Clinical trial NCT03847896
Conditions: Asthma
Sponsor: Bond Avillion 2 Development LP
Start date: 2019-03-20; Completion date: 2021-07-20
Enrollment: 1001 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, multicenter, parallel group study to compare 2 dose levels of budesonide/albuterol BDA MDI (PT027) to its components budesonide BD MDI (PT008) and albuterol AS MDI (PT007) on improvement in lung function and asthma symptoms after 12 weeks of treatment in adult, adolescent, and child subjects with symptomatic asthma currently being treated with a short/rapid-acting β2-adrenoreceptor agonist (SABA) as needed alone or with low-dose inhaled corticosteroid (ICS) maintenance therapy plus SABA as needed.

Detailed description:

Arms: arm 1: Budesonide/Albuterol sulfate BDA MDI (PT027) high dose arm 2: Budesonide/Albuterol sulfate BDA MDI (PT027) low dose arm 3: Budesonide BD MDI (PT008) arm 4: Albuterol sulfate AS MDI (PT007) arm 5: Placebo MDI
Interventions: intervention 1: Budesonide/albuterol sulfate metered dose inhaler / BDA MDI 160/180 μg (high dose) intervention 2: Budesonide/albuterol sulfate metered dose inhaler / BDA MDI 80/180 μg (low dose) intervention 3: Budesonide metered dose inhaler / BD MDI 160 µg intervention 4: Albuterol sulfate metered dose inhaler / AS MDI 180 μg intervention 5: Placebo metered-dose inhaler / Placebo MDI
Intervention descriptions: intervention 1: Budesonide/albuterol sulfate pressurized metered dose inhaler (BDA MDI) 160/180 micrograms (μg), given as 2 inhalations of BDA MDI 80/90 μg, four times a day (QID) intervention 2: Budesonide/albuterol sulfate pressurized metered dose inhaler (BDA MDI) 80/180 micrograms (μg), given as 2 inhalations of BDA MDI 40/90 μg, four times a day (QID) intervention 3: Budesonide pressurized metered dose inhaler (BD MDI) 160 micrograms (μg), given as 2 inhalations of BD MDI 80 μg, four times a day (QID) intervention 4: Albuterol sulfate pressurized metered dose inhaler (AS MDI) 180 micrograms (μg), given as 2 inhalations of AS MDI 90 μg, four times a day (QID) intervention 5: Placebo pressurized metered dose inhaler (Placebo MDI), given as 2 inhalations of Placebo MDI, four times a day (QID)

Protocol documents:
Prot_000.pdf: 
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This protocol contains trade secrets and confidential commercial information, disclosure of which is prohibited 
without providing advance notice to Bond Avillion 2 Development LP and opportunity to object. 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
 
A 12-week, Randomized, Double-blind, Placebo-controlled, Multicenter, 
Parallel Group, Phase III Study Evaluating the Efficacy and Safety of 
PT027 Compared to PT008 and PT007 Administered QID in Adults and 
Children 4 Years of Age or Older with Asthma (DENALI) 
 
 
International coordinating investigators 
 
 
 
 
 
 
 
Study site(s) and number of subjects planned 
Approximately 100 study sites are anticipated to randomize 1000 adult and adolescent 
subjects (≥12 years of age) with asthma. Subjects will be randomized 1:1:1:1:1 to 1 of 5 
treatment groups. Approximately 200 subjects per group: budesonide/albuterol metered-dose 
inhaler (BDA MDI) 80/180 μg 4 times daily (QID), BDA MDI 160/180 μg QID, budesonide 
metered-dose inhaler (BD MDI) 160 μg QID, albuterol sulfate metered-dose inhaler (AS 
MDI) 180 μg QID, or placebo MDI. In addition, up to 30 child subjects (aged 4 to 11 years) 
with asthma will be enrolled but will not receive high dose inhaled corticosteroid (ICS) and 
will be randomized 1:1:1 to receive low-dose BDA MDI 80/180 μg QID, AS MDI 180 μg 
QID, or placebo MDI. Approximately 2000 subjects will need to be screened, assuming an 
estimated screen failure rate of 50% prior to randomization. This Phase III study is planned to 
be conducted globally. 
 
Study design 
This is a 12-week, randomized, double-blind, placebo-controlled, multicenter, parallel group, 
Phase III study. The purpose of this study is to compare 2 dose levels of BDA MDI compared 
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to its constitute components BD MDI and AS MDI on improvement in lung function and 
asthma symptoms after 12 weeks of treatment in adults, adolescents, and child subjects, aged 
4 years and older, with symptomatic asthma currently being treated with short/rapid-acting β2-
adrenoreceptor agonist (SABA; eg, Ventolin) as needed (prn) alone or with low-dose ICS 
maintenance therapy plus SABA prn. 
Subjects meeting all entry criteria at the screening visit (Visit 1) will enter a 14 to 28-day 
screening (run-in) period. Only Sponsor-provided investigational product (IP) and Sponsor-
provided Ventolin to be used in response to asthma symptoms are allowed during the study. 
No other asthma medications are allowed during the study. 
During the screening (run-in) period, subjects will self-administer single-blind placebo MDI 
QID and Ventolin prn for asthma symptoms only. Subjects will be trained and instructed in 
the use of an electronic diary (eDiary) and peak flow meter at Visit 1 to record protocol 
required data into the eDiary twice daily. Eligible subjects will be randomized at Visit 2. 
Objectives 
Primary objective: 
Primary endpoint: 
To demonstrate the contribution of budesonide 
and albuterol in BDA MDI 80/180 μg and 
160/180 μg administered QID by comparing with 
mono-components (BD MDI 160 μg, AS MDI 180 
μg) and placebo on lung function 
Dual-primary endpoints: 
• 
Change from baseline in FEV1 AUC0-6 hours over 
12 weeks  
• 
Change from baseline in trough FEV1 at 
Week 12  
Secondary objective: 
Secondary endpoint: 
To characterize the effect of BDA MDI 80/180 μg 
and 160/180 μg administered QID on 
bronchodilation and asthma symptoms compared 
to the mono-components (BD MDI 160 μg, AS 
MDI 180 μg) and placebo 
• 
The time to onset (defined as 15% increase in 
FEV1 over the pre-treatment value on Day 1), 
and duration of response on Day 1  
• 
Number (%) of subjects who have an Asthma 
Control Questionnaire-7 (ACQ-7) score of ≥1.5 
at baseline who achieve a clinically meaningful 
improvement (a decrease of at least 0.5 units 
from baseline) in ACQ-7 at Week 12 
• 
Trough FEV1 at Week 1 
Safety objective: 
Safety endpoints: 
To evaluate the safety and tolerability of BDA 
MDI 80/180 μg and 160/180 μg administered QID 
compared to BD MDI (160 μg) and AS MDI (180 
μg) 
• 
AE/SAEs 
• 
Vital signs (ie, heart rate, blood pressure only) 
• 
Clinical chemistry and hematology parameters 
• 
Electrocardiogram (ECG) 
 
 
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Exploratory objective: 
Exploratory endpoints: 
To characterize the effect of BDA MDI 80/180 μg 
and 160/180 μg administered QID on 
bronchodilation and asthma symptoms compared 
to the mono-components (BD MDI 160 μg, AS 
MDI 180 μg) and placebo 
•
Deteriorations of asthma
•
Incidence of severe exacerbations
Change from baseline in: 
•
Trough FEV1 at individual time points
•
FEV1 AUC0-6 hours at individual time points
•
Peak change from baseline FEV1 at Day 1 and
Day 7
•
Morning and evening peak expiratory flow
(PEF)
•
Use of Ventolin therapy in response to asthma
symptoms
•
Asthma daytime/night-time symptoms
•
Asthma Control Questionaire-5 (ACQ-5) and
responder analysis at Week 12
•
Asthma Quality of Life Questionnaire +12 for
12 years and older (AQLQ+12)/Pediatric
Asthma Quality of Life Questionnaire (PAQLQ)
change from baseline at Week 12
Target Subject Population 
Male and female subjects ≥4 years of age, where approved, ≥18 years of age for all other 
countries, with a diagnosis of asthma as defined by Global Initiative for Asthma (GINA) 
criteria with pre-bronchodilator FEV1 of ≥50 to <85% predicted normal value (subjects ≥18 
years of age) and ≥50% predicted normal value for subjects 4 to 17 years of age, where 
approved, with demonstrated in-clinic FEV1 reversibility to Sponsor-provided SABA will be 
included. 
Subjects must be taking a stable dosing of asthma therapies (only prn SABA or stable 
low-dose ICS in addition to prn SABA) for at least the last 30 days prior to Visit 1 may be 
eligible for this study. 
Duration of Study/treatment 
The study will consist of 3 periods: 
•
A screening/run-in period (14 to 28 days).
•
A 12-week treatment period.
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• 
A safety follow-up period: where a safety follow-up telephone contact (TC) will occur 
2 weeks (±4 days) after the subject’s last dose of treatment (end-of-treatment [EOT]) or 
premature discontinuation visit (PDV). 
 
The end-of-study is defined as the last visit of the last subject undergoing the study, therefore 
end-of-study will occur when the last subject has completed his or her post-study follow-up 
TC. Subjects who discontinue IP will complete a PDV, and adverse events (AEs)/serious 
adverse events (SAEs) will be followed up if medically indicated. 
Investigational Product, Dosage, and Mode of Administration 
BDA MDI is formulated as both micronized budesonide and micronized albuterol 
co-suspended with spray-dried porous particles in a hydrofluoroalkane propellant. The 
co-suspension formulation ensures that subjects receive a consistent delivery of the drug from 
each actuation of the MDI. 
Only Sponsor-provided IP administered 4 times per day (QID) and Sponsor-provided Ventolin 
to be used in response to asthma symptoms are allowed during the study. No other asthma 
medications are allowed during the study. 
At randomization (Visit 2), adult (≥18 years of age) and adolescent subjects (aged 12 - 17 
years, where approved) who meet the eligibility criteria will be randomly assigned to 1 of the 
following 5 treatment groups in a 1:1:1:1:1 ratio: 
• 
BDA MDI 80/180 μg QID (given as 2 actuations of BDA MDI 40/90 μg per puff) 
• 
BDA MDI 160/180 μg QID (given as 2 actuations of BDA MDI 80/90 μg per puff) 
• 
BD MDI 160 μg QID (given as 2 actuations of BD MDI 80 μg per puff) 
• 
AS MDI 180 μg QID (given as 2 actuations of AS MDI 90 μg per puff) 
• 
Placebo MDI QID (given as 2 actuations) 
 
The maximum daily dosage of IP should not exceed 12 puffs per day. 
Subjects will be recommended not to take more than 8 puffs of Ventolin per day and advised 
to contact the investigator if their symptoms necessitate more than 8 puffs of Ventolin in a 
day. 
 
Statistical Methods 
Sample Size Calculation 
A preliminary sample size calculation was based on historical trial data. A sample size of 
600 subjects was initially proposed to provide 93% power to detect a difference in change 
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from baseline in trough FEV1 at week 12 of 100 mL for comparisons of BD MDI versus 
placebo MDI, BDA MDI versus placebo MDI, or BDA MDI versus AS MDI. This calculation 
was based on a standard deviation of 210 mL obtained from the placebo MDI group of Study 
PT008001 and an assumed dropout rate of 10% and 15% for active and placebo treatment 
group, respectively, prior to Week 12.  
Because the assumed variability from the lung function data has a large impact on the 
estimated sample size necessary to achieve a stated power, a blinded estimate of the variability 
of pre-dose trough FEV1 at Week 12 was calculated. The review was performed once 44% of 
subjects had completed Week 12, and prior to the 600th subject being randomized. The pooled 
estimate of variability across treatment groups was used to re-calculate the projected power.  
Decisions following the blinded sample size re-estimation 
The blinded sample size re-estimation was performed once 44% of subjects had completed 
Week 12.  Based on the blinded estimate of variability, approximately 1000 subjects are 
required in order to demonstrate 90% power. Consequently, the total number of randomized 
adult and adolescent subjects has been increased by 400 to 1000. 
Randomization of approximately 200 subjects to each treatment group will provide 90% 
probability to detect a 100 mL difference in the change from baseline in trough FEV1 at Week 
12 for comparison of BD MDI versus placebo MDI, BDA MDI versus placebo MDI, or BDA 
MDI versus AS MDI. This calculation is based on a standard deviation of 290 mL obtained 
from the blinded sample size re-estimation performed after 44% of subjects completed week 
12 and an estimated overall dropout rate of 11% prior to Week 12. 
The sample size of 200 subjects per treatment group will also provide >99% probability to 
detect a 130 mL difference in FEV1 AUC0-6 hours over 12 weeks for comparison of BDA MDI 
versus BD MDI (effect sizes for AS MDI or BDA MDI versus placebo MDI should be 
considerably larger). This calculation assumes 2% dropout prior to Week 1 and an effective 
standard deviation of 290 mL obtained from the blinded sample size re-estimation performed 
after 44% of subjects completed Week 12. 
Approximately 1000 adults (≥18 years of age) and adolescent subjects (12 - 17 years of age, 
where approved) with asthma will be randomized 1:1:1:1:1 to 1 of 5 treatment groups 
(approximately 200 subjects per group: BDA MDI 80/180 μg QID, BDA MDI 160/180 μg 
QID, BD MDI 160 μg QID, AS MDI 180 μg QID, or placebo MDI). In addition, where 
approved, up to 30 child subjects (aged 4 to 11 years) with asthma will be enrolled but will not 
receive high dose ICS and will be randomized 1:1:1 to receive low-dose BDA MDI 80/180 μg 
QID, AS MDI 180 μg QID, or placebo MDI. Approximately 2000 subjects will need to be 
screened, assuming an estimated screen failure rate of approximately 50% prior to 
randomization. This Phase III study is planned to be conducted globally. 
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A second blinded sample size re-estimation will be performed once approximately 65% of the 
revised sample has completed 12 weeks and prior to the last subject being randomized.  This 
will allow the re-assessment of variability in a larger sample and at a point where any impact 
on COVID-19 with respect to lung function variability and dropout rates can be quantified 
more accurately. Final total enrollment in the study will be confirmed following the second 
blinded sample size re-calculation in order to ensure 90% power.  
The potential increase in sample size will be capped at 1300, a 30% increase above the revised 
number of 1000 subjects. 
Primary Efficacy Analysis 
The first and second dual-primary variables, change from baseline in FEV1 AUC0-6 hours, and 
change from baseline in trough FEV1 will each be analyzed using a repeated measures (RM) 
linear model to compare treatment groups. The model will include baseline FEV1, percentage 
reversibility to Ventolin, and age as continuous covariates, and visit, treatment, the treatment-
by-visit interaction, and prior ICS use (Yes/No) as categorical covariates. Baseline will be 
defined as the average of the pre-dose assessments collected on randomization (Visit 2). 
An unstructured variance-covariance matrix will be implemented. If this model fails to 
converge, a heterogeneous Toeplitz (TOEPH) will be fit. 
Secondary Efficacy Analyses 
The median time to onset (defined as 15% increase in FEV1) over the pre-treatment value at 
randomization (Visit 2) will be compared among treatment groups using a Wilcoxon rank sum 
test. Confidence intervals for the median treatment difference will be calculated using the 
Hodges-Lehmann method. Descriptive statistics for duration of response will be reported by 
treatment group. Only the subjects who achieve the 15% increase in FEV1 within 30 minutes 
post-dose will be included in these calculations. 
The treatment effect for change from baseline in ACQ-7 will be estimated using a mixed 
model RM (MMRM) analysis. All data up to Week 12 will be included in the model, with 
terms for age, treatment, visit, treatment* visit, prior ICS use (Yes/No), baseline ACQ-7 score 
and baseline post-dose percent predicted FEV1. Visit will be fitted as a categorical variable, 
and the variance-covariance matrix will be assumed to be unstructured. If the procedure does 
not converge, then a heterogeneous Toeplitz (TOEPH) will be used instead. This model will 
be used to give an overall assessment of the treatment effect as well as 95% confidence 
intervals. 
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Estimands 
The primary estimand of interest is the efficacy estimand, defined as the effect of the 
randomized treatment in all subjects assuming continuation of randomized treatment for the 
duration of the study, regardless of actual compliance. This estimand could be considered as a 
while-on-treatment strategy or a hypothetical strategy as defined in the draft International 
Conference on Harmonization (ICH) E9 Addendum. 
The second estimand of interest is the attributable estimand, defined as the effect of treatment 
in subjects attributable to the randomized treatment. For this estimand, discontinuation of 
randomized treatment for reasons such as tolerability or lack of efficacy is considered a 
negative outcome. This estimand is a mixture of composite and hypothetical strategies as 
defined in the draft ICH E9 addendum. 
 
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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
VERSION HISTORY ................................................................................................................1 
CLINICAL STUDY PROTOCOL SYNOPSIS.........................................................................3 
TABLE OF CONTENTS .........................................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................16 
1 
INTRODUCTION ............................................................................................ . .18 
1.1 
Background .................................................................................................. . .....18 
1.2 
Rationale for study design, doses, and control groups ..........................................19 
1.3 
Benefit/risk and ethical assessment .................................................... .................20 
1.4 
Study design ................................................................................ .. ......................21 
1.5 
Study governance and oversight ............................................ ..............................23 
1.5.1 
Independent data monitoring committee ........................... . .................................23 
2 
STUDY OBJECTIVES .........................................................................................24 
2.1 
Primary objectives................................................. .............................................24 
2.2 
Secondary objectives.................................. ..... ..................................................24 
2.3 
Safety objectives .............................. ....................................................................24 
2.4 
Exploratory objectives ..........................................................................................25 
3 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, TREATMENT DISCONTINUATION, AND STUDY 
TERMINATION .................. ... ............................................................................25 
3.1 
Inclusion criteria ............ ......................................................................................25 
3.2 
Exclusion criteria ..................................................................................................27 
3.3 
Subject enrollment and randomization .................................................................30 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects ..................30 
3.5 
Methods for assigning treatment groups ...............................................................31 
3.6 
Methods for ensuring blinding ..............................................................................31 
3.7 
Methods for unblinding .........................................................................................31 
3.8 
Restrictions............................................................................................................32 
3.9 
Treatment discontinuation by subject and/or Sponsor ..........................................33 
3.10 
Study termination ..................................................................................................33 
3.11 
Screen failures .......................................................................................................34 
4 
STUDY PLAN AND TIMING OF PROCEDURES ............................................35 
4.1 
Screening and enrollment period ..........................................................................42 
4.2 
Randomization/treatment period ...........................................................................42 
4.3 
Treatment discontinuation visit .............................................................................43 
4.4 
Unscheduled visit ..................................................................................................44 
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4.5 
Safety Follow-up period........................................................................................44 
5 
STUDY ASSESSMENTS.....................................................................................44 
5.1 
Efficacy assessments .............................................................................................44 
5.1.1 
Lung function measurement by spirometry ..........................................................45 
5.1.1.1 
Reversibility test ...................................................................................................46 
5.1.1.2 
COVID-19 and Pulmonary Function Testing .......................................................47 
5.1.2 
Asthma Control Questionnaire-5 ..........................................................................47 
5.1.3 
Asthma Control Questionnaire-7 ..........................................................................48 
5.1.4 
Asthma Control Questionnaire-Interviewer-Administered ...................................48 
5.1.5 
Asthma Quality of Life Questionnaire+12/Pediatric Asthma Quality of Life 
Questionnaire ................................................................................................. ......48 
5.1.5.1 
Asthma Quality of Life Questionnaire+12.............................................. .............48 
5.1.5.2 
Pediatric Asthma Quality of Life Questionnaire................................ .................48 
5.1.6 
eDiary .............................................................................................. .....................49 
5.1.6.1 
Peak expiratory flow ................................................................. . ........................49 
5.1.6.2 
eDiary investigational product use ........................................ ...............................49 
5.1.6.3 
eDiary Ventolin therapy use .............................................. .................................49 
5.1.6.4 
eDiary recording of symptoms and alerts .............................................................49 
5.1.7 
Deterioration of asthma ........................................... . ...........................................50 
5.1.8 
Asthma exacerbation definition ................ ........
...............................................51 
5.1.8.1 
Definition of asthma symptom worsening ...... .....................................................51 
5.1.8.2 
Investigator justified asthma exacerbations ..........................................................51 
5.1.8.3 
Severe asthma exacerbations ................................................................................52 
5.1.8.4 
Treatment for severe asthma exacerbations ..........................................................52 
5.1.8.5 
Onset and duration of asthma exacerbations .........................................................52 
5.1.8.6 
Approach for capturing asthma exacerbations ......................................................53 
5.2 
Safety assessments ............. . ................................................................................53 
5.2.1 
Laboratory safety assessments ..............................................................................53 
5.2.2 
Resting 12-lead electrocardiogram .......................................................................54 
5.2.3 
Vital sign measurements .......................................................................................55 
5.2.4 
Adverse event assessments ...................................................................................55 
5.3 
Other assessments .................................................................................................55 
5.3.1 
Physical examination ............................................................................................55 
5.3.2 
Concomitant medications ......................................................................................55 
5.4 
Pharmacokinetics ..................................................................................................56 
5.5 
Pharmacodynamics ...............................................................................................56 
5.6 
Genetics .................................................................................................................56 
5.7 
Biomarker analysis ................................................................................................56 
6 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................56 
6.1 
Definition of adverse events .................................................................................56 
6.2 
Definitions of serious adverse event .....................................................................56 
6.3 
Recording of adverse events .................................................................................57 
6.3.1 
Period for collection of adverse events .................................................................57 
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6.3.2 
Follow-up of unresolved adverse events ...............................................................57 
6.3.3 
Variables ...............................................................................................................57 
6.3.4 
Causality collection ...............................................................................................58 
6.3.5 
Adverse events based on signs and symptoms ......................................................58 
6.3.6 
Adverse events based on examinations and tests ..................................................59 
6.3.7 
Hy’s Law ...............................................................................................................59 
6.3.8 
COVID-19 adverse events ....................................................................................59 
6.4 
Reporting of serious adverse events ......................................................................60 
6.5 
Overdose ...............................................................................................................60 
6.6 
Pregnancy ........................................................................................................... ..61 
6.6.1 
Maternal exposure .......................................................................................... ......61 
6.6.2 
Paternal exposure .................................................................................... .............62 
6.7 
Medication error ................................................................................. ..................62 
6.8 
Management of investigational product–related toxicities .......... .......................63 
7 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ...................63 
7.1 
Identity of investigational product(s) ................................. ..................................63 
7.2 
Dose and treatment regimens ................................................................................64 
7.3 
Labelling .............................................................. . .............................................65 
7.4 
Storage ........................................................... ......................................................66 
7.5 
Compliance ...................................... ....................................................................66 
7.6 
Accountability .......................................................................................................66 
7.7 
Metered-dose inhaler: handling and cleaning .......................................................67 
7.8 
Concomitant medications and other treatments ....................................................67 
7.8.1 
Investigational product and Ventolin therapies ....................................................67 
7.8.2 
Medications that may affect reversibility and FEV1 testing .................................67 
7.8.3 
Prohibited medications . .......................................................................................67 
8 
STATISTICAL ANALYSES ...............................................................................68 
8.1 
Statistical considerations .......................................................................................68 
8.1.1 
Estimands ... . ........................................................................................................68 
8.2 
Sample size estimate .............................................................................................68 
8.2.1 
Initial assumptions and estimates ..........................................................................68 
8.2.2 
Blinded sample size re-estimation ........................................................................69 
8.3 
Definitions of analysis sets ...................................................................................70 
8.3.1 
Full analysis set .....................................................................................................70 
8.3.2 
Safety analysis set .................................................................................................70 
8.4 
Violations and deviations ......................................................................................70 
8.5 
Outcome measures for analyses ............................................................................71 
8.5.1 
Primary efficacy analysis ......................................................................................71 
8.5.1.1 
Dual-primary efficacy endpoints ..........................................................................71 
8.5.2 
Secondary efficacy analyses .................................................................................71 
8.5.2.1 
Derivation for time to onset (15% increase in FEV1) on Day 1 and duration of 
effect on Day 1 ......................................................................................................71 
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8.5.2.2 
Derivation of Asthma Control Questionnaire-7 variables ....................................72 
8.5.3 
Exploratory efficacy analyses ...............................................................................72 
8.5.3.1 
Derivation of severe exacerbation endpoints ........................................................72 
8.5.3.2 
Derivation of deterioration of asthma variables ....................................................73 
8.5.3.3 
Derivation of peak FEV1 .......................................................................................73 
8.5.3.4 
Derivation of peak expiratory flow .......................................................................73 
8.5.3.5 
Derivation of Asthma Control Questionnaire-5 variables ....................................73 
8.5.3.6 
Derivation of Asthma Quality of Life Questionnaire +12 and Pediatric Asthma 
Quality of Life Questionnaire variables ................................................................73 
8.5.3.7 
Derivation of Ventolin therapy variables ..............................................................74 
8.5.3.8 
Derivation of other eDiary variables ............................................................... . ...74 
8.6 
Methods for statistical analyses ................................................................. ..........74 
8.6.1 
Analysis of the dual-primary variable ................................................... . .............74 
8.6.2 
Analysis of the secondary efficacy variables ........................................................76 
8.6.2.1 
Median time to onset (15% increase in FEV1) and duration of effect ..................76 
8.6.2.2 
Asthma Control Questionnaire-7 ............................................. ...........................76 
8.6.3 
Analysis of safety variables ............................................... ..................................77 
8.6.3.1 
Adverse events ................................................................ .....................................77 
8.6.3.2 
Vital signs ............................................................... .............................................77 
8.6.3.3 
Clinical chemistry and hematology ...................... . .............................................77 
8.6.3.4 
Electrocardiogram .................................. . ...........................................................77 
8.6.3.5 
Concomitant medication .......................................................................................78 
8.6.4 
Analysis of exploratory variables .. . .... . ............................................................78 
8.6.4.1 
Severe exacerbations .............................................................................................78 
8.6.4.2 
Deterioration of asthma .........................................................................................78 
8.6.4.3 
Peak FEV1 ........................ .. ..... .........................................................................78 
8.6.4.4 
Peak expiratory flow ............ ... ............................................................................78 
8.6.4.5 
Asthma Control Questionnaire-5 variables ...........................................................78 
8.6.4.6 
Asthma Quality of Life Questionnaire +12 and Pediatric Asthma Quality of Life 
Questionnaire .......... .............................................................................................79 
8.6.4.7 
Ventolin therapy ... ................................................................................................79 
8.6.4.8 
Other eDiary variables ..........................................................................................79 
8.6.5 
Subgroup analysis .................................................................................................80 
8.6.6 
Interim analysis .....................................................................................................80 
8.6.7 
Sensitivity analysis ................................................................................................80 
8.6.7.1 
Tipping point analysis ...........................................................................................80 
8.6.7.2 
Attributable estimand ............................................................................................80 
8.6.7.3 
COVID-19 pandemic impacts ...............................................................................81 
9 
STUDY AND DATA MANAGEMENT ..............................................................81 
9.1 
Training of study site staff ....................................................................................81 
9.2 
Monitoring of the study.........................................................................................81 
9.2.1 
Source data ............................................................................................................82 
9.2.2 
Study agreements ..................................................................................................82 
9.2.3 
Archiving of study documents ..............................................................................82 
9.3 
Study timetable and end-of-study .........................................................................83 
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9.4 
Data management ..................................................................................................83 
10 
ETHICAL AND REGULATORY REQUIREMENTS ........................................84 
10.1 
Ethical conduct of the study ..................................................................................84 
10.2 
Subject data protection ..........................................................................................84 
10.3 
Ethics and regulatory review .................................................................................84 
10.4 
Informed consent/assent ........................................................................................85 
10.5 
Changes to the clinical study protocol and informed consent/assent form ...........85 
10.6 
Audits and inspections ..........................................................................................86 
11 
SUMMARY OF CHANGES ......................................................................... . ....86 
11.1 
Changes to protocol amendment 2 (Version 3.0) .................................................86 
11.2 
Changes to protocol amendment 1 (Version 2.0) ............................... .................93 
12 
LIST OF REFERENCES ................................................................ .....................95 
APPENDIX A, AVILLION PROTOCOL SIGNATURE PAGE............. ..............................97 
APPENDIX B, PRIMARY INVESTIGATOR SIGNATURE PAGE ....................................98 
APPENDIX C, GLOBAL INITIATIVE FOR ASTHMA (GINA, 2018) ...............................99 
APPENDIX D, ADDITIONAL SAFETY INFORMATION . ..............................................101 
APPENDIX E, HY’S LAW ...................................................................................................103 
APPENDIX F, ASTHMA QUALITY OF LIFE +12 QUESTIONNAIRE ...........................108 
APPENDIX G, PEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE............114 
APPENDIX H, ASTHMA CONTROL QUESTIONNAIRE ................................................119 
APPENDIX I, ASTHMA CONTROL QUESTIONNAIRE-INTERVIEWER-
ADMINISTERED ........ . ....................................................................................123 
APPENDIX J, METERED-DOSE INHALER HANDLING AND CLEANING .................128 
APPENDIX K, SPIROMETRY ASSESSMENT CRITERIA...............................................138 
APPENDIX L, COVID-19 EMERGENCY MEASURES PERMITTED TO ENSURE 
SUBJECT SAFETY ............................................................................................140 
 
LIST OF TABLES 
Table 1 
Study assessments and procedures ..............................................................37 
Table 2 
Timed assessments at Visit 2 through Visit 6 and Premature 
Discontinuation Visit ...................................................................................40 
Table 3 
Schedule of FEV1 measurements at standard visits ....................................46 
Table 4 
Laboratory Safety Variables ........................................................................54 
Table 5 
Investigational Product Strength and Dosage Form ....................................64 
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LIST OF FIGURES 
Figure 1 
Study design ................................................................................................23 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
ACQ-5 
Asthma Control Questionnaire-5 
ACQ-7 
Asthma Control Questionnaire-7 
ACQ-IA 
Asthma Control Questionnaire-Interviewer-Administered 
AE 
adverse event 
AIT 
allergy immunotherapy 
ALT 
alanine aminotransferase  
AQLQ+12 
Asthma Quality of Life Questionnaire for 12 years and older 
AS MDI (PT007) 
albuterol sulfate metered-dose inhaler 
AST 
aspartate aminotransferase 
ATS/ERS 
American Thoracic Society/European Respiratory Society 
AUC0-6 hours 
area under the concentration curve from 0 to 6 hours 
BD MDI (PT008) 
budesonide metered-dose inhaler 
BDA MDI (PT027) 
budesonide/albuterol metered-dose inhaler 
β-hCG 
β-human chorionic gonadotropin 
BMI 
body mass index 
CFC 
chlorofluorocarbon propellant 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EOT 
end-of-treatment 
ePRO 
electronic patient reported outcome 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
GMP 
Good Manufacturing Practice 
HL 
Hy’s Law 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICS 
inhaled corticosteroid 
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Abbreviation or special 
term 
Explanation 
IDMC 
Independent Data Monitoring Committee 
International 
Coordinating investigator 
If a study is conducted in several countries, the International Coordinating 
investigator is the investigator coordinating the investigators and/or activities 
internationally.  
IP 
investigational product 
IWRS 
Interactive Web Response System 
LABA 
long-acting β2-agonist 
MDI 
metered-dose inhaler 
MID 
minimal important difference 
MMRM 
mixed model repeated measures 
PAQLQ 
Pediatric Asthma Quality of Life Questionnaire 
PDV 
premature discontinuation visit 
PEF 
peak expiratory flow 
PFT 
pulmonary function test 
PHL 
potential Hy’s Law 
prn 
as needed 
QID 
four times daily 
RM 
repeated measures 
SABA 
short/rapid-acting β2-adrenoreceptor agonist 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SCS 
systemic corticosteroids 
SMART 
budesonide/formoterol (Symbicort); approved for maintenance and reliever 
therapy 
TBL 
total bilirubin 
TC 
telephone contact 
ULN 
upper limit of normal 
WBDC 
Web Based Data Capture 
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1 
INTRODUCTION 
1.1 
Background  
Bond Avillion 2 Development LP (Sponsor) is developing budesonide/albuterol sulfate (PT027; 
hereafter referred to as budesonide and albuterol sulfate [hereafter referred to as albuterol] 
metered-dose inhaler [BDA MDI]) pressurized inhalation suspension in adults and children 4 
years of age or older with asthma. Please refer to the current Investigator Brochure for additional 
information. 
Albuterol is a short/rapid-acting β2-adrenoreceptor 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. In 
clinical practice, albuterol is used as an as needed (prn) reliever therapy (Global Initiative for 
Asthma [GINA] 2018). Albuterol is approved in many countries as salbutamol in multiple 
formulations for the treatment or prevention of bronchoconstriction. 
Budesonide is a well-established anti-inflammatory corticosteroid that exhibits potent 
glucocorticoid and weak mineralocorticoid activity and is approved worldwide in orally inhaled 
formulations for the treatment of asthma and chronic obstructive pulmonary disease both as a 
mono-product and in combination with a long/rapid-acting β2-agonist (LABA, formoterol).  
In vitro studies have demonstrated that inhaled corticosteroid (ICS) agents potentiate the effects 
of SABAs in reducing airway smooth muscle tone (Mendes 2008) and can reverse adrenergic 
receptor tolerance and desensitization (Cooper and Panettieri 2008). 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 (Mendes 2015). An 
analysis of 425 asthma exacerbations in patients from the Formoterol and Corticosteroids 
Establishing Therapy International Study Group study (Tattersfield 1999) revealed that asthma 
symptoms use were noted over several days before the start of an asthma exacerbation; increased 
reliever therapy (ie, albuterol) followed a similar pattern, providing rapid bronchodilation to treat 
the symptoms. Combining albuterol with budesonide in the proposed BDA MDI combination 
product should not only provide rapid bronchodilation, but also treat worsening airway 
inflammation by the addition of the budesonide component. Per current treatment guidelines 
(GINA 2018), ICS/formoterol maintenance and reliever can be used in patients with asthma. 
Studies of budesonide and a rapid-acting LABA (formoterol) as reliever therapy have 
demonstrated enhanced protection from severe exacerbations in patients already receiving 
combination therapy for maintenance without an increase in adverse effects (Rabe 2006; O'Byrne 
2005). In addition, budesonide/formoterol as maintenance and reliever therapy or ‘SMART’ 
(available commercially as the Symbicort Turbuhaler [Symbicort] in the European Union and 
other markets) significantly reduced severe exacerbation risk in pediatric patients (O'Byrne 
2007).  
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With SMART application, patients with asthma use Symbicort as maintenance inhalation 
medication and also prn in response to symptoms. The simultaneous administration of 
budesonide with formoterol when symptoms occur ensures that patients with asthma receive both 
a rapid-acting bronchodilator for symptom relief and anti-inflammatory medication to treat their 
persistent airway inflammation. BDA MDI would have added effect on improvement of lung 
function and achieving asthma improvement beyond what is seen with albuterol and budesonide 
alone. Current treatment guidelines (GINA 2018) recommend considering addition of low-dose 
ICS to SABA used as reliever medication as early as in 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-adrenoreceptor agonist. Anti-inflammatory and bronchodilation component in 
combination is expected to result with superior control and decreased risk of experiencing 
asthma symptoms. 
1.2 
Rationale for study design, doses, and control groups 
This is a 12-week, randomized, double-blind, placebo-controlled, multicenter, parallel group, 
Phase III study in adults, adolescents, and child subjects, aged 4 years and older, with 
symptomatic asthma currently being treated with SABA prn alone or with low-dose ICS 
maintenance therapy plus SABA prn. 
This 12-week Phase III study is a pivotal efficacy and safety study for approval of BDA MDI 
fixed dose combination product. This study is designed to investigate the benefit of 2 dose levels 
of BDA MDI compared to its constituent components budesonide metered-dose inhaler (BD 
MDI [PT008]) and albuterol sulfate metered-dose inhaler (AS MDI [PT007]) based on 
improvement in lung function and asthma symptoms after 12 weeks of treatment. This study will 
demonstrate the combination rule required by the Food and Drug Administration according to 
the 21 Code of Federal Regulations 300.50. 
Two dosage levels, of BDA MDI administered 4 times daily (QID), 80/180 μg (given as 
2 actuations of BDA MDI 40/90 μg per puff) and 160/180 μg (given as 2 actuations of BDA 
MDI 80/90 μg per puff), are included in this study to support final dose selection for approval. 
Children aged 4 to 11 years will only be randomized to the lower dosage level of BDA MDI 
(80/180 μg QID, or AS MDI [180 μg QID], or placebo MDI). 
The treatment duration of 12 weeks for each subject, is considered to be an appropriate duration 
to evaluate lung function benefit in asthma subjects. This is supported by a 12-week standard 
treatment duration being assessed in Symbicort® (budesonide/formoterol fumarate dihydrate), 
Breo Ellipta (fluticasone/furoate and vilanterol), and Advair® (fluticasone/propionate/salmeterol) 
lung function studies (Symbicort [Corren 2007 and Noonan 2006], Breo [Kerwin 2017], Advair 
[Kavuru 2000]).  
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Two dose levels of BDA MDI will be used to evaluate the dual-primary efficacy measures 
versus the mono-components BD MDI 160 μg QID and AS MDI 180 μg QID as active control 
groups in order to demonstrate the combination rule and to compare efficacy outcomes.  
Dual-primary efficacy measures have been selected to demonstrate the therapeutic contribution 
of each component of the combination to the overall bronchodilator efficacy: 
• 
Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 
from 0 to 6 hours (AUC0-6 hours) over 12 weeks  
• 
Change from baseline in trough FEV1 at Week 12  
1.3 
Benefit/risk and ethical assessment 
This study consists of 12 weeks of treatment and 2 weeks of safety follow-up designed to 
evaluate the effect of BDA MDI on asthma symptoms and lung function. This study with its 
typical design for lung function studies is complementary to the AV003 MANDALA study 
evaluating the effect of BDA MDI on the occurrence of severe asthma exacerbations and is part 
of the regulatory requirements for US registration of BDA MDI for an asthma indication. This 
study has 2 active control groups (BD MDI and AS MDI), and a placebo MDI control group, 
designed. SABA (Ventolin®) will also be provided to each subject prn in response to asthma 
symptoms. 
It should be noted that as part of this study design, some of the subjects who have not received 
ICS before may be assigned to treatment with BD MDI or BDA MDI. In addition, some subjects 
who have been receiving low-dose ICS may be randomized to either placebo MDI or AS MDI (ie, 
they will no longer be receiving ICS treatment). 
To mitigate potential risks, all subjects will be closely monitored to ensure subject safety 
throughout the study through a range of mechanisms including: 
• 
Frequently evaluated by investigator during clinic visits at Weeks 1, 4, 8, and 12.  
• 
Subjects will provide information to the electronic diary (eDiary) including; asthma 
symptoms score, use of Ventolin prn in response to asthma symptoms, dosing of Sponsor-
provided investigational product (IP, captured in eDiary in evenings only), and peak 
expiratory flow (PEF) twice daily. In the situation where the subject’s symptoms and/or 
Ventolin prn use has increased and/or PEF decreased over 2 days, an eDiary alert is created 
and sent to the subject, the investigator site, and the Sponsor’s medical monitoring team. 
This alert should initiate contact between the subject and the investigator site to determine 
the well-being of the subject. 
• 
The eDiary will be programmed to alert both the subject and study center to assess the well-
being of the subject and any possible asthma exacerbation.  
• 
An Independent Data Monitoring Committee (IDMC) will be established to assess the 
ongoing safety of the study. 
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• 
The Sponsor’s medical team will have medical oversight of blinded data for continuous 
subject safety evaluations. 
 
The Sponsor considers the risk and benefit profile of Study AV004-DENALI to be acceptable 
when considering and assessing all non-clinical and clinical data available for study treatments. 
COVID-19  
Recent information from the American Academy of Allery Asthma and Immunology (AAAAI) 
published on their website (https://www.aaaai.org/) on June 4, 2020 indicates that currently there 
is no evidence of increased infection rates in subjects with asthma and that it is best to “get and 
keep their asthma under control.” In the DENALI study, subjects are provided Ventolin for as 
needed use and have their asthma symptoms closely monitored through daily eDiary symptom 
alerts provided to the investigator and medical monitors. The Sponsor believes that the benefit-
risk assessment for trial participants to enroll and continue in the study remains positive.   
 
1.4 
Study design  
This is a 12-week, randomized, double-blind, placebo-controlled, multicenter, parallel group, 
Phase III study. The purpose of this study is to compare 2 dose levels of BDA MDI compared to 
its constitute components BD MDI and AS MDI on improvement in lung function and asthma 
symptoms after 12 weeks of treatment (Section 5.1.1) in adults, adolescents, and child subjects, 
aged 4 years and older, with symptomatic asthma currently being treated with SABA prn alone 
or with low-dose ICS maintenance therapy plus SABA prn.  
Subjects meeting all entry criteria at the screening visit (Visit 1) will enter a 14 to 28-day 
screening (run-in) period.  
Only Sponsor-provided IP administered 4 times per day (QID) and Sponsor-provided Ventolin to 
be used in response to asthma symptoms are allowed during the study. No other asthma 
medications are allowed during the study. 
During the screening (run-in) period, subjects will self-administer single-blind placebo MDI QID 
and Ventolin prn to be used in response to asthma symptoms only. Subjects will be trained and 
instructed in the use of an eDiary and peak flow meter at Visit 1 to record protocol required data 
into the eDiary twice daily (Section 5.1.6).   
Eligible subjects will be randomized at Visit 2.   
At randomization (Visit 2), adult and adolescent subjects (age ≥12 years) who meet the 
eligibility criteria will be randomly assigned to 1 of the following 5 treatment groups in a 
1:1:1:1:1 ratio:  
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• 
BDA MDI 80/180 μg QID (given as 2 actuations of BDA MDI 40/90 μg per puff) 
• 
BDA MDI 160/180 μg QID (given as 2 actuations of BDA MDI 80/90 μg per puff) 
• 
BD MDI 160 μg QID (given as 2 actuations of BD MDI 80 μg per puff) 
• 
AS MDI 180 μg QID (given as 2 actuations of AS MDI 90 μg per puff) 
• 
Placebo MDI QID (given as 2 actuations) 
 
Children aged 4 to 11 will be randomized in a 1:1:1 ratio only to the lower BDA MDI QID 
dosage, AS MDI QID, or placebo MDI QID.  
Ventolin will be provided to all subjects for prn use in response to asthma symptoms with a daily 
dosing recommendation not to exceed 8 puffs per day.  See Figure 1 for a graphical presentation 
of the study schema and Table 1 for a list of study assessments and Table 2 for timed 
assessments at Visit 2 through Visit 6. 
The study will consist of 3 periods:  
• 
A screening/run-in period (14 to 28 days).  
• 
A 12-week treatment period.  
• 
A safety follow-up period: where a safety follow-up TC will occur 2 weeks (±4 days) after 
the subject’s last dose of treatment (end-of-treatment [EOT]) or premature discontinuation 
visit (PDV). 
 
The study will be completed when the last subject has completed his or her safety follow-up 
telephone contact. Subjects who discontinue IP prior to the end of the 12-week treatment period 
will be withdrawn from the study and will be asked to complete a PDV, and adverse events 
(AEs)/serious AEs (SAEs) will be followed up if medically indicated. 
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Figure 1 
Study design  
 
Abbreviations:  AS MDI=albuterol metered-dose inhaler; BD MDI=budesonide metered-dose inhaler; 
BDA MDI=budesonide/albuterol metered-dose inhaler; N=number; placebo MDI=placebo metered-dose inhaler; 
PRN=as needed; QID=four time daily; R=randomization; SV=screening visit; W=week.  
 
1.5 
Study governance and oversight 
1.5.1 
Independent data monitoring committee 
An IDMC will be established to assess the ongoing safety of the study. The IDMC will review 
blinded data (open session) and unblinded safety data (closed session) to assess any safety 
related reasons why the study should continue, be modified, or stopped. Closed sessions will 
be supported by the unblinded statistician and responsibilities of the IDMC will be clarified 
within a charter before initiation of the study.  
The IDMC chair and all committee members will be independent investigators/specialists 
separate from the study team or contract research organization.   
All decisions made by the IDMC will be documented within written records of meetings and 
recommendation made to the Sponsor.  
 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary objectives 
Primary objective: 
Primary endpoints: 
To demonstrate the contribution of budesonide 
and albuterol in BDA MDI 80/180 μg and 
160/180 μg administered QID by comparing with 
mono-components (BD MDI 160 μg, AS MDI 180 
μg) and placebo on lung function 
Dual-primary endpoints: 
• 
Change from baseline in FEV1 AUC0-6 hours over 
12 weeks  
• 
Change from baseline in trough FEV1 at 
Week 12  
 
2.2 
Secondary objectives 
Secondary objective: 
Secondary endpoints: 
To characterize the effect of BDA MDI 80/180 μg 
and 160/180 μg administered QID on 
bronchodilation and asthma symptoms compared 
to the mono-components (BD MDI 160 μg, AS 
MDI 180 μg) and placebo 
• 
The time to onset (defined as 15% increase in 
FEV1 over the pre-treatment value on Day 1), 
and duration of response on Day 1  
• 
Number (%) of subjects who have an Asthma 
Control Questionnaire-7 (ACQ-7) score of ≥1.5 
at baseline who achieve a clinically meaningful 
improvement (a decrease of at least 0.5 units 
from baseline) in ACQ-7 at Week 12 
• 
Trough FEV1 at Week 1 
 
2.3 
Safety objectives 
Safety objective: 
Safety endpoints: 
To evaluate the safety and tolerability of BDA 
MDI 80/180 μg and 160/180 μg administered QID 
compared to BD MDI (160 μg) and AS MDI (180 
μg) 
• 
AE/SAEs 
• 
Vital signs (ie, heart rate, blood pressure only) 
• 
Clinical chemistry and hematology parameters 
• 
Electrocardiogram (ECG) 
 
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2.4 
Exploratory objectives 
Exploratory objective: 
Exploratory endpoints: 
To characterize the effect of BDA MDI 80/180 μg 
and 160/180 μg administered QID on 
bronchodilation and asthma symptoms compared 
to the mono-components (BD MDI 160 μg, AS 
MDI 180 μg) and placebo 
• 
Deteriorations of asthma  
• 
Incidence of severe exacerbations  
Change from baseline in: 
• 
Trough FEV1 at individual time points 
• 
FEV1 AUC0-6 hours at individual time points 
• 
Peak change from baseline FEV1 at Day 1 and 
Day 7 
• 
Morning and evening PEF 
• 
Use of Ventolin therapy in response to asthma 
symptoms 
• 
Asthma daytime/night-time symptoms 
• 
Asthma Control Questionaire-5 (ACQ-5) and 
responder analysis at Week 12 
• 
Asthma Quality of Life Questionnaire +12 for 
12 years and older (AQLQ+12)/Pediatric 
Asthma Quality of Life Questionnaire (PAQLQ) 
change from baseline at Week 12 
 
3 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, TREATMENT DISCONTINUATION, AND 
STUDY TERMINATION  
Each subject must meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  
No study-related procedures may be performed before the subject has signed the Ethics 
Committee (EC) approved Informed Consent Form (ICF)/assent form. 
3.1 
Inclusion criteria 
For inclusion in the study, subjects must fulfill the following criteria within the screening 
period: 
1 
Able and willing to provide written informed consent or sign age-appropriate forms; 
subjects below legal age of consent must have parent(s) or guardian sign the ICF before 
participation 
2 
Female or male aged ≥4 years at the time of informed consent.  In the Czech Republic, 
Germany, Serbia, Slovakia, and Ukraine only subjects ≥18 years will be included. 
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3 
Diagnosis of asthma as defined by GINA criteria with a documented history of the last 
6 months prior to Visit 1 
4 
Receiving 1 of the following inhaled asthma medications with stable dosing for at least 
30 days prior to Visit 1: 
(a) Only SABA used prn  
(b) Stable low-dose ICS (Appendix C, GINA 2018) in addition to prn use of SABA 
The following defines the minimally acceptable documentation required to support 
inclusion criterion 4: 
o 
Signed and dated notes from a referring physician, including name, dose, and 
duration of the SABA or SABA with low-dose ICS (or names and doses, if used 
as separate inhalers), if applicable, and/or 
o 
Evidence of prescriptions for SABA or SABA with low-dose ICS, if applicable, 
medications that demonstrate coverage for the duration specified in inclusion 
criteria 
5 
Pre-bronchodilator FEV1 of ≥50 to <85% predicted normal value for adults (≥18 years of 
age) and ≥50% predicted normal value for subjects aged 4 to 17 years after withholding 
SABA ≥6 hours at Visit 1. If subject took SABA or any bronchodilator in the morning of 
Visit 1, either the entire visit must be rescheduled or just PFT assessment rescheduled. 
Subjects 4 to 17 years of age who previously failed inclusion criteria 5 due to the upper 
FEV1 limit will be permitted to re-screen once and will be required to meet all eligibility 
criteria upon re-screening. 
6 
Demonstrate reversibility of airflow limitation defined as a ≥15% increase in FEV1 
relative to baseline after administration of Sponsor-provided SABA (Ventolin) at either 
Visit 1 or Visit 1a. One re-test for reversibility testing is allowed within the screening 
period prior to Visit 2 
7 
Demonstrate acceptable spirometry performance (ie, meet American Thoracic 
Society/European Respiratory Society [ATS/ERS]) acceptability/repeatability criteria 
(Appendix K, Spirometry Assessment Criteria). Subjects 4 to 11 years will be eligible if 
they provide 2 acceptable / repeatable measurements. 
8 
Taken Ventolin on ≥2 days out of 7 days prior to Visit 2 
9 
Willing and, in the opinion of the investigator, able to adjust current asthma therapy, as 
required by the protocol 
10 Demonstrate acceptable metered-dose-inhaler (MDI) administration technique as assessed 
by the investigator. Note:  spacer use is not allowed throughout the screening and 
randomized treatment periods 
11 Able to perform acceptable and reproducible PEF measurements as assessed by the 
investigator 
12 Body mass index (BMI) <40 kg/m2 
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13 Willing to remain at the study site as required per protocol and complete all visit 
assessments 
14 Negative pregnancy test (serum at Visit 1) for female subjects of childbearing potential 
15 Women of childbearing potential and sexually active in heterosexual relationships must 
agree to 1 of the following options to prevent pregnancy: 
(a) Practice complete abstinence defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study treatments. Periodic 
abstinence is not acceptable. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. Therefore, complete abstinence is an acceptable method of 
contraception only if it is consistent with the preferred and usual lifestyle of the 
subject. 
(b) If a female of childbearing potential agrees to prevent pregnancy by using 1 of the 
following effective methods of birth control from the date the ICF is signed until 2 
weeks after the final dose of IP is taken: 
i. 
Hormonal contraception (eg, oral contraceptive, contraceptive implant, or 
injectable hormonal contraceptive) 
ii. 
Double-barrier birth control (eg, a combination of male condom with either 
cap, diaphragm, or sponge with spermicide) 
iii. 
Maintenance of a monogamous sexual relationship with a male partner who has 
been surgically sterilized by vasectomy 
(c) Note: Women are considered to be of nonchildbearing potential if they are 
physiologically incapable of becoming pregnant, including any female who is 2 years 
postmenopausal, or surgically sterile, defined as having a bilateral oophorectomy, 
hysterectomy, tubal ligation, or other permanent birth control measures. For purposes 
of this protocol, menopausal women are defined as women that are amenorrheic for 
12 consecutive months or more after cessation of all exogenous hormonal treatment. 
Adolescent specific recommendations: if subject is female and has reached menarche 
or has reached Tanner stage 3 breast developments (even if not having reached 
menarche), the subject will be considered a female of child-bearing potential. 
16 Male subjects who are sexually active in heterosexual relationships must be surgically 
sterile or agree to use a double-barrier effective method of contraception (condom with 
spermicide) from the first dose of randomized IP until 2 weeks after their last dose. Male 
subjects must not donate sperm during their study participation period. 
3.2 
Exclusion criteria 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled within 
the screening period: 
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1 
Chronic obstructive pulmonary disease or other significant lung disease (eg, chronic 
bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or 
bronchopulmonary dysplasia) 
2 
Systemic corticosteroids (SCS) use (any dose and any indication) within 3 months before 
Visit 1  
3 
Chronic (≥3 weeks) use of SCS within 6 months prior to Visit 1 
4 
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, or any other prohibited medication 
5 
Current smokers, former smokers with >10 pack-years history, or former smokers who 
stopped smoking <6 months before Visit 1 (including all forms of tobacco, e-cigarettes 
[vaping], and marijuana) 
6 
Life-threatening asthma defined as any history of significant asthma episode(s) requiring 
admission to an intensive care unit, intubation associated with hypercapnia, respiratory 
arrest, hypoxic seizures, or asthma-related syncopal episode(s) within 5 years of Visit 1 
7 
Completed treatment for lower respiratory infection within 6 weeks prior to Visit 1 
8 
Upper respiratory infection involving antibiotic treatment not resolved within 7 days prior 
to Visit 1 
9 
Hospitalizations due to asthma within 6 months prior to Visit 1 
10 Have taken ≥12 actuations per day of Sponsor-provided Ventolin during the run-in period 
prior to Visit 2 according to the below criteria: 
(a) ≥2 days out of 14 days of run-in 
(b) ≥3 days out of 15 to 21 days of run-in 
(c) ≥4 days out of 22 or more days of run-in  
11 Unable to comply with study procedures including non-compliance with diary completion 
(ie, <70% subject completion of diary assessments in the last 7 days preceding Visit 2 or 
QID dosing, <80% compliance during the placebo run-in period) 
12 Clinically significant laboratory abnormalities, in the opinion of the investigator, or 
having any of the following results at Visit 1:  
(a) a serum creatinine value >1.5 times the upper limit of the reference range 
(b) a serum total bilirubin value (TBL) >1.5 times the upper limit of the reference range 
(c) a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2.5 times the upper limit of the reference range 
Note: Laboratory tests may be repeated once: if laboratory tests have to be repeated, the 
results must be available for review before Visit 2 (randomization). 
13 Any of the following results at Visit 1:  
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(a) an abnormal electrocardiogram (ECG) that is, in the investigator’s opinion, clinically 
significant 
(b) a QTCF interval >480 ms (subjects aged ≥12 years)/≥460 ms (subjects aged 4 to 
11 years, based on the Fridericia correction where QTcF=QT/RR0.33) 
14 Historical or current evidence of a clinically significant disease including, but not limited 
to: cardiovascular (eg, congestive heart failure, known aortic aneurysm, clinically 
significant cardiac arrhythmia, coronary heart disease), hepatic, renal, hematological, 
neuropsychological, endocrine (eg, uncontrolled diabetes mellitus, uncontrolled thyroid 
disorder, Addison’s disease, Cushing’s syndrome), or gastrointestinal (eg, poorly 
controlled peptic ulcer, gastroesophageal reflux disease) disorders. Significant is defined 
as any disease that, in the opinion of the investigator, would put the safety of the subject 
at risk through study participation, or that could affect the efficacy or safety analysis if the 
disease/condition exacerbated during the study. 
15 Cancer not in complete remission for at least 5 years before Visit 1 
Note: Subjects with squamous cell carcinoma of the skin, basal cell carcinoma of the skin, 
in situ carcinoma of the cervix, or localized prostate cancer are eligible, if in the opinion 
of the investigator, the condition has been clinically controlled and the subject’s 
participation in the study would not represent a safety concern. 
16 Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1 
17 History of psychiatric disease, intellectual deficiency, poor motivation, or other 
conditions if their magnitude is limiting informed consent validity 
18 Significant abuse of alcohol or drugs, in the opinion of the investigator 
19 A known or suspected hypersensitivity to albuterol/salbutamol, or budesonide and/or their 
excipients 
20 A scheduled/planned hospitalization during the study 
21 Inability to abstain from protocol-defined prohibited medications during the study 
22 Using any herbal products by inhalation or nebulizer within 2 weeks of Visit 1 and not 
agreeing to stop during the study duration 
23 Received a live attenuated vaccination within 7 days of Visit 1 
24 Currently pregnant or breastfeeding 
25 Study investigators, sub investigators, coordinators, and their employees or immediate 
family members, or employees of the Sponsor 
26 Treatment with any investigational treatment or device in another clinical study within the 
last 30 days (or 5 half-lives, whichever is longer) of Visit 1 
27 Currently participating in any interventional study 
28 Previously been randomized in this study or any other PT007 or PT027 clinical study. For 
pediatrics, see inclusion criterion 4. 
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Procedures for withdrawal of incorrectly enrolled subjects are described in Section 3.4. 
3.3 
Subject enrollment and randomization 
Approximately 1000 adults and adolescent subjects (≥12 years of age) with asthma will be 
randomized 1:1:1:1:1 to 1 of 5 treatment groups (approximately 200 subjects per group: BDA 
MDI 80/180 μg QID, BDA MDI 160/180 μg QID, BD MDI 160 μg QID, or AS MDI 180 μg 
QID or placebo MDI). In addition, up to 30 child subjects (4 to 11 years of age) with asthma 
will be enrolled but will not receive high dose ICS and will be randomized 1:1:1 to receive 
low-dose BDA MDI 80/180 μg QID, AS MDI 180 μg QID, or placebo MDI. Approximately 
2000 subjects will need to be screened, assuming an estimated screen failure rate of 50% prior 
to randomization. This Phase III study is planned to be conducted globally.   
The investigator(s) and/or study personnel will: 
1 
Obtain signed informed consent/assent (as applicable) from the potential subject and/or 
their guardian/legal representative before any study specific procedures are performed 
2 
Enter the subject data into the enrollment module in Rave Web Based Data Capture 
(WBDC) electronic case report form (eCRF) to enable the allocation of subject 
identification (Ecode) 
3 
Determine subject eligibility (Sections 3.1 and 3.2) 
4 
Enter the information required to enable the Interactive Web Response System (IWRS) to 
initiate randomization and generate the randomization code 
Randomization codes will be assigned through IWRS strictly sequentially to subjects eligible 
for randomization. If a subject withdraws from participation in the study, then his/her 
randomization code cannot be reused. 
3.4 
Procedures for handling incorrectly enrolled or randomized 
subjects 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive IP. There can be no waivers granted from the Sponsor for any subject 
not meeting inclusion or exclusion criteria.  
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on-treatment, the investigator should inform the medical monitor assigned 
to the project immediately, and a discussion should occur between the medical monitor 
assigned to the project and the investigator regarding whether to continue or discontinue the 
subject from treatment. The Sponsor’s medical monitor assigned to the project must ensure all 
decisions and protocol deviations, if any, 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 be prepared before the start of 
the treatment period. The designated statistical representative will follow their established 
standard operating procedures regarding generation, security, and distribution of the 
randomization schedule. Randomization will be centralized. 
Randomization for adults and adolescents will be centralized and stratified by pre-study 
background therapy consisting of either ICS or non-ICS (subjects not previously treated with 
ICS), by Asthma Control Questionnaire-7 (ACQ-7; ≤1.5, >1.5), and by age (≥12 to 17, ≥18). 
Children aged 4 to 11 years will not be stratified. 
Upon enrollment, subjects will be assigned a unique subject identification code (Ecode) which 
is automatically generated by the electronic data capture system (Rave WBDC) based on the 
order of entry. Once it has been determined that a subject meets all eligibility criteria, the 
subject information will be integrated into the IWRS (Randomization and Trial Supply 
Management) for randomization. 
3.6 
Methods for ensuring blinding 
The study blind is to be maintained until all subjects have completed the treatment period and 
until after the database has been locked. The study site receives documentation of subject 
study identification and kit allocation through the IWRS. The randomization code will not be 
available, with the exception of unblinding procedures described in Section 3.7, to the study 
team, study center personnel, Sponsor monitors, Sponsor project statisticians, or any other 
personnel employed or affiliated with the Sponsor, as well as investigators and subjects until 
after the database has been locked.  
The 5 different kit types of study IP are visually identical, protecting the blind through their 
similarity in appearance.  
3.7 
Methods for unblinding  
The treatment blind should not be broken except in medical emergencies and based on the 
investigator’s clinical judgement when the appropriate management and welfare of the subject 
requires knowledge of the treatment allocation. Individual treatment details, for each subject, 
will be available to the investigator(s) or pharmacists from the IWRS, if needed. If unblinding 
occurs, the investigator must notify the Sponsor as soon as possible, but without revealing the 
treatment assignment of the unblinded subject. Routines for this will be described in the IWRS 
user manual that will be provided to each center. The IWRS provides unblinding procedures, 
if needed. 
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The designated representative retains the right to break the code for SAEs that are unexpected 
and are suspected to be causally related to an IP and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual subject 
have been made and documented. 
With the exception of emergency unblinding as described above, all members of the study 
team, investigators, and site staff will be blinded. The only individuals who will have access 
to unblinded information during the conduct of the study in advance of the primary outcome 
database lock will be the unblinded statistician supporting the IDMC closed session review 
which will be performed in accordance with the IDMC charter.   
3.8 
Restrictions 
Subjects should be advised that marketed (eg, omalizumab, mepolizumab, reslizumab, 
benralizumab) or investigational biologic treatments are not allowed during the treatment 
period. Subjects requiring chronic SCS are excluded.  
Only Sponsor-provided IP and Sponsor-provided Ventolin to be used in response to asthma 
symptoms are allowed during the study. No other asthma medications are allowed during the 
study. Restrictions regarding concomitant medications are described in Section 7.8. 
Subjects should not take Sponsor-provided Ventolin ≤6 hours before a study visit (if Ventolin 
is needed in the morning of a study visit, either the entire visit must be rescheduled or just 
PFT assessment rescheduled). 
Subjects should avoid strenuous exercise for at least 30 minutes prior to a study visit. 
Subjects should avoid having a large meal at least 2 hours prior to a study visit.  
Subjects must not ingest xanthine and/or xanthine analogue (caffeine)-containing foods and 
beverages for at least 6 hours prior to and for the duration of each in-clinic study visit. 
Examples of such products include coffee, tea, chocolate, and cola. Decaffeinated beverages 
are acceptable. 
Illicit drugs or drugs of abuse will not be allowed from Visit 1 to the end of the follow-up 
telephone contact or to whenever the subject withdraws from the study. If any illicit drugs or 
drugs of abuse are used by the subject during the study, the dates of use and the amount will 
be documented, and the subject will be discontinued at the discretion of the Investigator. 
Medical marijuana is not an exclusionary drug if used for medical purposes, and there is no 
change in the dose or frequency of consumption. 
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3.9 
Treatment discontinuation by subject and/or Sponsor 
Subjects may be withdrawn from the study at any time at their own request, upon request of 
the investigator, or by the Sponsor at any time or for any reason.  The subject or his/her 
parent/legal representative is free to discontinue treatment at any time, without prejudice to 
further treatment. Other reasons for IP discontinuation may include: 
• 
An AE considered to jeopardize the safety of a subject participating in the study 
• 
Subjects who suffer 1 severe exacerbation should be considered for discontinuation if 
Sponsor and the investigator decide that it is in the best interest of the subject to 
discontinue randomized treatment and withdraw from the study  
• 
In the opinion of the investigator, the subject is non-compliant with the Clinical Study 
Protocol (eg, post-enrollment eligibility violation, failure to adhere to dosing compliance) 
or 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 subject) 
• 
If female subject becomes pregnant, the subject will automatically be discontinued from 
IP 
• 
In subjects who have elevated liver enzymes AST and/or ALT ≥3 times the upper limit of 
normal (×ULN) and total bilirubin ≥2×ULN (ie, meeting the criteria of at least potential 
Hy’s Law), IP will be suspended until the liver test values return to the normal range. If 
the AST, ALT, or total bilirubin reach these elevated levels again, after recommencement 
of IP, the subject will be discontinued from IP and withdrawn from the study. 
Subjects who discontinue IP prior to the end of the 12-week treatment period will be 
withdrawn from the study and will be asked to complete a PDV, and AEs/SAEs will be 
followed up if medically indicated. 
A subject that decides to discontinue IP will always be asked about the reason(s) and the 
presence of any AEs. If possible, they will be seen and assessed by an investigator(s). AEs and 
SAEs will be followed up (Section 6); eDiary and all IPs should be returned by the subject. 
3.10 
Study termination 
If the Sponsor, investigator, study monitor, IDMC, or regulatory officials discover conditions 
arising during the study that indicate that the subject’s safety and/or scientific value of the 
study and/or quality of the IPs have been compromised, the study may be halted or the study 
center’s participation may be terminated. Ongoing subjects will be discontinued from the 
study and assigned to receive treatment as per local standard of care.   
Conditions that may warrant termination of the study include, but are not limited to, the 
following list: 
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• 
The study may be stopped if, in the judgement of the Sponsor, study subjects are placed at 
undue risk because of findings that: 
- 
are considered significant 
- 
are assessed as causally related to IP 
- 
are not considered to be consistent with continuation of the study 
• 
The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study 
• 
A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the IP for any reason 
Conditions that may warrant termination of a study center’s participation include, but are not 
limited to, the following list: 
• 
Failure of the investigator to enroll subjects into the study at an acceptable rate or within 
an agreed timeline 
• 
Failure of the investigator to comply with pertinent governing body regulations 
• 
Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, medical officer, or regulatory official 
• 
Insufficient adherence to protocol requirements 
 
Regardless of the reason for termination, all data available for the subject 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 subjects’ interests. 
Study termination and follow-up will be performed in compliance with applicable governing 
body regulations. 
3.11 
Screen failures  
Screening failures are subjects who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomized. These subjects, who have a reason for not enrolling to the 
study, should be recorded as ‘Screen failure’. Subjects who are screen failures will not be re-
screened with the exception of children and adolescents who screen-failed because they did 
not meet the now obsolete upper FEV1 % predicted limit. Children and adolescents who 
previously failed to meet the upper FEV1 % predicted threshold, but who met all other 
eligibility requirements, may re-screen once. Upon re-screening, these subjects must meet all 
eligibility requirements in order to be randomized.   
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4 
STUDY PLAN AND TIMING OF PROCEDURES  
Table 1 presents study assessments and procedures and Table 2 presents timed assessments at 
Visit 2 through Visit 6. Repeat assessments, if needed, will be captured in unscheduled visits. 
General Considerations 
• 
For subjects who inadvertently took IP, SABA, or any bronchodilator in the morning of 
any study visit, either the entire visit must be rescheduled or just PFT assessment 
rescheduled. 
• 
Subjects must not ingest 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. 
• 
Subjects should avoid having a large meal at least 2 hours prior to a study visit. 
• 
Subjects will be required to return to the clinic at approximately the same time at Visit 2 
for all treatment visits (±2 hours) and dosing time should not exceed 10:00 AM and 
pulmonary function tests (PFTs) should be completed within ±1 hour of Visit 2. Subjects 
will be required to remain at clinic until completion of all protocol-defined assessments. 
In order to minimize diurnal variance, sites should make every effort to assess subjects at 
the same time throughout the study.  
• 
IP should be taken in the morning upon waking, and then distributed equally throughout 
the day with the final dose taken before going to sleep. The evening before clinic visits, 
subjects should be advised to take the last dose at 22:00 ±2 hours. 
• 
To ensure dosing time standardization, it is recommended that sites encourage subjects to 
maintain a dosing schedule consistent with their in-clinic dosing time and that sites call 
the subjects on the day before a scheduled visit to remind the subject of the following: 
− 
To take their last dose the evening before the scheduled visit 
− 
To withhold all inhaled medications (oral and intranasal) for at least 6 hours prior to 
PFTs  
− 
To bring their study medications and eDiary with them to the clinic 
Site personnel will instruct subjects not to take any inhaled medications, without site 
personnel permission, during a visit until all study procedures have been completed, and the 
subject is discharged. Site personnel should take every precaution to prevent subject use of 
asthma medications during the test day. Site personnel may request the subject to surrender all 
IP and Ventolin prior to the visit start before performing any study procedures and return the 
IP and Ventolin to the subject at the end of the visit when all study procedures are completed. 
Subjects will be asked to abstain wherever possible from using Ventolin during study visits. If 
a subject is experiencing severe symptoms and requires Ventolin in response to asthma 
symptoms at any time during a test day, site personnel must note the time and justification of 
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use in the subject’s chart and all subsequent spirometry assessments should be stopped. 
However, safety assessments should be continued at the discretion of the investigator. 
 
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Table 1 
Study assessments and procedures 
 
Screening (run-in)b 
Double-blind Treatment Period 
PDVd  
(if 
applicable) 
Safety Follow-up TC 
Visit a 
1 (1/1a) 
2 
3 
4 
5 
6c 
 
(2 weeks [±4 days] after 
treatment discontinuation) 
Week  
-4 to -2 
0 
1 
4 
8 
12 
Day 
-28 to -14 
1 
7±2 
28±2 
56±2 
84±2 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Routine clinical procedures 
Medical/surgical history 
(including any on-study 
medical/surgical procedures)e 
X 
X 
X 
X 
X 
X 
X 
 
Demography  
X 
 
 
 
 
 
 
 
Physical examinationf 
X 
 
 
 
 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
SABA reversibility testg 
X 
 
 
 
 
 
 
 
Safety measurements 
Vital signs (HR and BP only) 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
 
 
 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testh 
X 
X  
X 
X  
X 
X 
X  
 
Safety laboratory assessments 
(clinical chemistry, hematology) 
X 
 
 
 
 
X 
X 
  
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Screening (run-in)b 
Double-blind Treatment Period 
PDVd  
(if 
applicable) 
Safety Follow-up TC 
Visit a 
1 (1/1a) 
2 
3 
4 
5 
6c 
 
(2 weeks [±4 days] after 
treatment discontinuation) 
Week  
-4 to -2 
0 
1 
4 
8 
12 
Day 
-28 to -14 
1 
7±2 
28±2 
56±2 
84±2 
 
 
Efficacy measurements 
Spirometry (FEV1)i 
X 
X 
X 
X 
X 
X 
X 
 
ACQ-5 
X 
X 
X 
X 
X 
X 
X 
 
ACQ-7 
X 
X 
X 
X 
X 
X 
X 
 
AQLQ+12/PAQLQ 
 
X 
 
X 
X 
X 
X 
 
Review of PEF, use of Ventolin 
therapy, asthma daytime/night-
time symptoms, night-time 
awakenings due to asthma 
symptomsj 
 
X 
X 
X 
X 
X 
X 
 
Dispense/collect eDiary (AM3+) 
X 
 
 
 
 
X 
X 
 
Review compliance with eDiary 
 
X 
X 
X 
X 
X 
X 
 
Investigational product administration 
IP compliance 
 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
IP (dispense/collect)k 
d 
c/dk 
c/d 
c/d 
c/d 
c/dn 
c/dn 
 
Ventolin (collect/dispense) 
d 
c/dl 
c/dl 
c/dl 
c/dl 
c 
c 
 
Ventolin administration 
(recorded in MasterScope) 
X 
 
 
 
 
 
 
 
IP administration (recorded in 
MasterScope)m 
 
X 
X 
X 
X 
X 
X 
 
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Abbreviations: ACQ-5=Asthma Control Questionnaire-5; ACQ-7=Asthma Control Questionnaire-7; AQLQ+12= Asthma Quality of Life Questionnaire for 12 years and older; 
β-hCG= β -human chorionic gonadotropin; BP=blood pressure; c= collect; d=dispense; eDiary=electronic diary; ECG=electrocardiogram; FEV1= forced expiratory volume in 
1 second; HR=heart rate; IP=investigational product; PAQLQ=Pediatric Asthma Quality of Life Questionnaire; PDV= premature discontinuation visit; PEF= peak expiratory 
flow; QID=4 times daily; SABA=short/rapid-acting β2-adrenoreceptor agonist; TC=telephone contact; V=visit  
a 
Repeat assessments/visits, if needed, will be captured in unscheduled visits. 
b  
Screening (run-in) Period may be 14 to 28 days. Visit 1 may be split (used for repeated assessments, if needed) for the repeat assessment of SABA reversibility test, if 
applicable.   
c  
Planned end-of-treatment (EOT) will occur at Visit 6.  
d  
Subjects who prematurely withdraw (withdraw pre-week 12) from study treatment will undergo a PDV. 
e  
Details of any surgical procedures occurring during randomization and the treatment period will be also recorded. 
f 
Includes evaluation of height, body mass index, and weight at Visit 1 and weight only for Visit 6 or PDV. 
g 
Demonstrate reversibility at Visit 1, with an increase in FEV1 ≥15% relative to baseline after administration of Sponsor-provided Ventolin via central spirometry at either 
Visit 1 (reversibility must be demonstrated at either Visit 1 or Visit 1a); Visit 1a will be used for re-testing, if needed; with only 1 reversibility re-test permitted prior to 
randomization (Visit 2).  
h 
A serum pregnancy test (β-hCG) will be performed at Visits 1 and treatment discontinuation (EOT) or PDV; urine β-hCG test will be performed at all other visits (for women 
of childbearing potential only).  
i 
Pre-bronchodilator (Visit 1/Visit 1a)/ Pre-dose (Visit 2 onwards) FEV1 will be measured in the morning between 06:00 and 10:00 AM at the designated visits in Table 1, and 
within 1 hour of FEV1 measured at Visit 2. Pre-bronchodilator FEV1 of ≥50 to <85% predicted normal value for adults (≥18 years of age) and ≥50% predicted normal value for 
subjects aged 4 to 17 years after withholding SABA ≥6 hours (at Visit 1 or Visit 1a, if applicable). If subject took SABA within 6 hours in the morning of Visit 1, either the entire 
visit must be rescheduled or just PFT assessment rescheduled. At Visit 1, pre- and post- dose will be with respect to administration of Sponsor-provided bronchodilator (Ventolin). 
From Visit 2 onwards, pre- and post- dose measurements will be with respect to administration of IP. 
j 
The eDiary (AM3+) will be dispensed at screening. 
k 
All subjects will be assigned placebo during the run-in period for dosing QID. Compliance to dosing should be reviewed prior to randomization. 
l 
Ventolin usage to be reviewed at each collection/dispensing visit using eDiary. Replacement kit dispensed as required. The actuator should be cleaned once per week if used 
in the last 7 days according to instruction summarized in Appendix J, Metered-dose Inhaler Handling and Cleaning. 
m 
IP should be taken in the morning upon waking, and then distributed equally throughout the day with the final dose taken before going to sleep. The evening before clinic 
visits, subjects should be advised to take the last dose at 22:00 (10:00 PM) ±2 hours. For all on-treatment visits, IP should be administered before 10:00 AM in the clinic using 
newly dispensed IP. The actuator should be cleaned once per week if used in the last 7 days according to instruction summarized in Appendix J, Metered-dose Inhaler Handling 
and Cleaning. 
n 
IP will be dispensed at Visit 6 and PDV for performance of FEV1 measurements only, this will not be taken home by the subjects. IP dispensed at these visits will be retained 
at the site following the visit and reconciled for IP accountability. 
 
 
 
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Table 2 
Timed assessments at Visit 2 through Visit 6 and Premature Discontinuation Visit 
Clinical Variable 
Pre-Dose 
IP 
Dose 
Post-Dose 
-60 
min 
-30 
min 
0 min 
5 min 
15 min 
30 min 
45 min 
60 min 
120 
min 
180 
min 
240 
min 
300 
min 
360 
min 
IP Collectionh 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
IP Dispensingi 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
IP Dosingi 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Questionnaires 
ACQ-5 
ACQ-7 
AQLQ+12/PAQLQ 
Xa,b 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Electronic Diary 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc 
Xa,d 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
Xa,e 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory 
Testing 
Xa, f 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry (FEV1)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ACQ-7=Asthma Control Questionnaire 7, AQLQ+12= Asthma Quality of Life Questionnaire for 12 years and older; ECG=electrocardiogram; FEV1= forced 
expiratory volume in 1 second; IP=investigational product; min=minute; PAQLQ=Pediatric Asthma Quality of Life Questionnaire; PDV= premature discontinuation visit  
Note:  Time point for dosing is regarded as “0 minutes”.  When data collection time-points are concurrent, variables should be collected in the following order: Questionnaires, 
vital signs, ECG, clinical laboratory assessments, and spirometry. 
a. 
This is not a timed assessment.  Sites should plan to perform these activities to allow for collection of timed spirometry.   
b. 
Questionnaires (ACQ-5, ACQ-7, AQLQ+12, and PAQLQ) are collected at all visits (except Visit 3 AQLQ+12, and PAQLQ). 
c. 
Vital signs should be started (approximately 5 to 10 minutes) ahead of the specified time point to ensure spirometry will be conducted as close to the specified time points as 
possible. 
d. 
Pre-dose vital signs (heart rate, blood pressure) will be collected twice, at least 5 minutes apart. 
e. 
Pre-dose ECG will be collected at Visit 2, Visit 6, and PDV only, or as clinically indicated. 
f. 
All clinical laboratory tests (hematology and chemistry) will be assessed approximately 60 minutes prior to dosing at Visit 6 in advance of first spirometry measurement. 
Laboratory tests may be performed at all other visits as clinically indicated. 
g. 
Every effort should be made to assess subjects’ trough pre-dose and post-dose FEV1 at the same time throughout the study. Pre-dose FEV1 will be measured in the mornings 
between 06:00 and 10:00 AM, and within 1 hour of FEV1 measured at Visit 2. From Visit 2 onwards, pre- and post-dose measurements will be with respect to administration 
of IP (Table 3).  
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h. 
At the start of each treatment visit, subjects must withhold all asthma medications, including Sponsor-provided Ventolin for at least 6 hours prior to start of test day 
procedures. 
i. 
Dispense new IP to subjects for on-site dosing after trough pre-dose FEV1 measurement and for subsequent at-home use following the completion of all post-dose 
assessments. IP will be dosed before 10:00 AM following pre-dose FEV1 measurements at each visit. 
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4.1 
Screening and enrollment period 
Procedures will be performed according to study assessments and procedures presented in 
Table 1 and Table 2 for timed assessments at Visit 2 through Visit 6. The screening period will 
be 14 to 28 days. At screening, consenting subjects are assessed to ensure that they meet 
eligibility criteria. Subjects who do not meet these criteria must not be enrolled in the study.  
Subjects meeting all entry criteria at the screening visit (Visit 1) will enter a 14- to 28-day 
screening (run-in) period. Subjects will discontinue their usual asthma medications at Visit 1. 
The study procedures carried out during this period will include medical and surgical history, 
demographics, physical examination (including height, BMI, and weight), concomitant 
medications review, Sponsor-provided Ventolin reversibility test (reversibility must be 
demonstrated at either Visit 1 or Visit 1a; Visit 1a will be used for re-testing, if needed; with 
only 1 reversibility re-test permitted prior to randomization [Visit 2]), vital signs (heart rate, 
blood pressure only), 12-lead ECG, AEs, serum pregnancy test, blood samples for hematology 
and clinical chemistry, FEV1 determination, Asthma Control Questionnaire-5 (ACQ-5), Asthma 
Control Questionnaire-7 (ACQ-7), dispensing/collecting eDiary, dispensing Ventolin, and 
administration of single-blind placebo MDI. 
At Visit 1, placebo MDI and Sponsor-provided Ventolin prn to be used in response to asthma 
symptoms will be dispensed; during the screening (run-in) period, these will be the subject’s 
only asthma medications. At Visit 2, compliance to placebo MDI dosing in screening (run-in) 
will be assessed by review eDiary completion as specified in the exclusion criteria. Ventolin 
usage will be assessed at Visit 2 and subjects using prohibitively high Ventolin usage as 
specified in the exclusion criteria will be screen-failed. 
Demographic data and other characteristics will be recorded and will include the age and year of 
birth; gender, race, and/or ethnicity according to local regulations; alcohol consumption, and 
smoking history. 
A standard medical, medication, and surgical history will be obtained with review of the 
selection criteria with the subject.  
4.2 
Randomization/treatment period  
Procedures will be performed according to study assessments and procedures presented in 
Table 1 and Table 2 for timed assessments. 
Only Sponsor-provided IP administered QID and Ventolin prn to be used in response to asthma 
symptoms are allowed during the treatment period. IP should be taken in the morning upon 
waking, and then distributed equally throughout the day with the final dose taken before going 
to sleep. The evening before clinic visits, subjects should be advised to take the last dose at 
22:00 (10:00 PM) ±2 hours. 
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At Visit 2 onwards, both IP and Sponsor-provided Ventolin should not be administered 
≤6 hours prior to lung function testing (if Ventolin is needed within 6 hours of a study visit, 
either the entire visit must be rescheduled or just PFT assessment rescheduled). 
At randomization (Visit 2), eligible subjects will enter a 12-week double-blind treatment period. 
The planned end-of-treatment will occur at Visit 6, the end of the 12-week treatment period. 
Dispensation of IP:   
New IP will be dispensed to subjects at each visit where FEV1 measurements are taken and the 
new IP should be used in advance of all post-dose measurements. To allow for proper 
preparation of IP, it is recommended that the seal around the study day treatment box is opened 
15 to 30 minutes prior to dosing and the instructions for administration of IP followed: 
• After IP is primed and ready for use, provide assigned IP to subject 
• Administer IP at the clinic 
• Complete post-dose assessments 
The study procedures carried out during this period will include: medical and surgical 
procedures, physical examination (includes weight at Visit 6 only), concomitant medications 
review, vital signs (heart rate, blood pressure only), 12-lead ECG at Visits 2 and 6, AEs, urine 
pregnancy test at Visits 2 and 4 (additionally, Visits 3 and 5 in the Czech Republic and also for 
the safety follow up visit in Argentina), serum pregnancy test at treatment discontinuation (Visit 
6 or the PDV), blood samples for hematology and clinical chemistry, spirometry, ACQ-5, ACQ-
7, Asthma Quality of Life Questionnaire for 12 years and older (AQLQ+12)/Pediatric Asthma 
Quality of Life Questionnaire (PAQLQ), PEF, use of Ventolin therapy, asthma daytime/night-
time symptoms, night-time awakenings due to asthma symptom, dispensing/collecting eDiary, 
review compliance with eDiary, dispensing and/or collection of IP, dispensing and/or collection 
of Ventolin, recording in eDiary of IP use, IP compliance, and randomization. 
4.3 
Treatment discontinuation visit 
Planned end-of-treatment (EOT) will occur at Visit 6 (Week 12).  
Subjects who prematurely withdraw from study treatment (withdraw pre-week 12) will undergo 
a PDV. Procedures for planned EOT and PDV will be performed according to study 
assessments and procedures presented in Table 1.   
The study procedures carried out during the PDV visit will include: details of any surgical 
procedures will be recorded, physical examination (including weight), concomitant medications 
review, vital signs (heart rate, blood pressure only), 12-lead ECG, AEs, serum pregnancy test 
(at treatment discontinuation or PDV), blood samples for hematology and clinical chemistry, 
dispensation of IP (for spirometry only), dosing, spirometry, ACQ-5, ACQ-7, 
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AQLQ+12/PAQLQ, review of PEF, use of IP and Ventolin therapy, asthma daytime/night-time 
symptoms, night-time awakenings due to asthma symptoms, collecting eDiary, review 
compliance with eDiary, collection and final reconciliation of the IP and Ventolin, and IP 
compliance. 
4.4 
Unscheduled visit  
Repeat assessments/visits, if needed, will be captured in unscheduled visits and the procedures 
carried out during an unscheduled visit will be decided by the investigator. 
4.5 
Safety Follow-up period 
Procedures will be performed according to study assessments and procedures presented in 
Table 1. The safety follow-up telephone contact will occur 2 weeks (±4 days) after treatment 
discontinuation (Visit 6/EOT or PDV). 
The study procedures carried out during this period will include: recording of concomitant 
medications and AEs. 
5 
STUDY ASSESSMENTS 
The Rave WBDC system and the electronic patient reported outcome (ePRO; hereafter called 
eDiary) eDiary will be used for data collection and query handling. The investigator will ensure 
that data are recorded on the eCRF and in accordance with the instructions provided. 
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 eCRF. A copy of the completed eCRF will be archived at 
the study site. 
The laboratory safety assessments will be sent for analysis to a central laboratory.  
The spirometry and ECG assessments will be performed at site using MasterScope equipment 
provided by eResearch Technology. The eDiary (AM3+) will be dispensed at screening which 
will also be used to collect PEF measurements, use of IP or Ventolin therapy, asthma 
daytime/night-time symptoms, night-time awakenings due to asthma symptoms, ACQ-5, and 
ACQ-7, data. In addition to this, a tablet will be used to collect the AQLQ+12 data using the 
StudyWorks software. This data will be recorded in the vendor’s central database and 
transferred/reconciled with the eCRF data as summarized in Section 9.4. 
5.1 
Efficacy assessments 
Efficacy assessments include spirometry, ACQ-7, AQLQ+12/PAQLQ, PEF, use of Ventolin 
therapy, asthma daytime/night-time symptoms, and night-time awakenings due to asthma 
symptoms. 
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5.1.1 
Lung function measurement by spirometry 
Lung function will be measured by spirometry at the study site using equipment provided by a 
central vendor. Spirometry will be performed by the investigator or authorized delegate 
according to ATS/ERS guidelines (Miller 2005). 
The vendor providing central spirometry services will be responsible for assuring that the 
spirometer used by each site meets ATS/ERS recommendations, and that the study site 
personnel who will be performing the testing are properly certified. Spirometry calibration will 
be detailed in a separate spirometry procedures manual. 
Subjects should not take Ventolin (or IP during the treatment phase) ≤6 hours before a study 
visit. This restriction is particularly critical for efficacy measures taken during the treatment 
period but should also facilitate meeting the run-in FEV1 and reversibility eligibility criteria.  
Trough pre-dose and post-dose FEV1 will be performed on a MasterScope provided for the 
study by the central reader at Visit 1 (screening), Visit 2 (baseline), and through Visit 6/PDV 
(endpoint measurements). For Visit 1/Visit 1a, pre- and post-dose measurements will be with 
respect to Sponsor-provided bronchodilator (Ventolin) and from Visit 2 onwards, will be with 
respect to IP. 
It is important that all in-clinic dosing occurs prior to 10:00 AM and that in-clinic dosing at 
Visits 3 through 6 is administered ±1 hour in relation to the time of dosing at Visit 2.  
Preferably, the same study personnel should test the subject’s lung function throughout the 
study to reach optimal performance and to enhance reproducibility. The subject should rest at 
least 15 minutes prior to the test. For repeated measurements, eg, to assess best of at least 5, a 
pause of at least 1 minute between measurements is recommended.  
The timing of FEV1 assessment is presented in Table 3. Please note: the 5 minute post-IP dosing 
spirometry assessment at Visit 2 is crucial to accurately measure time of onset. The subject and 
site personnel should be adequately prepared for this assessment at the time of dosing.  
The measurements are to be made with the subject seated in an upright position (preferably), or 
if not comfortable standing position is also acceptable. The same position should be used for all 
spirometry measures during the entire study. The head must not be tilted during measurements. 
During the breathing maneuvers, the thorax should be able to move freely; hence tight clothing 
should be loosened.   
Measurement procedures should be performed in accordance with the user manual for the study. 
Timing of FEV1 assessments   
• 
Visit 1:  If a subject has not taken SABA or any bronchodilator ≤6 hours before lung 
function tests at Visit 1, they may proceed to pre-bronchodilator FEV1 measurement and 
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reversibility eligibility assessments. If they have dosed with SABA or any bronchodilator 
≤6 hours before study visit lung function tests, either the entire visit must be rescheduled or 
just PFT assessment rescheduled. Reversibility assessment will be performed in accordance 
with Section 5.1.1.1. Considerations for medications that may impact reversibility testing 
are stated in Section 7.8.2. 
• 
Visit 2:  Subjects should withhold administration of Sponsor-provided Ventolin or any 
bronchodilator for at least 6 hours before lung function tests at Visit 2. Trough pre-dose 
measurements should be taken at -60 and -30 minutes before administration of IP. Post-
dose measurements will commence at 5 minutes after administration of IP followed by 
measurements at all subsequent times as listed in Table 3. If a subject has taken 
Sponsor-provided Ventolin before Visit 2, either the entire visit must be rescheduled or just 
PFT assessment rescheduled. 
• 
Visit 3 onwards:  Subjects should withhold administration of Sponsor-provided Ventolin 
and IP for at least 6 hours before lung function tests at Visit 3 through 6  In-clinic dosing 
will be administered prior to 10:00 AM and within 1 hour of the dosing at Visit 2. Trough 
pre-dose measurements should be taken at -60 and -30 minutes before administration of 
newly dispensed IP. Post-dose measurements will commence at 5 minutes after 
administration of IP followed by measurements at all subsequent times as listed in Table 3. 
If a subject has taken IP or Sponsor-provided Ventolin before any on-treatment visit, either 
the entire visit must be rescheduled or just PFT assessment rescheduled. 
 
Table 3 
Schedule of FEV1 measurements at standard visits 
Timing of Spirometry Assessmentsa 
 
Assessment Window 
Pre- dose PFT -60 min 
 
±15 min 
Pre- dose PFT -30 min 
 
±5 min 
Post- dose PFT +5 min 
 
±2 min 
Post- dose PFT +15 min 
 
±3 min 
Post- dose PFT +30 min 
 
±5 min 
Post- dose PFT +45 min 
 
±5 min 
Post- dose PFT +60 min 
 
±5 min 
Post- dose PFT +120 min 
 
±10 min 
Post- dose PFT +180 min 
 
±10 min 
Post- dose PFT +240 min 
 
±10 min 
Post- dose PFT +300 min 
 
±10 min 
Post- dose PFT +360 min 
 
±10 min 
Abbreviation: min=minute; PFT=pulmonary function test  
a 
Pre- and post- dose PFT measurements will be performed in relation to Ventolin at Visit 1, Visit 2 onward,  
pre- and post- dose PFT measurements will be performed in relation to IP. 
5.1.1.1 
Reversibility test 
To fulfill the reversibility inclusion criterion, the increase in FEV1 relative to baseline must be 
≥15% approximately 30 minutes after inhalation of Sponsor-provided Ventolin. 
Reversibility testing will be performed as follows: 
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1. Perform pre-dose PFTs after at least 15 minutes of rest, and before administration of 
Ventolin. 
2. Subjects aged ≥12 years should administer 4 puffs of Ventolin. Subjects aged <12 years 
should administer 2 puffs of Ventolin.   
3. Perform post-dose PFTs approximately 30 minutes after the administration of Ventolin. 
The reversibility is calculated as follows: 
 
 
Reversibility=([Post FEV1-Pre FEV1]/Pre FEV1)X100  
Pre-and post-dose FEV1 measurements will be captured within the MasterScope. If the 
reversibility inclusion criterion is not met at Visit 1, the reversibility test may be repeated at 
Visit 1a prior to Visit 2 (randomization). Pre- and post-dose FEV1 measurements are related to 
Sponsor-provided bronchodilator (Ventolin). 
5.1.1.2 
 COVID-19 and Pulmonary Function Testing 
In-clinic spirometry assessments should not be performed for subjects exhibiting signs and 
symptoms for COVID-19. Any suspected prior or active cases should have a diagnostic test to 
confirm COVID-19 status. Any subjects with confirmed COVID-19 should not perform 
spirometry assessments within 14 days of the cessation of symptoms and until the investigator 
considers the subject is no longer infectious. Device cleaning and hygiene guidance should be 
followed at all times.   
 
5.1.2 
Asthma Control Questionnaire-5  
International guidelines for the treatment of asthma have identified that the primary clinical goal 
of asthma management is to optimize asthma control (minimization of symptoms, activity 
limitation, bronchoconstriction, and rescue β2 -agonist use) and thus reduce the risk of 
life-threatening exacerbations and long-term morbidity. The ACQ-5 (Appendix H, Asthma 
Control Questionnaire) was developed to meet these criteria. It measures both the adequacy of 
asthma control and change in asthma control, which occurs either spontaneously or as a result of 
treatment. 
The ACQ-5 will be administered using the eDiary during site visits as indicated in Table 1 
(Visits 1, 2, 3, 4, 5, 6, and PDV) and Table 2 for timed assessments at Visits 2, 4, 3, 5, 6, and 
PDV. The ACQ-5 self-administered adult version will be used for adults and adolescents aged 
11 years and older. The Asthma Control Questionnaire-Interviewer-Administered [ACQ-IA] 
will be used for subjects aged <11 years; Section 5.1.4.  
Subjects will be asked to complete the ACQ-5, consisting of 5 questions on symptom control; 
each of the questions will be scored on a 7-point scale (0=excellent asthma control; 6=extremely 
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poor control). The questions take approximately 2 to 3 minutes to complete. Linguistically 
validated translations of the ACQ-5 into local languages will be used. 
5.1.3 
Asthma Control Questionnaire-7 
The ACQ-7 will be administered using the eDiary during site visits as indicated in Table 1 and 
Table 2 for timed assessments at Visits 2, 3, 4, 5, 6, and PDV. 
The ACQ-7 will be assessed at Visits 1, 2, 3, 4, 5, 6, and PDV and consists of the top scoring 
5 symptoms from the ACQ-5 with 2 additional questions regarding FEV1% predicted value and 
daily rescue bronchodilator use (Appendix H, Asthma Control Questionnaire). Linguistically 
validated translations of the ACQ-7 into local languages will be used. 
5.1.4 
Asthma Control Questionnaire-Interviewer-Administered 
The ACQ-IA version will be used for subjects aged <11 years and will be interviewer-
administered (Appendix I, Asthma Control Questionnaire-Interviewer-Administered). 
Linguistically validated translations of the ACQ-IA into local languages will be used, with the 
results of the interviewer-administered version recorded into the eCRF. 
5.1.5 
Asthma Quality of Life Questionnaire+12/Pediatric Asthma Quality of 
Life Questionnaire  
5.1.5.1 
Asthma Quality of Life Questionnaire+12 
The AQLQ+12 will be self-administered in all subjects aged ≥12 years using the eDiary during 
site visits as indicated in Table 1 and Table 2 for timed assessments at Visit 2 through Visit 6. 
Linguistically validated translations of the AQLQ+12 into local languages will be used. 
The AQLQ was developed to measure the functional problems (physical, emotional, social, and 
occupational) that are most troublesome to adults with asthma Appendix F, Asthma Quality of 
Life +12 Questionnaire). 
There are 32 questions in the AQLQ+12 and they are in 4 domains (symptoms, activity 
limitation, emotional function, and environmental stimuli). The activity domain contains 
5 subject-specific questions. This allows subjects to select 5 activities in which they are most 
limited and these activities will be assessed at each follow-up. Subjects are asked to think about 
how they have been during the previous 2 weeks and to respond to each of the 32 questions on a 
7-point scale (7=not impaired at all; to 1=severely impaired). The overall AQLQ+12 score is the 
mean of all 32 responses and the individual domain scores are the means of the items in those 
domains. 
5.1.5.2 
Pediatric Asthma Quality of Life Questionnaire 
The PAQLQ will be self-administered during site visits as indicated in Table 1 and Table 2 for 
timed assessments at Visit 2 through Visit 6 in subjects aged 7 to 11 years. Responses to 
PAQLQ will be provided on paper and transcribed to the eCRF by site staff.  
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Subjects aged 4 to 6 years will complete the questionnaire with the help of a caregiver. The 
subject/caregiver will complete the PAQLQ on paper and responses will also be transcribed to 
the eCRF by site staff. As the PAQLQ is not validated for children <7 years of age, data for 
subjects who are aged 4 to 6 years will be excluded from the analyses of PAQLQ endpoints. 
Linguistically validated translations of the PAQLQ into local languages will be used. The 
PAQLQ has 23 questions in 3 domains (symptoms, activity limitation, and emotional function). 
The activity domain contains 3 subject-specific questions.  
The PAQLQ, was developed to measure the functional problems (physical, emotional, and 
social) that are most troublesome to children with asthma (Appendix G, Pediatric Asthma 
Quality of Life Questionnaire). 
5.1.6 
eDiary  
The eDiary will be utilized by all subjects enrolled in the study including children. Children, as 
necessary, will be assisted by a caregiver for the performance of assessments and navigation of 
the applicable questions. 
5.1.6.1 
Peak expiratory flow 
Subjects will be trained at Visit 1. Throughout the study, subjects will record 3 PEF measures 
on rising in the morning and before going to bed in the evening prior to taking any asthma 
therapy. 
5.1.6.2 
eDiary investigational product use 
Use of QID blinded IP will be collected using the eDiary. Subjects will be asked in the evenings 
to enter into their eDiary (device called AM3+), how many times they administered IP that day. 
The times of the administration and number of puffs will be recorded.  
5.1.6.3 
eDiary Ventolin therapy use  
Monitoring of Ventolin therapy in response to asthma symptoms use will be done only through 
the eDiary, where the number of Ventolin puffs taken in response to symptoms will be captured 
twice daily (in the mornings and in the evenings). Sponsor-provided Ventolin will be dispensed 
from Visit 1 and inhalers will be reconciled for accountability. 
Subjects will be recommended not to take more than 8 puffs of Ventolin per day and advised to 
contact the investigator if their symptoms necessitate more than 8 puffs in a day. 
5.1.6.4 
eDiary recording of symptoms and alerts  
The subject will use the eDiary for daily symptom reporting, entering symptoms twice daily.  
The eDiary will be programmed to alert both the subject and study center when the below 
prespecified alert thresholds are crossed. Alerts will include: 
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• 
Decrease in morning peak flow ≥20% on at least 2 consecutive days compared with 
baseline, and/or 
• 
An increase in rescue medication use of ≥4 puffs on at least 2 consecutive days compared 
with the average use during baseline, and/or 
• 
>12 puffs of Ventolin in one day, and/or 
• 
A night-time asthma symptom score of >baseline night-time score and ≥2 for at least 
2 consecutive days, and/or 
• 
A daytime asthma symptom score of 3 for at least 2 consecutive days 
• 
>12 puffs of IP per day 
 
The purpose of the alerts is to trigger a documented contact between the site and subject for 
further evaluation if deemed necessary by the investigator. The Sponsor will also receive 
programmed alerts to monitor subject follow-up. Alerts will include: 
• 
Triggers in the eDiary will alert the subjects to signs of change of asthma and to contact 
their physician 
• 
A dedicated person from the Sponsor will review the eDiary and compliance alerts 
(2 consecutive days of missing data) and contact the site 
• 
Triggers in the eDiary will alert subjects if IP is dosed more than 12 puffs a day as a 
possible sign of potential overdose   
• 
In case of eDiary or compliance alerts, a qualified person from the site will contact the 
subject. For eDiary alerts, the subject’s asthma status should be evaluated, and it will be 
determined if a clinic visit is necessary 
 
An eDiary alert is not an asthma exacerbation per se. 
Although the eDiary alert may initiate contact between the subject and the investigational site, 
the investigator or designee will always assess the subject’s symptoms and determine whether 
to treat the subject for an exacerbation (Section 5.1.8). 
Asthma symptoms should be captured in the eDiary by the subject every morning and evening. 
5.1.7 
Deterioration of asthma  
In this study, deterioration of asthma is defined as 1 or more of the following items for 
≥2 consecutive days:  
• 
PEF: a decline of ≥20% from baseline 
• 
Ventolin therapy use: >4 puffs/day and ≥2×baseline  
• 
Symptoms: night-time score that is >baseline and ≥2 OR a daytime score that is >baseline 
and =3 
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Daytime is defined as the time period between the morning PEF assessment (upon rising in the 
morning) and the evening PEF assessment. 
Night-time is defined as the time period between the evening PEF assessment (at bedtime) and 
the morning PEF assessment.  
5.1.8 
Asthma exacerbation definition 
An asthma exacerbation is defined as deterioration of asthma which includes:  
• 
Worsening of asthma signs/symptoms (Section 5.1.8.1) 
• 
Increased use of ‘as needed’ reliever therapy 
• 
Deterioration of lung function  
• 
A medical intervention as described below (Section 5.1.8.3) 
These descriptions above are provided for definition, however, only severe asthma 
exacerbations will be assessed during this study (Section 5.1.8.3) 
5.1.8.1 
Definition of asthma symptom worsening 
The worsening/onset of symptoms must include at least one of the following: 
• 
shortness of breath 
• 
wheezing 
• 
chest tightness 
• 
cough 
• 
sputum 
• 
night-time awakening due to asthma 
• 
activity limitation due to asthma 
• 
decreased PEF 
• 
decreased FEV1 
5.1.8.2 
Investigator justified asthma exacerbations 
A vast majority of asthma exacerbations are associated with worsening of the symptoms 
described in Section 5.1.8.1. However, clinical presentations may vary among subjects. If a 
subject’s symptoms and the overall clinical findings support the diagnosis of a severe asthma 
exacerbation (defined by required medical intervention as described in Section 5.1.8.3), but the 
symptomatic worsening does not meet the definition in Section 5.1.8.1 the investigator must 
justify the decision for defining the event as an exacerbation and document the reasoning in the 
eCRF. 
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5.1.8.3 
Severe asthma exacerbations 
All protocol-defined severe asthma exacerbations need to fulfill the symptom criteria as defined 
in Section 5.1.8.1 and be supported by an eDiary alert or an investigator justification. 
An asthma exacerbation will be considered severe if it results in at least 1 of the following: 
• 
A temporary bolus/burst of SCS for at least 3 consecutive days to treat symptoms of asthma 
worsening; a single depo-injectable dose of corticosteroids will be considered equivalent to 
a 3-day bolus/burst of SCS  
• 
An emergency room or urgent care visit (defined as evaluation and treatment for <24 hours 
in an emergency department or urgent care center) due to asthma that required SCS (as per 
the above) 
• 
An in-patient hospitalization (defined as admission to an in-patient facility and/or 
evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma 
5.1.8.4 
Treatment for severe asthma exacerbations 
The treatment for a severe asthma exacerbation is at least 3 consecutive days of SCS. 
• 
The recommended treatment (GINA 2018) for a severe exacerbation is prednisolone 
(1 mg/kg/day up to 50 mg for adults and adolescents) once per day (preferably in the 
morning) for 5 to 7 days 
• 
Tapering the prednisolone dose is not needed if the treatment has been given for <2 weeks 
(GINA 2018) 
 
Treatment for <3 days does not constitute a severe asthma exacerbation, except if the subject is 
hospitalized due to asthma. 
5.1.8.5 
Onset and duration of asthma exacerbations 
For severe exacerbations, the duration is defined by the prescribed treatment. 
For severe exacerbations: 
• 
The start date will be defined as the start date of prescribed treatment with a SCS 
• 
The stop date will be defined as the last day of prescribed treatment with a SCS 
• 
A single depot injectable dose of corticosteroids will be considered equivalent to a 3-day 
course of SCS. The corresponding stop date for this treatment will consequently be 
determined as the date of administration plus 2 days 
• 
If multiple treatments are prescribed for the same exacerbation, the earliest start date and 
the latest stop date will be used 
• 
For a severe asthma exacerbation requiring hospitalization with no documented 
corticosteroid treatment, hospitalization admission/discharge dates, or emergency visit date 
will be used as start/stop dates 
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5.1.8.6 
Approach for capturing asthma exacerbations 
5.1.8.6.1 
Asthma exacerbation eCRF 
All post-screening severe asthma exacerbations (including investigator justified asthma 
exacerbations) must be captured using the Severe Asthma Exacerbation eCRF.  
If a severe asthma exacerbation requires hospitalization, the exacerbation should be reported as 
an SAE (Section 3.9) as well as on the Severe Asthma Exacerbation eCRF. 
Severe asthma exacerbations will be considered study efficacy endpoints and will not be 
reported as AEs unless considered an SAE. 
5.2 
Safety assessments 
Safety assessments include clinical laboratory (hematology, chemistry, and pregnancy tests for 
females of childbearing potential) parameters, 12-lead ECG readings, vital sign measurements, 
and collection of AEs. 
5.2.1 
Laboratory safety assessments 
Blood samples for determination of clinical chemistry and hematology will be taken at the times 
indicated in Table 1 and Table 2 for timed assessments at Visit 2 through Visit 6. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator.  
The clinical chemistry and hematology assessments will be performed using a centralized 
laboratory. Sample tubes and sample sizes may vary depending on laboratory method used and 
routine practice at the site. 
The following laboratory variables described in Table 4 will be measured: 
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Table 4 
Laboratory Safety Variables 
Hematology/Hemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
Red blood cells (erythrocytes) 
Albumin 
Hemoglobin  
ALT 
Hematocrit 
ALP 
Mean Corpuscular Hemoglobin 
AST 
Mean Corpuscular Hemoglobin Concentration 
Bilirubin, total 
Mean Corpuscular Volume 
Calcium, total 
White blood cells (leukocytes)  
Chloride 
Basophils (%) 
Cholesterol, total 
Basophils Abs 
Creatinine 
Eosinophils (%) 
Creatine kinase 
Eosinophils Abs 
Gamma-glutamyl transpeptidase 
Lymphocytes (%) 
Glucose (random) 
Lymphocytes Abs 
Magnesium 
Monocytes (%) 
Phosphate  
Monocytes Abs 
Potassium  
Neutrophils (%) 
Protein, total 
Neutrophils Abs 
Sodium 
Platelet count 
Triglycerides 
Urine 
Urea 
Urine β-hCG pregnancy (at all other clinic visits, except 
Visit 1 and EOT or PDV) 
Serum β-hCG pregnancy (Visit 1 and treatment 
discontinuation [EOT or PDV]) 
Abbreviations: Abs=absolute; ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate 
transaminase β-hCG=β-human chorionic gonadotropin; EOT=end-of-treatment; PDV premature discontinuation 
visit 
 
If a subject shows an AST or ALT ≥3× the upper limit of normal (ULN) and TBL ≥2×ULN 
please refer to Section 3.9 and Appendix E, Hy’s Law for further instructions. 
5.2.2 
Resting 12-lead electrocardiogram 
A 12-lead ECG will be performed at the visits detailed in Table 1 and Table 2 for timed 
assessments at Visits 2, 6, and PDV. The timing and number of ECGs may be adjusted in 
response to the emerging safety profile. 
Twelve-lead ECGs will be obtained using a centralized laboratory after the subject has been 
resting semi supine for at least 10 minutes. All ECGs should be recorded with the subject in the 
same physical position. A standardized ECG machine should be used and the subject should be 
examined using the same machine throughout the study, where feasible. 
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After paper ECGs have been recorded, the investigator or designated physician will review each 
of the ECGs and may refer to a local cardiologist, if appropriate. A paper copy should be filed 
in the subject’s medical records. If an abnormal ECG finding at screening/baseline is considered 
to be clinically significant by the investigator, it should be reported as an AE. For all ECGs, 
details of rhythm, PR, RR, QRS, and QT intervals, an overall evaluation will be recorded. 
5.2.3 
Vital sign measurements 
Vital signs including resting pulse, and blood pressure, should be assessed at the visits detailed 
in Table 1 and Table 2 for timed assessments at Visit 2 and Visit 6. Measurements should be 
taken in the sitting position after at least 10 minutes of rest. 
Any clinically significant changes in vital signs should be recorded as an AE if applicable. 
5.2.4 
Adverse event assessments 
AEs will be collected from time of signature of informed consent/assent through to the follow-
up period as described in Section 6. 
5.3 
Other assessments 
5.3.1 
Physical examination 
A complete physical examination will be performed at screening (Visit 1), Visit 6, and PDV (if 
applicable) as detailed in Table 1. This will include an assessment of the following items: height 
in centimeters and BMI (both at Visit 1 only), weight, 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.  
5.3.2 
Concomitant medications 
The collection and recording of all concomitant medications, including all pre-enrollment 
asthma therapies, will be performed at the visits detailed in Table 1. Permitted and restricted 
concomitant medications are described in Section 7.8. 
All prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications 
taken within 3 months before screening (Visit 1) will be recorded as previous medications. All 
medications taken after screening and through the safety follow-up visit will be recorded as 
concomitant therapy.   
Subjects will be maintained, after Visit 1, on IP and Ventolin to be used in response to asthma 
symptoms throughout the treatment period.  
For restrictions relating to concomitant medications see Sections 3.1 and 3.2.   
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5.4 
Pharmacokinetics 
Not applicable. 
5.5 
Pharmacodynamics 
Not applicable. 
5.6 
Genetics 
Not applicable. 
5.7 
Biomarker analysis  
Not applicable. 
6 
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. 
SAEs 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. 
6.1 
Definition of adverse events 
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 IP has been administered. 
6.2 
Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, after the signing of the informed 
consent/assent through to the safety follow-up visit), 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  
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• 
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 D, Additional safety 
information to the Clinical Study Protocol. 
6.3 
Recording of adverse events 
6.3.1 
Period for collection of adverse events 
Adverse events and SAEs will be collected from time of signature of informed consent/assent, 
through the safety follow-up period. 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’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. The Sponsor or a 
 Safety and Pharmacovigilance Department 
representative retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study (after the subject’s final study visit) and capture that 
information in the eCRF, if judged necessary  
6.3.3 
Variables  
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Maximum severity 
• 
Seriousness 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to IP 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date investigator became aware of SAE 
• 
Reason why the AE is considered serious 
• 
Treatment given for the SAE 
• 
Date of hospitalization 
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• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether autopsy is performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
• 
Description of AE 
 
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 6.2. 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 6.2. 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 6.2. 
The severity of the event should be assessed as mild, moderate, or severe. 
6.3.4 
Causality collection 
The investigator and the Sponsor will assess causal relationship between IP 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 IP?’ 
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 D, Additional safety 
information of this Clinical Study Protocol. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the child had any health problems since the 
previous visit/you were last asked?’ or revealed by observation will be collected and recorded in 
the eCRF. When collecting AEs, the recording of diagnosis is preferred (when possible) over 
recording 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: 
 
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• 
The sign or symptom is serious 
• 
The subject discontinues IP due to the sign or symptom 
• 
The sign or symptom is new to the subject or not consistent with the subject’s pre-existing 
asthma history (defined as within 1 year of Visit 1) as judged by the investigator 
 
6.3.6 
Adverse events based on examinations and tests 
The results from the Clinical Study Protocol mandated laboratory tests, ECGs, vital signs, and 
other safety assessments will be summarized in the Clinical Study Report. Deterioration from 
baseline in these parameters should therefore only be reported as an AE if it fulfills any of the 
AE criteria or is the reason for discontinuation of treatment with the IP or is considered 
'clinically significant'. 
The criteria for determining whether the mandated laboratory tests, ECGs, vital signs, and other 
safety 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, ECG, vital sign, or other safety assessment is associated 
with clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result/vital sign 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 findings at the baseline assessment will be reported as an AE. 
6.3.7 
Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST and/or ALT ≥3×ULN combined with TBL ≥2×ULN may require IP 
suspension/discontinuation and study withdrawal, and may need to be reported as SAEs. Please 
refer to Section 3.9 and Appendix E, Hy’s Law for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law. 
6.3.8 
COVID-19 adverse events 
For subjects experiencing signs and symptoms indicating respiratory infection, confirmatory 
testing for COVID-19 is expected in line with national guidelines. 
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Non-serious confirmed COVID-19 AEs will be recorded within the clinical database but 
additional information may be collected within the safety database and/or narratives as required. 
If serious COVID-19 infection is confirmed via testing, it should be reported with the diagnosis 
“COVID-19 confirmed” in the SAE report form.  If COVID-19 infection is suspected, 
symptoms (eg, cough, fever, etc.) should be recorded in the SAE report form until diagnosis is 
confirmed.  If test is not available and signs and symptoms, as judged by the investigator, are 
highly suspicious of COVID-19 infection, “COVID-19 suspected” should be reported.  
All SAEs in relation to COVID-19 shall be reported in line with the instructions for SAE 
reporting described in Section 6.4. 
6.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel should 
inform 
 Safety and Pharmacovigilance Department within 1 day ie, immediately 
but no later than 24 hours of when he or she becomes aware of it. 
Should the eCRF system become non-operational, SAEs shall be sent in paper form to: 
 Safety and Pharmacovigilance Department 
  
 
 
 Safety and Pharmacovigilance Department works with the investigator to ensure 
that all the necessary information is provided. 
For fatal or life-threatening SAEs where important or relevant information is missing, active 
follow-up is undertaken immediately.   
Investigators or other site personnel should inform the 
 Safety and 
Pharmacovigilance Department of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately, but no later than 24 hours of when he or she becomes 
aware of it. 
6.5 
Overdose 
For the purpose of this study, an accidental or deliberate intake of blinded treatment of more 
than 12 puffs during one day is defined as an overdose and must be reported as such as 
described below. 
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All overdoses must be recorded on 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 an overdose occurs during the course of the study which has an associated SAE, then the 
investigator or other site personnel will inform the 
 Safety and Pharmacovigilance 
Department immediately, or no later than 24 hours of when he or she becomes aware of the 
overdose. 
The 
 Safety and Pharmacovigilance Department works with the investigator to 
ensure that all relevant information is provided to the 
 Safety and 
Pharmacovigilance Department representative. 
For overdoses associated with an SAE, the standard SAE reporting timelines apply, see 
Section 6.4.   
6.6 
Pregnancy 
All pregnancies and outcomes of the pregnancy should be reported to the 
 Safety 
and Pharmacovigilance Department representative except if the pregnancy is discovered before 
the study subject has received any IP. 
6.6.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately, ‘Pregnancy’ recorded as the reason for discontinuation on the eCRF, and the 
subject will be withdrawn from the study. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should be followed up and documented even if the subject was 
discontinued from the study. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
will inform the 
 Safety and Pharmacovigilance Department within 1 day ie, 
immediately, but no later than 24 hours of when he or she becomes aware of it. Any 
conception occurring from the date of dosing through the safety follow-up visit should be 
reported. 
The 
 Safety and Pharmacovigilance Department will work with the investigator to 
ensure that all relevant information is provided. 
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The same timelines apply when outcome information is available. 
6.6.2 
Paternal exposure  
Pregnancy of a subject’s partner is not considered to be an AE. However, any conception 
occurring from the date of dosing through the safety follow-up visit should be reported to the 
 Safety and Pharmacovigilance Department representative and followed up for its 
outcome. 
6.7 
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 IP that either causes harm to the subject or has the 
potential to cause harm to the subject.  
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 site staff or subject. 
Medication error includes situations where an error:  
 
• 
Occurred 
• 
Was identified and intercepted before the subject received the drug 
• 
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 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the subject 
• 
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 subject received the medication (excluding IWRS errors) 
• 
Wrong drug administered to subject (excluding IWRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
 
• 
Errors related to or resulting from IWRS-including those which lead to 1 of the above listed 
events that would otherwise have been a medication error  
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• 
Accidental overdose (will be captured as an overdose) 
• 
Subject failed to return unused medication or empty packaging 
• 
Errors related to background medication, or standard of care medication in open-label 
studies, even if it is a Sponsor’s product 
 
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 site personnel will inform the 
 Safety and 
Pharmacovigilance Department immediately, or no later than 24 hours of when he or she 
becomes aware of the medication error. 
The 
 Safety and Pharmacovigilance Department will work with the investigator to 
ensure that all relevant information is provided to 
 Safety and Pharmacovigilance 
Department representative. For medication errors associated with an SAE, the standard SAE 
reporting timelines apply, Section 6.4. 
6.8 
Management of investigational product–related toxicities 
In the absence of a specific antidote, management of toxicities can be dealt with on the basis of 
the symptoms. 
7 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
BDA MDI is formulated (Table 5) as both micronized budesonide and micronized albuterol 
co-suspended with spray-dried porous particles in a hydrofluoroalkane propellant. The 
co-suspension formulation ensures that subjects receive a consistent delivery of the drug from 
each actuation of the MDI.  
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Table 5 
Investigational Product Strength and Dosage Form 
Investigational 
product name 
and dose 
Product strength 
Dosage Form/ 
Fill Count 
Administration 
Manufacturer 
BDA MDI 
80/180 μg  
BDA MDI  
40 μg budesonide 
and 90 μg 
albuterola per puff 
MDI/120 
actuations 
Taken as 2 actuations 
 
BDA MDI 
160/180 μg 
BDA MDI  
80 μg budesonide 
and 90 μg 
albuterola per puff 
MDI/120 
actuations 
Taken as 2 actuations 
 
BD MDI 160 μg 
80 μg budesonide 
per puff 
MDI/120 
actuations 
Taken as 2 actuations 
 
AS MDI 180 μg 
AS MDI 
 90 μg albuterol 
per puffa 
MDI/120 
actuations 
Taken as 2 actuations 
 
Placebo MDI 
0 μg of active 
productb 
MDI/120 
actuations 
Taken as 2 actuations 
 
Additional study medication (Ventolin therapy) 
Ventolin HFAc 
108 μg albuterol 
sulfate (90 μg 
albuterol base) as 
an aerosol 
formulation 
Albuterol 
(salbutamol) 
sulfate inhalation 
aerosol; 200 puffs 
per canister 
Use for reversibility testing 
during screening and (Section 
5.1.1.1) as needed (generally 
2 actuations per dose) during 
screening and treatment 
periods 
 
 
Abbreviations:  AS MDI=albuterol metered-dose inhaler; BD MDI=budesonide metered-dose inhaler; BDA 
MDI=budesonide/albuterol metered-dose inhaler; HFA=hydrofluoroalkane.  
Ventolin is a non-investigational medicinal product since it is taken as directed for reversibility testing (Visit 1 and 
repeat Visit 1a, if necessary) and as needed for symptoms during the screening period. 
a Each puff contains 108 μg albuterol sulfate corresponding to 90 µg albuterol base per actuation. 
b Each puff contains 183 μg of porous particles and 63 μg of HFA-134a propellant made to be identical in 
appearance to BDA MDI, BD MDI, and AS MDI. 
c This table represents commercially available Ventolin formulation for the United States, each country 
participating in the study will utilize commercially available Ventolin in that country, product strength may vary. 
 
7.2 
Dose and treatment regimens 
Treatment groups include:  
• 
BDA MDI 80/180 μg QID (given as 2 actuations of BDA MDI 40/90 μg per puff) 
• 
BDA MDI 160/180 μg QID (given as 2 actuations of BDA MDI 80/90 μg per puff) 
• 
BD MDI 160 μg QID (given as 2 actuations of BD MDI 80 μg per puff) 
• 
AS MDI 180 μg QID (given as 2 actuations of AS MDI 90 μg per puff) 
• 
Placebo MDI QID (given as 2 actuations) 
 
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Randomization for adults and adolescents will be centralized and stratified by pre-study 
background therapy consisting of either ICS or non-ICS (subjects not previously treated with 
ICS), by ACQ-7 (≤1.5, >1.5), and by age (≥12 to 17, ≥18). Randomization for children aged 4 
to 11 years will not be stratified.   
The maximum daily dosage of IP is 12 puffs per day. Subjects should not take more than 8 
puffs of Ventolin per day (Section 6.5 for overdose). The evening before clinic visits, subjects 
should be advised to take the last dose at 22:00 (10 PM) ±2 hours. 
Handling and cleaning instructions for the MDI device will be available for the site to train 
subjects and also for the subjects to retain throughout the study (Appendix J, Metered dose 
Inhaler Handling and Cleaning). 
7.3 
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 subject will receive a kit containing 2 MDI devices, individually wrapped in foil bags held 
within a carton. The MDI devices provided in this study and the packaging and labelling of the 
kits are visually identical to maintain the blind. A kit will be dispensed for every 15 days of 
treatment. Subjects will receive 2 kits at some visits. 
Each kit will contain the following blinded labels: 
• 
Single panel canister label (English only) 
• 
Single panel actuator label or multilanguage actuator booklet label 
• 
MDI device shield label (single panel, English only) 
• 
Foil bag label (single panel, English only) or multilanguage booklet label 
• 
Single panel carton label or multilanguage carton booklet label 
 
The labels will include the following information: 
• 
Name of Sponsor (Bond Avillion 2 Development LP – Clinical Development Company: 
Avillion LLP) 
• 
Investigational product dosage form, route of administration, and quantity of dosage units 
(blinded across all treatment groups) 
• 
Storage conditions 
• 
Study Trial Reference 
• 
Medication ID number 
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• 
Directions for use 
• 
The name of the investigator, where applicable (this will be added on the label manually 
when the IP is dispensed) 
• 
The period of use eg, expiry date 
 
The label will include the following standard statements: 
• 
‘For clinical study use only’ (or the required local statement) 
• 
‘Keep out of reach of children’ 
7.4 
Storage 
Blinded supplies: BDA MDI 40/90 μg per puff, BDA MDI 80/90 μg per puff, BD MDI 80 μg 
per puff, AS MDI 90 μg per puff, and placebo should be stored below 25°C (77°F) in a dry 
place. Excursions permitted up to 30°C (86°F). 
Ventolin supplies: Store between 15°C and 25°C (59°F and 77°F). Store the inhaler with the 
mouthpiece down. For best results, the inhaler should be at room temperature before use. Do not 
use or store near heat or open flame. Exposure to temperatures above 120°F (49°C) may cause 
bursting. Never throw into a fire or incinerator. Temperature readings of the storage area 
(minimum/maximum) should be recorded on every working day at a minimum. 
7.5 
Compliance 
The administration of all IPs will be captured in the subject’s eDiary and not recorded in the 
eCRF, with the exception of the details of any interruptions for which the dates and reason for 
interruption will be recorded. The IP accountability will be recorded in the eCRF including the 
dose indicator readings for the returned kits. Data from the dose indicator will be compared with 
the subject’s eDiary entries and any discrepancies will be used to help in training the subject to 
accurately capture all IP administration in the eDiary. 
During the screening period, Ventolin usage will be reviewed to ensure the Study 
inclusion/exclusion criteria are adhered to. Ventolin will be dosed prn; therefore, compliance 
will not be applicable, other than the number of devices dispensed/returned and the usage being 
monitored.   
7.6 
Accountability 
The IPs provided for this study will be used only as directed in the Clinical Study Protocol. 
All IPs will be returned to the approved study returns vendor for destruction after accountability 
and reconciliation is complete.  
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7.7 
Metered-dose inhaler: handling and cleaning 
Detailed handling instructions will be provided to the site in the form of a ‘Site Manual’ 
document, which will cover all aspects of the study with regards to IP. An ‘Instructions For 
Use’ document can be found in Appendix J, Metered-dose Inhaler Handling and Cleaning, 
focusing on the IP MDI device.  
The importance of the device cleaning and priming requirements should be emphasised to 
subjects. Priming of the IP MDI must occur. Device priming should not be conducted in the 
same room as spirometry assessments are being conducted. 
7.8 
Concomitant medications and other treatments  
7.8.1 
Investigational product and Ventolin therapies 
Only Sponsor-provided IP dosed QID and Sponsor-provided Ventolin therapy to be used in 
response to asthma symptoms are allowed during the study. No other asthma medications are 
allowed during the study. 
Subjects on maintenance allergy immunotherapy (AIT) are allowed to continue their AIT; the 
new initiation of AIT during the study is not allowed  
7.8.2 
Medications that may affect reversibility and FEV1 testing 
Subjects are only eligible for enrollment on the DENALI study if they are taking SABA alone 
prn or with low-dose ICS; subjects presenting at Visit 1 being treated with any other asthma 
medication are ineligible. Therefore, the only restriction for eligible subjects’ reversibility 
testing at Visit 1 (or 1A, if applicable) is the requirement not to take SABA (Visit 1) or 
Sponsor-provided Ventolin (Visit 1A) within 6 hours of lung function testing. At Visit 2 
onwards, both IP and Sponsor-provided Ventolin should not be administered within 6 hours 
prior to lung function testing.  
7.8.3 
Prohibited medications 
Prohibited concomitant medications during the study include: 
• 
Oral, parenteral, or rectal corticosteroids (except if required to treat asthma exacerbation) 
• 
Any other asthma medication except Sponsor-provided IP and Ventolin 
• 
Montelukast, for any indication 
• 
Inhaled disodium cromoglycate or inhaled nedocromil sodium 
• 
5-lipoxygenase inhibitors (ie, zileuton) 
• 
Inhaled anticholinergics 
• 
Phosphodiesterase inhibitors (ie, roflumilast) 
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• 
Omalizumab, benralizumab, mepolizumab, reslizumab, dupilumab or any other monoclonal 
or polyclonal antibody therapy for any reason (intra-ocular administration of monoclonal or 
polyclonal antibody therapy is allowed) 
• 
Beta2-adrenergic blockers including eye-drops (specific cardio-selective beta-blockers in 
low daily doses, eg, metoprolol in doses up to 100 mg/d, are allowed) 
• 
Systemic treatment with potent cytochrome P450 3A4 inhibitors (eg, ketoconazole, 
itraconazole, and ritonavir) 
8 
STATISTICAL ANALYSES  
8.1 
Statistical considerations 
All personnel involved with the analysis of the study will remain blinded until database lock 
and identification of Clinical Study Protocol violators are identified. 
Analyses will be performed by the Sponsor or its representatives. 
The IDMC will have access to unblinded data in closed sessions with an unblinded statistician 
upon their request (see IDMC charter). 
A comprehensive statistical analysis plan (SAP) will be prepared prior to first subject 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to the unblinding of the data. 
8.1.1 
Estimands 
Two estimands are of interest in this study: 
The primary estimand of interest is the efficacy estimand, defined as the effect of the 
randomized treatment in all subjects assuming continuation of randomized treatment for the 
duration of the study, regardless of actual compliance. This estimand could be considered as a 
while-on-treatment strategy or a hypothetical strategy as defined in the draft International 
Conference on Harmonization (ICH) E9 Addendum. 
The second estimand of interest is the attributable estimand, defined as the effect of treatment in 
subjects attributable to the randomized treatment. For this estimand, discontinuation of 
randomized treatment for reasons such as tolerability or lack of efficacy is considered a negative 
outcome. This estimand is a mixture of composite and hypothetical strategies as defined in the 
draft ICH E9 addendum. 
8.2 
Sample size estimate 
8.2.1 
Initial assumptions and estimates 
A blinded sample size re-estimation was performed once 44% of subjects had completed Week 
12.  Based on the blinded estimate of variability, approximately 1000 subjects are required in 
order to demonstrate at least 90% power. Consequently, the total randomized adult and 
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adolescent subjects has been increased to 1000. This section details the initial assumptions of 
variability prior to calculating the blinded sample size re-estimation. Please refer to 
Section 8.2.2 for details on the sample size and power calculations following the blinded sample 
size re-estimation. 
Prior to the blinded sample size re-estimation, randomization of approximately 120 subjects to 
each treatment group expected provide at least 93% probability to detect a 100 mL difference in 
the change from baseline in trough FEV1 at Week 12 for comparison of BD MDI versus placebo 
MDI, BDA MDI versus placebo MDI, or BDA MDI versus AS MDI. This calculation was 
based on a standard deviation of 210 mL obtained from the placebo MDI group of Study 
PT008001 and an assumed dropout rate of 10% and 15% for active and placebo treatment 
group, respectively, prior to Week 12. 
Prior to the blinded sample size re-estimation, it was assumed that the sample size of 120 
subjects per treatment group would also provide >99% probability to detect a 130 mL difference 
in FEV1 AUC0-6 hours over 12 weeks for comparison of BDA MDI versus BD MDI (effect sizes 
for AS MDI or BDA MDI versus placebo MDI should be considerably larger). This calculation 
assumed a 2% dropout prior to Week 1 and an effective standard deviation of 140 mL which 
was derived from the following: a per visit standard deviation of 200 mL (ProAir Respiclick 
Studies 301 and 304 and the AS MDI Dose-Ranging Study DC6930C00001), a correlation 
between visits of 65%, and projected subject completion of 4 out of 5 visits. 
8.2.2 
Blinded sample size re-estimation 
Following the blinded sample size re-estimation, randomization of approximately 200 subjects 
(≥18 years of age) to each treatment group will provide 90% probability to detect a 100 mL 
difference in the change from baseline in trough FEV1 at Week 12 for comparison of BD MDI 
versus placebo MDI, BDA MDI versus placebo MDI, or BDA MDI versus AS MDI. This 
calculation is based on a standard deviation of 290 mL obtained from the blinded sample size 
re-estimation performed after 44% of subjects completed Week 12 and an estimated overall 
dropout rate of 11% prior to Week 12. 
Following the blinded sample size re-estimation, the sample size of 200 subjects (≥18 years of 
age) per treatment group will also provide >99% probability to detect a 130 mL difference in 
FEV1 AUC0-6 hours over 12 weeks for comparison of BDA MDI versus BD MDI (effect sizes for 
AS MDI or BDA MDI versus placebo MDI should be considerably larger). This calculation 
assumes 2% dropout prior to Week 1 and an effective standard deviation of 290 mL obtained 
from the blinded sample size re-estimation performed after 44% of subjects completed Week 
12. 
Approximately 1000 adults (≥18 years of age) and adolescent subjects (12 - 17 years of age, 
where approved) with asthma will be randomized 1:1:1:1:1 to 1 of 5 treatment groups 
(approximately 200 subjects per group: BDA MDI 80/180 μg QID, BDA MDI 160/180 μg QID, 
BD MDI 160 μg QID, AS MDI 180 μg QID, or placebo MDI). In addition, where approved, up 
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to 30 child subjects (aged 4 to 11 years) with asthma will be enrolled but will not receive high 
dose ICS and will be randomized 1:1:1 to receive low-dose BDA MDI 80/180 μg QID, AS MDI 
180 μg QID, or placebo MDI. Approximately 2000 subjects will need to be screened, assuming 
an estimated screen failure rate of approximately 50% prior to randomization. This Phase III 
study is planned to be conducted globally. 
A second blinded sample size re-estimation will be performed once approximately 65% of the 
revised sample size has completed 12 weeks and prior to the last subject being randomized.  
This will allow the re-assessment of variability in a larger sample and at a point where any 
impact from COVID-19 with respect to lung function variability and dropout rates can be 
quantified more accurately. Final total enrollment in the study will be confirmed following the 
second blinded sample size re-calculation in order to ensure 90% power. 
Any further potential increase in sample size will be capped at 1300, a 30% increase above the 
revised 1000 subjects. 
8.3 
Definitions of analysis sets 
8.3.1 
Full analysis set 
The full analysis set is defined as all subjects who are randomized to treatment and take any 
amount of IP. Subjects will be analyzed according to the treatment they were assigned at 
randomization.   
All efficacy analyses will be conducted on the full analysis set. 
The efficacy and attributable estimand will include all data obtained before subjects discontinue 
randomized treatment. 
8.3.2 
Safety analysis set 
The safety analysis set is defined as all subjects receiving any amount of the IP. Subjects will be 
classified on the basis of treatment they actually received. If a subject receives >1 IP, he or she 
will be summarized according to the treatment the subject received the most. All safety 
summaries will be based on the safety analysis set.  
8.4 
Violations and deviations 
Important protocol deviations will be listed and summarized by randomized treatment group. A 
per protocol analysis excluding subjects with significant protocol deviations is not planned. 
All subjects 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 subjects failing any of the inclusion/exclusion criteria and will be based on the full analysis 
set. 
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8.5 
Outcome measures for analyses 
8.5.1 
Primary efficacy analysis 
The primary analysis will include all data obtained before subjects discontinue randomized 
treatment and will use the full analysis set, in accordance with the primary estimand (Section 
8.1.1). 
8.5.1.1 
Dual-primary efficacy endpoints 
The primary efficacy analysis comprises of 2 dual-primary endpoints of change from baseline in 
FEV1 AUC0-6 hours over 12 weeks and change from baseline in trough FEV1 at Week 12. 
Baseline FEV1 will be taken as the average of the 60- and 30-minute pre-dose spirometry 
measures at randomization (Visit 2). 
8.5.1.1.1 
Derivation for FEV1 AUC0-6 hours 
FEV1 AUC0-6 hours will be calculated for the changes from the baseline (randomization visit) 
using the trapezoidal rule and will be normalized by dividing by the time (in hours) from dosing 
to the last measurement included (typically 6 hours). 
8.5.1.1.2 
Derivation for trough FEV1 
Trough FEV1 will be taken as the average of the 60- and 30-minute pre-dose spirometry 
measures prior to dosing of IP. 
In subjects with only 1 pre-dose assessment for trough, the value will be calculated from the 
single measurement. 
8.5.2 
Secondary efficacy analyses 
The secondary analyses will include all data obtained before subjects discontinue randomized 
treatment and will use the full analysis set, in accordance with the primary estimand 
(Section 8.1.1). 
8.5.2.1 
Derivation for time to onset (15% increase in FEV1) on Day 1 and duration of 
effect on Day 1 
Time to onset (minutes) on Day 1 will be calculated as the time from dosing on Day 1 
(randomization day; Visit 2) to the first instance within 30 minutes in which a percentage 
change from baseline in FEV1 greater or equal to 15% is observed: 
Time of first 15% increase in percentage change from baseline in FEV1 – Time of dosing on 
Day 1 (randomization, Visit 2) 
The duration of effect for each subject will be defined as the time from onset of at least a 15% 
increase in FEV1 to the offset of the 15% increase in FEV1 relative to baseline. If the offset of 
response was not achieved during the assessment period, the last available time of assessment 
will be used as the offset. If a subject had a second onset of response subsequent to achievement 
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of offset, their data for that subsequent period will be excluded from the duration of response 
calculation. 
8.5.2.2 
Derivation of Asthma Control Questionnaire-7 variables  
All 7 items are assessed on a 7-point scale (0=good control; 6=poor control). The overall score 
is the mean of the 7 items. At least 6 out of the 7 items are needed to provide an ACQ-7 score. 
The minimal important difference (MID) in ACQ-7 score is estimated to be 0.5 (Juniper 2005). 
On the basis of the MID, responders at Week 12 are defined as subjects achieving a decline 
from baseline of at least 0.5: 
• 
Responder: (Week 12 – baseline) ≤-0.5 
• 
Non-responder: (Week 12 – baseline) >-0.5 
Subjects who discontinue treatment for any reason before Week 12 will be classified as non-
responders. Baseline is defined as the most recent non-missing score before the first dose of 
randomized IP. 
Additionally, an exploratory endpoint will be considered to assess the changes from baseline 
ACQ-7 overall score at Week 12 as the following 3-level factor: 
• Improvement: (Week 12 – baseline) ≤ -0.5 
• No Change: -0.5 < (Week 12 – baseline) < 0.5 
• Worsening: (Week 12 – baseline) ≥ 0.5 
Subjects who discontinue treatment for any reason before Week 12 will be classified as non-
responders. 
The interviewer-administered version will be implemented for children aged 4 to 10 years. As 
the ACQ-7 is not validated for children <6 years old, data for subjects who are 4 or 5 years of 
age will be excluded from the analyses of ACQ-7 endpoints. 
8.5.3 
Exploratory efficacy analyses 
The exploratory analyses will include all data obtained before subjects discontinue randomized 
treatment and will use the full analysis set, in accordance with the primary estimand 
(Section 8.1.1). 
8.5.3.1 
Derivation of severe exacerbation endpoints 
For the production of summary statistics, the raw annualized severe asthma exacerbation rate 
will be calculated according to the following formula: 
Annualized severe exacerbation rate=∑ number of severe exacerbations*365.25/∑ follow-up, 
where the summations are over all subjects within a treatment group.  
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For subjects who do not prematurely discontinue, the follow-up is calculated as:  
Date of latest follow-up-date of randomization (Visit 2) + 1. 
Otherwise, follow-up is calculated as the discontinuation date of randomized treatment:  
Date of randomized treatment discontinuation-date of randomization (Visit 2) + 1. 
8.5.3.2 
Derivation of deterioration of asthma variables 
The deterioration of asthma rate will be calculated in a similar way as the raw annualized severe 
asthma exacerbation rate (Section 8.5.3.1). 
8.5.3.3 
Derivation of peak FEV1 
Peak change from baseline in FEV1 will be calculated using the largest FEV1 value measured 
following dosing of IP. 
8.5.3.4 
Derivation of peak expiratory flow 
The best of at least 3 PEF measurements will be recorded by the subject in the morning and 
before going to bed in the evening prior to taking any asthma therapy. PEF will be analyzed 
separately for the morning and evening. 
8.5.3.5 
Derivation of Asthma Control Questionnaire-5 variables  
Derivations for responder status for ACQ-5 will be performed as described in Section 8.5.3.2. 
At least 4 out of the 5 symptom items are needed to provide an overall ACQ-5 score. 
8.5.3.6 
Derivation of Asthma Quality of Life Questionnaire +12 and Pediatric Asthma 
Quality of Life Questionnaire variables 
AQLQ consists of 32 questions in 4 domains and PAQLQ consists of 23 questions in 
3 domains. Both are assessed on separate 7-point Likert scales from 1 to 7, with higher values 
indicating better health-related quality of life.  
For overall health-related quality of life and for each of the domains, the MID has been 
determined to be a change in score of 0.5 (Juniper 1994). On the basis of the MID, responders at 
Week 12 are defined as subjects achieving an increase from baseline of at least 0.5: 
• 
Responder: (Week 12 – baseline) ≥0.5 
• 
Non-responder: (Week 12 – baseline) <0.5 
 
Subjects who discontinue treatment before Week 12 for any reason will be classified as non-
responders. Baseline is defined as the most recent non-missing score before the first dose of 
randomized IP.  
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8.5.3.7 
Derivation of Ventolin therapy variables 
Ventolin therapy will be analyzed through the average number of administrations (puffs) per 
day.  
Total daily number of puffs will be calculated for each subject as the sum of the cumulative 
puffs of Ventolin therapy divided by the number of days the subject was in the study prior to 
treatment discontinuation. 
Total daily number of puffs will be further characterized within 4-weekly time intervals 
throughout the randomized treatment period. Further details will be provided in the SAP. 
Baseline number of puffs per day will be based on the last 10 days of the run-in period prior to 
before the first dose of randomized IP.  
8.5.3.8 
Derivation of other eDiary variables 
Symptom-free days 
A symptom-free day is defined as the fulfillment of both of the following criteria: 
• 
A day and night with no asthma symptoms (ie, asthma symptom score=0) 
• 
A night with no awakenings due to asthma symptoms 
Asthma control days 
An asthma control day is defined as the fulfillment of all of the following criteria: 
• A day and night with no asthma symptoms (ie, asthma symptom score=0) 
• A night with no awakenings due to asthma symptoms 
• A day and night with no use of prn Ventolin therapy 
8.6 
Methods for statistical analyses 
All tests will be 2-sided and at 5% level of significance unless otherwise stated.  
In addition to the analyses described below, all variables will be summarized descriptively 
where appropriate. 
8.6.1 
Analysis of the dual-primary variable 
The first and second dual-primary variables, change from baseline in FEV1 AUC0-6 hours, and 
change from baseline in trough FEV1 will each be analyzed using a repeated measures (RM) 
linear model to compare treatment groups. The model will include baseline FEV1, percentage 
reversibility to Ventolin, and age as continuous covariates, and visit, treatment, the treatment-
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by-visit interaction, and prior ICS use (Yes/No) as categorical covariates. Baseline will be 
defined as the average of the pre-dose assessments collected on randomization (Visit 2).   
An unstructured variance-covariance matrix will be implemented. If this model fails to 
converge, a heterogeneous Toeplitz (TOEPH) will be fit.  
FEV1 AUC0-6 hours over 12 weeks will be calculated using an appropriate contrast. Two-sided 
p-values and point estimates with two-sided 95% confidence intervals will be calculated for 
each pairwise treatment contrast. More details will be provided in the SAP. 
The planned treatment comparisons for the primary analysis will be sequentially tested in the 
8 step sequence as specified below. Comparisons will stop if a non-statistically significant result 
occurs. All comparisons are of superiority. Formally, the null and alternative hypotheses for 
each comparison are: 
H0:Difference between treatment =0, 
 HA: Difference between treatment ≠0. 
Change from baseline in FEV1 AUC0-6 hours over 12 weeks: 
1. AS MDI 180 μg QID versus placebo MDI QID 
2. BDA MDI 160/180 μg QID versus placebo MDI QID 
3. BDA MDI 160/180 μg QID versus BD MDI 160 μg  
Change from baseline in trough FEV1 at Week 12: 
4. BD MDI 160 μg QID versus placebo MDI QID 
5. BDA MDI 160/180 μg QID versus placebo MDI QID 
6. BDA MDI 160/180 μg QID versus AS MDI 180 μg QID 
Statistical testing for BDA 80/180 μg will proceed in a similar manner as for BDA 160/180 μg, 
as shown below: 
Change from baseline in trough FEV1 at Week 12: 
7. BDA MDI 80/180 μg QID versus placebo MDI QID 
8. BDA MDI 80/180 μg QID versus AS MDI 180 μg QID  
The Type I error will be controlled sequentially by testing in the above order. If a comparison is 
significant (alpha=0.05, two-sided), testing will proceed to the next comparison. 
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The above tests in steps 1 to 8 will exclude children (age 4 to 11 years). The analysis will be 
repeated to include children, but will be considered a supportive analysis of the dual-primary 
endpoint. In the supportive analysis including all ages, the comparison of BDA MDI 160/180 
μg versus AS MDI 180 μg will exclude the child subjects aged 4 to 11 years as they will not be 
randomized to BDA MDI 160/180 μg. However, the comparison of BDA MDI 80/180 μg 
versus AS MDI 180 μg and BDA MDI 80/180 μg versus placebo MDI will include subjects 
from all age groups. 
The comparisons of BDA MDI 80/180 μg QID versus placebo MDI QID and BDA MDI 80/180 
μg QID versus BD MDI 160 μg QID for FEV1 AUC0-6 hours over 12 weeks are not included in 
the Type I error control procedure as they redundantly evaluate the contribution of albuterol to 
the combination, which is already captured in Steps 2 and 3. However, these comparisons will 
be reported for completeness. 
All subjects who are randomized and are part of the full analysis set will be analyzed according 
to the strata they were allocated to in IVRS/IWRS in this primary analysis. A sensitivity 
analysis will be conducted based on subjects’ actual strata to assess the impact of miss-
stratification on the model results. 
8.6.2 
Analysis of the secondary efficacy variables 
For all secondary analyses the same treatment comparisons as for the primary analysis will be 
conducted (Section 8.6.1).  
8.6.2.1 
Median time to onset (15% increase in FEV1) and duration of effect 
The median time to onset (defined as 15% increase in FEV1) over the pre-treatment value at 
randomization (Visit 2) will be compared among treatment groups using a Wilcoxon rank sum 
test. Confidence intervals for the median treatment difference will be calculated using the 
Hodges-Lehmann method. 
Descriptive statistics for duration of response will be reported by treatment group. 
Only the subjects who achieve the 15% increase in FEV1 within 30 minutes post-dose will be 
included in these calculations. 
8.6.2.2 
Asthma Control Questionnaire-7 
The primary analyses of ACQ-7 will be conducted in subjects that are uncontrolled at baseline 
(ie, baseline ACQ-7 ≥1.5) as these are the subjects capable of demonstrating a clinically 
meaningful response with treatment.  
The responder variable described in Section 8.5.2.2 at Week 12 will be analyzed using a logistic 
regression model with treatment and previous ICS use (Yes/No) as categorical covariates, and 
baseline ACQ-7 score, baseline post-dose percent predicted FEV1 and age as continuous 
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covariates. From the logistic regression model treatment effects will be estimated by odds ratios 
and its corresponding 95% confidence interval along with p-values. 
Baseline is defined as the most recent non-missing score before the first dose of randomized IP. 
Subjects who discontinue treatment for any reason will be classified as non-responders. The 
frequency and percentage of responders will be summarized descriptively for all study visits. 
The treatment effect for change from baseline in ACQ-7 will be estimated using a mixed model 
RM (MMRM) analysis. All data up to Week 12 will be included in the model, with terms for 
age, treatment, visit, treatment*visit, prior ICS use (Yes/No), baseline ACQ-7 score and 
baseline post-dose percent predicted FEV1. Visit will be fitted as a categorical variable, and the 
variance-covariance matrix will be assumed to be unstructured. If the procedure does not 
converge, then a heterogeneous TOEPH will be used instead. This model will be used to give an 
overall assessment of the treatment effect as well as 95% confidence intervals. 
Change from baseline will also be described descriptively for all study visits. 
8.6.3 
Analysis of safety variables 
The safety analyses will include all data obtained before subjects discontinue randomized 
treatment and will use the safety analysis set.  
8.6.3.1 
Adverse events 
Adverse events will be summarized by treatment group, system organ class and preferred term 
assigned to the event by the Medical Dictionary for Regulatory Activities. AEs will also be 
listed for each subject.  
8.6.3.2 
Vital signs 
Change from baseline throughout the study will be assessed for vital signs variables collected 
on the eCRF. 
Baseline is defined as the most recent non-missing measurement before the first dose of 
randomized IP  
8.6.3.3 
Clinical chemistry and hematology 
Clinical chemistry and hematology parameters will be summarized by treatment group and Visit 
and will also be listed by subject. 
Baseline is defined as the most recent non-missing measurement before the first dose of 
randomized IP. 
8.6.3.4 
Electrocardiogram 
ECG parameters will be summarized by treatment group and Visit and will also be listed by 
subject. 
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Baseline is defined as the most recent non-missing measurement before the first dose of 
randomized IP. 
8.6.3.5 
Concomitant medication 
The number and percentage of subjects who take allowed concomitant medications, and those 
who take disallowed concomitant medications during the study, will be presented by treatment 
group. 
8.6.4 
Analysis of exploratory variables 
The treatment comparisons in the secondary analyses given below are compared in the same 
way as the primary analysis. 
8.6.4.1 
Severe exacerbations 
The raw annualized exacerbation rate will be summarized descriptively by treatment, using the 
derivation described in Section 8.5.3.1. 
8.6.4.2 
Deterioration of asthma 
Annualized deterioration of asthma will be summarized in the same way as the annualized 
severe asthma exacerbation rate (Section 8.6.4.1)  
8.6.4.3 
Peak FEV1 
Peak FEV1 at Day 1 (Visit 2) and Day 7 (Visit 3) will be analyzed using the same method as for 
trough FEV1 and FEV1 AUC0-6 hours. Baseline will be defined as the average of the pre-dose 
assessments collected on Day 1. 
8.6.4.4 
Peak expiratory flow 
The mean value of change from baseline in PEF data during the randomized treatment period 
will be analyzed by analysis of covariance with treatment, ACQ-7 at randomization (≤1.5/>1.5), 
and prior ICS use (Yes/No) as factors, and age and baseline PEF score as continuous covariates. 
The summary measure for the comparison of treatments will be the estimated mean difference, 
presented with the corresponding 95% confidence interval. 
Additionally, an RM analysis will be conducted and will be partitioned into 4-weekly time 
intervals across the randomized treatment period. The analysis model will additionally include 
time point and treatment*time point as factors. 
8.6.4.5 
Asthma Control Questionnaire-5 variables  
The responder variable for ACQ-5 at Week 12 will be analyzed using a logistic regression 
model in the same way as ACQ-7 (Section 8.6.2.2). 
The treatment effect for change from baseline in ACQ-5 will be estimated using an MMRM 
analysis in the same way as ACQ-7 (Section 8.6.2.2). 
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The 3-factor categorization of ACQ-7 (Improvement; No change; Worsening) will be 
considered in an exploratory analysis using a logistic regression model adjusted for the same 
covariates as for the binary response of ACQ-7 (Section 8.6.2.2). 
8.6.4.6 
Asthma Quality of Life Questionnaire +12 and Pediatric Asthma Quality of 
Life Questionnaire 
The responder analysis will be conducted in the same way as ACQ-7 (Section 8.6.2.2). 
The domain scores as well as the overall scores are calculated from the unweighted arithmetic 
means of the individual question scores. The treatment effect for change from baseline in 
AQLQ+12 and PAQLQ overall scores up to Week 12 will be estimated in the same way as 
ACQ-5, using an MMRM analysis.  
Change from baseline will also be described descriptively for all study visits for each of the 
domains and the overall scores. 
In all the scenarios above, baseline is defined as the most recent non-missing measurement 
before the first dose of randomized IP. 
As the PAQLQ is not validated for children <7 years of age, data for subjects who are aged 4 to 
6 years will be excluded from the analyses of PAQLQ endpoints. 
8.6.4.7 
Ventolin therapy 
Change from baseline in Ventolin therapy use compared with the mean value of available data 
during the study. The data will be analyzed using analysis of covariance with treatment, ACQ-7 
at randomization (≤1.5/>1.5), and prior ICS use (Yes/No) as factors, and age and baseline daily 
number of puffs as continuous covariates. The summary measure for the comparison of 
treatments will be the estimated mean difference, presented with the corresponding 95% 
confidence interval. 
Additionally, an RM analysis will be conducted on the change from baseline Ventolin therapy 
partitioned into 4-weekly time intervals across the randomized treatment period. The analysis 
model will additionally include time point and treatment*time point as factors. 
8.6.4.8 
Other eDiary variables 
Asthma daytime/night-time symptoms and night-time awakenings due to asthma will be 
compared with the mean value of available data during the study. The data will be analyzed 
using analysis of covariance with treatment, ACQ-7 at randomization (≤1.5/>1.5), and prior ICS 
use (Yes/No) as factors, and age and baseline as continuous covariates. The summary measure 
for the comparison of treatments will be the estimated mean difference, presented with the 
corresponding 95% confidence interval. 
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Additionally, an RM analysis will be conducted on the aforementioned eDiary endpoints, 
partitioned into 4-weekly time intervals across the randomized treatment period. The analysis 
model will additionally include time point and treatment*time point as factors. 
Change from baseline will also be summarized for each subject by treatment group using 
summary statistics. In all the scenarios above, baseline is defined as the most recent score 
before the first dose of randomized IP. 
8.6.5 
Subgroup analysis 
The assessment of treatment effect will also be investigated in the stratification variables and 
other clinically important subgroups and will be defined in more detail in the SAP. 
8.6.6 
Interim analysis 
No interim analyses will be conducted in this study and the study blind is to be maintained until 
all subjects have completed the treatment period and until after the database has been locked. 
8.6.7 
Sensitivity analysis 
8.6.7.1 
Tipping point analysis 
Multiple imputations tipping point analysis under the missing not at random assumption 
(MNAR) will be conducted. For subjects in the BDA MDI groups, and subjects in AS MDI and 
BD MDI when comparing to placebo MDI, this method will impute missing values post-study 
discontinuation for lack of asthma control assuming they were more likely to have a worse 
outcome than as implied under the missing at random assumption (MAR). The tipping point 
analysis will incrementally penalize the missing data under the missing not at random 
assumption until a non-statistically significant comparison is observed.  
The tipping point approach described above will be repeated and all missing data over the 
randomized treatment period will be imputed under the MNAR assumption. Further details will 
be provided in the SAP. 
8.6.7.2 
Attributable estimand 
Analysis of the attributable estimand will be conducted in the full analysis set, but data that are 
missing due to treatment discontinuation will be imputed based on the 95th or the 5th percentile 
of the reference group’s distribution if the reason is reasonably attributable to tolerability or lack 
of efficacy. The 95th percentile would apply to an endpoint for which a higher value is a worse 
outcome, while the 5th percentile would apply to an endpoint for which a higher value is a 
better outcome. More detail about the computation of the attributable estimand will be provided 
in the SAP.  
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8.6.7.3 
COVID-19 pandemic impacts 
As the trial is ongoing during the coronavirus disease (COVID-19) pandemic, it will be 
necessary to evaluate any potential intercurrent events due to COVID-19 and quantify their 
impact on the efficacy and safety profile of the study. 
At a minimum, the number of missed visits, premature withdrawals, and efficacy assessments 
not done will be summarized descriptively by treatment group and overall across treatment 
groups. Where appropriate, the subject level data for missed visits and assessments will listed 
along with the corresponding link to COVID-19, as recorded in the eCRF. It is not anticipated 
that missing data and premature withdrawals due to COVID-19 will be related to randomized 
treatment. Therefore, missing data due to COVID-19 will be assumed missing at random in 
accordance with the efficacy estimand. If further sensitivity analyses are deemed necessary 
following a blinded review of missing efficacy due to COVID-19, further details will be 
provided in the statistical analysis plan, prior database lock and unblinding. 
Similarly, at a minimum, the number of missed scheduled safety assessments due to COVID-19 
will be summarized descriptively by treatment group and across treatment groups. Subjects with 
suspected or confirmed diagnosis of COVID-19, and/or COVID-19 related AEs and SAEs will 
be summarized descriptively.  Subject level listings of missed safety assessments and 
COVID-19 related (S)AEs will be listed. 
9 
STUDY AND DATA MANAGEMENT  
9.1 
Training of study site staff 
Before the first subject is entered into the study, a designated representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the Rave WBDC 
system(s) utilized. 
The investigator 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 will maintain a record of all individuals involved in the study (medical, 
nursing, and other staff). 
9.2 
Monitoring of the study 
During the study, the Sponsor or a designated representative will have regular contacts with the 
study site, including visits to: 
• 
Provide information and support to the investigator(s) 
• 
Confirm that facilities remain acceptable 
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• 
Confirm that the investigational team is adhering to the Clinical Study Protocol, that data 
are being accurately and timely recorded in the eCRFs, that biological samples are handled 
in accordance with the Laboratory Manual, and that IP accountability checks are being 
performed 
• 
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent/assent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts) 
• 
Ensure all SAEs and AEs have been captured and reported correctly, providing oversight of 
subject safety while on study 
• 
Verify the correct storage, handling, dispensation, and return of all IP  
• 
Ensure withdrawal of informed consent/assent to the use of the subject’s biological samples 
is reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject 
 
The designated representative will be available between visits if the investigator(s) or other staff 
at the center needs information and advice about the conduct of the study. 
9.2.1 
Source data 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
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/participating center should comply with all the terms, conditions, and 
obligations of the Clinical Study Protocol, or equivalent, for this study.   
Clinical Trial Agreements with the investigator/participating center should be in place before 
any study-related procedures can take place, or subjects are enrolled. 
9.2.3 
Archiving of study documents 
The investigator follows the principles outlined in the Clinical Trial Agreement. 
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9.3 
Study timetable and end-of-study 
The end-of-study is defined as ‘the last visit of the last subject undergoing the study’. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (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 BDA MDI. 
9.4 
Data management  
Data management will be performed by the Data Management Team at 
 
according to the Data Management Plan.  
The data collected through third party sources will be obtained and reconciled against study 
data. Data from third parties will be transferred in accordance with data transfer specifications 
and reconciled in accordance with the Data Management Plan. 
AEs and medical/surgical history will be classified according to the terminology of the latest 
version of the Medical Dictionary for Regulatory Activities at the time of database lock. 
Medications will be classified according to the World Health Organization Drug Dictionary. All 
coding will be performed by the Medical Coding Team at 
 
Data queries will be raised for inconsistent, impossible, or missing data. All entries to the study 
database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan. Quality control procedures 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. The Data Management Plan will also clarify the roles and responsibilities 
of the various functions and personnel involved in the data management process. 
Serious adverse event reconciliation 
SAE reconciliation reports are produced and reconciled with the applicable 
 
Safety and Pharmacovigilance Department safety database and/or the investigational site.  
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 applicable data standards. 
Final database lock 
Database lock will occur once ‘the last visit of the last subject participating in the study has 
been completed’ all data have been coded, validated, signed, and locked, and clean file has been 
declared. 
 
 
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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 informed consent/assent form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
Subjects 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 subject identifiable will not be transferred. Subjects must be 
informed that his/her personal study-related data will be used by the Sponsor in accordance with 
local data protection law. The level of disclosure must also be explained to the subject. Subjects 
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 Clinical Study Protocol, including the final version of the 
informed consent/assent form and any other written information and/or materials to be provided 
to the subjects. The investigator will ensure the distribution of these documents to the applicable 
EC and to the study site staff. 
The opinion of the EC should be given in writing. The investigator should submit the written 
approval to the Sponsor or designated representative before enrollment of any subject into the 
study.  
The EC should approve all advertising used to recruit subjects for the study. 
The Sponsor or designated representative should approve any modifications to the informed 
consent/assent form that are needed to meet local requirements. 
If required by local regulations, the Clinical Study Protocol should be re-approved by the EC 
annually. 
Before enrollment of any subject into the study, the final Clinical Study Protocol, including the 
final version of the informed consent/assent form, is approved by the national regulatory 
authority or a notification to the national regulatory authority is done, according to local 
regulations. 
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The Sponsor or designated representative handles the distribution of any of these documents to 
the national regulatory authorities. 
The Sponsor or designated representative will provide regulatory authorities, ECs, and 
investigators with safety updates/reports according to local requirements. 
10.4 
Informed consent/assent 
The investigator(s) at each center will: 
• 
Ensure each subject and/or parent/legal representative (as applicable) is given full and 
adequate oral and written information about the nature, purpose, possible risks, and benefit 
of the study 
• 
Ensure each subject and/or parent/legal representative is notified that they are free to 
discontinue from the study at any time 
• 
Ensure that each subject and/or parent/legal representative is given the opportunity to ask 
questions and allowed time to consider the information provided 
• 
Ensure each subject and/or parent/legal representative provides signed and dated informed 
consent/assent before conducting any procedure specifically for the study 
• 
Ensure the original, signed informed consent/assent form(s) is/are stored in the 
investigator’s study file 
• 
Ensure a copy of the signed informed consent/assent form is given to the subject 
• 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in the 
informed consent/assent form that is approved by an EC 
 
10.5 
Changes to the clinical study protocol and informed consent/assent 
form 
Study procedures will not be changed without the mutual agreement of the international 
coordinating investigator and the Sponsor. 
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol. 
The new version of the Clinical Study Protocol 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 Clinical Study Protocols. 
The Sponsor will distribute any new versions of the Clinical Study Protocol to each 
investigator(s) for distribution to EC see Section 10.3. 
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If a change to a Clinical Study Protocol requires a change to a center’s informed consent/assent 
form, the Sponsor and the center’s EC are to approve (or a notification to the national regulatory 
authority is submitted where applicable for) the revised informed consent/assent form 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 and 
analyzed and accurately reported according to the Clinical Study Protocol, 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. 
11 
SUMMARY OF CHANGES 
The following table provides a brief summary of major changes. It does not include all non-
substantial changes (eg, formatting, minor clerical, and typographical corrections).  
11.1 
Changes to protocol amendment 2 (Version 3.0)  
Section  
Changes to Protocol Amendment 2 (Version 3.0)  
Clinical Protocol Synopsis 
Updated the number of adult and adolescent subjects 
randomized from 600 to 1000, the number of subjects 
within each treatment arm from 120 to 200, and the 
number of subjects screened from 1000 to 2000. Updated 
the estimated screen failure rate from 40% to 50%. 
 
Exploratory endpoint: Specified that the change from 
baseline in the Asthma Control Questionaire-5 (ACQ-5) 
and responder analysis is at Week 12. 
 
Target subject population: Clarified to include subjects 
≥4 years of age, where approved, ≥18 years of age for all 
other countries. 
 
Clarified ages for adult (≥18 years of age) and adolescent 
subjects (aged 12-17 years, where approved). 
 
Added Subjects will be recommended not to take more 
than 8 puffs of Ventolin per day and advised to contact 
the investigator if their symptoms necessitate more than 8 
puffs of Ventolin in a day. 
 
Addition of initial assumptions for calculations of sample 
size and information about the blinded sample size-re-
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Section  
Changes to Protocol Amendment 2 (Version 3.0)  
estimation. Re-estimation was performed once 44% of 
subjects had completed Week 12. 
 
Updated to describe and justify a second blinded same size 
re-estimation once approximately 65% of the revised 
sample size completes 12 weeks of the study and before 
the last subject is randomized.   
 
Modified the cap in sample size to 1300, and specified this 
is a 30% increase above the revised number of 1000 
subjects as opposed to the previously calculated cap of 
800, a 33% increase above the planned number of 600 
subjects. 
1 Introduction 
1.1 Background 
 
Added Albuterol is approved in many countries as 
salbutamol in multiple formulations for the treatment or 
prevention of bronchoconstriction. 
 
1.3 Benefit/risk and ethical assessment 
 
Added justification to continue study enrollment and 
treatment during the COVID-19 pandemic. 
 
1.4 Study design 
 
Added recommendation to not exceed 8 puffs of Ventolin 
per day. 
 
Figure 1: Updated to reflect new sample size estimates. 
 
2 Study Objectives 
2.4 Exploratory objectives 
 
Specified that the change from baseline in the Asthma 
Control Questionaire-5 (ACQ-5) and responder analysis is 
at Week 12 
3 Subject selection, enrollment, 
randomization, restrictions, 
treatment, discontinuation and study 
termination  
3.1 Inclusion criteria 
 
Inclusion criteria 2 updated to add In the Czech Republic, 
Germany, Serbia, Slovakia, and Ukraine only subjects 
≥18 years will be included. 
 
Inclusion criteria 5 updated the predicted normal value of 
pre-bronchodilator FEV1 for subjects age 4-7 to ≥50% 
(from ≥50 to < 90%) and to add Subjects 4 to 17 years of 
age who previously failed inclusion criteria 5 due to the 
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Changes to Protocol Amendment 2 (Version 3.0)  
upper FEV1 limit will be permitted to re-screen once and 
will be required to meet all eligibility criteria upon re-
screening. 
 
Inclusion criteria 7 updated: Subjects 4 to 11 years will be 
eligible if they provide 2 acceptable / repeatable 
measurements. 
 
Inclusion criteria 15 revised to define the practice of 
complete abstinence, to remove highly when describing 
methods of effective birth control methods, and modified 
to clarify appropriate methods of double-barrier birth 
control. The definition of menopausal women was updated 
to remove the reference to ≥50 years of age. 
 
Inclusion criteria 16 modified to remove the word highly 
when referring to effective methods of double-barrier 
contraception.   
 
3.2 Exclusion criteria 
 
Exclusion criteria 4 updated to include dupilumab 
 
Exclusion criteria 24 updated to include Currently 
pregnant or breastfeeding. 
 
Exclusion criteria 28 updated to previously been 
randomized from enrolled and to add For pediatrics, see 
inclusion criterion 4. 
 
3.3 Subject enrollment and randomization 
 
Updated the number of adult and adolescent subjects 
randomized from 600 to 1000, the number of subjects 
within each treatment arm from 120 to 200, and the 
number of subjects screened from 1000 to 2000. Updated 
the estimated screen failure rate from 40% to 50%. 
 
3.7 Methods for unblinding 
 
Clarified methods for unblinding and specified that 
decisions will be based on the investigator’s clinical 
judgement. The requirement that the investigator should 
discuss with the Sponsor medical monitor or other 
appropriate personnel, when possible, was removed. 
 
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Changes to Protocol Amendment 2 (Version 3.0)  
3.9 Treatment discontinuation by subject and/or 
Sponsor 
 
The following reason for IP discontinuation was added: In 
subjects who have elevated liver enzymes AST and/or 
ALT ≥3 times the upper limit of normal (×ULN) and 
total bilirubin ≥2×ULN (ie, meeting the criteria of at 
least potential Hy’s Law), IP will be suspended until the 
liver test values return to the normal range. If the AST, 
ALT, or total bilirubin reach these elevated levels again, 
after recommencement of IP, the subject will be 
discontinued from IP and withdrawn from the study. 
 
3.11 Screen failures 
 
The following exception for screen failures was added: 
Subjects who are screen failures will not be re-screened 
with the exception of children and adolescents who 
screen-failed because they did not meet the now obsolete 
upper FEV1 % predicted limit.  Children and adolescents 
who previously failed to meet the upper FEV1 % 
predicted threshold, but who met all other eligibility 
requirements, may re-screen once.  Upon re-screening, 
these subjects must meet all eligibility requirements in 
order to be randomized.  
Section 4 Study plan and timing of 
procedures 
Table 1:  Added pregnancy testing to Visits 3 and 5, 
added Ventolin administration (recorded in 
MasterScope) to Screening, and removed IP 
administration (recorded in MasterScope) at Screening.  
Footnote h: Updated from Visits 2 and 4 to all other visits 
for pregnancy testing.  
Footnote i: updated upper threshold values for FEV1 to 
≥50% from ≥50-<90% in subjects aged 4-17 years. 
 
4.2 Randomization/treatment period 
 
Added urine pregnancy testing at Visits 3 and 5 in the 
Czech Republic and at the safety follow up visit in 
Argentina. Clarified that serum pregnancy tests are 
required at Visit 6 or the premature discontinuation visit 
(PDV). 
5 Study Assessments 
Administrative changes 
 
5.1.1.1 Reversibility test 
 
Clarified that pre-dose PFTs are to be done after at least 
15 minutes of rest and before administration of Ventolin. 
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Section  
Changes to Protocol Amendment 2 (Version 3.0)  
 
5.1.1.2 COVID-19 and Pulmonary Function Testing 
 
New section added to specify that spirometry should not 
be done if subjects are showing signs and symptoms of 
COVID-19 and to indicate that participants with suspected 
COVID-19 should receive a test to confirm diagnosis. 
 
5.1.2 Asthma Control Questionnaire-5 
 
Sentence revised to Linguistically validated translations of 
the ACQ-5 into local languages will be used (removed 
with results transcribed into the eCRF). 
 
5.1.3 Asthma Control Questionnaire-7 
 
Sentence revised to Linguistically validated translations of 
the ACQ-7 into local languages will be used (removed 
with results transcribed into the eCRF). 
 
5.1.6.1 Peak expiatory flow 
 
Modified to record 3 PEF measures from the best of at 
least 3. 
 
5.1.6.3 eDiary Ventolin therapy use 
 
Added recommendation that subjects should not take more 
than 8 puffs of Ventolin per day and to contact the 
investigator if more than 8 puffs are needed.  
 
5.1.8.5 Treatment for severe asthma exacerbations 
 
Clarified that treatment for less than 3 days doesn’t 
constitute a severe asthma exacerbation except if the 
subject is hospitalized due to asthma. 
 
Table 4 Laboratory safety variables 
 
Updated urine pregnancy test timing, added PDV to list of 
abbreviations, and added a reference to section 3.9.  
6 Safety reporting and medical 
management 
6.3.7 Hy’s Law 
 
Updated that occurrences of AST and/or ALT ≥3×ULN 
combined with TBL ≥2×ULN may require IP 
suspension/discontinuation and study withdrawal and 
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Changes to Protocol Amendment 2 (Version 3.0)  
may need to be reported as SAEs. A reference to section 
3.9 was also added. 
 
6.3.8 COVID-19 adverse events 
 
Added to provide instructions on how to handle AEs 
related to the COVID-19 pandemic. 
7 Investigational product and other 
treatments 
7.2 Dose treatment regimens 
 
Updated that subjects should not take more than 8 puffs 
of Ventolin per day. 
 
7.5 Compliance 
 
Updated that Ventolin usage will be monitored during the 
study. 
 
7.8.1 Investigational product and Ventolin therapies 
 
Added Subjects on maintenance allergy immunotherapy 
(AIT) are allowed to continue their AIT; the new 
initiation of AIT during the study is not allowed.  
 
7.8.3 Prohibited medications 
 
Clarified the use of oral, parenteral, or rectal 
corticosteroids to include (except if required to treat 
asthma exacerbation).   
 
Added Montelukast, for any indication  
 
Dupilumab was added to the list of prohibited monoclonal 
or polyclonal antibodies and the use of intra-ocular 
monoclonal or polyclonal antibody therapy was clarified 
to be allowed.  
 
Clarified the use of beta2-adrenergic blockers including 
eye-drops specific cardio-selective beta-blockers in low 
daily doses, eg, metoprolol in doses up to 100 mg/d, are 
allowed. 
8 Statistical analysis 
8.2 Sample size estimate 
 
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Section  
Changes to Protocol Amendment 2 (Version 3.0)  
Added Section 8.2.1 to describe the initial assumptions for 
sample size estimates and Section 8.2.2 to describe the 
process for blinded sample size re-estimation. This re-
estimation resulted in updates to the number of adult and 
adolescent subjects randomized from 600 to 1000, the 
number of subjects within each treatment arm from 120 to 
200, and the number of subjects screened from 1000 to 
2000. The screen failure rate was updated from 40% to 
50%.  The potential increase in sample size cap was 
increased from 800 to 1300. 
 
Described processes for a second blinded sample size re-
estimation. 
 
8.5.1.1 Dual-primary efficacy endpoints 
 
Specified that baseline FEV1  will be taken as the average 
of the 60- and 30-minute pre-dose spirometry measures at 
randomization and not on or before randomization. 
 
8.5.2.2 Derivation of Asthma Control Questionnaire-7 
variables 
  
Added an exploratory endpoint for the 3 factor endpoint 
categorization (Improved, No change, Worsening) from 
baseline to Week 12. 
 
8.5.3.4 Derivation of peak expiratory flow 
 
The best of at least 5 PEF measurements was updated to at 
least 3 PEF measurements. 
 
8.6.1 Analysis of the dual-primary variable 
 
Clarified that primary comparisons will exclude the 
children (ages 4-11 years) and specified that the analysis 
will be repeated to include children, but will be 
considered a supportive analysis of the dual-primary 
endpoint.   
 
Added supportive analysis of participants randomized 
according to actual strata they were allocated to. 
 
8.6.4.5 Asthma Control Questionnaire-5 variables 
 
Added exploratory analysis of the 3-factor categorization 
endpoint for ACQ-7. 
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Section  
Changes to Protocol Amendment 2 (Version 3.0)  
 
8.6.7.3 COVID-19 pandemic impacts 
 
Added to describe statistical methods that will be used to 
evaluate the impact of the COVID-19 pandemic on 
efficacy and safety variables. 
12 List of References 
Added reference to the American Academy of Allergy 
Asthma and Immunology for information regarding 
COVID-19 and Asthma. 
Appendix E, Hy’s Law 
Indicated when subjects with elevated liver enzymes will 
be suspended from or discontinued from IP.  
 
Updated definitions of potential Hy’s Law and Hy’s Law. 
Appendix L, COVID-19 emergency 
measures permitted to ensure 
subject safety 
Added processes to ensure subject safety during the 
COVID-19 pandemic. Instructions for management of 
subjects with or suspected COVID-19 infection, delayed 
visits, remote visits, subject discontinuation, shipment of 
study drug to subjects, laboratory testing, and spirometry 
testing are provided. 
 
11.2 
Changes to protocol amendment 1 (Version 2.0)  
Section 
Changes to Protocol Amendment 1 (Version 2.0) 
Clinical Study Protocol Synopsis 
Administrative change. 
Clarification provided on the target subject population. 
Clarification on Sponsor-provided IP dose frequency 
(QID). 
4.0 Study plan and timing of 
procedures 
Administrative changes.     
Table 1: Addition of and adjustments to 
table/footnote(s) to confirm that new IP will be 
dispensed and used for FEV1 measurements and that at 
Visit 6 and PDV, IP will be dispensed for the purposes 
of completing FEV1 measurements but will not be taken 
home by the subjects.  
Table 2: Table title updated to Timed assessments at 
Visit 2 through Visit 6 and Premature Discontinuation 
Visit. 
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Adjustments to the table to clarify drug dispensing and 
dose timing.  
4.2 Randomization/treatment period  
Clarification and instructions regarding proper IP 
preparation, dispensing, and dosing for post-dose 
assessments (ie, new IP in relation to FEV1) at each in-
clinic dosing visit.  
Addition of new recommendation for opening the seal 
around the study day treatment box. 
4.3 Treatment discontinuation 
Addition of dispensation of IP (for spirometry only) and 
dosing to procedures carried out during PDV visit. 
5.0 Study assessments 
 
5.1.1 Lung function measurement by spirometry 
Administrative changes including clarification that IP 
should be dosed before 10:00 AM in all in-clinic dosing 
visits. 
5.1.1.1 Reversibility test 
Clarification that pre- and post-dose FEV1 measurements 
are in relation to Sponsor-provided bronchodilator 
(Ventolin). 
5.1.6 eDiary 
Administrative changes. 
5.2.3 Vital signs measurements 
Removal of supine as position for measuring blood 
pressure. 
7.8 Concomitant medications and 
other treatments 
 
7.8 Concomitant medications and other treatments 
Addition of medications to the title. 
7.8.1 Investigational product and Ventolin therapies 
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Clarification on Sponsor-provided IP dose frequency 
(dosed QID). 
7.8.3 Prohibited medications 
Correction of naming for cytochrome P450 3A4 
inhibitors. 
 
 
12 
LIST OF REFERENCES 
1. American Academy of Allergy Asthma and Immunology (AAAAI). COVID-19 and 
Asthma: What Patients Need to Know. 04 Jun 2020. Accessed 19 Jun 2020. 
https://www.aaaai.org/conditions-and-treatments/library/asthma-library/covid-asthma. 
2. Bond Avillion 2 Development LP, 2018. Investigator’s Brochure. Budesonide/Albuterol 
Sulfate Pressurized Inhalation Suspension (BDA MDI, PT027); Budesonide Pressurized 
Inhalation Suspension (BD MDI, PT008); Albuterol Sulfate Pressurized Inhalation 
Suspension (AS MDI, PT007). 
3. 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. 
4. Corren J. Summary information for inhaled corticosteroid and long-acting β2-adrenergic 
agonist combination product use in patients in the united states who have asthma or chronic 
obstructive pulmonary disease. Clin Ther. 2007;29:823-843. 
5. Global Initiative for Asthma. Global strategy for asthma management and prevention. 2018. 
Available from: http://ginasthma.org/2018-gina-report-global-strategy-for- asthma-
management-and-prevention/. 
6. Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in 
a disease-specific quality of life questionnaire. J Clin Epidemiol. 1994;47(1):81-87. 
7.  Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med. 
2005;99(5):553-558. 
8. Kerwin E, Barnes N, Gibbs M, et al. Fluticasone furoate/vilanterol once daily improves 
night-time awakenings in asthma patients with night symptoms; post-hoc analyses of three 
randomized controlled trials. J Asthma. 2017; Epub ahead of print. DOI: 
10.1080/02770903.2017.1362429. 
9. Kavuru M, Melamed J, Gross G, Laforce C, House K, Prillaman B, et al. Salmeterol and 
fluticasone propionate combined in a new powder inhalation device for the treatment of 
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asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 
2000;105(6 Pt 1):1108-1116. 
10. 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. 
11. 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.  
12. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. 
Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338.  
13. Noonan M, Rosenwasser L, Martin P, O’Brian C, and O’Dowd. Efficacy and safety of 
budesonide and formoterol in one pressurised metered-dose inhaler in adults and 
adolescents with moderate to severe asthma. Drugs. 2006;66:2235-2254. 
14. O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, et al. 
Budesonide/formoterol combination therapy as both maintenance and reliever medication 
in asthma. Am J Respir Crit Care Med. 2005;171(2) 129-136. 
15. O'Byrne PM. Acute asthma intervention: insights from the STAY study. J Allergy Clin 
Immunol. 2007;119(6):1332-1336. 
16. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in 
combination with formoterol for reliever therapy in asthma exacerbations: a randomized 
controlled, double-blind study  Lancet. 2006;368(9537):744-753. 
17. Tattersfield AE, Postma DS, Barnes PJ, Svensson K, Bauer CA, O’Byrne PM, et al. 
Exacerbations of asthma:  a descriptive study of 425 severe exacerbations. The FACET 
International Study Group. Am J Respir Crit Care Med. 1999;160(2):594-599. 
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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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Triamcinolone acetonide 
400-800 
>800-1200 
>1200 
Abbreviations: CFC=chlorofluorocarbon propellant; DPI=dry powder inhaler; HFA=hydrofluoroalkane 
propellant; NA=not applicable 
a 
Beclometasone dipropionate CFC is included for comparison with other literature. 
 
Low Daily Doses of Inhaled Corticosteroids for Children 5 Years and Younger 
DRUG 
Low daily dosage (µg) 
(age group with adequate safety and effective data) 
Beclometasone dipropionate (HFA) 
100 (ages ≥5 years) 
Budesonide nebulized 
500 (ages ≥1 year) 
Fluticasone propionate (HFA) 
100 (ages ≥4 years) 
Mometasone furoate 
110 (ages ≥4 years) 
Budesonide pMDI + spacer 
Not sufficiently studied in this age group 
Ciclesonide 
Not sufficiently studied in this age group 
Triamcinolone acetonide 
Not sufficiently studied in this age group 
Abbreviations: HFA=hydrofluoroalkane propellant; pMDI=pressurized metered-dose inhaler 
 
 
 
 
 
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APPENDIX D, ADDITIONAL SAFETY INFORMATION 
Further guidance on the definition of a serious adverse event 
 
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 an AE occurred in a more severe form, 
it might have caused death (eg, hepatitis that resolved without hepatic failure). 
 
Hospitalization 
Outpatient 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. 
 
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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: 
• 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? 
• De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
• No alternative cause. The AE cannot be reasonably explained by another cause such as 
the underlying disease, other drugs, and other host or environmental factors. 
• Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? The Sponsor would not normally recommend or support a 
re-challenge. 
• 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 after 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 judgement. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated because of lack of 
effect should be classified as no reasonable possibility. 
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APPENDIX E, HY’S LAW 
Introduction 
This Appendix describes the process to be followed to identify and appropriately report cases 
of Hy’s Law. It is not intended to be a comprehensive guide to the management of elevated 
liver biochemistries.   
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. In subjects who have elevated liver enzymes AST and/or ALT ≥ 3×ULN and 
total bilirubin ≥ 2×ULN, IP will be suspended until the liver test values return to the normal 
range. If the AST, ALT, or total bilirubin reach these elevated levels again, after 
recommencement of IP, the subject will be discontinued from IP and withdrawn from the 
study. The investigator is responsible for determining whether a subject meets potential Hy’s 
Law criteria at any point during the study. 
The investigator participates, with the Sponsor’s clinical project representatives, in review and 
assessment of cases meeting potential Hy’s Law (PHL) criteria to agree whether Hy’s Law 
(HL) criteria are met. Hy’s Law criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than drug induced liver injury caused by the IP.  
The investigator is responsible for recording data pertaining to potential HL/HL cases and for 
reporting AEs and SAEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
Definitions 
Potential Hy’s Law  
Aspartate aminotransferase and/or alanine transaminase ≥3× ULN combined with TBL 
≥2×ULN at any point during the study after the start of IP irrespective of an increase in 
alkaline phosphatase.  
Hy’s Law 
AST and/or ALT ≥3×ULN combined with TBL ≥2×ULN, where no other reason, other than 
the IP, can be found to explain the combination of increases, eg, elevated alkaline phosphatase 
indicating cholestasis, viral hepatitis, or another drug.   
For potential HL and HL, the elevation in transaminases must precede or be coincident with 
(ie, on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur. 
Identification of potential Hy’s Law cases 
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To identify cases of PHL it is important to perform a comprehensive review of laboratory data 
for any subject who meets any of the following identification criteria in isolation or in 
combination: 
• ALT ≥3×ULN 
• AST ≥3×ULN 
• TBL ≥2×ULN 
When a subject meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the investigator and the medical monitor 
assigned to the project.  
The investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met; where this is the case, the investigator will: 
- 
Notify the medical monitor assigned to the project. 
- 
Request a repeat of the test (new blood draw) by the central laboratory. 
- 
Contact the medical monitor to discuss the elevated local laboratory values and 
whether these constitute an AE. Where an AE is entered due to elevations of local 
laboratory values, the AE will be queried in the eCRF and elevated local laboratory 
values, units and ranges will be entered to the query response. 
- 
When the identification criteria are met from central or local laboratory results, the 
investigator will without delay: 
- 
Determine whether the subject meets PHL criteria by reviewing laboratory 
reports from all previous visits (including both central and local laboratory 
results). 
- 
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met, will: 
- 
Notify the medical monitor assigned to the project. 
- 
Determine whether the subject meets PHL criteria by reviewing laboratory 
reports from all previous visits. 
- 
Promptly enter the laboratory data into the laboratory eCRF. 
Follow-up 
Potential Hy’s Law criteria not met 
If the subject does not meet PHL criteria the investigator will: 
Inform the medical monitor assigned to the project that the subject has not met PHL criteria. 


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Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol. 
Potential Hy’s Law criteria met 
If the subject does meet PHL criteria, the investigator will: 
Determine whether PHL criteria were met at any study visit before starting IP (Actions 
required when potential Hy’s Law criteria are met before and after starting IP) 
Notify the medical monitor assigned to the project who will then inform the central study team  
The medical monitor assigned to the project will discuss the issue with the investigator to 
provide guidance and agree an approach for the study subjects’ follow-up and the continuous 
review of data. Subsequent to this contact the investigator will: 
Monitor the subject until liver biochemistry parameters and appropriate clinical symptoms and 
signs return to normal or baseline levels, or as long as medically indicated  
Investigate the cause of the event and perform diagnostic investigations as discussed with the 
medical monitor assigned to the project. For studies using a central laboratory add: This 
includes deciding which the tests available in the HL laboratory kit should be used.  
Complete the 3 Liver eCRF modules as information becomes available  
If at any time (in consultation with the medical monitor assigned to the project) the PHL case 
meets serious criteria, report it as an SAE using standard reporting procedures. 
Review and assessment of potential Hy’s Law cases 
No later than 3 weeks after the biochemistry abnormality was initially detected, the medical 
monitor assigned to the project contacts the investigator to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than drug induced 
liver injury caused by the IP. The medical monitor assigned to the project and global safety 
physician will also be involved in this review with other subject matter experts, as appropriate.   
According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE: 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
If the alternative explanation is an AE/SAE, record the AE/SAE in the eCRF accordingly and 
follow the Sponsor’s standard processes 


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
Report an SAE (report term ‘Hy’s Law’) according to the Sponsor’s standard processes.  
− 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply. 
− 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
Report an SAE (report term ‘potential Hy’s Law’) applying serious criteria and causality 
assessment as per above 
Continue follow-up and review according to agreed plan. Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria 
are met. Update the SAE report according to the outcome of the review amending the reported 
term if an alternative explanation for the liver biochemistry elevations is determined. 
Actions required when potential Hy’s Law criteria are met before and after starting IP  
This section is applicable to subjects who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit before starting IP. 
At the first on study treatment occurrence of PHL criteria being met the investigator will: 
Determine if there has been a significant change in the subjects’ condition compared with the 
last visit where PHL criteria were met 
− 
If there is no significant change no action is required. 
− 
If there is a significant change, notify the Sponsor representative, who will inform the 
central study team, then follow the subsequent process described in Potential Hy’s 
Law criteria met of this Appendix. 
 
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor assigned to the project if there is any 
uncertainty. 


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Actions required for repeat episodes of potential Hy’s Law 
This section is applicable when a subject meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.   
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study or did the subject meet PHL criteria before starting study treatment 
and at their first on study treatment visit as described in Actions required when potential Hy’s 
Law criteria are met before and after starting IP. 
If No: follow the process described in Potential Hy’s Law criteria met of this Appendix. 
If Yes: 
Determine if there has been a significant change in the subject’s condition compared with 
when PHL criteria were previously met 
If there is no significant change, no action is required 
If there is a significant change: 
A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator; this 
may be in consultation with the medical monitor assigned to the project if there is any 
uncertainty. 
 






























































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APPENDIX K, SPIROMETRY ASSESSMENT CRITERIA  
Acceptable Versus Usable Tests 
Acceptable Tests must meet the following Criteria: 
1. Acceptable start of exhalation with brisk upstroke, no hesitation or false start, and back 
extrapolation volume  <5% of forced vital capacity (FVC) or 0.150 L, whichever is the 
greater (see example in Figure  1) 
2. No cough during the first second 
3. No valsalva maneuver 
4. No leak 
5. No obstruction of mouthpiece 
6. No extra breaths 
7. Plateau achieved: ie, the volume-time curve shows no change in volume (<0.025 L) for 
≥1second, and the subject has tried to exhale for at least 6 seconds 
 
An acceptable test meets all 7 criteria listed. This is to be considered the “gold standard”. 
Usable spirometry tracings are those that only meet criteria 1 and 2. When this occurs, repeat 
testing up to 8 attempts for pre-dose and 5 attempts for post-dose assessments, in an effort to 
obtain 3 acceptable spirograms. If only usable tests are obtained, report results based on the 
3 best usable trials with observed limitations. 
Figure 1 
Example of a Usable Spirogram 
 
EV=back extrapolation volume 
 


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The expanded version of the early part of a subject’s volume-time spirogram, illustrating back 
extrapolation through the steepest part of the curve, where flow is PEF rate, to determine the 
new “time zero”. Forced vital capacity -4.291 L; EV – 0.123 L (2.9% FVC):  back 
extrapolation line through peak expiratory flow. 
Between-Maneuver Reproducibility Criteria 
Pre-dose Assessments 
After 3 acceptable spirograms have been obtained, apply the following tests: 
• The 2 largest values of FVC must be within 0.150 L of each other 
• The 2 largest values of FEV1 must be within 0.150 L of each other 
 
If these criteria are met, the spirometry testing for that time point may conclude, however, if 
possible, please continue collecting additional spirograms to a maximum of 8 pre-dose and 
5 post-dose attempts. The highest FEV1 and the highest FVC obtained at each testing time 
point (even if from different reproducible tracings), will be collected. 
If acceptability criteria are not met, continue testing until they are met, or the subject cannot/ 
should not continue (maximum of 8 attempts). 
Post-dose Assessments 
• 
After 2 acceptable spirograms have been obtained, apply the following tests: 
• 
The 2 largest values of FVC are within 0.150 L of each other and/or 
• 
The 2 largest values of FEV1 are within 0.150 L of each other 
 
If these criteria are met, the spirometry testing for that time point may conclude. The highest 
FEV1 and the highest FVC obtained at each testing time point (even if from different 
reproducible tracings), will be collected. 
If acceptability/reproducibility criteria are not met, continue testing until they are met, or the 
subject cannot/ should not continue (maximum of 5 attempts). 
 
 


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APPENDIX L, COVID-19 EMERGENCY MEASURES PERMITTED TO ENSURE 
SUBJECT SAFETY 
The following activities were 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. 
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 site staff or enables an 
on-site subject visit.  
• If a return to lockdown is announced or the site is on lockdown 
and cannot process a visit, if possible, visits should be 
rescheduled to earlier/later as required to safeguard subjects 
and site staff.   
• Randomization:  If a subject is in screening and cannot 
complete the randomisation visit within 28 days due to local 
COVID-19 lockdown restrictions, the screening period may be 
extended to a maximum of 9 weeks. In the event of an 
extension to the screening period >28 days due to COVID, the 
following safety measurements should be repeated in advance 
of randomisation: safety laboratory assessments, ECG, vital 
signs, concomitant medications, and medical/surgical history.   
• Visit 6/Week 24:  All efforts should be made to complete the 
associated assessments in the clinic, even if this is visit is 
delayed. If necessary, while waiting for the time to complete 
this visit, an unscheduled call and drug dispensing should be 
done to ensure the subject has sufficient IP during this time. 


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Remote Visits  
• Where subjects have COVID-19 infection or infectious, the site 
is on lock down, local restrictions prohibit attendance, or 
similar, a telephone visit should be completed. All assessments 
performed should be documented in the same way they would 
if the visit would have happened on-site.  
• Before performance of a remote visit, verbal consent must be 
obtained and documented in the subject’s medical notes to 
ensure that the subject understands the implications of 
continuing in the study when face to face visits are temporarily 
not possible due to COVID 19 restrictions. Where possible, the 
Principal Investigator should ask the subject to confirm their 
agreement in writing either by email or via a letter. Where 
multiple in-clinic visits will be missed, written consent of the 
subject will be required.   
• If a remote visit is completed and it is considered appropriate 
and safe to continue study drug, this could be dispatched direct 
to the subject by courier.   
• Randomization visits cannot be conducted remotely and 
therefore subjects in screening who do not wish to attend an 
on-site visit should be screen-failed as 'withdrawal of consent'. 
Subject 
Discontinuation 
• Where repeated visits are likely to be missed, the site should 
discuss with the subject and consider ongoing treatment 
options. Where a subject does not wish to attend further clinic 
visits, a PDV visit should be scheduled. 
Shipment of Drug 
from Site to Subjects 
 
• Subjects should provide verbal consent via a telephone call to 
use their personal details to complete the site to subject 
shipment request. Consent must be documented in the subject 
medical records and preferably confirmed in writing via an 
email or other written means (eg, via post) via a phone call 
initially and followed up by written consent at the earliest 
possibility. 
Safety Labs 
• Where central analysis is not possible, local testing is 
permitted. Lab normal ranges would need to be made available. 


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• In the event that routine safety lab tests are missed due to 
temporary inability of subject to get to site due to COVID-19, 
an unscheduled lab should be done at their next clinic visit if 
possible.  
Spirometry  
• The investigator should request confirmation from the subjects 
to confirm that they are not aware of having been exposed to 
COVID-19 that they are not currently infected or infectious, 
and should exercise their medical judgement with respect to 
this information prior to conducting spirometry assessments.  
Sites should continue to follow hygiene and cleaning guidance 
within the manuals to minimize possible cross-contamination.   
Subjects with 
Confirmed COVID-
19 Infection 
• If a subject has confirmed COVID-19 this is to be reported as 
an AE/SAE, but is not per se a reason to withdraw the subject. 
• The investigator should determine whether the subject’s IP 
should continue, be interrupted, or stopped in accordance with 
the Clinical Study Protocol. 
• 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 once the infection has resolved and the subject is no 
longer considered to be infectious. 
• 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 4 
weeks after having a negative result. 
 

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Statistical Analysis Plan 
Study Code 
AV004 
Edition Number 
3.0 
Date 
28/07/2021 
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1. 
STUDY DETAILS ............................................................................................... 10 
1.1 
Study objectives .................................................................................................... 10 
1.1.1 
Primary objective .................................................................................................. 10 
1.1.2 
Secondary objective .............................................................................................. 10 
1.1.3 
Safety objective .................................................................................................... 10 
1.1.4 
Exploratory objective............................................................................................ 11 
1.2 
Study design ......................................................................................................... 11 
1.3 
Number of subjects ............................................................................................... 20 
1.3.1 
Sample Size Calculation ....................................................................................... 20 
2. 
ANALYSIS SETS ................................................................................................ 22 
2.1 
Definition of analysis sets ..................................................................................... 22 
2.1.1 
Full analysis set..................................................................................................... 22 
2.1.2 
Safety analysis set ................................................................................................. 22 
2.1.3 
All patients enrolled .............................................................................................. 23 
2.2 
Protocol deviations ............................................................................................... 23 
3. 
DEMOGRAPHY AND SUBJECT CHARACTERISTICS VARIABLES .......... 23 
3.1 
Demographics ....................................................................................................... 23 
3.2 
Medical, asthma and smoking history .................................................................. 24 
3.3 
Concomitant medications ..................................................................................... 25 
3.4 
Spirometry at study entry...................................................................................... 25 
4. 
PRIMARY AND SECONDARY VARIABLES ................................................. 25 
4.1 
General Definitions ............................................................................................... 25 
4.1.1 
Definition of baseline ........................................................................................... 25 
4.1.2 
Absolute and percent change from baseline ......................................................... 25 
4.1.3 
Reversibility .......................................................................................................... 26 
4.1.4 
Study day calculation ............................................................................................ 26 
4.1.5 
Visit windowing ................................................................................................... 26 
4.1.6 
Daily eDiary variables .......................................................................................... 28 
4.1.7 
Treatment average ................................................................................................ 29 
4.1.8 
Imputation rules .................................................................................................... 29 
4.1.9 
Spirometry assessments ........................................................................................ 30 
4.1.10 
Derived stratification factors for patients aged 4 to 11 years ............................... 30 
4.2 
Treatment exposure .............................................................................................. 31 
4.3 
Primary Efficacy Measure .................................................................................... 31 
4.3.1 
Dual-primary efficacy endpoints .......................................................................... 31 
4.3.2 
Derivation for FEV1 AUC0-6 hours .......................................................................... 31 
4.3.3 
Derivation for trough FEV1 .................................................................................. 32 
4.4 
Secondary Efficacy Measures............................................................................... 32 
4.4.1 
Derivation for time to onset (15% increase in FEV1) on Day 1 and duration of 
effect on Day 1...................................................................................................... 32 
4.4.2 
Derivation of Trough FEV1 at Week 1 ................................................................. 33 
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4.4.3 
Derivation of Asthma Control Questionnaire-7 variables .................................... 33 
5. 
EXPLORATORY EFFICACY MEASURES ...................................................... 33 
5.1 
Derivation of severe exacerbation endpoints ........................................................ 33 
5.2 
Derivation of deterioration of asthma variables ................................................... 34 
5.3 
Derivation of peak FEV1 ...................................................................................... 35 
5.4 
Derivation of peak expiratory flow....................................................................... 35 
5.5 
Derivation of Asthma Control Questionnaire  7 exploratory variables .............. 36 
5.6 
Derivation of Asthma Control Questionnaire  5 variables ................................. 37 
5.7 
Derivation of Asthma Quality of Life Questionnaire + 12 and Pediatric 
Asthma Quality of Life Questionnaire variables .................................................. 37 
5.8 
Derivation of Ventolin therapy variables ............................................................. 37 
5.9 
Derivation of other eDiary variables .................................................................... 38 
5.10 
Safety variables ..................................................................................................... 40 
5.10.1 
Vital signs ............................................................................................................. 40 
5.10.2 
Adverse events (including Serious Adverse Events) ............................................ 40 
5.10.3 
Laboratory Safety Variables ................................................................................. 42 
5.10.4 
Resting 12-lead electrocardiogram ....................................................................... 44 
5.11 
Other variables ...................................................................................................... 44 
5.11.1 
Concomitant medications ..................................................................................... 44 
5.11.2 
Discontinuation of investigational product ........................................................... 45 
5.11.3 
Study Withdrawal ................................................................................................. 46 
5.11.4 
Screen Failures...................................................................................................... 46 
5.11.5 
Compliance of study medication .......................................................................... 46 
6. 
ANALYSIS METHODS ...................................................................................... 47 
6.1 
Statistical Considerations...................................................................................... 47 
6.1.1 
Estimands .............................................................................................................. 47 
6.1.2 
Discontinuation of randomized treatment due to lack of efficacy ........................ 48 
6.1.3 
Type I error control ............................................................................................... 48 
6.2 
Analysis methods .................................................................................................. 48 
6.2.1 
Subject Disposition ............................................................................................... 49 
6.2.2 
Demographic and Baseline Characteristics .......................................................... 49 
6.2.3 
Treatment Exposure .............................................................................................. 50 
6.2.4 
Analysis of the dual-primary endpoints ................................................................ 50 
6.2.5 
Analysis of the secondary efficacy variables........................................................ 53 
6.2.6 
Analysis of safety variables .................................................................................. 54 
6.2.7 
Analysis of exploratory variables ......................................................................... 56 
6.2.8 
Subgroup analysis ................................................................................................. 60 
6.2.9 
Supportive analysis ............................................................................................... 62 
6.2.10 
COVID-19 impacts ............................................................................................... 66 
7. 
HANDLING OF DUPLICATE PATIENTS ........................................................ 69 
8. 
CHANGES OF ANALYSIS FROM PROTOCOL .............................................. 70 
8.1 
Baseline derivation ............................................................................................... 70 
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8.2 
Changes to the primary analyses .......................................................................... 70 
8.3 
Stratification factors recorded at randomisation ................................................... 70 
8.4 
Time to onset and duration of response FEV1 endpoints ..................................... 70 
8.5 
Exploratory analysis of ACQ-5 and ACQ-7 Changes from baseline ................... 70 
8.6 
Additional subgroup analyses ............................................................................... 71 
8.1 
COVID-19 impacts ............................................................................................... 71 
9. 
REFERENCES ..................................................................................................... 72 
 
 
 
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AMENDMENT HISTORY 
Date (version) 
Brief description of change 
16th March 2021 
(V2.0) 
Included text on decision following the second blinded sample size reassessment 
(section 1.3.1.3). 
 
In order to support the integrated summary of safety analyses, the total daily number 
of puffs of randomized treatment, grouped by actual treatment received and based on 
the safety analysis set will be displayed in summaries of exposure (see section 6.2.3). 
 
In order to support the integrated summary of safety analyses, additional adverse 
events summary tables will now be reported with incidence rates/event rates, as 
appropriate (see section 6.2.6.1). 
 
In order to support the integrated summary of safety, summaries of adverse events and 
serious adverse events will be reported within subgroups specified in section 6.2.8.2. 
 
Clarification added to section 6.2.7.11 for exploratory endpoints of night-time 
awakenings and asthma symptom score. 
28th July 2021 
(V3.0) 
Added the COVID-19 estimand. 
 
Added supportive analysis to the primary endpoint where the data collected following 
the onset of a COVID-19 related adverse event or dose interruption are excluded from 
the analysis. 
 
Derivation of stratification factors for patients aged 4 to 11 years added. 
 
Detailed methodology for handling duplicate patients. 
 
Clarified how the analyses populations will be used when making treatment group 
comparisons in sections 2.1, 6.2.5 and 6.2.7. 
 
 
 
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1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective 
Primary objective: 
Primary endpoint: 
To demonstrate the contribution of budesonide 
and albuterol in BDA MDI 
QID by comparing with 
mono-components (BD MDI 160 
, AS MDI 180 
) and placebo on lung function 
Dual-primary endpoints: 
Change from baseline in FEV1 AUC0-6 hours 
over 12 weeks  
Change from baseline in trough FEV1 at 
Week 12 
 
1.1.2 
Secondary objective 
Secondary objective: 
Secondary endpoint: 
To characterize the effect of BDA MDI 
QID on 
bronchodilation and asthma symptoms compared 
to the mono-components (BD MDI 160 
, AS 
MDI 180 
) and placebo 
The time to onset (defined as 15% increase in 
FEV1 over the pre-treatment value on Day 1), 
and duration of response on Day 1  
Number (%) of subjects who have an Asthma 
Control Questionnaire-7 (ACQ-
at baseline who achieve a clinically meaningful 
improvement (a decrease of at least 0.5 units 
from baseline) in ACQ-7 at Week 12 
Trough FEV1 at Week 1 
 
1.1.3 
Safety objective 
Safety objective: 
Safety endpoints: 
To evaluate the safety and tolerability of BDA 
MDI 
 (180 
 
Adverse events (AE) / serious adverse events 
(SAE) 
Vital signs (i.e., heart rate, blood pressure only) 
Clinical chemistry and hematology parameters 
Electrocardiogram (ECG) 
 
 
 
 
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See Figure 1 for a graphical presentation of the study schema, Table 1 for a list of study 
assessments and Table 2 for timed assessments at Visit 2 through to Visit 6. 
Subjects meeting all entry criteria at the screening visit (Visit 1) will enter a 14- to 28-day 
screening (run-in) period.  
Only Sponsor-provided investigational product (IP) and Sponsor-provided Ventolin to be used 
in response to asthma symptoms are allowed during the study. No other asthma medications 
are allowed during the study. 
During the screening (run-in) period, subjects will self-administer single-blind placebo 
metered-dose inhaler (Placebo MDI) QID and Ventolin prn for asthma symptoms only. 
Subjects will be trained and instructed in the use of an electronic diary (eDiary) and peak flow 
meter at Visit 1 to record protocol required data into the eDiary twice daily. Eligible subjects 
will be randomized at Visit 2.   
A randomization schedule will be generated by a designated statistical representative 
performing statistical support for the study. This schedule will be prepared before the start of 
the treatment period. Randomization for adults and adolescents will be centralized and 
stratified by pre-study background therapy consisting of either ICS or non-ICS (subjects not 
previously treated with ICS), by Asthma Control Questionnaire-7 (ACQ-
 
At randomization 
(Visit 2), adult and adolescent 
randomly assigned to 1 of the following 5 treatment groups in a 1:1:1:1:1 ratio:  
 
 
 
 
Placebo MDI QID (given as 2 actuations) 
 
Children aged 4 to 11 will be randomized in a 1:1:1 ratio only to the lower BDA MDI QID 
dosage, AS MDI QID, or placebo MDI QID. 
 
The maximum daily dosage of randomized treatment should not exceed 12 puffs per day. 
 
 
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The study will consist of 3 periods:  
Screening and run-in period (14 to 28 days).  
12-week treatment period.  
Safety follow-up period: where a safety follow-up telephone contact will occur 2 weeks 
(±4 
-of-treatment [EOT]) or premature 
discontinuation visit (PDV). 
 
The treatment duration of 12 weeks has been set for each of the subjects, as this is an 
appropriate duration of time to evaluate lung function benefit in asthma subjects.  
 
Dual-primary efficacy measures have been selected to demonstrate the therapeutic 
contribution of each component of the combination to the overall bronchodilator efficacy: 
Change from baseline in FEV1 AUC0-6 hours over 12 weeks  
Change from baseline in trough FEV1 at Week 12  
 
The end-of-study is defined as the last visit of the last subject undergoing the study, therefore 
will occur when the last subject has completed his or her post study follow-up telephone 
contact (TC). Subjects who discontinue randomized treatment will complete a PDV, and 
AE/SAE will be followed up if medically indicated. 
 
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Figure 1: Study design 
 
 
Abbreviations:  AS MDI=albuterol metered-dose inhaler; BD MDI=budesonide metered-dose inhaler; 
BDA MDI=budesonide/albuterol metered-dose inhaler; N=number; Placebo MDI=placebo metered-dose inhaler; PRN=as 
needed; QID=four time daily; R=randomization; SV=screening visit; W=week. 
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Table 1 Study Assessments and Procedures 
 
 
Screening (run-in)b 
Double-blind Treatment Period 
PDVd  
(if 
applicable) 
Safety Follow-up TC 
Visit a 
1 (1/1a) 
2 
3 
4 
5 
6c 
 
(2 weeks [±4 days] after 
treatment discontinuation) 
Week  
-4 to -2 
0 
1 
4 
8 
12 
Day 
-28 to -14 
1 
7±2 
28±2 
56±2 
84±2 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
Routine clinical procedures 
Medical/surgical history 
(including any on-study 
medical/surgical procedures)e 
X 
X 
X 
X 
X 
X 
X 
 
Demography  
X 
 
 
 
 
 
 
 
Physical examinationf 
X 
 
 
 
 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
SABA reversibility testg 
X 
 
 
 
 
 
 
 
Safety measurements 
Vital signs (HR and BP only) 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
X 
 
 
 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testh 
X 
X  
X 
X  
X 
X 
X  
 
Safety laboratory assessments 
(clinical chemistry, hematology) 
X 
 
 
 
 
X 
X 
  
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Screening (run-in)b 
Double-blind Treatment Period 
PDVd  
(if 
applicable) 
Safety Follow-up TC 
Visit a 
1 (1/1a) 
2 
3 
4 
5 
6c 
 
(2 weeks [±4 days] after 
treatment discontinuation) 
Week  
-4 to -2 
0 
1 
4 
8 
12 
Day 
-28 to -14 
1 
7±2 
28±2 
56±2 
84±2 
 
 
Efficacy measurements 
Spirometry (FEV1)i 
X 
X 
X 
X 
X 
X 
X 
 
ACQ-5 
X 
X 
X 
X 
X 
X 
X 
 
ACQ-7 
X 
X 
X 
X 
X 
X 
X 
 
AQLQ+12/PAQLQ 
 
X 
 
X 
X 
X 
X 
 
Review of PEF, use of Ventolin 
therapy, asthma daytime/night-
time symptoms, night-time 
awakenings due to asthma 
symptomsj 
 
X 
X 
X 
X 
X 
X 
 
Dispense/collect eDiary (AM3+) 
X 
 
 
 
 
X 
X 
 
Review compliance with eDiary 
 
X 
X 
X 
X 
X 
X 
 
Investigational product administration 
IP compliance 
 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
IP (dispense/collect)k 
d 
c/dk 
c/d 
c/d 
c/d 
c/dn 
c/dn 
 
Ventolin (collect/dispense) 
d 
c/dl 
c/dl 
c/dl 
c/dl 
c 
c 
 
IP administration (recorded in 
MasterScope)m 
X 
X 
X 
X 
X 
X 
X 
 
 
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Table 2 Timed assessments at Visit 2 through Visit 6 
 
 
r
 
 
 
 
6  
 
 
 
 
n 
 
 
 m n 
 
 
 
 
 mi  
 
 
1
 
n 
 
 
 
 
 
 
IP Collectionh 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
IP Dispensingi 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
IP Dosingi 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Questionnaires 
ACQ-5 
ACQ-7 
AQLQ+12/PAQLQ 
Xa,b 
 
 
 
 
 
 
 
 
 
 
 
 
Review of Electronic Diary 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsc 
Xa,d 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
Xa,e 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Testing 
Xa, f 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry (FEV1)g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ACQ-7=Asthma Control Questionnaire 7, AQLQ+12= Asthma Quality of Life Questionnaire for 12 years and older; ECG=electrocardiogram; FEV 1= forced 
expiratory volume in 1 second; IP=investigational product; min=minute; PAQLQ=Pediatric Asthma Quality of Life Questionnaire  
Note:  
When data collection time-points are concurrent, variables should be collected in the following order: Questionnaires, 
vital signs, ECG, clinical laboratory assessments, and spirometry. 
a. 
This is not a timed assessment.  Sites should plan to perform these activities to allow for collection of timed spirometry.   
b. 
Questionnaires (ACQ-5, ACQ-7, AQLQ+12, and PAQLQ) are collected at all visits (except Visit 3 AQLQ+12, and PAQLQ). 
c. 
Vital signs should be started (approximately 5 to 10 minutes) ahead of the specified time point to ensure spirometry will be conducted as close to the specified time points as 
possible. 
d. 
Pre-dose vital signs (heart rate, blood pressure) will be collected twice, at least 5 minutes apart. 
e. 
Pre-dose ECG will be collected at Visit 2, Visit 6, and PDV only, or as clinically indicated 
f. 
All clinical laboratory tests (hematology and chemistry) will be assessed approximately 60 minutes prior to dosing at Visit 6 in advance of first spirometry measurement. 
Laboratory tests may be performed at all other visits as clinically indicated. 
g. 
Every effort should be made to assess subjects pre-bronchodilator and post-dose FEV1 at the same time throughout the study). Pre- bronchodilator FEV1 will be measured in 
the mornings between 06:00 and 10:00 AM, and within 1 hour of FEV1 measured at Visit 2. From Visit 2 onwards, pre- and post-dose measurements will be with respect to 
administration of IP (Table 4). 
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h. 
At the start of each treatment visit, subjects must withhold all asthma medications, including Sponsor-provided Ventolin for at least 6 hours prior to start of test day 
procedures. 
i. 
Dispense IP to subject for at-home use following the completion of all post-dose assessments.  IP will not be dispensed at Visit 6. 
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1.3 
Number of subjects 
 4 years of age with a 
diagnosis of asthma as defined by Global Initiative for Asthma (GINA) criteria. To be eligible 
for the study they must have been taking a stable dosing of asthma therapies (prn SABA or 
stable low-dose ICS in addition to prn SABA) for at least the last 30 days prior to Visit 1.  
 
In line with the blinded sample size re-estimation (see section 1.3.1.2), the sample size of 
approximately 1000 adults and adolescent subjects with asthma will be randomized, with 
approximately 200 subjects per treatment group. In addition, up to 30 child subjects with 
asthma will be enrolled but will not receive high dose ICS and will be randomized 1:1:1 to 
receive low-dose BDA MDI 80/180 
Approximately 2000 subjects will need to be screened, assuming an estimated screen failure 
rate of 50% prior to randomization.  
 
Each subject must meet all the inclusion criteria and none of the exclusion criteria for this 
study. It must be noted that no study-related procedures may be performed before the subject 
has signed the Ethics Committee (EC) approved Informed Consent Form (ICF). 
1.3.1 
Sample Size Calculation 
1.3.1.1 
Initial assumptions and estimates 
A blinded sample size re-estimation was performed once 44% of subjects had completed week 
12.  Based on the blinded estimate of variability, approximately 1000 subjects are required in 
order to demonstrate at least 90% power. Consequently, the total randomised adult and 
adolescent subjects has been increased to 1000 in order to ensure sufficient power. This 
section details the initial assumptions of variability prior to calculating the blinded sample size 
re-estimation. Please refer to section 1.3.1.2 for details on the sample size and power 
calculations following the blinded sample size re-estimation. 
Prior to the blinded sample size re-estimation, randomization of approximately 120 subjects to 
each treatment group expected provide at least 93% probability to detect a 100 mL difference 
in the change from baseline in trough FEV1 at Week 12 for comparison of BD MDI versus 
placebo MDI, BDA MDI versus placebo MDI, or BDA MDI versus AS MDI. This calculation 
was based on a standard deviation of 210 mL obtained from the placebo MDI group of Study 
PT008001 and an assumed dropout rate of 10% and 15% for active and placebo treatment 
group, respectively, prior to Week 12. 
Prior to the blinded sample size re-estimation, it was assumed that the sample size of 120 
subjects per treatment group would also provide >99% probability to detect a 130 mL 
difference in FEV1 AUC0-6 hours over 12 weeks for comparison of BDA MDI versus BD MDI 
(effect sizes for AS MDI or BDA MDI versus placebo MDI should be considerably larger). 
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This calculation assumed a 2% dropout prior to Week 1 and an effective standard deviation of 
140 mL which was derived from the following: a per visit standard deviation of 200 mL 
(ProAir Respiclick Studies 301 and 304 and the AS MDI Dose-Ranging Study 
DC6930C00001), a correlation between visits of 65%, and projected subject completion of 
4 out of 5 visits. 
1.3.1.2 
Results from the first blinded sample size re-estimation 
Following the first blinded sample size re-estimation, randomization of approximately 200 
subjects 
 to each treatment group will provide 90% probability to detect a 
100 mL difference in the change from baseline in trough FEV1 at Week 12 for comparison of 
BD MDI versus placebo MDI, BDA MDI versus placebo MDI, or BDA MDI versus AS MDI. 
This calculation is based on a standard deviation of 290 mL obtained from the blinded sample 
size re-estimation performed after 44% of subjects completed week 12 and an estimated 
overall dropout rate of 11% prior to Week 12. 
Following the blinded sample size re-estimation, the sample size of 200 subjects 
 of 
age) per treatment group will also provide >99% probability to detect a 130 mL difference in 
FEV1 AUC0-6 hours over 12 weeks for comparison of BDA MDI versus BD MDI (effect sizes 
for AS MDI or BDA MDI versus placebo MDI should be considerably larger). This 
calculation assumes 2% dropout prior to Week 1 and an effective standard deviation of 290 
mL obtained from the blinded sample size re-estimation performed after 44% of subjects 
completed week 12. 
Approximately 1000 
and adolescent subjects (12 - 17 years of age, 
where approved) with asthma will be randomized 1:1:1:1:1 to 1 of 5 treatment groups 
(approximately 200 subjects per group: BDA MDI 80/180 
 QID
 
QID, 
AS MDI 180 
 QID, or placebo MDI). In addition, where 
approved, up to 30 child subjects (aged 4 to 11 years) with asthma will be enrolled but will not 
receive high dose ICS and will be randomized 1:1:1 to receive low-dose BDA MDI 80/180 
 
QID, AS MDI 
 QID, or placebo MDI. Approximately 2000 subjects will need to be 
screened, assuming an estimated screen failure rate of approximately 50% prior to 
randomization. This Phase III study is planned to be conducted globally. 
A second blinded sample size re-estimation will be performed once approximately 65% of the 
revised sample size has completed 12 weeks and prior to the last subject being randomized.  
This will allow the re-assessment of variability in a larger sample and at a point where any 
impact from COVID-19 with respect to lung function variability and dropout rates can be 
quantified more accurately. Final total enrolment in the study will be confirmed following the 
second blinded sample size re-calculation in order to ensure 90% power. 
Any further potential increase in sample size will be capped at 1300, a 30% increase above the 
revised 1000 subjects.  
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1.3.1.3 
Results from the second blinded sample size re-estimation 
Randomization of approximately 200 subjects 
 to each treatment group will 
provide 85% probability to detect a 100 mL difference in the change from baseline in trough 
FEV1 at Week 12 for the comparison of BD MDI versus placebo MDI, BDA MDI versus 
placebo MDI, or BDA MDI versus AS MDI. This calculation is based on a standard deviation 
of 320 mL obtained from the blinded sample size re-estimation performed after 65% of 
subjects completed week 12. An overall dropout rate of 7% prior to Week 12 was calculated 
from this data. 
Although the variability has slightly increased since the first blinded sample size estimation, 
the drop-out rate is lower than originally estimated. Whilst there is still at least 80% power, 
the sample size will not be further increased beyond 2000 subjects. 
2. 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
2.1.1 
Full analysis set 
The full analysis set (FAS) is defined as all subjects who are randomized, take at least 1 puff 
of randomized treatment and have at least one efficacy assessment. Subjects will be analyzed 
according to the treatment they were assigned to at randomization. Additionally, data 
suspected to be fraudulent will be reviewed on a case-by-case basis and may lead to exclusion 
from the full analysis set. Such exclusions will be fully documented and all data will be 
readily available in the SDTM and ADaM datasets.  
For primary, secondary and exploratory efficacy analyses, a subpopulation of the FAS 
including patients aged 12 years and older will be used to make comparisons between the 
treatment groups. All efficacy analyses will be repeated on the FAS including all ages. Further 
details are provided in Section 6. 
The efficacy and attributable estimand will include all data obtained before subjects 
discontinue randomized treatment, see section 6.1.1. 
2.1.2 
Safety analysis set 
 
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2.1.3 
All patients enrolled 
 
2.2 
Protocol deviations 
Important protocol deviations (IPDs) are defined as a subset of protocol deviations that may 
significantly affect the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a subject's rights, safety, or well-being. All protocol deviations classified 
as important will be listed along with the full deviation term and coded term as collected in the 
Protocol Deviations CRF page. The important deviations will be summarised in terms of the 
number and percentage of subjects meeting the pre-defined protocol deviation coded term as 
defined in the Protocol Deviations CRF page. IPDs will be identified by the sponsor prior to 
the primary database lock and unblinding of the study results. 
A per protocol analysis excluding subjects with important protocol deviations is not planned. 
However, any subjects or site activity identified or suspected to be fraudulent (e.g. subjects 
who are enrolled on this clinical study more than once or another interventional clinical study, 
subjects re-enrolling onto the study or fabricated data) will be excluded from the analysis 
populations defined in section 2.1. Such instances will be reviewed on a case-by-case basis 
and fully documented by the Sponsor prior to unblinding. 
All subjects 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 subjects failing any of the inclusion/exclusion criteria and will be based on the 
FAS. 
An indication on whether protocol deviations are linked to COVID-19 will be recorded on the 
eCRF. Incidence of COVID-19 related protocol deviations will be also summarized. 
Any miss-stratified patients will be identified as important protocol deviations. All patients 
who are randomized and are part of the full analysis set will be analyzed according to the 
strata they were allocated to in IVRS/IWRS, as opposed to their actual strata. 
3. 
Demography and Subject Characteristics Variables  
3.1 
Demographics 
The following demographic characteristics will be collected at Screening. 
Ethnicity* 
Race* 
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Sex 
* Race and/or ethnicity will be collected depending on local regulations. 
Additionally, age will be collected at randomization. The age group strata will be derived 
based on the age at randomisation and will be categorised as 
 
 12 to 17 
 
 18. 
Subjects must meet the eligibility criteria, assessed during screening, to be randomized to 
treatment. The list of inclusion and exclusion criteria are provided in the protocol. Eligibility 
criteria not met are collected on the eCRF. 
Vital signs collected at screening will include height (cm), weight (kg) and a derivation of 
body mass index (BMI) (kg/m2), as collected in the eCRF. BMI will be re-calculated based on 
the collected height and weight measurements recorded at screening to allow greater precision 
compared to the BMI collected on the eCRF, which was recorded to 0 decimal places. BMI 
will be re-calculated as [weight (kg)]*[height (m)]2. 
The stratification factors which are recorded at randomization are the pre-study background 
therapy (ICS, non-ICS) and the subject s ACQ-7 score at randomization 
). The 
children 
their pre-study background therapy and ACQ-7 
score in the randomization to treatment, frequencies shown are for informative purposes only. 
Country will also be collected at randomization and included in the Demographics SDTM 
dataset. 
3.2 
Medical, asthma and smoking history 
Medical (including surgical), asthma (including exacerbations) and smoking history will be 
recorded on the eCRF at Visit 1. General medical history will be categorized into past and 
current medical history. Current medical history will be defined as a condition that is either 
classified as on-going, or ending after the first dose of randomized treatment. 
Additionally, the time since diagnosis of asthma (years) will be calculated as 
(Date of randomization (Visit 2) - Date of diagnosis of asthma +1)/365.25. 
Partial dates for the above calculations will be handled as per section 4.1.8. 
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3.3 
Concomitant medications 
All concomitant medication will be recorded on the eCRF throughout the study. Disallowed 
medications will be identified by a physician on review of the data which will be completed 
prior to database lock. All identified medications which are disallowed will be considered for 
flagging as an IPD during the protocol deviation reviews, prior to database lock and 
unblinding. 
3.4 
Spirometry at study entry 
Lung function measurements of FEV1 (L), FVC (L), FEV1/FVC (%)  will be recorded at 
screening and randomization. At screening, assessments are collected at pre-ventolin and post-
ventolin timepoints. At randomization, the spirometry assessments are performed as per Table 
4. The calculation for reversibility in FEV1 is provided in section 4.1.3. The definition of 
baseline spirometry assessments are provided in Section 4.1.1. 
4. 
PRIMARY AND SECONDARY VARIABLES  
4.1 
General Definitions 
4.1.1 
Definition of baseline  
The general definition for non-ediary and non-spirometry data is defined as the most recent 
non-missing measurement before the first dose of the randomized treatment on the day of 
randomization. Unscheduled visits will not be used when assigning a baseline value. 
Baseline FEV1 and FVC will be taken as the average of the 60- and 30- minute pre-dose 
measures on the day of randomization (Visit 2). If either of the 60- or 30- minute pre-dose 
spirometry measures are missing, then the available non-missing pre-dose FEV1 value will be 
used. If both the 60- and 30- pre-dose spirometry measurements are then the baseline FEV1 
measure will be missing. 
For patient reported outcomes in the eDiary, baseline will be calculated as the mean over the 
last 10 days of the run-in period prior the first dose of randomized treatment. See section 4.1.6 
for the derivation of daily scores from the eDiary. 
Any exceptions to the above will be described in the relevant variable derivation section.  
4.1.2 
Absolute and percent change from baseline 
Absolute change from baseline outcome variables is computed as  
Absolute change from baseline = (post-randomization value  baseline value).  
Percent change from baseline is computed for FEV1 on Day 1 for onset and duration of 
response and is computed as  
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Percentage change from baseline = [(post-randomization value  baseline value) / 
baseline value] * 100%. 
Please note that for symptom-free days and asthma control days the change from baseline is 
represented as the absolute change of percentages as opposed to the percent change from 
baseline (section 6.2.7.11).  
If either the post-randomization value or the baseline value is missing, then the absolute or 
percent change from baseline value will also be set to missing. 
4.1.3 
Reversibility 
The reversibility is calculated as follows: 
Reversibility = [(Post FEV1-Pre FEV1)/Pre FEV1] *100%. 
Pre-and post-dose FEV1 measurements will be captured within the MasterScope. If the 
reversibility inclusion criterion is not met at Visit 1, the reversibility test may be repeated at 
Visit 1a prior to Visit 2 (randomization).  
4.1.4 
Study day calculation 
Study day will represent the number of days since first dose of randomized treatment of an 
observation and will be calculated as: 
Pre-dose study day = date of assessment  date of first dose of randomized treatment 
Post-dose study day = date of assessment  date of first dose of randomized treatment + 1 
If either the date of assessment or date of first dose of randomized treatment are missing, then 
the assigned study day will be missing. 
4.1.5 
Visit windowing 
Visit windowing will be applied to spirometry assessments, laboratory measures, vital signs 
and ECG. The visit windows which will be applied to the scheduled study visits collected are 
as follows:  
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Table 3 Visit windowing 
Visit 
Target Day 
Adjusted windows for analyses (days): 
Baseline (Week 0) 
1 
1 
Week 1 
7 
2  12 (± 5 days) 
Week 4 
28 
21  35 (± 7 days) 
Week 8 
56 
49  63 (± 7 days) 
Week 12 
84 
70  98 (± 14 days) 
 
Table 3 shows how the planned clinic visits will be assigned an appropriate scheduled visit 
from the VISIT module. If more than one scheduled visit occurs within the window, then the 
visit closest to the target day will be flagged for analysis. If there are two (or more) visits 
equidistant to the target day, then choose the most recent assessment to be used in analysis. 
Unscheduled visits are listed and will note be windowed, but will be considered in 
minimum/maximum on treatment results. Data collected at the PDV will be windowed to a 
visit as per Table 3.  
Pulmonary function tests (PFTs) will be performed both before administration of randomized 
treatment (pre-dose) and following the morning dose of randomized treatment (post-dose). 
The timing of the PFTs carried out by the investigator are provided in Table 4. The assessment 
windows defined as per protocol will be used for guidance for the sites. No formal analysis 
windows are defined for serial spirometry measures; all spirometry assessments will be 
considered, and will be based on the actual clock time. Derivations based on post-dose serial 
spirometry will only be calculated if there is at least 1 non-missing FEV1 result within 2 hours 
post-dose. More information on the derivation of serial spirometry endpoints is provided in 
Section 4.3.1. 
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Table 4 Schedule of FEV1 measurements at standard visits 
Timing of Spirometry Assessments a 
Assessment Window 
Pre  dose PFT -60 min 
±15 min 
Pre  dose PFT -30 min 
±5 min 
Post  dose PFT +5 min 
±2 min 
Post  dose PFT +15 min 
±3 min 
Post  dose PFT +30 min 
±5 min 
Post  dose PFT +45 min 
±5 min 
Post  dose PFT +60 min 
±5 min 
Post  dose PFT +120 min 
±10 min 
Post  dose PFT +180 min 
±10 min 
Post  dose PFT +240 min 
±10 min 
Post  dose PFT +300 min 
±10 min 
Post  dose PFT +360 min 
±10 min 
Abbreviation: min=minute; PFT=pulmonary function test  
a 
Pre- and post- dose PFT measurements will be performed in relation to Ventolin at Visit 1, Visit 2 
onward, pre- and post- dose PFT measurements will be performed in relation to randomized treatment. 
 
4.1.6 
Daily eDiary variables  
The eDiary will be filled in by the subject twice daily, once in the morning upon awaking to 
record information relating to the previous night-time and once in the evening prior to bedtime 
and to record information relating to the daytime period. 
For the purpose of analyses, daytime results recorded on the evening of day n and night-time 
results recorded on the morning of day n +1 will correspond to the analysis day n. As such, 
daily totals for eDiary variables will be calculated as: 
Daily total for eDiary variable for analysis day n = (daytime result recorded in the evening on 
day n) + (night-time result recorded in the morning on day n+1) 
This rule is not applicable to the assignment of daily lung function data (e.g. daily PEF) as 
these results do represent the timepoint at which they were recorded in the ediary.  
Where applicable, daily totals will only be calculated if both the daytime and night-time 
components are non-missing. The daily totals are calculated for; asthma symptom score, 
Ventolin reliever therapy inhalation, night-time awakenings, symptom free days and asthma 
control days.    
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4.1.7 
Treatment average 
For ACQ-5, ACQ-7 and AQLQ variable summaries, the treatment average score will be 
calculated by averaging the overall scores collected during the randomized treatment period. 
The treatment average will also be calculated within each of the individual domain scores. 
For daily eDiary variables, the treatment average will be calculated as the sum of all daily 
totals over the randomized treatment period and dividing by the number of evaluable days in 
the randomized treatment period. An evaluable day corresponds to the days where both the 
night-time result and the subsequent daytime result collected on the same day are non-
missing. As the result recorded in the morning of study day 1 corresponds to pre-dose, this 
day will not be included in the treatment average calculations for daily total eDiary results.  
4.1.8 
Imputation rules 
In order to classify adverse events and concomitant medications as occurring during the run-in 
period (prior to randomization), during the randomized treatment period (on-treatment), or 
post randomized treatment discontinuation, a conservative imputation rule will be applied in 
the instances where partial start and/or stop dates are recorded. The date imputation algorithm 
should be performed in the following sequence: 
Partial end date 
1. If missing day [--/mm/yyyy] then impute as the minimum (end of the month, treatment 
discontinuation /completion date). 
2. If missing month [--/--/yyyy] then impute as minimum ([31/12/yyyy], treatment 
discontinuation/ completion date). 
3. If completely missing, then impute as date of treatment discontinuation/ completion. 
Partial start date 
4. If missing day [--/mm/yyyy] then impute as the minimum of: 
Start of the month [01/mm/yyyy] unless mm/yyyy is same as first dose of 
randomized treatment then impute as the date of first dose of randomized 
treatment; 
End date of medication/ event (after partial date handling has been applied). 
5. If missing month [--/--/yyyy] then impute as the minimum of: 
Start of the year [01/01/yyyy]  
End date of medication/ event (after partial date handling has been applied). 
6. If completely missing, then impute as the minimum of: 
Date of first dose of randomized treatment; 
End date of medication/ event (after partial date handling has been applied). 
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The raw, original dates will be presented in any listings produced. The intention for date 
imputation is to facilitate a programmatical decision making process to classify on-treatment 
observations. 
For responder analysis variables of ACQ-7, AQLQ+12 and FEV1 on Day 1, a non-responder 
imputation will be carried out for missing endpoints. Further details will be provided in the 
relevant endpoint derivation sections. 
The dual primary endpoints of trough FEV1 and change from baseline FEV1 AUC0-6 hours 
will be imputed under a MNAR assumption under the supportive analysis conducted in 
accordance of the attributable estimand. Please see section 6.2.9 for more detail of these 
imputation methods. 
4.1.9 
Spirometry assessments 
Spirometry assessments will be collected at each study visit and provided by ERT. For each 
planned timepoint in the serial spirometry, multiple efforts will be performed by the subject. 
Of all efforts made at a planned time point, the best effort will be identified and included in 
the SDTM data. The primary, secondary and exploratory spirometry analyses, with the 
exception of time to onset and duration of response FEV1 endpoints (section 6.2.5.1), the best 
efforts and their associated times of collection will be used in the analyses and derivation of 
endpoints. For the analysis of time to onset and duration of response endpoints, derivations 
will consider all spirometry efforts collected. 
4.1.10 
Derived stratification factors for patients aged 4 to 11 years 
Patients aged >=12 years old will be stratified according to their background therapy (ICS; 
non-ICS) and ACQ-7 score at baseline (<=1.5; >1.5). This information will be collected on 
the eCRF for this age range. However, since this information will not be available for patients 
ages <12 years it will be derived based on concomitant medication and baseline ACQ-7/ACQ-
IA results available in the database. This is required such that patients aged <12 years 
contribute to statistical analyses adjusted by these strata. 
Baseline ACQ-7 will be calculated at baseline for all patients and the category (<=1.5; >1.5) 
will be assigned to patients aged <12 years. Patients aged >=12 years will use the strata 
allocated at randomization. 
Background study medication (ICS; non-ICS) will be derived for patients aged <12 years 
based on data available in the prior/concomitant medications module. Background 
maintenance ICS will be identified as records satisfying the following criteria: 
Prior medication (starts and/or ends prior to first dose of randomized treatment) 
 
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ATC 5th level classification codes of: 
o
R03BA  
o
R03AK 
o
R01AD 
o
R03AL 
Patients aged <12 years without concomitant medication records satisfying this criteria will be 
-
 
4.2 
Treatment exposure  
The exposure to the study medication is the total duration (days) from the first dose to the last 
dose (inclusive) of the randomized study drug and is calculated as: 
Date of last dose of randomized study drug - Date of first dose of randomized study drug + 1 
4.3 
Primary Efficacy Measure 
4.3.1 
Dual-primary efficacy endpoints 
The primary efficacy analysis comprises dual-primary endpoints of change from baseline in 
FEV1 AUC0-6 hours over 12 weeks and change from baseline in trough FEV1 at Week 12. 
Baseline FEV1 will be taken as the average of the 60- and 30-minute pre-dose spirometry 
measures on or before randomization (Visit 2).  
4.3.2 
Derivation for FEV1 AUC0-6 hours 
FEV1 AUC0-6 hours will be calculated for the changes from the baseline (randomization visit) 
using the trapezoidal rule and will be normalized by dividing by the time from dosing to the 
last measurement included (typically 360 minutes). 
 
For FEV1 change from baseline results 
 recorded  minutes after the morning dose (actual 
clock time) at 
 actual timepoints. If all timepoints are available, then 
according to Table 4. Only FEV1 
 
(investigator assigned) quality will be used in the derivation of FEV1 AUC0-6 hours. If an FEV1 
result is missing 
 at 
the scheduled assessment, then the assessment will be excluded from the calculation of FEV1 
AUC0-6 hours. To calculate FEV1 AUC0-6hours, there must be at least 1 non-missing post-dose 
FEV1 within 0 to 2 hours post-dose. Missing FEV1 post-dose measures will not be imputed. 
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4.3.3 
Derivation for trough FEV1 
At each of the post-randomization visits, trough FEV1 will be taken as the average of the 60- 
and 30-minute pre-dose spirometry measures prior to dosing of randomized treatment. 
In subjects with only 1 evaluable pre-dose assessment, the trough FEV1 will be calculated 
from the single measurement. If both pre-dose assessments are unevaluable, then the trough 
FEV1 will be missing. The 60- and 30- minute pre-dose assessments with an assigned quality 
unacceptable
1. 
4.4 
Secondary Efficacy Measures 
4.4.1 
Derivation for time to onset (15% increase in FEV1) on Day 1 and 
duration of effect on Day 1 
Time to onset (minutes) on Day 1 will be calculated as the time from dosing on Day 1 
(randomization day; Visit 2) to the first instance within 30 minutes in which a percentage 
change from baseline in FEV1 greater or equal to 15% is observed: 
Time of first 15% increase in percentage change from baseline in FEV1  Time of dosing on 
Day 1 (randomization, Visit 2) 
The time to event is only calculated for those patients who have an observed percentage of at 
least 15%.  
The duration of effect will be calculated for each subject as the period, in minutes, in which 
the post-dose FEV1 is at least 15% higher than baseline. If the subject does not achieve a 15% 
increase from baseline FEV1 within the first 30 min of their post-dose assessments on day 
1, the duration of effect will be zero. If a 15% increase is observed and is sustained until the 
last post-dose assessment of FEV1 on day 1, the duration will be calculated up to the last 
available assessment. If a subject has multiple periods of effect throughout the Day 1 FEV1 
profile, only the first continual period of effect will be considered in the analyses. 
When identifying the 15% increase from baseline FEV1, only acceptable and borderline 
acceptable spirometry assessments will be considered when deriving the above endpoints. 
Unacceptable quality FEV1 measurements should be considered as unevaluable. The time to 
onset and duration of effect will be primarily calculated based on all effort results provided by 
the patient and included in the SDTM. Additionally, patients will be categorized into those 
who achieve a 15% increase in FEV1 within the 30-minute post-dose on Day 1: 
 change from baseline in maximum FEV1 within 30 minutes post-
dose. 
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Non-responder <15% change from baseline in maximum FEV1 within 30 minutes 
post-dose. 
The maximum FEV1 will be based on the non-missing spirometry assessments up to 30 
minutes post-dose and assigned a quality grade of acceptable or borderline acceptable. If all 
post-dose measurements are missing or assigned an unacceptable quality up to 30-minutes 
post-dose on Day 1, then the patient will be categorized as a non-responder.  
4.4.2 
Derivation of Trough FEV1 at Week 1 
The secondary efficacy endpoint of trough FEV1 will be derived in the same manner as the 
dual-primary endpoint of trough FEV1 at Week 12 (Section 4.3.3) 
4.4.3 
Derivation of Asthma Control Questionnaire-7 variables 
All 7 items are assessed on a 7-point scale (0=good control; 6=poor control). The overall score 
is the mean of the non-missing 7 items. At least 6 out of the 7 items are needed to provide an 
ACQ-7 score. 
The minimal important difference (MID) in overall ACQ-7 score is estimated to be 0.5 
(Juniper 2005). Based on the MID, responders at Week 12 are defined as subjects achieving a 
decline from baseline of at least 0.5: 
Responder: (Week 12  
 -0.5 
Non-responder: (Week 12  baseline) > -0.5 
 
Subjects who discontinue treatment for any reason before Week 12 will be classified as non-
responders.  
The interviewer-administered version will be implemented for children aged 4 to 10 years. As 
the ACQ-7 is not validated for children <6 years old, data for subjects who are 4 or 5 years of 
age will be excluded from the analyses of ACQ-7 endpoints. 
5. 
EXPLORATORY EFFICACY MEASURES 
5.1 
Derivation of severe exacerbation endpoints 
The raw annualized severe asthma exacerbation rate will be calculated according to the 
following formula: 
Annualized severe exacerbation rate = 
 
where the summations are over all subjects within a treatment group.  
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For subjects who do not prematurely discontinue randomized treatment, the follow-up is 
calculated as:  
Date of treatment completion - date of first dose of randomized treatment + 1. 
Otherwise, follow-up is calculated as the discontinuation date of randomized treatment:  
Date of randomized treatment discontinuation - date of first dose of randomized 
treatment + 1. 
Date of randomized treatment completion and premature discontinuation will be collected on 
the eCRF. 
5.2 
Derivation of deterioration of asthma variables 
The subject will use the eDiary for daily symptom reporting, entering symptoms twice daily. 
In particular the subject will record their daytime symptoms (0=No asthma symptoms; 1=You 
were aware of your asthma symptoms but you can easily tolerate the symptoms; 2=Your 
asthma was causing you enough discomfort to cause problems with normal activities; 3=You 
were unable to do your normal activities because of your asthma), night-time symptoms 
(0=No symptoms; 1= You were aware of your asthma symptoms but you can easily tolerate 
the symptoms; 2= your asthma was causing you enough discomfort to cause problems with 
sleep; 3=You were unable to sleep because of your asthma), and their rescue medication use 
)). 
In this study, deterioration of asthma is defined as 1 or more of the following items for at least 
2 consecutive days:  
PEF: a decline of at least 20% from baseline in either the morning or evening result 
Ventolin reliever therapy use: >4 puffs per day and at least twice as frequent than 
recorded at baseline (per day) 
Symptoms: night-time score that is greater than baseline and at least 2 OR a daytime 
score that is greater than baseline and 3 (most severe outcome) 
Severe asthma exacerbation1 
 
Ventolin reliever therapy use and symptom scores will be recorded in the eDiary. Baseline 
reliever therapy use will be calculated as the average number of puffs per day during the last 
10 days of the run-in period.  
Daytime is defined as the time period between the morning PEF assessment (upon rising in 
the morning) and the evening lung function assessment. 
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Night-time is defined as the time period between the evening PEF assessment (at bedtime) and 
the morning lung function assessment. 
If the above criteria are met for 2 consecutive days, it will be considered as one deterioration 
of asthma until the criteria are no longer met or becomes unevaluable. Typically, the date in 
which the criteria is no longer met will determine the end date of a deterioration of asthma. If 
the number of days separation between two asthma deteriorations are less than 3 consecutive 
days, then they will be classed as a single asthma deterioration. 
Missing eDiary results will not be considered as a deterioration of asthma. 
1Severe asthma exacerbations will also be considered to be deterioration of asthma and 
included in the analyses of this endpoint. Severe exacerbations will be recorded on the Severe 
Exacerbation module and 1 record corresponds to 1 severe exacerbation. 
The deterioration of asthma rate will be calculated in a similar way as the raw annualized 
severe asthma exacerbation rate (Section 5.1). 
5.3 
Derivation of peak FEV1 
Peak FEV1 is derived as the maximum FEV1 post dose assessment of randomized treatment in 
the 6-hour profile period with an assigned quality grade of acceptable or borderline 
acceptable. Following this, the change from baseline to peak FEV1 will be calculated at each 
visit by computing the difference between the peak and baseline FEV1 values. Baseline FEV1 
is calculated as described in Section 4.3.1. 
5.4 
Derivation of peak expiratory flow 
The best of 3 PEF measurements will be recorded by the subject in the morning and before 
going to bed in the evening prior to taking any asthma therapy and will be captured in the 
eDiary  
Morning and evening peak expiratory flow will be grouped into 4-weekly averages across the 
12-week randomized treatment period. The 4-weekly time intervals are defined as 28-day long 
periods starting from the date of first dose of randomized treatment. The following Table 5 
illustrates how the periods will be assigned using the study day of each record (See section 
4.1.4 for the calculation of study day). 
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Table 5 4-Weekly Time Intervals 
Period 
Start Day 
End Day 
Period 1  
Day 1 (Date of randomization) 
Day 28 
Period 2  
Day 29 
Day 56 (Day 29 + 27) 
Period 3 
Day 57 
Day 84 (Day 57 + 27) 
 
Only PEF measurements prior to the last dose of randomized study drug will contribute to the 
period averages.  
Additionally, overall averages of morning and evening PEF measurements will be calculated 
across the randomized treatment period, from first dose of randomized study treatment to the 
last dose of study treatment. PEF measurements after the last dose of study drug will not 
contribute to the average. 
Only non-missing records will be considered in the 4-weekly and overall randomized 
treatment period averages and the denominator will be equal to the number of non-missing 
PEF measurements in the average calculation. A minimum of 5 days of non-missing PEF 
results are required to derive a 4-weekly average. A minimum of 15 non-missing PEF days are 
required to derive the overall randomized treatment period average.  
In addition, following a review of 
irregularities that may impact a few AM3 devices, causing a higher frequency of inadequate 
efforts or false readings of the PFT signal leading to abnormally high PEF values (i.e. 
700L/min and above). Such cases have been investigated and concluded that the abnormal 
measurements are due to manufacturing issues with the AM3 device. All PEF data will be 
provided in the SDTM, but a flag assigned by ERT which will to indicate whether the PEF 
result was estimated from a faulty AM3 device. These unreliable results will be considered as 
unacceptable quality PEF measurement and excluded from the analyses. The faulty devices 
have been recalled and are to be exchanged. 
5.5 
Derivation of Asthma Control Questionnaire  7 exploratory 
variables 
The changes from baseline ACQ-7 overall score at Week 12 will be categorized into the 
following 3-level factor: 
Improvement: (Week 12  baseline)  -0.5 
No Change: -0.5 < (Week 12  baseline) < 0.5 
Worsening: (Week 12  baseline)  0.5 
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Subjects who discontinue treatment for any reason before Week 12 will be classified as non-
responders. 
5.6 
Derivation of Asthma Control Questionnaire  5 variables 
Derivations for responder status for ACQ-5 will be performed as described in Section 5.2. At 
least 4 out of the 5 symptom items are needed to provide an overall ACQ-5 score. 
5.7 
Derivation of Asthma Quality of Life Questionnaire + 12 and 
Pediatric Asthma Quality of Life Questionnaire variables 
AQLQ+12 consists of 32 questions in 4 domains and PAQLQ consists of 23 questions in 
3 domains. Both are assessed on separate 7-point Likert scales from 1 to 7, with higher values 
indicating better health-related quality of life.  
For overall health-related quality of life and for each of the domains, the MID has been 
determined to be a change in score of 0.5 (Juniper 1994). Based on the MID, responders at 
Week 12 are defined as subjects achieving an increase from baseline of at least 0.5: 
Responder: (Week 12  
 0.5 
Non-responder: (Week 12  baseline) < 0.5 
 
Subjects who discontinue treatment before Week 12 for any reason will be classified as non-
responders.  
5.8 
Derivation of Ventolin therapy variables 
Ventolin therapy will be analyzed through the average number of administrations (puffs) per 
day.  
Total daily number of puffs will be calculated for each subject as the sum of the cumulative 
number of puffs of Ventolin therapy divided by the number of evaluable days the subject has 
until treatment discontinuation. An evaluable day is a day in which the subject has a complete 
diary entry on the number of puffs of Ventolin they have taken. 
Total daily number of puffs will be further characterized within 4-weekly time intervals 
throughout the randomized treatment period. The 4-weekly time intervals will be calculated in 
the same manner as for peak expiratory flow (Section 5.3). 
The average number of puffs for each 4-weekly, and overall average across the randomized 
treatment period will only consider evaluable eDiary days, where a record of Ventolin 
administrations is provided. Days with missing data will not contribute to the numerator or 
denominator of the average calculations. 
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Baseline number of puffs per day will be based on the last 10 days of the run-in period prior to 
before the first dose of randomized treatment. 
5.9 
Derivation of other eDiary variables 
Asthma symptom score 
Asthma symptom score, a 4-point scale ranging from 0 (no asthma symptoms) to 3 (most 
severe asthma symptoms), will be collected twice daily in the morning and evening in the 
eDiary. Please refer to section 4.1.6 for the assignment of study day, and the derivation of the 
total symptom score. The average day, night and total asthma symptom score will be 
calculated over the randomized treatment period, and in 4-weekly intervals as per daily PEF 
(section 5.4). 
Night-time awakenings 
Night-time awakenings will be collected every morning in the eDiary. Please refer to section 
4.1.6 for the assignment of study day. The percentage of night-time awakenings will be 
calculated over the randomized treatment period, and in 4-weekly invervals as per daily PEF 
(section 5.4). 
Symptom-free days 
A symptom-free day is defined as the fulfillment of both of the following criteria: 
A day and night with no asthma symptoms (ie, asthma symptom score=0) 
A night with no awakenings due to asthma symptoms 
The percentage of symptom free days will be calculated for each subject as the number of 
symptom-free days during the randomized treatment period divided by the number of 
evaluable days during the randomized treatment period. For both the denominator and 
numerator, the randomized treatment period is defined from the date of first dose to the date of 
last dose of randomized treatment. 
For the asthma symptom score component, it is important to consider the daytime and night-
time score separately. For example, a daytime score > 0, but missing night-time score would 
correspond to a day with symptoms and vice versa.  
An unevaluable symptom-free day occurs when it cannot be unequivocally determined 
whether an analysis day was symptom free. Table 6 illustrates the daily status of a symptom-
free day when there are missing components to the endpoint: 
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5.10 
Safety variables 
5.10.1 
Vital signs 
The following vital signs measurements will be conducted at the visits as shown in Table 1 
and for timed assessments at Visit 2 and Visit 6. Measurements should be taken in the sitting 
position after at least 10 minutes of rest: 
Pulse rate (beats/min) 
Systolic blood pressure (mmHg) 
Diastolic blood pressure (mmHg) 
Any clinically significant changes in vital signs will be recorded as an AE if applicable. 
5.10.2 
Adverse events (including Serious Adverse Events) 
5.10.2.1 Definition of adverse event 
An AE is the development of any untoward medical occurrence in a 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 randomized treatment has been administered. 
5.10.2.2 Definitions of serious adverse event 
An SAE is an AE occurring during any study phase (ie, after the signing of the informed 
consent/assent through to the safety follow-up visit), that fulfills 1 or more of the following 
criteria: 
Death 
Immediately life-threatening 
Requires in-subject 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 
All SAEs will be identified by the investigator and entered in 
 
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5.10.2.3 Collection of AEs and SAEs 
AEs and SAEs will be collected from time of signature of informed consent/assent, through 
the safety follow-up period. 
The following variables will be collected for each AE: 
AE term (verbatim) 
The date when the AE started and stopped  
YYYY/MMM/DD 
Maximum intensity  
Mild 
Moderate 
Severe 
Serious  
Yes or no 
Investigator causality rating against the randomized treatment  
Yes or no 
Action taken regarding randomized treatment 
Dose not changed 
Drug interrupted 
Drug permanently discontinued 
Not applicable 
Outcome 
Recovered/resolved  
Recovering/resolving 
Recovered/resolved with sequelae 
Not recovered/not resolved 
Fatal 
5.10.2.4 Definition of adverse event leading to discontinuation of investigational 
product (DAE) 
Adverse events 
being reported as general AEs). 
5.10.2.5 Adverse events data handling 
Adverse events will be reported as starting during the run-in period if the AE start date is on 
or after the first date of run-in medication (Ventolin), and prior to the first dose of randomized 
medication. 
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Adverse events will be considered as starting during the treatment period if the onset date is 
on or after the first dose of randomized treatment and onset is no later than the last day of 
randomized treatment.   
Adverse events will be considered as starting during the follow-up period if the onset date is 
after the last day of randomized treatment. 
If an AE has a missing onset date, then, unless the stop date of the AE indicates otherwise, this 
will be considered as starting during the randomized treatment period. Similarly, if an AE has 
a partial onset date, then unless the partial onset date or the stop date indicates otherwise, this 
will be considered as starting during the randomized treatment period. 
Please refer to Section 4.1.8 for the imputation rule to programmatically determine the 
classification of AEs when there are partial start and/or stop dates are recorded. 
5.10.3 
Laboratory Safety Variables 
The following laboratory variables described in Table 7 will be measured throughout the 
course of this study: 
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: 
 
 
 
 
 
 
 
5.10.4 
Resting 12-lead electrocardiogram 
A 12-lead electrocardiogram (ECG) will be performed at the visits detailed in Table 1 for 
timed assessments at Visits 2, 6, and PDV. The timing and number of ECGs may be adjusted 
in response to the emerging safety profile. 
Twelve-lead ECGs will be obtained using a centralized laboratory after the subject has been 
resting semi supine for at least 10 minutes. All ECGs should be recorded with the subject in 
the same physical position. A standardized ECG machine should be used and the subject 
should be examined using the same machine throughout the study, where feasible. 
5.11 
Other variables 
5.11.1 
Concomitant medications 
The collection and recording of all concomitant medications, including all pre-enrollment 
asthma therapies, will be performed at the visits detailed in Table 1. 
All prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications 
taken within 3 months before screening (Visit 1) will be recorded as previous medications. All 
medications taken after screening and through the safety follow-up visit will be recorded as 
concomitant therapy.   
If a concomitant medication is recorded with partial start date and/or end date of 
administration, a conservative approach will be considered such that unless it can be 
unequivocally determined that the medication started and ended prior to the first dose of 
randomized study drug, based on available information from the partial date(s), the 
medication will be classified as concomitant. To facilitate this decision-making process 
programmatically, the imputation process defined in section 4.1.8 will be considered. 
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Subjects will be maintained, after Visit 1, on randomized treatment and Ventolin to be used in 
response to asthma symptoms throughout the treatment period.  
5.11.2 
Discontinuation of investigational product 
Subjects may be withdrawn from the study at any time at their own request, their parent/legal 
upon request of the investigator, or by the Sponsor at any time. The 
subject is free to discontinue treatment at any time for any reason, without prejudice to further 
treatment. Reasons for discontinuation of randomized treatment collected on the eCRF 
include: 
Subject Decision 
Adverse Event 
Severe non-compliance to protocol 
Condition under investigation worsened 
Lack of Therapeutic Response 
Development of study specific discontinuation criteria 
A severe exacerbation event 
Pregnancy 
Subject lost to follow-up 
Completed 
Other 
Subjects who discontinue randomized treatment prior to the end of the 12-week treatment 
period will be withdrawn from the study and asked to complete a PDV and the presence of 
any AEs. If possible, they will be seen and assessed by an investigator(s) and followed up if 
medically indicated. 
 
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5.11.3 
Study Withdrawal 
Patients who discontinue treatment prior to the end of the 12-week treatment period will be 
withdrawn from the study. The following criteria are recorded when a subject is discontinued 
from the study: 
Adverse Event  
Completed 
Death 
Lost to Follow-Up 
Protocol Deviation 
Screen Failure 
Withdrawal by Subject 
Withdrawal by Parent/Guardian 
Other (specify) 
 
5.11.4 
Screen Failures 
Screen failures are subjects who do not fulfill the eligibility criteria for the study, and 
therefore must not be randomized. These subjects, who have a reason for not enrolling to the 
study, should be recorded as a 
F
 on the disposition eCRF page. Subjects who 
are screen failures will not be rescreened. 
 
5.11.5 
Compliance of study medication  
The administration times and number of puffs of randomized study treatment will be recorded 
in the eDiary daily. The compliance of randomized study treatment will be calculated as 
 
Where the expected number of puffs would be as follows: 
 
Subjects are expected to take 1 dose of randomized study drug on their last scheduled visit, 
therefore the final 3 doses (6 puffs) are subtracted from the final day of the randomized 
treatment period. This is due to the final PFT being on week 12 and the PFT should not occur 
after 10:00 am.  
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Any missing eDiary data for randomized treatment administration will be assumed to be zero 
doses when calculating overall compliance. 
Ventolin will be dosed prn; therefore, compliance will not be applicable. 
6. 
ANALYSIS METHODS 
6.1 
Statistical Considerations 
All personnel involved with the analysis of the study will remain blinded until database lock 
and identification of protocol deviations are identified.   
Analyses described within this Statistical Analysis Plan will be performed by 
 
6.1.1 
Estimands 
Three estimands are of interest in this study: 
The primary estimand of interest is the efficacy estimand, defined as the effect of the 
randomized treatment in all subjects assuming continuation of randomized treatment for the 
duration of the study, regardless of actual compliance. This estimand could be considered as a 
while-on-treatment strategy or a hypothetical strategy as defined in the draft International 
Conference on Harmonization (ICH) E9 Addendum. Subjects who prematurely discontinue 
randomized treatment will also be discontinued from the study. For the primary, secondary 
and exploratory endpoint missing data will be assumed to be missing at random (MAR) under 
the efficacy estimand. Further details are provided in section 6.2. 
The second estimand of interest is the attributable estimand, defined as the effect of treatment 
in subjects attributable to the randomized treatment. For this estimand, discontinuation of 
randomized treatment for reasons such as tolerability or lack of efficacy is considered a 
negative outcome. This estimand is a mixture of composite and hypothetical strategies as 
defined in the draft ICH E9 addendum. Further details are provided in section 6.2.9. 
The third estimand of interest is the COVID-19 estimand. This estimand is supportive to the  
efficacy estimand, defined as the effect of the randomized treatment in all subjects assuming 
continuation of randomized treatment for the duration of the study in the absence of COVID-
19 impacts. The dual-primary endpoints for the study will be analyzed under the COVID-19 
estimand. COVID-19 related treatment emergent adverse events can be identified through a 
pre-defined list of preferred terms in MedDRA. Dose interruptions are investigator identified 
breaks in medication that are collected in the eCRF, the investigator will also flag whether or 
not the interruption was related to COVID-19 in the eCRF. 
 
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6.1.2 
Discontinuation of randomized treatment due to lack of efficacy 
The attributable estimand will consider missing data when the primary reason for 
discontinuation is due to tolerability or lack of efficacy a negative outcome in the analyses. 
The primary reason for treatment discontinuation will be collected on the eCRF. The 
following reasons for discontinuation will be indicative of a lack of asthma control: 
Subject decision (where specific reasons are): 
o
Subject perceives the investigational product to be ineffective 
o
Subject wishes to take a treatment that is not allowed in this study 
o
Subject perceives the logistics to be unacceptable 
Adverse event related to treatment1 
Condition under investigation worsened 
Lack of therapeutic response 
Development of study specific discontinuation criteria (where specific reasons are): 
o
A severe exacerbation event 
Death due to asthma11Reasons for discontinuation that are attributable to lack of efficacy will 
be reviewed by the Sponsor and finalized prior to database lock and unblinding of the study.  
6.1.3 
Type I error control 
The Type I error for the primary analysis will be controlled using a sequential testing strategy, 
such that to reject a null hypothesis 
of a pre-defined order 
, the null 
hypotheses, 
to 
must all be rejected beforehand. Please see Section 6.2.4 for further 
details about the dual primary endpoint analyses and the implementation of this multiple 
testing strategy. 
6.2 
Analysis methods 
All tests will be 2-sided and at 5% level of significance unless otherwise stated.  
When appropriate, statistical analysis models will be adjusted to include the stratification 
factors used at randomization. All patients who are randomized and are part of the full 
analysis set will be analyzed according to the strata they were allocated to in IVRS/IWRS. 
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Any patients who are miss-stratified will be identified as important protocol deviations and 
listed in the CSR. 
In addition to the analyses described below, all variables will be summarized descriptively 
where appropriate. 
Unless otherwise stated, descriptive summaries of continuous endpoints will include: The 
number of evaluable subjects in the analysis (n); Mean; Standard Deviation; Median; 
Minimum; Maximum. Summaries of categorical endpoints will include the absolute counts 
and percentage, with the denominator used in the percentage calculation clearly defined in the 
footnote of the table. Unless stated otherwise, the denominator will be the number of subjects 
in the analysis set used for the descriptive summary. 
6.2.1 
Subject Disposition 
Subject disposition will be summarised for all subjects who have been enrolled and have 
provided informed consent. The number of subjects who were enrolled, run-in and not run-in 
will be summarised.  The number and percentage of subjects will be presented by the 
following categories; randomized, not randomized (and reasons), randomized who received 
study treatment, randomized who did not receive study treatment (and reasons), completed, 
and discontinued the study (and reasons). If the reason for premature discontinuation is 
standard text, will be reported as a sub-field in the summary table. For categories that are post-
randomization, summaries will be further split by treatment group. 
A separate table will present the number and percentage of subjects randomized to each 
treatment group, by country and centre. This table will be based on the FAS.   
6.2.2 
Demographic and Baseline Characteristics 
The summary of demographic and baseline characteristics will be performed on the full 
analysis set. Summary statistics will be repeated for FAS patients aged >=12 years. 
Demographic characteristics of age (years), sex, race and ethnic group will be summarized by 
treatment group (including total across treatment).  
Patient height (cm), weight (kg) and BMI (kg/m2) will be summarized by treatment group 
(including total across treatment). 
Lung function endpoints of FEV1 (L), FVC (L), FEV1/FVC (%) and reversibility (%) will be 
summarized at screening and baseline descriptively, within treatment group and across 
treatment groups. Pre- and post-bronchodilator will be presented at screening in these 
descriptive summaries. Summary statistics will presented for the FAS (all ages) and repeated 
for FAS patients aged >=12 years. 
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ACQ-5, ACQ-7, AQLQ+12, PAQLQ and PEF recorded at baseline will be summarized 
descriptively, within treatment group and across treatment groups. Summary statistics will 
presented for the FAS (all ages) and repeated for FAS patients aged >=12 years. 
Medical (past and current) and surgical histories will be summarised by MedDRA preferred 
term within MedDRA system organ class. 
Smoking status will be summarised categorically as the number of subjects who have never 
smoked, are current smokers or are former smokers and grouped by randomized treatment 
group. Nicotine pack years, e-cigarette pack years and total (nicotine + e-cigarette) pack years 
will be summarised as a continuous endpoint by randomized treatment group. 
Additionally, asthma history variables collected on the eCRF will be summarised 
descriptively. Time since diagnosis of asthma will be summarised as a continuous scale and 
present the median, minimum and maximum result by treatment group. 
6.2.3 
Treatment Exposure 
The duration of treatment will be summarised as the period in days from the date of first dose 
to the date of last dose of randomized study treatment, inclusive: 
Duration of exposure = Date of last dose of randomized treatment  Date of first dose of 
randomized treatment  + 1. 
This summary of duration of exposure will be based on the safety analysis set. Additionally, 
the total daily number of puffs of randomized treatment will be summarised descriptively and 
based on the safety analysis set. For exploratory efficacy analyses of reliever therapy use, 
please refer to section 6.2.7.10. 
6.2.4 
Analysis of the dual-primary endpoints 
The dual-primary endpoints, change from baseline in FEV1 AUC0-6 hours over the 12-week 
period, and change from baseline in trough FEV1 at week 12 will each be analyzed using a 
repeated measures (RM) linear model to compare treatment groups. The model will include 
baseline FEV1, percentage reversibility to Ventolin, and age as continuous covariates, and 
visit, treatment, the treatment-by-visit interaction, and Pre-study background therapy (ICS, 
non-ICS) as categorical covariates. Under the efficacy estimand, only windowed data (Section 
4.1.5) prior to treatment discontinuation will be included in the primary analysis. The 
presentation of analysis results will include the least squares mean estimates for each 
treatment and the least squares mean differences between the treatment groups, along with 
associated 95% confidence intervals and p-values. 
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An unstructured variance-covariance matrix will be implemented. If this model fails to 
converge, a heterogeneous Toeplitz (TOEPH) will be fit.  
The planned treatment comparisons for the primary analysis will be sequentially tested in the 
8-step sequence as specified below. Comparisons will stop if a non-statistically significant 
result occurs. All comparisons are of superiority. Formally, the null and alternative hypotheses 
for each comparison are: 
H0: Difference between treatments = 0, 
HA: Difference between treatments  0. 
 
Change from baseline in FEV1 AUC0-6 hours over 12 weeks: 
1.
 
2.
 QID versus placebo MDI QID 
3. BDA MDI 160/180 g QID versus BD MDI 160 g  
Change from baseline in trough FEV1 at Week 12: 
4.
 
5.
 
6.
 
160/180 
 
Change from baseline in trough FEV1 at Week 12: 
7.
 
8.
 
The Type I error will be controlled sequentially by testing in the above order. If a comparison 
is significant (alpha=0.05, two-sided), testing will proceed to the next comparison. 
 
 
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The above tests in steps 1 to 8 will exclude children (age 4 to 11 years). The analysis will be 
repeated to include children, but will be considered a supportive analysis of the dual primary 
endpoint. 
FEV1 AUC0-6 hours over 12 weeks are not 
included in the Type I error control procedure as they redundantly evaluate the contribution of 
albuterol to the combination, which is already captured in Steps 2 and 3. However, these 
comparisons will be reported for completeness. 
The associated p-values for the treatment differences will be presented for all comparisons as 
per the 8-step testing strategy defined above. In the primary results table there will be an 
accompanying column to aid interpretation of each hypothesis test with respect to the overall 
type-I error control being used. 
FEV1 AUC0-6 hours over 12 weeks will be calculated using an appropriate contrast. Two-sided 
p-values and point estimates with two-sided 95% confidence intervals will be calculated for 
each pairwise treatment contrast. An example SAS code is provided below.  
proc mixed data = <<input datasets>> alpha = 0.05; 
  class avisit ICS trtp usubjid; 
  model CHG = trtp avisit trtp*avisit ICS blfev rev1 age/ddfm = kr; 
  repeated avisit / type = UN subject = usubjid; 
  lsmeans trtp trtp*avisit/diff cl; 
run; 
Abbreviations: age = age; avisit = visit; ICS = prior ICS treatment; trtp = treatment group; usubjid = subject id no. chg = 
change from baseline in primary endpoint; blfev = baseline FEV1; rev1 = percentage reversibility to Ventolin.  
All patients who are randomized and are part of the full analysis set will be analyzed 
according to the strata they were allocated to in IVRS/IWRS in this primary analysis. A 
sensitivity analysis will be conduc
miss-stratification on the model results.  
A supportive analysis will be performed where data collected post a COVID-19 related 
treatment emergent adverse event, or a COVID-19 treatment interruption will be excluded 
from the dual primary endpoint derivation. 
Forest plots of the dual primary endpoint analyses under the efficacy estimand will be 
programmed and show the LS means differences and associated 95% confidence intervals for 
the treatment group comparisons specified in the 8-step testing sequence. 
 
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6.2.5 
Analysis of the secondary efficacy variables 
For all secondary analyses the same treatment comparisons as for the primary analysis will be 
conducted (Section 6.2.4), will be conducted on the FAS >=12 years and will be repeated on 
the FAS including all ages. 
6.2.5.1 
Median time to onset (15% increase in 
) and duration of response 
The median time to onset (defined as 15% increase in FEV1) over the pre-treatment value at 
randomization (Visit 2) will be compared among treatment groups using a Wilcoxon rank sum 
test. Confidence intervals for the median treatment difference will be calculated using the 
Hodges-Lehmann method. Only the patients who achieve the 15% increase in FEV1 within 30 
minutes post-dose will be included in the analysis. 
For these secondary analyses, all efforts from the serial spirometry will be used (see 4.1.9). 
Additionally, the proportion of patients achieving a 15% increase in FEV1 within 30 minutes 
post-dose on Day 1 will be analyzed using a logistic regression model with treatment and pre-
study background therapy (ICS, Non-ICS) as categorical covariates, and baseline FEV1 score 
and age as continuous covariates. The odds ratios and corresponding 95% confidence interval 
along with p-values will be estimated from the model. 
Descriptive statistics for duration of response will be reported by treatment group. 
6.2.5.2 
Asthma Control Questionnaire-7 
The primary analyses of ACQ-7 will be conducted in subjects that are uncontrolled at baseline 
(i.e., baseline ACQ-
ating a clinically 
meaningful response with treatment. Only data from first dose up to the last dose of 
randomized treatment will contribute to analyses of ACQ-7. The analysis of ACQ-7 in the 
population of patients indicating partially controlled to uncontrolled asthma at baseline  
(ACQ-7  0.75) will be considered as an exploratory analysis (section 6.2.7.7). 
The responder variable described in Section 4.4.3 at Week 12 will be analyzed using a logistic 
regression model with treatment and previous ICS use (Yes/No) as categorical covariates, and 
baseline ACQ-7 score, baseline post-dose percent predicted FEV1 and age as continuous 
covariates. From the logistic regression model treatment effects will be estimated by odds 
ratios and corresponding 95% confidence interval along with p-values. 
Subjects who discontinue treatment for any reason will be classified as non-responders. The 
frequency and percentage of responders will be summarized descriptively for all study visits. 
The treatment effect for change from baseline in ACQ-7 will be estimated using a repeated 
measures analysis. All data up to Week 12 will be included in the model, with terms for age, 
treatment, visit, treatment*visit, prior ICS use (Yes/No), baseline ACQ-7 score and baseline 
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post-dose percent predicted FEV1. Visit will be fitted as a categorical variable, and the 
variance-covariance matrix will be assumed to be unstructured. If the procedure does not 
converge, then a heterogeneous TOEPH will be used instead. This model will be used to give 
an overall assessment of the treatment effect as well as 95% confidence intervals. Data post-
discontinuation of randomized treatment will not contribute to the analyses. 
Change from baseline will also be described descriptively for all study visits. 
6.2.6 
Analysis of safety variables 
The safety analyses will include all data obtained before subjects discontinue randomized 
treatment and will use the safety analysis set. Adverse events obtained post-treatment 
discontinuation, occurring in the safety follow-up will be reported separately. Safety data 
collected during screening will be listed. 
6.2.6.1 
Adverse events 
Adverse events will be summarized by treatment group, system organ class and preferred term 
assigned to the event by the Medical Dictionary for Regulatory Activities, using the most 
recent version available at the time of database lock. The following summaries will be 
included: 
Number of subjects with any AE in any category for both randomized treatment period 
and run in period. 
Adverse events in the randomized treatment period by SOC and PT, which will 
include the number of subjects with any AE; number of subjects with SAE; number of 
sponsor to be significant. 
Incidence rates will be provided by SOC and PT for all subjects with AEs and SAEs 
during the randomized treatment period. 
Event rates will be provided by SOC and PT for all AEs and SAEs during the 
randomized treatment period.2 
Adverse events in the run in period by SOC and PT, which will include the number of 
subjects with any AE.  
Number of subjects with AE with outcome of death by SOC and PT. 
Adverse events with outcome of death. 
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The most common AEs, defined as preferred terms accounting for at least 2% of all 
AEs within any treatment group. 1 
Non-serious adverse events accounting for at least 2% of subjects. 1 
term and maximum reported intensity. 1 
term and relationship to IP, as assessed by the investigator. 1 
Serious adverse events during the entire study 
Adverse events leading to discontinuation of randomized treatment. 1 
Number of patients with SAE during the randomized treatment period, by system 
organ class and preferred term.1 
1AEs occurring during the randomized treatment period will include the incidence rate. The 
incidence rate is defined as the number of subjects who have experienced the event per 100 
subject treatment years.   
2Number of events and event rates for AEs and SAEs will also be presented.  Event rates are 
defined as the total number of events across all subjects in the treatment group per 100 subject 
treatment years. 
All adverse events, including adverse events occurring during the follow-up period will be 
listed for each subject.  
6.2.6.2 
Vital signs 
Absolute values and changes from baseline in vital signs variables (Section 5.10.1) will be 
descriptively summarised by visit and treatment group whilst also being listed by subject. 
Visit windows will be applied to the vital signs as per section 4.1.5. 
Baseline is defined as the most recent non-missing measurement before and including 
randomization (Visit 2). 
6.2.6.3 
Clinical chemistry and hematology 
Absolute values and changes from baseline in clinical chemistry and haematology parameters 
will be summarized by treatment group and visit and will also be listed by subject. Absolute 
values will be compared to the relevant reference range and classified as low (below range), 
normal (within range or on limits) or high (above range). All values (absolute and change) 
falling outside the reference ranges will be flagged. Additionally, shift tables presenting the 
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shift from baseline reference range indicator (Low; Normal; High) to the minimum and 
maximum on-treatment result will be summarized descriptively by randomized treatment 
group and laboratory parameter. 
Baseline is defined as the most recent non-missing measurement before and including 
randomization (Visit 2). Visit windows will be applied to the central laboratory descriptive 
summaries labs as per section 4.1.5. 
Section 5.10.3) will be 
additionally listed. Scatter plots grouped by randomized treatment will show the maximum 
post-baseline ALT and bilirubin concentrations, as multiples of the ULN, on the x and y-axis 
respectively. Reference lines of ALT (multiple of ULN) = 3 and bilirubin (multiple of ULN) = 
5.10.3) will be added to the figure. 
6.2.6.4 
Electrocardiogram 
ECG parameters will be summarized by treatment group and visit and will also be listed by 
subject. Visit windows will be applied to ECG descriptive summaries as per section 4.1.5. 
Baseline is defined as the most recent non-missing measurement taken before the first dose of 
randomized treatment. 
6.2.6.5 
Concomitant medication 
The number and percentage of subjects who take allowed concomitant medications, and those 
who take disallowed concomitant medications during the study, will be presented by treatment 
group. 
Listings will be grouped by prior medication, medication occurring during the randomized 
treatment period. Concomitant medication listings will be split into those taken in response to 
an adverse event, those taken in response to a severe exacerbation and an overall listing of 
concomitant medication. 
6.2.7 
Analysis of exploratory variables 
The exploratory analyses will include all data obtained before subjects discontinue 
randomized treatment and will use the FAS for patients aged >=12 years, in accordance with 
the primary estimand (Section 6.1.1). As per the primary analysis, the exploratory efficacy 
analyses will be repeated on the FAS including all ages. 
6.2.7.1 
Trough FEV1 at individual time points 
The analyses specified in Section 6.2.4 for trough FEV1 will be used to present the least 
squares mean estimates for each treatment and the least squares mean differences between the 
treatment groups at each scheduled visit, along with associated 95% confidence intervals and 
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p-values. Descriptive summaries of absolute values and changes from baseline trough FEV1 
will also be presented. 
6.2.7.2 
FEV1 AUC0-6 hours at individual time points 
The analyses specified in Section 6.2.4 for FEV1 AUC0-6 hours will be used to present the least 
squares mean estimates for each treatment and the least squares mean differences between the 
treatment groups at each scheduled visit, along with associated 95% confidence intervals and 
p-values. Descriptive summaries of FEV1 AUC0-6 hours will also be presented. 
Additionally, the mean change from baseline FEV1 will be plotted at each post-dose timepoint 
over the randomized treatment period. For these summaries the nominal assessment time will 
be used, rather than the actual times. 
6.2.7.3 
Severe exacerbations 
Severe asthma exacerbations will be summarised descriptively as the frequency and 
percentage of subjects with at least 1 severe exacerbation, the number of severe exacerbations 
prior to discontinuation of the randomized treatment and the total number of severe 
exacerbations per treatment-year. Number of severe exacerbations per treatment-year will be 
calculated as described in section 5.1. The aforementioned descriptive statistics will be 
summarised for all severe exacerbations and will be further broken down into: severe 
exacerbations requiring systemic corticosteroid use; severe exacerbations requiring 
hospitalization; severe exacerbations requiring emergency room visit; severe exacerbations 
requiring urgent care visit. 
An overall summary of severe asthma exacerbations during the treatment period will be 
summarized descriptively, presenting the frequency and percentage of subjects who had at 
least one severe exacerbation during the study (Yes/No) and the number of exacerbations per 
subject, described both as a categorical and as a continuous endpoint.  
The cumulative total days of severe exacerbations will be summarized by treatment group. 
The total number of days of severe exacerbations per subject will be summarized as a 
continuous endpoint. 
The signs and symptoms of asthma worsening are collected on the eCRF severe exacerbation 
module. These will be summarised categorically as the frequency each symptom is observed 
per severe exacerbation. The denominator for percentage calculations will be the number of 
exacerbations.  
For all the aforementioned summaries of severe exacerbations, only the events with a start 
date equal or prior to the date of discontinuation of randomized treatment will be included. 
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6.2.7.4 
Deterioration of asthma 
Annualized deterioration of asthma will be summarized in the same way as the annualized 
severe asthma exacerbation rate (Section 6.2.7.3). 
6.2.7.5 
Peak 
 
Change from baseline to Peak FEV1 at Day 1 (Visit 2) and Day 7 (Visit 3) will be analyzed 
using the same method as for trough FEV1. The repeated measures model will include only 
the Day 1 and Day 7 timepoints. Baseline will be defined as the average of the pre-dose 
assessments collected on Day 1. 
6.2.7.6 
Peak expiratory flow 
The mean value of change from baseline in PEF data during the randomized treatment period 
will be analyzed by analysis of covariance with treatment, ACQ-7 at randomization 
prior ICS use (Yes/No) as factors, and age and baseline PEF score as 
continuous covariates. The summary measure for the comparison of treatments will be the 
estimated mean difference, presented with the corresponding 95% confidence interval. 
Morning PEF and evening PEF will be analysed separately. 
Additionally an RM analysis will be conducted and will be partitioned into 4-weekly time 
intervals across the randomized treatment period. The analysis model will additionally include 
time point and treatment*time point as factors and associated p-value. 
Only the data prior to the date of randomized treatment discontinuation will be considered for 
analyses of PEF. 
6.2.7.7 
Asthma Control Questionnaire-7 exploratory variables  
The 3 factor categorization of ACQ-7 (Improvement; No change; Worsening) will be analysed 
using a logistic regression model adjusted for the same covariates as for the binary response of 
ACQ-7, see Section 6.2.5.2. The analysis will only include patients in the FAS who are 
uncontrolled at baseline (i.e. baseline ACQ-7  1.5). 
The secondary analysis of the ACQ-7 binary response variable (section 6.2.5.2) will be 
repeated and exclude patients who have remote Week 12 visits. This will allow an assessment 
of variability of the secondary endpoint due to potential COVID-19 impacts and to quantify 
the impact of missing question 7 data due to COVID-19 on the overall response. Data that are 
excluded from the analysis due to patients having a remote assessment will be considered 
missing at random in the analysis, as opposed to being imputed as a non-responder. 
6.2.7.8 
Asthma Control Questionnaire-5 variables  
The responder variable for ACQ-5 at Week 12 will be analyzed using a logistic regression 
model in the same way as ACQ-7 (Section 6.2.5.2). 
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The treatment effect for change from baseline in ACQ-5 will be estimated using a repeated 
measures analysis in the same way as ACQ-7 (Section 6.2.5.2). 
6.2.7.9 
Asthma Quality of Life Questionnaire +12 and Pediatric Asthma Quality of 
Life Questionnaire 
The responder analysis will be conducted in the same way as ACQ-7 (Section 6.2.5.2). 
The domain scores as well as the overall scores are calculated from the unweighted arithmetic 
means of the individual question scores. The treatment effect for change from baseline in 
AQLQ+12 and PAQLQ overall scores up to Week 12 will be estimated in the same way as 
ACQ-5, using a repeated measures analysis.  
Change from baseline will also be tabulated descriptively for all study visits for each of the 
domains and the overall scores. 
As the PAQLQ is not validated for children <7 years of age, data for subjects who are aged 4 
to 6 years will be excluded from the analyses of PAQLQ endpoints. 
Only data collected prior to discontinuation of randomized treatment will contribute to 
AQLQ+12 and PAQLQ analyses described above. 
6.2.7.10 
Ventolin therapy 
Change from baseline in Ventolin (reliever) therapy use will be compared with the mean value 
of available data during the run-in portion of the study. The data will be analyzed using 
analysis of covariance with treatment, ACQ-
(Yes/No) as factors, and age and baseline daily number of puffs as continuous covariates. The 
summary measure for the comparison of treatments will be the estimated mean difference, 
presented with the corresponding 95% confidence interval. 
Additionally, a repeated measures analysis will be conducted on the change from baseline 
Ventolin therapy partitioned into 4-weekly time intervals across the randomized treatment 
period. The analysis model will additionally include time point and treatment*time point as 
factors. 
6.2.7.11 
Other eDiary variables 
Asthma daytime/ night-time symptoms and night-time awakenings due to asthma, asthma 
control days, asthma symptom score (total, daytime and night-time) and symptom free days 
will be compared with the mean value of available data during the run-in portion of the study. 
The data will be analyzed using analysis of covariance with treatment, ACQ-7 at 
pre-study background therapy (ICS, Non-ICS) as factors, and 
age and baseline as continuous covariates. The summary measure for the comparison of 
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Number of patients (and incidence rate) with SAEs during the randomized treatment 
period, by system organ class and preferred term. 
6.2.9 
Supportive analysis 
6.2.9.1 
Tipping point analysis 
Tipping point analysis under the missing not at random assumption (MNAR) will be 
conducted using multiple imputation. For subjects in the BDA MDI groups, and subjects in 
AS MDI and BD MDI when comparing to placebo MDI, this method will impute missing 
values post-study discontinuation for lack of asthma control assuming they were more likely 
to have a worse outcome than as implied under the missing at random assumption (MAR). 
The tipping point analysis will incrementally penalize the missing data under the missing not 
at random assumption until a non-statistically significant comparison is observed in the 
sequential testing strategy (Section 6.2.4). 
The MNAR imputation step 
The SAS procedure PROC MI will be used to impute missing data. The MNAR assumption 
s of 
the dual-primary endpoints of change from baseline in trough FEV1 and FEV1 AUC0-6 hours. A 
will correspond to smaller imputed values. A penalty of zero 
  
In the MNAR imputation step, only the post-study treatment discontinuation will be imputed 
under a MNAR assumption if the reason for discontinuation is due to a lack of asthma control. 
Missing data occurring prior to treatment discontinuation, and missing data post-treatment 
discontinuation which cannot be attributable to a lack of asthma control will be imputed under 
a MAR assumption. Please refer to section 6.1.2 for reasons for discontinuation due to lack of 
efficacy. 
Whilst the above list can directly link a randomized treatment discontinuation event as being 
due to a lack of efficacy, the list is not exhaustive. As a result, a sponsor review will be 
conducted on a case-by-case basis to identify any additional discontinuation events which can 
be attributed to a lack of asthma control. The final review of randomized treatment 
discontinuation reasons will be conducted prior to database lock and unblinding of the study.  
Missing data that are attributable to a lack of asthma control in the following treatment groups 
will be imputed under the MNAR assumption:  
BDA MDI 160/180 ug QID (higher dose) 
BDA MDI 80/180 ug QID (lower dose) 
BD MDI 160 ug QID 
AS MDI 180 ug QID 
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For each step, estimates and standard errors for the treatment differences will be output from 
the analysis model procedure for each of the 50 imputed datasets. The analysis results are 
combined to produce an aggregate p-value for each analysis step using 
 (Rubin, 
1987). The SAS procedure PROC MINANLYZE will be used for this process, example code 
below is provided as a reference. 
proc mianalyze data = <<treatment difference dataset>>; 
    modeleffects estimate; 
    stderr StdErr; 
    ods output parameterestimates = <<output dataset>>; 
run; 
Tipping point algorithm 
The tipping point analysis will be conducted by iteratively performing the MAR imputation 
step, the MNAR imputation step and the analysis step.  
The MAR imputation step will be conducted first and will impute all missing pre-treatment 
discontinuation data, and post-treatment discontinuation data under a MAR assumption 
(  = 0). 
Once the MAR step has been carried out, the post-treatment discontinuation data due to lack 
of asthma control for the treatment groups identified in Table 9 will be imputed under a 
treatment groups for this study, the penalty will be assumed to be equal across the treatment 
groups which are imputed under the MNAR assumption. 
Upon completion of the MAR and MNAR steps, the 50 multiple imputed datasets of complete 
(Rubin, 1987) as 
outlined in the analysis step above.  
If the null 
hypotheses are rejected for steps 1-
will be incremented by 0.1 and 
the algorithm will be repeated 
 equal to 2 times the difference between the change 
from baseline result of AS MDI 180 ug QID and Placebo QID is reached. The smallest 
penalty which fails to reject any of the null hypotheses specified in steps 1 to 8 of the primary 
analysis (Section 6.2.4) will denote the tipping point and the algorithm can be stopped when 
this occurs. 
6.2.9.2 
Attributable estimand 
Analysis of the attributable estimand will be conducted in the FAS and will act as a supportive 
analysis to the dual-primary endpoint. Data that are missing due to treatment discontinuation 
is reasonably attributable to tolerability or lack of efficacy (see Section 6.1.2). Imputing based 
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on the 5th percentile of the reference group will correspond to a smaller change from baseline 
imputed value for the dual-primary endpoints. 
For this supportive analysis the attributable estimand will repeat steps 1-8 of the primary 
analysis (Section 6.2.4). Imputation of intermittent missing data will be under a MAR 
assumption using the mu
tipping point analysis and creating 50 imputed datasets. Following this all post-treatment 
discontinuation data which are due to a lack of asthma control will be imputed based on the 5th 
percentile of the corresponding control group relevant to each analysis step 1 to 8. For this a 
single imputation method will be used within each of the 50 datasets. Similarly to the tipping 
point analysis step, the 50 imputed datasets will be analysed separately as per the primary 
analysis model 
 (Rubin, 1987). 
6.2.10 
COVID-19 impacts 
Denali is an on-going trial throughout the coronavirus disease 2019 (COVID-19) outbreak. It 
is important to be able to identify any potential intercurrent events due to COVID-19 and to be 
able to quantify their impact on the efficacy and safety profile of the study. 
6.2.10.1 Visits impacted due to COVID-19 
Any missed visits due to COVID-19 will be summarized by the scheduled visit that was 
missed and treatment group and will present the number and percentage of patients in the full 
analysis set with a missed visit due to COVID-19. For each visit, the reason for missingness 
will be further split into the following categories as collected on the eCRF: 
Subject decision due to pandemic concerns 
Pandemic related logistic issues 
Other 
Similarly, visits that have been delayed, or completed remotely will be summarized 
descriptively by treatment group. 
A listing will be provided to show the patient level information for all visits that have been 
impacted by COVID-19. 
6.2.10.2 Premature discontinuation due to COVID-19 
If a subject cannot continue with procedures and scheduled assessments due to COVID-19 
post-randomization, they will be withdrawn from the trial and will be asked to complete the 
PDV. An additional field has been provided on the discontinuation of investigational product 
eCRF page to indicate whether or not the main reason for discontinuation is a result of 
COVID-19 complications.  
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All premature discontinuations due to COVID-19 will be summarized descriptively providing 
the number and percentage of patients in the full analysis set grouped by randomized 
treatment. 
A separate listing of subjects who prematurely withdraw due to COVID-19 will be provided. 
The listing will detail the reason for withdrawal and relationship to COVID-19. The listing of 
premature withdrawals due to COVID-19 will be based on the full analysis set.  
It is not expected that premature withdrawals will be related to randomized treatment. 
Therefore, the missing data subsequent to withdrawal will be considered as missing at 
random, in accordance with the efficacy estimand. 
6.2.10.3 Treatment interruptions due to COVID-19 
Treatment interruptions will be listed by patient and the length of each dose interruption that 
are due to complications imposed by COVID-19. 
6.2.10.4 Assessments not done due to COVID-19 Spirometry assessments 
Any subject that has not performed serial spirometry assessments at a post-randomization visit 
will be listed. The listing will provide the subject ID, the scheduled visit name and the 
corresponding reason for the missed assessment, detailing how COVID-19 impacted the 
missed assessment. The listing of missed spirometry data will be presented in the full analysis 
set. 
Any missed spirometry data due to COVID-19 is not anticipated to be related to randomized 
treatment and as such, missed spirometry assessments will be considered missing at random, 
in accordance with the efficacy estimand. 
6.2.10.5 ACQ-7 data collected remotely due to COVID-19 
ACQ-7 data which is collected remotely will not include the question 7 result of FEV1 %PN. 
As a result, a supportive analysis of the secondary analysis of responder status (section 
6.2.5.2) will be repeated, but excluding the assessments collected remotely. This data will be 
assumed missing at random in the analysis. 
Scheduled safety assessments 
Any scheduled safety data, including clinical laboratory, pregnancy tests, ECG and vital signs 
that are missing due to COVID-19 will be listed for each subject. The listing will detail the 
safety procedure missed and its relationship to COVID-19. The listing of missed safety 
assessments will be presented in the safety analysis set. 
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6.2.10.6 Adverse events and serious adverse events due to COVID-19 
All subjects with a suspected or confirmed diagnosis of COVID-19 will be listed. The listing 
will present any AEs with either a suspected or confirmed relationship to COVID-19. The 
relationship between an AE and COVID-19 will be determined by the investigator and 
appropriately captured in the eCRF. The listings will provide an indication of whether the AE 
was serious or non-serious. 
Listings of adverse events linked to COVID-19 will be based on the safety analysis set. 
6.2.10.7 Overall descriptive summary 
A high-level descriptive summary will be provided and grouped by randomized treatment 
group and total number of subjects (across treatment groups). The following frequencies and 
percentages of subjects in the full analysis set will be presented: 
1. Number of subjects affected by COVID-19 [a] 
2. Number of patients with dose interruptions due to COVID-19 
3. Number of premature withdrawals due to COVID-19 
4. Number of patients with any missed visit due to COVID-19 
5. Number of patients with a missing Week 12 visit due to COVID-19 
6. Number of subjects with any spirometry not done due to COVID-19 
7. Number of patients with Week 12 spirometry not done due to COVID-19 
8. Number of patients with any ACQ-7 not done due to COVID-19 
9. Number of patients with Week 12 ACQ-7 not done due to COVID-19 
10. Number of patients with any ACQ-7 performed remotely due to COVID-19 
11. Number of patients with Week 12 ACQ-7 performed remotely due to COVID-19 
12. Number of subjects with clinical laboratory not done due to COVID-19 
13. Number of subjects with pregnancy tests not done due to COVID-19 
14. Number of subjects with ECG not done due to COVID-19 
15. Number of subjects with vital signs not done due to COVID-19 
16. Number of subjects with COVID-19 related AEs 
17. Number of subjects with COVID-19 related SAEs 
[a] Defined as the number of subjects who meet at least one of the listed criteria in points 2-9. 
 
 
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8. 
CHANGES OF ANALYSIS FROM PROTOCOL 
The following table provides a brief summary of changes of analysis from the protocol 
Version 1.0 ( finalised 
 
 
8.1 
Baseline derivation 
The protocol text specifies that the baseline derivation will be based as the most recent, non-
missing measurement prior to first dose of randomised study treatment, typically this should 
be the result recorded at Visit 2. If missing the result is taken from the screening period. 
However, due to patients not being sufficiently run-in at the screening visit, the results 
collected at this point will not be suitable values for baseline. As such for this trial, baseline 
will be defined as the pre-dose value collected on Visit 2 (randomisation visit). 
8.2 
Changes to the primary analyses 
Analysis of the dual-primary endpoints of trough FEV1 and FEV1 AUC0-6 hours has been 
changed to be conducted where all treatment comparisons exclude children (aged 4-11 years) 
and then repeated with children included. The analyses excluding children will be considered 
primary. 
The justification for this change is due to a small proportion of pediatric patients to be 
enrolled, and the expectation that early drop out will occur at a higher percentage in this age 
group than compared to the adolescent/adult population.  
8.3 
Stratification factors recorded at randomisation 
The stratification factors used to assign patients to a randomized treatment group will be 
adjusted for in the inferential models of this study. Clarifying text has been added to the SAP 
to state that in any cases of miss-stratification, patients will be analysed according to their 
assigned stratum in IVRS/IWRS. As a sensitivity analysis, the primary endpoints will be 
analysed using the actual strata of patients. 
8.4 
Time to onset and duration of response FEV1 endpoints 
The endpoints for time to onset and duration of response (defined as a 15% increase from 
baseline) on Day 1 will be calculated using all spirometry efforts spirometry data, as opposed 
to the best effort data which is used in the other primary and secondary analyses of spirometry 
data. The justification for this change is to allow for a more precise approximation for the time 
in which the event is observed to have started. 
8.5 
Exploratory analysis of ACQ-5 and ACQ-7 Changes from 
baseline 
ACQ-5 and ACQ-7 changes from baseline will be assessed as the following 3-level factor: 
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Improvement: (Week 12  baseline) -0.5 
No Change: -0.5 < (Week 12  baseline) < 0.5 
Worsening: (Week 12  baseline) 
 
The endpoint will be analysed using an ordinal logistic regression. Please see section 6.2.7.7 
for further details. 
8.6 
Additional subgroup analyses 
Exploratory analyses stratified by age have been specified to additionally represent the elderly 
 
A subgroup focusing on USA vs non-USA patients has been specified as an additional 
subgroup. 
Subgroup analyses for adverse events have been specified (see section 6.2.8.2). 
 
8.1 
COVID-19 impacts 
Additional analyses have been specified to quantify the impact of the Coronavirus outbreak 
2019 (COVID-19) on the trial data. Please refer to section 6.2.10 for full details. 
 
 
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9. 
REFERENCES 
 
1. Juniper, EF., Guyatt, GH., Willan, A. and Griffith, LE. Determining a minimal important 
change in a disease-specific quality of life questionnaire. J Clin Epidemiol. 
1994;47(1):81-87. 
2. Juniper, EF., Svensson, K., Mörk, AC. and Ståhl, E. Measurement properties and 
interpretation of three shortened versions of the asthma control questionnaire. Respir 
Med. 2005;99(5):553-558. 
3.
Rubin, DB.  Multiple Imputation for Nonresponse in Surveys. Wiley: New York, 1987 
 
 
 
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