 9 will be base d o n t he all 
s u bjects ra n d o mize d a n al ysis s et.  
4. 2. 7. 2
A d v erse e ve nts a n d s eri o us a d v erse e ve nts d ue t o C O VI D- 1 9 
C O VI D- 1 9 tests f or s u bj ects or c are gi ver/ p are nt ma y b e c o n d uct e d pr oacti vel y pri or t o 
i n cl usi o n or site visits at a n y p oi nt t hr o u g h o ut t he st u d y i n a cc or da nce wit h l oc al a n d nati o nal 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


Statisti cal A nal ysis Pl a n  
A villi o n 
A V 0 0 6 1. 0   
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 0 of 3 0
g ui d a nce. T his will be d o c u me nte d as a n u nsc h e d ule d pr o ce d ure wit h a p ositi v e res ult 
rec or d e d as a n A E.  
All s u bjects wit h a s us pecte d or c o nfir me d di a g n osis of C O VI D- 1 9 will be liste d. T he listi n g 
will prese nt a n y A Es wit h eit her a s us p ecte d or c o nfir me d relati o ns hi p t o C O VI D- 1 9. T h e 
relati o ns hi p bet wee n a n A E a n d C O VI D- 1 9 will be d eter mi ne d b y t he i n v esti gat or a n d 
a p pr o priatel y ca pt ure d i n t he e C R F. T he listi n gs will pr o vi de a n i n dicati o n of w het h er t h e A E 
was seri o us or n o n-seri o us. 
Listi n gs of a d verse e ve nts li n ke d t o C O VI D- 1 9 will b e b ase d o n t he safet y a n al ysis s et. 
4. 2. 7. 3
O ver all d escri pti ve s u m m a r y 
A hi g h-le vel descri pti ve s u m mar y will be pr o vi d e d a n d gr o u pe d b y ra n d o miz e d se q ue nce a n d 
t otal n u m b er of s u bj ects ( acr oss se q u e nces). T he f oll o wi n g fre q u e nci es a n d perce nt a ges of 
s u bjects i n t h e P K a nal ysis set will b e prese nte d: 
1.
N u m ber of s u bjects affecte d b y C O VI D- 1 9 [a]
2.
N u m ber of pre m at ure wit h dra wals d ue t o C O VI D- 1 9
3.
N u m ber of s u bjects wit h C O VI D- 1 9 relat e d P Ds 
4.
N u m ber of s u bjects wit h C O VI D- 1 9 relat e d A Es 
5.
N u m ber of s u bjects wit h C O VI D- 1 9 relat e d S A Es 
[a] Defi n e d as t h e n u m ber of s u bjects w h o meet at l east o ne of t he list e d criteria i n p oi nts 2- 5.
5.  
C H A N G E S O F A N A L Y SI S F R O M P R O T O C O L 
N/ A 
R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n


R E D A C T E D C O P Y 
T hi s d o c u m e nt m u st n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n or a n y v ari ati o n or e xt e n si o n of s u c h a p pli c ati o n