Clinical trial NCT05505734
Conditions: Asthma
Keywords: Metered-dose inhaler (MDI) Leukotriene receptor agonist (LTRA) Inhaled corticosteroid (ICS) Short -acting β2agonist (SABA)
Sponsor: Bond Avillion 2 Development LP
Start date: 2022-09-02; Completion date: 2024-08-22
Enrollment: 2516 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a US study comparing the efficacy and safety of BDA MDI \[Budesonide/Albuterol Sulfate (BDA) metered dose inhaler (MDI)\] with AS \[Albuterol Sulfate\] MDI, both are administered as needed for up to 12 months.

Detailed description:
This is a phase IIIb, multicenter, randomized, double-blind, parallel-group, event-driven, variable-length, decentralized study.

Participants from around 40 to 50 centers located in the US will be screened and randomized 1:1 to receive one of the following two treatments to be used as needed: BDA MDI (160/180 μg) and AS MDI (180 μg). Participants 12 years of age and older with asthma will be recruited with all visits conducted virtually.

Eligible participants must be using as-needed SABA (Short -acting β2agonist) alone, or as-needed SABA on a background of either low-dose ICS (Inhaled corticosteroid) or a LTRA (Leukotriene receptor agonist), for the treatment of asthma.

Participants will be stratified by pre-study asthma medication (SABA only, low-dose ICS + SABA and LTRA + SABA) and number of prior severe exacerbations (0, ≥1) in the 12 months prior to the Screening visit.

Arms: arm 1: Participants will receive Budesonide and Albuterol Sulfate Pressurised Inhalation Suspension 160/180 μg up to a maximum of 12 inhalations to max dose. arm 2: Participants will receive Albuterol Sulfate Pressurised Inhalation Suspension 180 μg up to a maximum of 12 inhalations to max dose.
Interventions: intervention 1: BDA MDI intervention 2: AS MDI
Intervention descriptions: intervention 1: Participants will receive Budesonide and Albuterol Sulfate MDI 80/90 μg per Actuation 1 to 6 doses (2 inhalations/dose) per day as needed via Oral inhalation route. intervention 2: Participants will receive Albuterol Sulfate MDI 90 μg per Actuation 1 to 6 doses (2 inhalations/dose) per day as needed via Oral inhalation route.

Protocol documents:
Prot_000.pdf: 
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This Clinical Study Protocol has been subject to a peer review according to Bond Avillion 2 Development 
dStandard procedures. The Clinical Study Protocol is publicly registered, and the results are disclosed and/or 
published according to the Bond Avillion 2 Development LP Global Policy on Bioethics and in compliance with 
prevailing laws and regulations.
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.
Protocol Number: AV007
Amendment Number: 2
Study Investigational Medicinal Products (IMP): PT027 (budesonide/albuterol 80/90 μg 
metered-dose inhaler) (BDA MDI); PT007 (albuterol 90 μg metered-dose inhaler) (AS MDI)
Study Phase: Phase IIIb
Short Title: A comparison of PT027 vs PT007 used as needed in participants with Asthma.
Study Physician Name and Contact Information will be provided separately.
International Coordinating Investigator
Craig LaForce, MD
North Carolina Clinical Research
2615 Lake Drive, Suite 301
Raleigh, NC 27607
United States


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TABLE OF CONTENTS
TITLE PAGE.............................................................................................................................1
VERSION HISTORY................................................................................................................2
TABLE OF CONTENTS...........................................................................................................4
1
PROTOCOL SUMMARY......................................................................................8
1.1
Synopsis..................................................................................................................8
1.2
Schema..................................................................................................................16
1.3
Schedule of Activities...........................................................................................17
2
INTRODUCTION................................................................................................21
2.1
Study Rationale.....................................................................................................21
2.2
Background...........................................................................................................21
2.3
Benefit/Risk Assessment ......................................................................................23
2.3.1
Risk Assessment ...................................................................................................24
2.3.2
Benefit Assessment...............................................................................................25
2.3.3
Overall Benefit: Risk Conclusion.........................................................................25
3
OBJECTIVES AND ENDPOINTS......................................................................26
4
STUDY DESIGN .................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design ..................................................................32
4.2.1
Participant Input into Design................................................................................33
4.3
Justification for Dose............................................................................................34
4.4
End of Study Definition........................................................................................34
5
STUDY POPULATION .......................................................................................35
5.1
Inclusion Criteria ..................................................................................................35
5.2
Exclusion Criteria.................................................................................................37
5.3
Diversity and Inclusion of Racial and Ethnic Populations in the Study...............39
5.4
Screen Failures......................................................................................................39
5.5
Re-screening .........................................................................................................39
6
STUDY INVESTIGATIONAL MEDICINAL PRODUCT..................................41
6.1
Study IMP(s) Administered..................................................................................41
6.1.1
Investigational Medicinal Products ......................................................................41
6.2
Preparation/Handling/Storage/Accountability......................................................42
6.2.1
Dose and Treatment Regimens.............................................................................42
6.2.2
Labeling................................................................................................................43
6.2.3
Storage..................................................................................................................44
6.2.4
Accountability.......................................................................................................44
6.2.5
Metered-dose Inhaler: Handling and Cleaning.....................................................44


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6.3
Measures to Minimize Bias: Randomization and Blinding..................................44
6.3.1
Methods for Assigning Treatment Groups............................................................44
6.3.2
Methods for Ensuring Blinding ............................................................................45
6.4
Study IMP Compliance.........................................................................................45
6.5
Concomitant Therapy ...........................................................................................46
6.5.1
Rescue Medicine...................................................................................................46
6.5.2
Maintenance Asthma Therapies............................................................................47
6.5.3
Allowed and Prohibited Medication.....................................................................47
6.6
IMP After the End of the Study ............................................................................49
7
DISCONTINUATION OF STUDY IMP AND PARTICIPANT WITHDRAWAL 
FROM STUDY.....................................................................................................50
7.1
Discontinuation of Study IMP..............................................................................50
7.1.1
Planned Discontinuation of Study IMP................................................................50
7.1.2
Premature Discontinuation of IMP.......................................................................50
7.2
Participant Withdrawal from the Study ................................................................51
7.3
Lost to Follow-up .................................................................................................52
8
STUDY ASSESSMENTS AND PROCEDURES ................................................53
8.1
Screening and Critical Baseline Assessments.......................................................54
8.2
Efficacy Assessments............................................................................................55
8.2.1
Asthma Exacerbation Definition ..........................................................................55
8.2.1.1
Definition of Worsening of Asthma Signs/Symptoms.........................................55
8.2.1.2
Investigator Justified Asthma Exacerbations........................................................55
8.2.1.3
Severe Asthma Exacerbations ..............................................................................56
8.2.1.4
Onset and Duration of Asthma Exacerbations......................................................56
8.2.1.5
Approach for Capturing Asthma Exacerbations...................................................56
8.2.2
Patient-Reported Outcomes..................................................................................57
8.2.2.1
Asthma Impairment and Risk Questionnaire (AIRQ)TM ......................................57
8.2.2.2
EuroQol-5 Dimension 5 Level (EQ-5D-5L) ........................................................57
8.3
Safety Assessments...............................................................................................58
8.4
Adverse Events and Serious Adverse Events .......................................................58
8.4.1
Time Period and Frequency for Collecting AE and SAE Information.................58
8.4.2
Follow-up of AEs and SAEs.................................................................................58
8.4.3
Causality Collection..............................................................................................59
8.4.4
Adverse Events Based on Signs and Symptoms ..................................................60
8.4.5
Adverse Events of Special Interest.......................................................................60
8.4.6
Disease Under Study (DUS).................................................................................60
8.4.7
Reporting of Serious Adverse Events...................................................................60
8.4.8
Pregnancy .............................................................................................................61
8.4.8.1
Maternal Exposure................................................................................................61
8.4.9
Medication Error...................................................................................................62
8.5
Overdose...............................................................................................................62
8.6
 
 Mobile Software Application.....................................................63


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8.7
Unscheduled Visits following ‘Yes’ Response to 
 
 bi-weekly 
Message ................................................................................................................63
8.8
Sensor, Portal and App.............................................................................64
8.9
Medical Resource Utilization and Health Economics..........................................64
9
STATISTICAL CONSIDERATIONS...................................................................66
9.1
Statistical Hypotheses...........................................................................................66
9.2
Sample Size Determination ..................................................................................66
9.3
Populations for Analyses ......................................................................................68
9.4
Statistical Analyses...............................................................................................68
9.4.1
General Considerations.........................................................................................68
9.4.2
Efficacy.................................................................................................................69
9.4.2.1
Primary Endpoint..................................................................................................69
9.4.2.2
Multiplicity adjustments.......................................................................................70
9.4.2.3
Secondary Endpoint(s)..........................................................................................71
9.4.2.4
Tertiary/Exploratory Endpoint(s) .........................................................................74
9.4.3
Safety....................................................................................................................74
9.4.3.1
Adverse Events.....................................................................................................74
9.4.3.2
Other Safety Endpoint(s) ......................................................................................74
9.4.4
Other Analyses......................................................................................................74
9.5
Interim Analyses...................................................................................................75
9.6
Data Monitoring Committee.................................................................................75
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS ............................................................................................77
11
SUMMARY OF CHANGES..............................................................................102
11.1
Changes to Protocol Amendment 2 (Version 3.0) ..............................................102
11.2
Changes to Protocol Amendment 1 (Version 2.0) ..............................................104
12
REFERENCES ...................................................................................................117
LIST OF FIGURES
Figure 1
Study Design ...............................................................................................16
Figure 2 
Metered Dose Inhaler (MDI) ......................................................................91
Figure 3
Actuation Counter Dial ...............................................................................91
Figure 4
Instructions for Removing the Cap from the MDI......................................92
Figure 5
Ways to Hold the MDI for Use...................................................................93
Figure 6
Diagram of How to Use the MDI................................................................93
Figure 7
Cleaning the Actuator .................................................................................94


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LIST OF TABLES
Table 1
Schedule of Activities .................................................................................17
Table 2
Risk Assessment..........................................................................................24
Table 3
Objectives and Endpoints............................................................................26
Table 4
Investigational Medicinal Products (IMP)..................................................41
Table 5
Allowed and Prohibited Medications..........................................................48
Table 6
Populations for Analysis .............................................................................68
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations..........................77
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................82
Appendix C
Asthma Impairment and Risk Questionnaire (AIRQTM).............................87
Appendix D
Avillion Protocol Signature Page................................................................88
Appendix E
Primary Investigator Signature Page...........................................................89
Appendix F
Instructions for Use.....................................................................................90
Appendix G
Daily Metered doses of Inhaled Corticosteroids in Adults/Adolescents 12 
years and older ............................................................................................99
Appendix H
Abbreviations ............................................................................................100


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multicenter, Randomized, Double-blind, Parallel group, Event-driven, 
Decentralized, Phase IIIb Study comparing PT027 with PT007 Administered as needed 
in Participants 12 years of age and older with Asthma (BATURA)
Short Title:
A comparison of PT027 vs PT007 used as needed in participants with Asthma.
Rationale:
The purpose of this Phase IIIb study is to evaluate the efficacy and safety of 
budesonide/albuterol 160/180 μg metered-dose inhaler [MDI]; PT027; BDA MDI, used as 
needed in participants with asthma previously receiving short-acting β2-agonists (SABA) 
alone or SABA as needed plus on a background of either low-dose inhaled corticosteroids 
(ICS) or a leukotriene receptor antagonist (LTRA). The rationale for BDA MDI to be used as a 
rescue therapy is based on the provision of rapid relief of asthma symptoms by albuterol while 
simultaneously treating underlying inflammation with budesonide. Use of BDA MDI will be 
driven by day-to-day symptom levels and will follow a patient’s natural behavior to treat 
symptoms when they arise and thus treatment for inflammation will be provided when needed 
most. Safety and efficacy of BDA MDI will be compared with albuterol (PT007; AS MDI) 
because albuterol is the standard of care rescue therapy in the United States (US).
The study will evaluate the efficacy of as-needed BDA MDI (used at a dose of 
budesonide/albuterol 160/180 μg) in reducing the risk of severe asthma exacerbations 
compared with AS MDI as needed (used at a dose of albuterol 180 μg) either alone or on top 
of participants' usual low-dose ICS or LTRA maintenance therapy in approximately 
1910 participants 12 years of age and older. The study will also investigate the effect of BDA 
MDI on the rate of severe asthma exacerbations, total annualized systemic corticosteroid 
(SCS) use, asthma-related healthcare resource utilization, asthma control and health-related 
quality-of-life. Safety will be assessed through the collection of adverse events (AEs) and 
serious adverse events (SAEs). The study will be fully decentralized for all participants, with 
no planned in-clinic visits, ie, all study visits will be conducted virtually. By employing a 
decentralized study delivery model, it is anticipated to reach a broader population of asthmatic 
patients who typically might not consider participating in clinical trials due to travel or time 
commitments.




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Objectives
Estimands* descriptions/Endpoints
To evaluate the efficacy of BDA 
MDI as needed compared with AS 
MDI as needed on the risk of severe 
asthma exacerbations, participants 
≥18 years
x
Population: Adult participants (≥18 years) with asthma 
previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: time to first severe asthma exacerbation 
x
IE handling: A Treatment Policy strategy will be implemented in 
which all observed data while participants are in the study, 
regardless of IEs or whether they are on randomized study 
treatment, will be included in the estimation procedure
x
Summary measure: Adjusted hazard ratio
To evaluate the efficacy of BDA 
MDI as needed compared with AS 
MDI as needed on the rate of severe 
asthma exacerbations, participants 
≥12 years
x
Population: Adult and adolescent participants (≥12 years) with 
asthma previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: annualized rate of severe asthma exacerbations
x
Summary measure: Adjusted rate ratio
x
Treatment and strategy for IEs are the same as for the primary 
objective
To evaluate the efficacy of BDA 
MDI as needed compared with AS 
MDI as needed on the rate of severe 
asthma exacerbations, participants 
≥18 years
x
Population: Adult participants (≥18 years) with asthma 
previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: annualized rate of severe asthma exacerbations
x
Summary measure: Adjusted rate ratio
x
Treatment and strategy for IEs are the same as for the primary 
objective
To evaluate the effect of BDA MDI 
as needed compared with AS MDI 
as needed on systemic 
glucocorticoid exposure associated 
with asthma management,
participants ≥12 years
x
Population: Adult and adolescent participants (≥12 years) with 
asthma previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: total amount (mg/year) per participant of systemic 
glucocorticoid exposure 
x
Summary measure: Difference in unadjusted treatment means
x
Treatment and strategy for IEs are the same as for the primary 
objective
x
Endpoint: total days of systemic glucocorticoid exposure 
x
Summary measure: Difference in unadjusted treatment means




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Eligible participants must be using as-needed SABA alone, or as-needed SABA on a 
background of either low-dose ICS or a LTRA, for the treatment of asthma. Participants must 
have had either ≥2 prescriptions for a SABA inhaler or ≥1 prescription for a SABA inhaler 
plus ≥1 prescription for a low-dose ICS inhaler or a LTRA in the 12 months prior to 
enrollment. Participants continue their own maintenance treatment, if receiving. In addition, 
participants must have used a SABA on ≥2 days, for the relief of asthma symptoms, in the 
previous 2 weeks prior to Visit 2 and have an Asthma Impairment and Risk Questionnaire 
(AIRQ)TM score ≥2 at Screening.
In order to achieve 350 first severe asthma exacerbation events, approximately 
1910 participants from 40 to 50 centers located in the US will be randomized 1:1 to receive 
one of the following two treatments, to be used as needed:
x
BDA MDI 160/180μg (given as 2 inhalations of BDA MDI 80/90 μg per actuation) up 
to a maximum of 12 inhalations per day
x
AS MDI 180μg (given as 2 inhalations of AS MDI 90 μg per actuation) up to a 
maximum of 12 inhalations per day
Participants will be stratified by pre-study asthma medication: SABA only, low-dose ICS + 
SABA, and LTRA + SABA and number of prior severe exacerbations (0, ≥1) in the 12 months 
prior to Screening visit.
The study will be double-blind with BDA and AS MDIs being identical in appearance. 
Participants will also receive a 
 sensor attachment (referred to as an MDI sensor, or 
sensor) compatible with the study inhalers that will be used to capture each actuation of the 
inhaler throughout the study. Refer to Section 8.8 for further information on 
sensor 
and app.
The study will employ a decentralized design with all planned participant assessment visits 
being conducted virtually ie, no in-clinic visits.
Disclosure Statement: This is a parallel-group treatment study with 2 arms that are 
participant and investigator blinded.
Number of Participants:
In order to achieve 350 first severe asthma exacerbations events, it is estimated that 
approximately 2122 participants will be enrolled/screened to ensure 1910 randomly assigned 
to study IMP, ie, approximately a 10% screen fail rate. If the observed first severe 
exacerbation rate is higher than expected, then the required number of events may be met with 
less participants and recruitment will be stopped prior to reaching 1910 participants 
randomized. If the observed first exacerbation rate is lower than predicted, the number of 


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participants randomized may be increased to approximately 2500. Any assessment of 
accumulating data will be performed on pooled, blinded data. The timing and procedure for 
blinded sample size assessment will be documented in the statistical analysis plan (SAP).
Note: “Enrolled” means a participant, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the electronic informed consent form 
(eICF) process. Potential participants who are screened for the purpose of determining 
eligibility for the study but are not randomly assigned/assigned in the study, are considered 
“screen failures”, unless otherwise specified by the protocol. 
Investigational Medicinal Product (IMP) Groups and Duration:
Participants who are not females of child-bearing potential and who meet all the inclusion 
criteria and none of the exclusion criteria at screening may be screened and randomized at the 
same visit or on separate visits. For females of child-bearing potential, following the initial 
screening assessment, a urine pregnancy test with high sensitivity is required. Female 
participants of child-bearing potential will only be randomized following confirmation of a 
negative urine pregnancy test. Therefore, the enrollment, screening assessments and 
randomization may occur on separate days within a 28-day period, if required.
Study-related supplies will be shipped directly to the participant. The randomization step will 
trigger a shipment of IMP and IMP sensors. As IMP is being sent direct to the participant’s 
home, the Treatment Initiation visit (Visit 3) will occur once the participant is in receipt of the 
study medication (expected to be within 7 days following randomization). A total of 2 sensors 
will be sent to allow more than 1 inhaler to be used at the same time (eg, stored in different 
locations). Training on how to use the study inhaler and inhaler sensor attachment will be 
provided at the Treatment Initiation visit (Visit 3) with additional training materials available.
Following treatment initiation, the treatment period for any individual will be for a maximum 
of 52 weeks but may be shortened to a minimum of 12 weeks, depending on when a 
participant is randomized into the study and when the required number of first severe asthma 
exacerbations events is reached (defined as the Primary Completion Date [PCD]). Subsequent 
visits will be performed after 4 weeks (Week 4) and then at 12-weekly intervals (Weeks 16, 
28, 40 and 52) or until the PCD has been reached. Providing participants have received a 
minimum of 12 week’s treatment, an end of study (EOS) treatment visit will scheduled within 
4 weeks of the PCD. Between scheduled visits, participants will receive a message via a 
smartphone application (
 
 app) bi-weekly to inquire as to whether they have 
needed to seek medical help as a result of their asthma worsening or any asthma-related 
unscheduled healthcare related contacts/visits.
Data Monitoring Committee
An independent, external Data Monitoring Committee (DMC) will be set up to review safety 


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data at three time points during the study. At a single time point (Interim Analysis), DMC will 
review the primary efficacy endpoint and the first secondary endpoint to determine stopping 
early for overwhelming efficacy, see Section 9.6. Further details of this planned review and 
the experts involved will be covered in a separate charter.
Statistical Methods
Primary Efficacy Analysis 
The primary endpoint is time to first severe asthma exacerbation and is defined as the length 
in days from start of the IMP period until the first date when the event occurs, up to end of the 
study. The primary estimand will adopt a While on Treatment strategy in the Full analysis set 
(FAS), in which participants will be censored if they have not experienced a severe 
exacerbation event prior to an intercurrent event (IE).
The primary analysis will be based on a two-sided hypothesis testing approach. The statistical 
null hypothesis for the primary efficacy summary measure is that the adjusted hazard ratio for 
the primary treatment comparison is equal to 1 versus the alternative hypothesis that it is not 
equal to 1. 
x
The time to first severe asthma exacerbation from the start of the IMP period up to end of 
treatment will be analyzed using a Cox proportional hazards regression model. Treatment 
comparisons will be performed using a model including treatment, pre-study asthma 
therapy (SABA only, low-dose ICS + SABA, LTRA + SABA) and the number of prior 
severe exacerbations (0, ≥1) in the 12 months prior to Screening visit. The estimated 
adjusted hazard ratio for the primary treatment comparison will be displayed along with
the associated Wald two-sided 95% confidence interval and p-value. 
The key secondary endpoint will be the time to first severe exacerbation based on the 
estimand utilizing a Treatment Policy strategy. 
Sample Size Estimate
In order to achieve 350 first severe asthma exacerbation events, it is planned that 
1910 participants (955 participants per arm) will be randomized. It is expected that most 
participants in the proposed US asthma population will be on SABA only. Randomization will 
be stratified by pre-study asthma therapy (SABA only, low-dose ICS + SABA, and 
LTRA +SABA and number of prior severe exacerbations (0, ≥1) in the 12 months prior to the 
Screening visit) to ensure treatment balance within each stratum. The target number of events 
required is estimated from the sample size determinations based on the analysis of the 
secondary endpoint time to first severe asthma exacerbation targeting the estimand utilizing a  
Treatment Policy strategy.


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The primary endpoint of time to first severe exacerbation targeting the estimand adopting a 
While on Treatment strategy assumes a 30% reduction in the risk of first severe exacerbation 
with BDA MDI versus AS MDI and is supported by results from the MANDALA study where 
the reduction in the rate of severe asthma exacerbations was 27% in participants ≥12 years old 
receiving BDA MDI 160/180 μg compared to AS MDI 180 μg. Assuming a 1-year first severe 
exacerbation event rate in the AS MDI arm of 21%, 345 events are needed to achieve 90.8% 
power, with a 2-sided significance of 5%.
For the secondary endpoint of time to first severe asthma exacerbation targeting an estimand 
utilizing a Treatment Policy strategy, it is assumed that 10% of participants in the study will 
discontinue IMP or step-up maintenance therapy resulting in a null treatment effect in this 
group of participants, such that the estimated overall hazard ratio is increased by 0.025. 
Therefore assuming, a 27.5% reduction in the risk of a first severe exacerbation with BDA 
MDI compared to AS MDI and a 1 year first severe exacerbation event rate of 21% in the AS 
MDI arm, 350 first severe exacerbation events are required to achieve 85% power, with a 2-
sided significance of 5%.
The estimated total number of participants to be randomized to treatment is 1910 to achieve 
the overall target number of 350 events. However, if during the study the observed first severe 
exacerbation rate is higher than expected then the required number of events may be met with 
less participants and recruitment will be stopped prior to reaching 1910 participants 
randomized. Similarly, if during the study the observed blinded first exacerbation rate is lower 
than predicted, the number of participants randomized may be increased to approximately 
2500 to ensure the required number of first severe exacerbations is achieved. Any assessment 
of accumulating data will be performed on pooled, blinded data. The timing and procedure for 
blinded sample size assessment will be documented in the SAP. 
An unblinded interim analysis for efficacy is planned once 50% of the events have been 
observed (172 events total), based on the primary analysis of the primary endpoint. Alpha 
spending will be governed through the O’Brien-Fleming approach, where 0.003 will be spent 
at the interim to assess significance. If efficacy cannot be established at the 50% of target 
number of event threshold, the study will continue until 350 total first events are observed or 
approximately 2500 participants have been randomized and completed treatment and assessed 
at alpha=0.049. If more than 172 events are available, the alpha will be adjusted accordingly 
(DeMets, 1994). The interim analysis, with unblinding firewalls, will be addressed in the Data 
Review Committee charter and administered by a separate unblinded analysis team. 
If the study completes, ie, all participants are treated for one year, without reaching the 
required number of events then all planned analyses will be conducted with the number of 
events that have occurred as of completion of the study.


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1.2
Schema
Figure 1
Study Design
Abbreviations: R = randomization; ICS: Inhaled corticosteroids; LTRA: Leukotriene receptor agonist; 
SABA: Short -acting β2 agonist








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j AIRQ version with 12-month recall period will be used at Screening, Randomization and EOS or Early Study/ IMP Discontinuation visits. AIRQ version with a 
3-month recall will be used at other visits as indicated above. AIRQ is performed at both screening/re-screen and randomization, however, where 
screening/re-screen and randomization is performed on the same day, the AIRQ questionnaire will only be completed once. 
k AEs & SAEs collected from time of eConsent.
l IMP will be dispatched at randomization (V2) and will only be dispatched between V3and V8 if required
m Participants will be trained on the correct MDI technique and management of the device and sensors in accordance with the IFU before administering the first 
dose at V3. The first dose will be taken during the telemedicine visit to enable site personnel to assess MDI inhalation technique and ensure the sensor is 
attached appropriately as part of participant training.
n At each visit site staff to check if participants have sufficient supplies and any concerns with equipment use (including inhalers and the digital sensor 
attachments).
o Pre-paid packaging for the return of all IMP will be provided to participants. At the EOS or at early study/IMP discontinuation, participants will place all 
remaining used and unused IMP in the pre-paid packaging and return to Sponsor.
p The interval between screening and randomization may be up to 28 days. The screening period may be extended to collect documentation to confirm the asthma 
diagnosis only in the event that information has not been received within 28 days of consent. The screening period cannot be extended >56 days for any reason. 
See Section 5.1 for details.
q Participants who initially screen failed due to failure to receive confirmatory medical records within the original 28-day screening period, use of corticosteroids 
within 6 weeks of Screening Visit 1 or who were hospitalized for asthma within 3 months of Screening Visit 1 may re-screen once. Participants who re-screen 
must complete all Visit 1 procedures during re-screening and satisfy eligibility criteria before being permitted to randomize into the study. Participants who fail 
to satisfy eligibility criteria during re-screening cannot be re-screened for a second time.


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2
INTRODUCTION
Bond Avillion 2 Development LP (Sponsor) is studying BDA MDI (budesonide/albuterol) 
pressurized inhalation suspension product in patients with asthma, in partnership with 
AstraZeneca. BDA MDI was approved by the Food and Drug Administration on 10 Jan 2023 
for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of 
exacerbations in patients with asthma 18 years of age and older (NDA 214070); AstraZeneca 
Pharmaceuticals LP is the New Drug Application (NDA) holder. Please refer to the current 
Investigator’s Brochure (IB) for additional information on BDA MDI and the AS MDI 
(albuterol) pressurized inhalation suspension product.
2.1
Study Rationale
The aim of this study is to evaluate the efficacy and safety of BDA MDI, used as needed, in 
participants with asthma previously receiving SABA alone or SABA as needed plus on a 
background of either low-dose ICS or LTRA. The rationale for BDA MDI to be used as a 
rescue therapy is based on the provision of rapid relief of asthma symptoms by albuterol while 
simultaneously treating underlying inflammation with budesonide. Use of BDA MDI will be 
driven by day-to-day symptom levels and will follow a patient’s natural behavior to treat 
symptoms when they arise and thus treatment for inflammation will be provided when needed 
most. Safety and efficacy of BDA MDI will be compared with AS MDI because albuterol is 
the standard of care rescue therapy in the US. 
The study will evaluate the efficacy of as-needed BDA MDI (used at a dose of 
budesonide/albuterol 160/180 μg) in reducing the risk of severe asthma exacerbations 
(Section 8.2.1.3), compared with AS MDI as needed (used at a dose of albuterol 180 μg) 
either alone or on top of participants' usual low-dose ICS or LTRA maintenance therapy in 
approximately 1910 participants 12 years of age and older. The study will also investigate the 
effect of BDA MDI on the rate of severe asthma exacerbations, total annualized SCS use, 
asthma-related healthcare resource utilization, asthma control and health-related quality-of-
life. Safety will be assessed through the collection of AEs and SAEs. By employing a 
decentralized study delivery model, with all visits conducted virtually, it is anticipated to reach 
a broader population of asthmatic patients who typically might not consider participating in 
clinical trials due to travel or time commitments.
2.2
Background
Asthma is a common, chronic disease; it is estimated that globally over 300 million people are 
living with asthma (Dharmage, 2019). With an estimated prevalence of 7.8%, approximately 
25 million individuals in the US were living with asthma in 2019 (CDC, 2022). Despite recent 
advances in our understanding, the frequency of emergency department visits due to asthma 
has remained relatively unchanged in the last 15 years and in 2018, there were more than 
1.6 million emergency department visits due to asthma (CDC, 2022), indicating there 


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continues to be substantial unmet patient needs for improved treatment alternatives to reduce 
asthma exacerbations. 
Asthma is an unpredictable and heterogeneous disease with a variable clinical course driven 
by airway inflammation, leading to bronchial hyperreactivity and corresponding symptoms 
(GINA, 2022). Patients tend to focus on immediate symptom relief leading to a reliance on 
rescue medication, such as albuterol, a short-acting β-agonist [SABA] (Partridge, 2006; 
Lugogo, 2019). Data from a US claims database from between 2010 and 2017 showed that in 
patients ≥12 years, 51% were receiving SABA only (IBM® Market Scan). SABAs induce 
smooth muscle airway relaxation and improve asthma symptoms short-term, but do not 
address underlying airway inflammation and exacerbation risk increases with increased SABA 
use (Lugogo, 2019). Preventing severe exacerbations is imperative as they pose a significant 
burden to patients and have potentially life-threatening consequences. Severe exacerbations 
require treatment with SCS; SCS address inflammation, but also increase risk of short- and 
long-term adverse reactions. Reliance on SABA is consistent across all asthma severities and 
age groups and regardless of maintenance therapy (Lugogo, 2020). 
Asthma exacerbations typically follow exposure to environmental triggers (Lambrecht, 2012; 
Lambrecht, 2015; Yawn, 2008). Increases in airway inflammation contribute to worsening of 
asthma symptoms, prompting patients to use their rescue medication. Inhaled corticosteroids 
(ICS), such as budesonide, treat inflammation and there is evidence of a ‘window of 
opportunity’ during periods of worsening symptoms in which the timely administration of ICS 
can prevent symptoms developing into an exacerbation (Tattersfield, 1999; Balter, 2008; 
Larsson, 2020; Thomas, 2015). 
The clinical efficacy of concomitant anti-inflammatory ICS and rapid-acting bronchodilators 
has been demonstrated in patients with moderate to severe asthma using ICS-formoterol as 
rescue on top of ICS-long-acting beta-2-agonist (LABA) maintenance. This combination 
reduced the relative risk of severe exacerbations by more than 30% compared with patients 
using ICS-LABA as maintenance and SABA as rescue (Kuna, 2007; O’Byrne, 2005; 
Rabe, 2006; Bousquet, 2007). Data also show that in mild asthma, patients taking the fixed-
dose combination of budesonide-formoterol as needed have greater protection from severe 
exacerbations versus those taking as-needed SABA alone, with no increase in adverse effects 
(Bateman, 2018; O’Byrne, 2018, Beasley, 2019). 
These results are reflected in the 2022 Global Initiative for Asthma (GINA) report, where as-
needed ICS-formoterol is the preferred (Track 1) rescue therapy at all treatment steps in 
patients 12 years of age and older, and also as an alternative option for patients aged 6 to11 
years (GINA, 2022). The recently updated US National Asthma Education and Prevention 
Program (NAEPP) Expert Panel Report-4 (EPR-4; 2020) also recommends the use of 
concomitant ICS plus SABA as needed for patients 12 years and older with mild persistent 


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asthma.
BDA MDI is a fixed-dose combination product containing an ICS (budesonide) and a SABA 
(albuterol), two established asthma medications with well-known safety and efficacy profiles, 
in a novel Co-suspension Delivery Technology™ formulation. BDA MDI is being developed 
to provide a rescue alternative for the control of acute symptoms and to provide prevention 
against worsening of asthma symptoms and severe asthma exacerbations requiring systemic 
steroids or hospitalization in patients with asthma aged 4 years and older. BDA MDI is 
planned to be used as needed alone or on top of any regularly scheduled maintenance asthma 
therapy. BDA MDI would be the first fixed-dose rescue medication containing both albuterol 
and an ICS in the US, addressing the need to further reduce the risk of severe asthma 
exacerbations.
Results from the recently completed Phase III MANDALA study demonstrated a significant 
reduction in the risk of severe asthma exacerbations with BDA MDI compared with albuterol, 
both used as needed, in participants with moderate to severe asthma on a background of ICS 
containing maintenance therapy without an increase in ICS related AEs (Papi, 2022).
The current study will further evaluate the effect of BDA MDI on the reduction of 
exacerbation risk in participants with asthma using either no maintenance therapy or receiving 
either low-dose ICS or LTRA.
A detailed description of the chemistry, pharmacology, efficacy, and safety of BDA MDI is 
provided in the IB.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of BDA 
MDI may be found in the IB. 


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2.3.1
Risk Assessment
Table 2
Risk Assessment
Risk Category
Potential risk of 
clinical significance
Summary of data/rationale 
for risk
Mitigation strategy
Study IMP(s) BDA 
MDI
x
Increased local or 
systemic 
corticosteroid 
side-effects
x
Participants using >12 
inhalations daily may 
potentially be at an 
increased risk of local 
or systemic 
corticosteroids side 
effects including 
adrenal suppression and, 
in adolescent 
participants, growth 
retardation
x
Participants instructed 
to take no more than 
12 inhalations in a 24-
hour period
x
Investigators to assess 
overall inhaler usage 
to check for excessive 
use
Study procedures
x
Fully decentralized 
study delivery 
model with no in-
person contact with 
study participants
x
Exclusion of 
participants due to 
the reliance on 
technology
x
Difficulty ensuring the 
participant has 
understood how to use 
the study inhaler and 
sensor attachment 
correctly
x
Lack of engagement due 
to virtual visits
x
Loss of data due to 
connection issues
x
Digital exclusion for 
participants either due 
to age, socio-economic 
factors, or a dislike of 
technology
x
Participants will be 
required to 
demonstrate correct 
inhaler technique 
during the 
telemedicine 
Treatment Initiation 
visit (Visit 3) and be 
required to watch a 
training video which 
demonstrates best 
practice
x
Initiatives to enhance 
the participant 
experience
x
Use of the 
participant’s own 
smartphone. 
x
Ensuring the 
technology is simple 
to use
x
Dedicated technical 
support desk
BDA: Budesonide/albuterol; MDI: Metered-dose inhaler


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2.3.2 Benefit Assessment
For participants randomized to BDA MDI, the combination of budesonide and albuterol may 
provide benefits to participants in terms of potential reduction in the risk of asthma 
exacerbation and improvement in the control of asthma symptoms beyond what is typically 
seen with albuterol alone. For those participants randomized to receive AS MDI, the benefit of 
the treatment is unchanged. 
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures to minimize risk to participants in this study, the potential 
risks identified in association with BDA MDI are justified by the anticipated benefits that may 
be afforded to participants with asthma.




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Objectives
Estimand* description/Endpoints
To evaluate the efficacy of BDA 
MDI as needed compared with AS 
MDI as needed on the risk of severe 
asthma exacerbations, participants 
≥18 years
x
Population: Adult participants (≥18 years) with asthma 
previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: time to first severe asthma exacerbation 
x
IE handling: A Treatment Policy strategy will be implemented in 
which all observed data while participants are in the study, 
regardless of IEs or whether they are on randomized study 
treatment, will be included in the estimation procedure
x
Summary measure: Adjusted hazard ratio
To evaluate the efficacy of BDA 
MDI as needed compared with AS 
MDI as needed on the rate of severe 
asthma exacerbations, participants 
≥12 years
x
Population: Adult and adolescent participants (≥12 years) with 
asthma previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: annualized rate of severe asthma exacerbations
x
Summary measure: Adjusted rate ratio
x
Treatment and strategy for IEs are the same as for the primary 
objective
To evaluate the efficacy of BDA 
MDI as needed compared with AS 
MDI as needed on the rate of severe 
asthma exacerbations, participants 
≥18 years
x
Population: Adult participants (≥18 years) with asthma 
previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: annualized rate of severe asthma exacerbations
x
Summary measure: Adjusted rate ratio
x
Treatment and strategy for IEs are the same as for the primary 
objective
To evaluate the effect of BDA MDI 
as needed compared with AS MDI 
as needed on
systemic glucocorticoid exposure 
associated with asthma 
management, participants ≥12 years
x
Population: Adult and adolescent participants (≥ 12 years) with 
asthma previously receiving SABA alone or SABA as needed on a 
background of low-dose ICS or a LTRA
x
Endpoint: total amount (mg/year) per participant of systemic
glucocorticoid exposure 
x
Summary measure: Difference in unadjusted treatment means
x
Treatment and strategy for IEs are the same as for the primary 
objective
x
Endpoint: total days of systemic glucocorticoid exposure
x
Summary measure: Difference in unadjusted treatment means 




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Objectives
Estimand* description/Endpoints
To evaluate the effect of BDA MDI 
as needed compared with AS MDI 
as needed on quality of life
x
Change from baseline in EQ-5D-5L domain score, at Week 4, 
Week 28 and Week 52
* See Section 9.4, Statistical Analyses, for additional details.
AE: Adverse events; AIRQ: Asthma Impairment and Risk Questionnaire; AS: Albuterol Sulfate: BDA: 
Budesonide/albuterol; EQ-5D-5L: EuroQol-5 Dimension 5 Level; HCRU: Healthcare resource use; ICS: Inhaled 
corticosteroid; IE: Intercurrent event; IMP; Investigational Medicinal Product; LTRA: Leukotriene receptor 
agonist; MDI; Metered-dose inhaler; SABA: short-acting β2-agonist; SAE: Serious adverse event. 


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4
STUDY DESIGN
4.1
Overall Design
This is a phase IIIb, US, multicenter, randomized, double-blind, parallel-group, event-driven, 
variable-length, decentralized study comparing the efficacy and safety of BDA MDI (used at a 
dose of budesonide/albuterol 160/180 μg) with AS MDI (used at a dose of albuterol 180 μg), 
both administered as needed for up to 12 months. Participants 12 years of age and older with 
asthma will be recruited with all visits conducted virtually.
Eligible participants must be using as-needed SABA alone, or as-needed SABA on a 
background of either low-dose ICS or a LTRA, for the treatment of asthma. Participants must 
have had ≥2 prescriptions for either a SABA inhaler or ≥1 prescription for a SABA inhaler 
plus ≥1 prescription for an ICS inhaler or a LTRA in the 12 months prior to enrollment. 
Participants continue their own maintenance treatment, if receiving. In addition, participants 
must have used a SABA on≥2 days, for the relief of asthma symptoms, in the previous 2 
weeks prior to Visit 2 plus an AIRQ score of ≥2 at Screening.
In order to achieve 350 first severe asthma exacerbation events, approximately 
2122 participants from around 40 to 50 centers located in the US will be screened to ensure 
1910 participants randomized 1:1 to receive one of the following two treatment to be used as 
needed:
x
BDA MDI 160/180μg (given as 2 inhalations of BDA MDI 80/90 μg per actuation) up 
to a maximum of 12 inhalations per day
x
 AS MDI 180μg (given as 2 inhalations of AS MDI 90 μg per actuation) up to a 
maximum of 12 inhalations per day
Participants will be stratified by pre-study asthma medication (SABA only, low-dose ICS + 
SABA and LTRA + SABA) and number of prior severe exacerbations (0, ≥1) in the 12 months 
prior to Screening visit. 
Participants who are not females of child-bearing potential and who meet all the inclusion 
criteria and none of the exclusion criteria at screening may be screened and randomized 
(Visit 1 & Visit 2) at the same visit or on separate visits. For females of child-bearing 
potential, following the initial screening assessment, a urine pregnancy test, with high 
sensitivity is required. Female participants of child-bearing potential will only be eligible for 
randomization following confirmation that the urine pregnancy test is negative. The interval 
between screening and randomization may be up to 28 days. The screening period may be 
extended to collect documentation to confirm the asthma diagnosis only in the event that 
information has not been received within 28 days of consent. The screening period cannot be 
extended > 56 days for any reason. See Section 5.1 and Schedule of Activities (SoA) (Table 1) 


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for details. 
The maximum daily dose of BDA or AS MDIs should not exceed 12 inhalations (6 doses) 
during one calendar day. Asthma maintenance medication (low-dose ICS or LTRA) will be 
continued throughout the study for participants enrolled on these medications.
All visits will be conducted virtually with study-related supplies shipped directly to the 
participant. The randomization step will trigger a shipment of the investigational medicinal 
product (IMP). As the IMP is being sent direct to the participant’s home, the Treatment 
Initiation Visit (Visit 3) will occur once the participant is in receipt of the study medication 
(expected to be within 7 days following randomization). Participants will also receive a 
 sensor attachment (referred to as an MDI sensor, or sensor [see Section 8.8]) 
compatible with the study inhalers that will be used to capture each actuation of study inhaler 
use throughout the study. A total of 2 sensors will be sent to allow more than 1 inhaler to be 
used concurrently (eg, kept in different locations for convenience). Training on how to use the 
study inhaler and inhaler sensor will be provided at the Treatment Initiation visit (Visit 3) with 
additional training materials available.
Following treatment initiation, the treatment period for any individual will be for a maximum 
of 52 weeks and a minimum of 12 weeks depending on when a participant is randomized 
(Visit 2) into the study and when the required number of severe asthma exacerbations events is 
reached (defined as the Primary Completion Date [PCD]). Subsequent visits will be performed 
after 4 weeks (Week 4) and then at 12-weekly intervals (Weeks 16, 28, 40 and 52) or until the 
PCD has been reached. Providing participants have received a minimum 12 weeks treatment, 
the last EOS treatment visit will then be scheduled within 4 weeks of the PCD. 
Between scheduled visits, participants will receive a message via a smartphone app 
(
 
) bi-weekly to inquire as to whether they have needed to seek medical help as 
a result of their asthma worsening or any asthma-related unscheduled healthcare related 
contacts/visits. 
If the participant replies yes, then the Investigator/site staff will receive a notification to 
contact the participant to collect further information.
During any scheduled or unscheduled contact, the Investigator or site staff will review and 
query the participant regarding:
o
AEs and SAEs 
o
Any documentation available suggesting or supporting of a severe asthma exacerbation 
including:
x
Any medical review (primary care/emergency room/hospitalization)


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x
Any SCS use
x
Any changes in asthma medication
x
The details of any asthma signs/symptoms experienced before the exacerbation 
o
Any change in concomitant medication(s)
o
Any issues using the inhalers/digital sensors or the study portal/app
o
Review number of doses/inhalers used and whether new study inhalers are required by 
the participant 
o
Healthcare utilization related to asthma and absences from work/school due to asthma 
Between visits participants will be advised to contact the Investigator immediately if:
o
They need to seek medical help for worsening asthma (eg, go to their General 
Practitioner, urgent care or hospital) or start SCS
o
Their usual healthcare provider makes any changes to their asthma treatment
o
They are concerned they will run out of IMP prior to the next study visit
o
They are concerned the allocated inhalers and/or digital sensors are not operating 
correctly
o
They wish to withdraw from the study
The study will be completed when the last participant has EOS or premature discontinuation 
(Early Study/ IMP Discontinuation) visit. Participants who discontinue IMP prematurely from 
the randomized treatment period will be encouraged to complete all scheduled study visits and 
assessments.
An Independent DMC is planned for this study to review unblinded data at the time of the 
Interim Analysis.
4.2
Scientific Rationale for Study Design
The Phase III MANDALA study including patients with moderate to severe asthma 
demonstrated that BDA MDI used as needed, significantly reduced the risk of a severe asthma 
exacerbation compared with albuterol alone by 27%. 
Patients with asthma often rely on SABAs for symptom-relief. Studies with 
formoterol/budesonide (Bateman, 2018; Beasley, 2019; Hardy, 2019; O’Byrne, 2018; 


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O’Byrne, 2021) and with albuterol/beclomethasone (Papi, 2007) used as needed in patients 
who were previously receiving SABAs alone, or a SABA in addition to maintenance treatment 
with low-dose ICS demonstrated a reduction in exacerbation risk compared with SABA alone. 
In the proposed study, it is anticipated that BDA MDI used as needed, will reduce the risk of 
severe asthma exacerbations compared with albuterol as needed alone in patients previously 
treated with SABA as needed alone or with low-dose ICS or LTRA.
Exacerbations are a significant manifestation of asthma and they are physically threatening 
and emotionally significant for many patients (Sastre, 2016). The use of SCS to manage 
exacerbations is associated with undesirable long-term adverse effects, even when used 
relatively infrequently (Bleecker, 2020; Price, 2018) and the treatment of exacerbations has 
additional associated healthcare related costs. Time to first severe asthma exacerbation has 
therefore been chosen as the primary efficacy endpoint, to provide both a reliable and valid 
measurement of the treatment effect.
A decentralized study design, with all visits conducted virtually and no planned in-clinic 
visits, has been chosen as a means of widening study participation to patients who might 
otherwise not have considered enrolling into a clinical trial due to time or geographical 
constraints. By conducting all the visits virtually, it is hoped to allow participants to attend 
visits at their convenience, without the need to travel to sites.
All study-related supplies will be delivered directly to the participant’s home. As the mono 
components for BDA MDI, ie, budesonide and albuterol, have been approved for many years 
and have been widely used in clinical practice for the management of asthma for over 
40 years, the safety profiles for both drugs are well documented. The tolerability of BDA MDI 
was also demonstrated in the Phase III program. Furthermore, all participants will already 
have been using a SABA (likely to be albuterol) to be eligible for the study. Therefore, it is 
considered acceptable to deliver the study medication directly to the participant and for safety 
monitoring to be limited to the collection of AEs and SAEs.
4.2.1 Participant Input into Design
Interviews were conducted with 9 individuals with asthma, 4 with mild and 5 with moderate 
disease. Although the current study is targeted towards milder asthma, the feedback with 
regards to the decentralized study model was felt to be equally applicable from the 
participants with mild or moderate asthma. 
Participants were enthusiastic about the decentralized model seeing it as way of improving 
convenience and increasing accessibility to trial participation, although they indicated that 
there may be some individuals who would prefer more in-person contact and less reliance on 
technology. Participants highlighted a number of areas of importance to themselves, including 
the ready availability of study-related information and the importance of data privacy. 


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Participants mentioned their concern about having their reliever/rescue inhaler replaced with 
study medication. The participant information will emphasize that the study inhaler will 
contain similar medication as their current reliever/rescue medication (ie, albuterol) or similar 
medication but with an additional medication (ie, budesonide) included. Participants also 
mentioned that visits should be described as ‘virtual’ rather than ‘remote’ or ‘telemedicine’ 
visits, the meaning of which were less intuitive. The term virtual (rather than remote) to 
describe the visits will be used in all participants facing material.
4.3
Justification for Dose
For this study, the term “dose” refers to 2 inhalations from the MDI.
The MANDALA Phase III study demonstrated that BDA MDI, taken as needed at the now 
approved dose of budesonide/albuterol 160/180 μg, was both efficacious and well-tolerated in 
a population with moderate to severe asthma. A reduction in the risk of severe asthma 
exacerbation and a reduction in total SCS exposure was shown with BDA MDI compared with 
albuterol 180 μg alone. There was no increase in the frequency of ICS related AEs compared 
with albuterol alone. The pattern of as-needed usage was similar between BDA MDI and AS 
MDI.
4.4
End of Study Definition
For the majority of participants, they will be considered to have completed the study if they 
have completed 52 weeks of treatment and the EOS visit. If the target number of the 350 
required first severe asthma exacerbations is reached (PCD) before all participants have 
completed 52 weeks, then participants still in the trial after this timepoint will complete an 
EOS once they have received ≥12 weeks of treatment. The EOS visit should be completed 
within 4 weeks of the PCD, provided that the participant has received ≥12 weeks of treatment. 
The study completion is defined as the date of the last visit of the last participant in the study.


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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be ≥12 years of age, at the time of signing the electronic informed 
consent form (eICF).
Note: For participants from 12 years of age to age of majority, their parents/legal guardian 
must provide signed consent, as appropriate, and participants will sign an assent form.
Type of Participant and Disease Characteristics
2. Diagnosis of asthma by a prescribing healthcare professional (HCP). The asthma diagnosis 
should be confirmed and documented; suitable documentation includes:
a.
Medical records or electronic medical records
b. A letter from or documented telephone conversation with the treating HCP office
c.
Electronic medical (health) record (eg, MyChart) documentation of the presence of 
asthma in a written exchange between the participant and treating HCP 
d. Insurance forms or other equivalent documentation with asthma diagnosis code
e.
Other forms of documentation may be considered for suitability by the Medical 
Monitor.
3. Participants actively using SABA alone or SABA on a background of either low-dose ICS 
or LTRA with the following requirements:
a) SABA alone: ≥2 prescriptions for a SABA inhaler in the past 12 months prior 
to enrollment.
b) SABA on a background of low-dose ICS monotherapy: ≥1 prescription for a 
SABA inhaler and ≥1 prescription for a low-dose ICS inhaler in the 12 months 
prior to enrollment.
Note: Refer to Appendix G for doses of ICS
c) SABA on a background of a LTRA: ≥1 prescription for a SABA inhaler and 
≥1 prescription for a LTRA in the 12 months prior to enrollment.


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Participants must present their medication including any inhaler(s) during 
Screening Visit 1 and a picture of the medication(s) are required to be captured 
in the 
 platform. For participants on SABA alone, verbal 
confirmation by the participant that they have used at least one additional 
inhaler in the past 12 months will be considered acceptable.
4. Self-reported use of a SABA on ≥2 occasions, in response to symptoms (ie, not for 
exercise prophylaxis only), in the previous 2 weeks prior to enrollment, Visit 2.
5. An AIRQ score of ≥2 at Screening (Visit1/re-screen) and Randomization (Visit2) where 
applicable. Note, where screening Visit1/re-screen and randomization occur on the same 
day, AIRQ will only be completed once.
Reproduction
6. Females of child-bearing potential must have a negative pregnancy test prior to 
randomization and 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 participant. 
Therefore, complete abstinence is an acceptable method of contraception only if it is 
consistent with the preferred and usual lifestyle of the participant.
(b) If a female of child-bearing potential agrees to prevent pregnancy by using 1 of the 
following effective methods of birth control from the date the eICF is signed until 2 weeks 
after the last dose of IMP is taken:
i. Hormonal contraception (eg, oral contraceptive, contraceptive implant, or injectable 
hormonal contraceptive)
ii. Single-barrier birth control (eg, male condom, cap, diaphragm, or sponge with 
spermicide)
iii. Maintenance of a monogamous sexual relationship with a male partner who has 
been surgically sterilized by vasectomy
x
Highly effective birth control methods include: sexual abstinence (periodic 
abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods, 
declaration of abstinence for the duration of exposure to the study IMP and 
withdrawal are not acceptable methods of contraception), a vasectomized partner, 
Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel 


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intrauterine system, Depo-Provera™injections, oral contraceptive, and Evra 
Patch™, Xulane™, or NuvaRing®.
(c) Note: Females are considered to be of non child-bearing 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 or 
bilateral salpingectomy, hysterectomy, tubal ligation, or other permanent birth control 
measures. For purposes of this protocol, menopausal females are defined as females that 
are amenorrheic for 12 consecutive months or more after cessation of all exogenous 
hormonal treatment prior to the planned date of randomization.
(d) Participants 12 years and over specific recommendations: if participant is female and 
has reached menarche or has reached Tanner stage 3 breast developments (even if not 
having reached menarche), the participant will be considered a female of child-bearing 
potential.
7. Male participants who are in heterosexual relationships must be surgically sterile or agree 
to use an effective method of contraception (condom) if the female partner does not use 
contraception from the date the eICF is signed until 2 weeks after their last dose. Male 
participants must not donate sperm during their study participation period.
Informed Consent
8. Capable of giving signed eICF (including assent with parental / legal guardian consent in 
12 years of age to age of majority) as described in Appendix A which includes compliance 
with the requirements and restrictions listed in the eICF and in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Any evidence of significant lung disease other than asthma, such as chronic obstructive 
pulmonary disease, emphysema, idiopathic pulmonary fibrosis, sarcoidosis etc or any 
other significant disease (like malignancies or severe chronic diseases) that by 
Investigator judgment would interfere with the participant being able to comply with 
study procedures or complete the study. 
2
Hospitalization due to asthma in the 3 months prior to enrollment or self-reported 
admission to the Intensive Care Unit with life-threatening asthma at any time in the past. 
Participants who were screen-failed due to hospitalization within the 3 months prior to 
enrollment may be re-screened once when the participant is more than 3 months 
post-hospitalization. Participants who reported an Intensive Care Unit admission with life 
threatening asthma may not be re-screened.


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Prior/Concomitant Therapy
3
Self-reported use of inhaled LABA, theophylline, inhaled anticholinergic agent, cromone
or medium/high dose ICS daily, as regular maintenance asthma therapy in the 3 months 
prior to enrollment.
Note: Refer to Appendix G for doses of ICS
4
Self-reported use of SCS for the treatment of asthma and any other condition in the 6 
weeks prior to enrollment. Participants screen failed for this reason may be re-screened 
once, with their re-screening visit scheduled >6 weeks after last use of SCS.
5
Participants with a home supply of oral corticosteroids (OCS) to be used in the case of an 
asthma exacerbation or any other condition that could require a course of OCS, that are 
not willing to commit to the treating physician to stop using this medication for the 
duration of the study.
6
Receipt of any marketed (eg, omalizumab, mepolizumab, reslizumab, benralizumab, 
dupilumab, tezepelumab) or investigational biologic for the treatment of asthma at any 
time in the past.
7
Receipt of bronchothermoplasty.
8
Use of a SABA prophylactically primarily to prevent exercise induced bronchospasm and 
not to treat symptoms.
9
Currently receiving systemic treatment with potent cytochrome P3A4 inhibitors (eg, 
ketoconazole, itraconazole, and ritonavir).
Prior/Concurrent Clinical Study Experience
10 Participation in another clinical study with an IMP for any condition administered in the 
last 3 months or 5 half-lives prior to randomization, whichever is longer.
11 Participants with a known hypersensitivity to albuterol, budesonide or any of the 
excipients of the IMP.
Other Exclusions
12 Involvement in the planning and/or conduct of the study (applies to AstraZeneca, Bond 
Avillion 2, Avillion LLP, contract research organization (CRO)/third-party vendor staff 
and/or staff at the study site).
13 Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
14 Previous screening enrollment or randomization in the present study, except where 
re-screening is permitted (see Section 5.5).
15 For females only– currently pregnant (confirmed with positive pregnancy test) or breast-
feeding.


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16 Participants without access to a smartphone or the internet.
17 Study Investigators, sub-Investigators, coordinators, and their employees or immediate 
family members, or employees of the Sponsor or any trial site.
18 Participants where a member of their household is currently enrolled in the study.
5.3
Diversity and Inclusion of Racial and Ethnic Populations in the 
Study
Asthma symptoms affect all races and ethnicities. Data collected from 2017 to 2019 indicate 
that within the racial, non-Hispanic populations of the US, the prevalence of asthma is 7.7% 
among Whites, 10.6% among Blacks, 3.8% among Asians, 10.7% among native populations 
(American Indians/Native Americans), and 12.6% among multiple races (identifies with more 
than one racial group). Prevalence among the ethnic Hispanic population is 6.6% 
(CDC, 2022). This decentralized study may have greater potential to recruit under-represented 
populations, which are often limited in enrollment to clinical studies, due in part to the lack of 
proximity to clinical sites and related transportation challenges. The recruitment strategy is a 
multi-media outreach campaign across the US including areas in which diverse populations 
can be found (eg, urban areas, border regions), and Investigators should make every effort to 
enroll a racially and ethnically diverse population in the study. The Sponsor plans to capture 
race and ethnicity in the study demographics and report results in the clinical study report, 
together with gender and age.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study IMP. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details (reason for screen failure), eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
only be re-screened once for specific reasons as specified within Section 5.1, Section 5.2 and 
Section 5.5.
5.5
Re-screening
Participants may be eligible to re-screen only under the following circumstances:
1. Participants originally consented under protocol version 1.0 who were unable to provide 
medical records satisfying asthma diagnosis or asthma medications within 28 days of 
Screening Visit 1 and were therefore screen-failed for this reason.


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2. Participants who had been hospitalized due to asthma within 3 months of Screening 
Visit 1 may re-screen once they are outside the exclusionary window.
3. Participants who had received SCS within 6 weeks of Screening Visit 1 may re-screen 
once they are outside the exclusionary window.
Participants cannot re-screen for any other reason and can only re-screen once. All procedures 
at Visit 1 must be repeated and eligibility confirmed during re-screening.


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6
STUDY INVESTIGATIONAL MEDICINAL PRODUCT
Study IMP is defined as any IMP(s), marketed product(s) or placebo intended to be 
administered to or medical device(s) utilized by a study participant according to the study 
protocol.
Study IMP in this protocol includes BDA MDI and AS MDI and will be referred to as IMP.
6.1
Study IMP(s) Administered
6.1.1
Investigational Medicinal Products
BDA MDI is formulated (Table 4) as micronized budesonide and micronized albuterol co-
suspended with spray-dried particles in a hydrofluoroalkane propellant. The co-suspension
formulation ensures that participants receive a consistent delivery of the drugs from each 
actuation of the MDI.
Table 4
Investigational Medicinal Products (IMP)
Arm name
PT027
PT007
IMP name
Budesonide and Albuterol Sulfate 
Pressurised Inhalation Suspension
Albuterol Sulfate 
Pressurised Inhalation Suspension
Type 
Combination
Monotherapy
Dose formulation
Pressurised Inhalation Suspension
Pressurised Inhalation Suspension
Unit dose 
strength(s)
80/90 μg per Actuation
90 μg per Actuation
Dosage level(s)
1 to 6 doses (2 inhalations/dose) per 
day as needed
1 to 6 doses (2 inhalations/dose) per 
day as needed
Route of 
administration
Oral inhalation
Oral inhalation
Use
Experimental
Experimental
Sourcing
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and 
labeling
Study IMP will be provided in an 
MDI. Each MDI will be labeled as 
required in the US
Study IMP will be provided in an MDI. 
Each MDI will be labeled as required 
in the US
Current/former 
name(s) or alias(es)
PT027, BDA MDI
PT007, AS MDI
AS: Albuterol Sulfate; BDA: Budesonide and Albuterol; IMP: Investigational Medicinal Products; 
MDI: metered-dose inhaler; US: United States


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6.2
Preparation/Handling/Storage/Accountability
1)
An order for the study IMP will be raised by the Investigator or designee through the 
Randomization and Trial Supply Management system (RTSM) and will be automatically 
sent to a central depot for processing.
2)
Participants will be given information about the delivery of their IMP at Visit 2 including 
what is included in the delivery, expected timelines and IMP storage information.
3)
The study IMP, including Instructions for Use (IFU) contained within a Home Study 
Guide, will be sent directly to the participants’ home by designated courier from the 
central depot.
4)
The courier delivering the study IMP to the participant will ensure that appropriate 
temperature conditions were maintained during transit for all study IMP received. Any 
study IMP where the temperature conditions were not met will not be handed over by 
courier to the participant and will be returned by the courier to the central depot to be 
replaced.
5)
Only participants randomized in the study may receive study IMP.
6)
The Investigator is responsible for study IMP accountability, reconciliation, and record 
maintenance (ie, confirming receipt by the participant, and reconciliation/final disposition 
records from the central depot). The Investigator or designee will check with the 
participant that they have received the study IMP allocated to them and will check the 
participant’s usage and the remaining quantity of IMP at visits. Should a resupply of IMP 
or a replacement sensor be required, the Investigator or designee will raise an order within 
the RTSM system.
6.2.1
Dose and Treatment Regimens
Study IMP will be used as needed, either to treat asthma symptoms or prophylactically before 
exercise to prevent symptoms. No other reliever products will be used during the treatment 
period.
At randomization (Visit 2), participants who meet the eligibility criteria will be randomly 
assigned to 1 of the following 2 treatment groups in a 1:1 ratio as reliever therapy on top of 
usual care:
x
BDA MDI 160/180μg (given as 2 inhalations of budesonide/albuterol 80/90 μg per 
actuation) as needed
x
AS MDI 180μg (given as 2 inhalations of albuterol 90 μg per actuation) as needed
Randomization will be stratified by pre-study asthma medication (SABA only, low-dose ICS + 
SABA and LTRA + SABA) and number of prior severe exacerbations (0, ≥1) in the 12 months 


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prior to Screening visit.
The maximum daily dosage of study IMP should not exceed 12 inhalations during one 
calendar day (see Section 8.5 for overdose).
Handling instructions for the MDI device will be available for the site to train participants and 
also for the participants to refer to throughout the study.
6.2.2
Labeling
Labels will be prepared in accordance with Good Manufacturing Practice and US regulatory 
guidelines.
The participant will receive a starter shipment containing a suitable number of IMP kits for 
that participant to begin treatment. Each kit contains 2 MDI devices individually wrapped in 
foil bags held within a carton. The MDI devices provided in this study and the packaging and 
labeling of the kits are visually identical to maintain the blind. Additional kits will only be 
dispensed if required and will be ordered through the RTSM by the Investigator. Each kit will 
contain the following blinded labels:
x
Single panel canister label (English only)
x
Single panel actuator label
x
MDI device shield label (single panel, English only) 
x
Foil bag label (single panel, English only) 
x
Single panel carton label
The labels will include the following information:
x
Investigational medicinal product dosage form, route of administration, and quantity of 
dosage units (blinded across all arms)
x
Storage conditions
x
Study Trial Reference
x
Medication ID number
x
Directions for use
The label will include the following standard statements:
x
‘Caution: New Drug – Limited by Federal (or US) law to investigational use.
x
‘Keep out of reach of children’.


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6.2.3
Storage
Study IMP, once received by the participant, should be stored under appropriate conditions: at 
room temperature between 68°F and 77°F (20°C and 25°C, with allowable excursions 
between 15°C and 30 °C) avoiding humid or wet environments and ensuring the inhaler and 
attachment are kept out of reach of children. Participants will receive information on IMP 
storage in a Home Study Guide, and the label in the IMP carton also specifies the appropriate 
storage temperature.
6.2.4
Accountability
Study IMP provided will be used only as directed in the Clinical Study Protocol.
All study IMP will be returned to the approved central depot by the participant at the end of 
their treatment period. Pre-paid packages will be provided to participants to return IMP upon 
completion of their study obligations or on withdrawal from the study. The central depot will 
be responsible for the destruction of IMP after the accountability and reconciliation has been 
performed by the Investigator.
6.2.5
Metered-dose Inhaler: Handling and Cleaning
Detailed handling instructions will be provided to the participant which will cover all aspects 
of using and handling the MDIs. This ‘Instructions for Use’ document (Appendix F) focuses 
on the MDI device. 
The importance of the device cleaning and priming requirements should be emphasized to 
participants. An instructional video will be made available to the participants which will detail 
the instructions for use and cleaning of the device. This will be shown to the participant at 
Visit 3.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Methods for Assigning Treatment Groups
All participants will be centrally assigned to randomized study IMP using a RTSM system. 
Before the study is initiated, the log-in information and directions for the RTSM will be 
provided to each site. Randomization codes will be assigned strictly sequentially in each 
stratum as participants become eligible for randomization. Participants will be stratified by 
background therapy (SABA only, low-dose ICS + SABA and LTRA + SABA) and number of 
prior severe exacerbations (0, ≥1) in the 12 months prior to Screening visit.
Participants who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be randomized or receive IMP. There can be no exceptions to this rule. If a 
participant withdraws from the study after randomization, then his/her participant’s ID number 
cannot be reused. Withdrawn participants will not be replaced.


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Returned study IMP will not be re-dispensed to participants.
6.3.2
Methods for Ensuring Blinding
This is a double-blind study in which BDA MDI and AS MDI are visually identical. 
Participants will be randomly assigned in a 1:1 ratio to receive IMP. Investigators, 
investigational site staff, blinded Sponsor and participants will remain blinded to each 
participant’s assigned IMP throughout the course of the study.
The RTSM will provide the Investigator(s) the kit identification number allocated to the 
participant at the randomization visit and at any subsequent visit where resupply is necessary.
Instructions for this will be described in the RTSM user manual that will be provided to each 
center.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The Investigator will document and report the action to the Sponsor and/or its 
representative, CRO, without revealing the treatment given to participant to the Sponsor 
and/or its representing staff.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to the IMP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented and the database is locked.
The RTSM will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded study IMP will affect the immediate management 
of the participant’s condition, the Investigator has the sole responsibility for determining if 
unblinding of a participants’ IMP assignment is warranted. Participant safety must always be 
the first consideration in making such a determination. If a participant’s IMP assignment is 
unblinded, the Sponsor/CRO must be notified within 24 hours after breaking the blind. The 
Investigator will document and report the action to Sponsor/CRO, without revealing the 
treatment given to participant to the Sponsor/CRO staff.
6.4
Study IMP Compliance
As the study medication is being taken as needed, no assessment of compliance will be made. 
However, the Investigator / authorized delegate will check overall inhaler usage at each 
contact with the participant to ensure that the participant has enough inhalers. The number of 
MDIs sent to the participant, as well as the number of inhalers returned by the participant to 
the central depot at the end of the trial will be captured in the RTSM as well as documented 


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and stored in the Investigator File.
The frequency and timing of actuations of the study IMP will be automatically logged in the 
 app via the participant’s smartphone cellular or wi-fi connection. Data is collected via 
the sensor attached to the MDI and transmitted via Bluetooth. The sensor is provided by 
. In the event there is no connection to upload the data in real time, the sensor has 
offline storage capabilities and will complete the data upload when back online. The usage 
data generated will be visible to the Investigator via
 portal, but not to the 
participant. For the Investigator, this portal will provide additional data to any information 
already provided verbally by the participant as to the how frequently they used the study IMP. 
A total of two sensors will be sent to each participant with their initial ‘starter-shipment’ of 
IMP to allow more than one study inhaler to be used at once. Instructions on attaching the 
sensor to an MDI and pairing the sensor attachment to a smartphone will be provided to the 
participant. Further information on the sensor attachment can be found in the site IMP manual.
6.5
Concomitant Therapy
The Investigator/authorized delegate will collect and record any medication taken from the 
time of Screening (Visit 1) until the final study visit (Visit 8) at virtual study visits. All 
background asthma medications (eg, SABA, ICS and LTRAs) and all other medications taken 
for any reason in the 3 months prior to enrollment, and any concomitant medication(s) during 
the study must be recorded in the electronic Case Report Form (eCRF) along with:
x
Reason for use
x
Dates of administration including start and end dates
x
Dosage information including dose, frequency and route
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants are prohibited from receiving certain concomitant medications (described in 
Section 6.5.3).
Medications or therapies that are not prohibited and neither compromise participant safety nor 
affect study data, as judged by the Investigator, will be permitted and recorded in the 
appropriate sections of the eCRF.
6.5.1 Rescue Medicine
The study IMP will replace the participant’s current asthma rescue medication. It is important 
that the participant is instructed to stop using their current asthma rescue medication (ideally 
storing it somewhere they are unlikely to use it in error for the duration of their study 


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participation) and only use the study medication provided as their asthma rescue medication, 
to be taken as needed, throughout the treatment period.
6.5.2
Maintenance Asthma Therapies
Existing low-dose ICS or LTRA asthma maintenance therapy are permitted to be used as 
maintenance therapy on study as specified in the inclusion criteria. 
During the study, participants should maintain stable dosing of their maintenance therapy as 
presented at baseline, however, dose changes to maintenance therapy are permitted if 
clinically indicated. Where possible, Investigators should contact the study medical monitors 
in advance of any proposed change to maintenance therapy for study participants; 
considerations should be made to participant drug compliance and other factors in advance of 
making changes to maintenance therapy. 
All changes in asthma maintenance therapy should be clearly documented in the eCRF.
6.5.3
Allowed and Prohibited Medication
The inclusion and exclusion criteria sections of the protocol define concomitant medications 
that, if taken in the period prior to randomization, would lead to participant screen failure.
In addition, unless clinically indicated as determined by a physician, the following 
medications are allowed or prohibited (for the time periods stated):


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Table 5
Allowed and Prohibited Medications
Medication
Allowed/Prohibited
Details
SABA (short-acting β2-agonists, 
eg, albuterol, levalbuterol)
Prohibited
Participants should stop using their 
existing SABA and replace it with the 
study IMP MDI provided
Background (maintenance) asthma 
medication:
Low-dose ICS or a LTRA
Allowed, only for 
participants receiving 
maintenance therapy at 
baseline or if clinically 
indicated.
Participants should maintain their 
existing low-dose ICS or their LTRA. If 
the medication is stopped, or the dose 
adjusted during the trial this must be 
recorded in the eCRF
Background (maintenance) asthma 
medication:
Inhaled LABA, theophylline, 
inhaled anticholinergic agent, 
cromone or medium/high dose ICS 
daily
(Refer to Appendix G for doses of 
ICS)
Prohibited
Prohibited as regular maintenance 
asthma therapy within 3 months of 
enrollment per exclusion criterion 3.
Systemic corticosteroids
Prohibited unless to treat a 
severe asthma exacerbation 
or in an equivalent acute 
situation
Systemic corticosteroid use is only 
permitted to treat severe asthma 
exacerbation events or for unavoidable 
medical events if clinically indicated. 
Chronic use of systemic corticosteroids 
is prohibited. Use of systemic 
corticosteroids is prohibited within 6 
weeks of enrollment. 
Biologics for the treatment of 
asthma
Prohibited
Receipt of any marketed (eg, 
omalizumab, mepolizumab, reslizumab, 
benralizumab, dupilumab, tezepelumab) 
or investigational biologic for the 
treatment of asthma at any time in the 
past
Potent cytochrome P3A4 
inhibitors
Prohibited
Current treatment with potent 
cytochrome P3A4 inhibitors (eg, 
ketoconazole, itraconazole, and 
ritonavir) 
Topical (dermal) and intraarticular 
corticosteroids
Allowed


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Medication
Allowed/Prohibited
Details
Antihistamines
Allowed
Allergen Immunotherapy
Allowed
Stable allergen immunotherapy a (AI) is 
allowed, initiation of AI is not allowed.
AI: Allergen immunotherapy; eCRF: Electronic Case Report Form; IMP: Investigational Medicinal Product; ICS: 
Inhaled corticosteroids; LABA: Long-acting β2-agonist; LTRA: Leukotriene receptor agonist; MDI: 
Metered-dose inhaler; OCS: Oral corticosteroids; SABA; Short-acting β2 agonist
a Stable allergen immunotherapy is defined as when the participant has reached the target dose and is on regular 
maintenance dosing for at least 4 weeks.
6.6
IMP After the End of the Study
Following the completion of the EOS or the Early Study/IMP Discontinuation visit, the 
participant should revert to the rescue medication they were using prior to enrollment. All 
further treatment will be at the discretion of the participant’s regular treating physician.


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7
DISCONTINUATION OF STUDY IMP AND PARTICIPANT 
WITHDRAWAL FROM STUDY
7.1
Discontinuation of Study IMP
7.1.1
Planned Discontinuation of Study IMP
Participants receive IMP for a minimum of 12 weeks and a maximum of 52 weeks. Unless 
participants prematurely discontinue IMP, they will continue treatment until 52 weeks of 
treatment or until the PCD has been achieved. If the PCD is achieved before a participant 
reaches 52 weeks of treatment, provided they have received at least 12 weeks of treatment, the 
participant will be asked to discontinue IMP within 4 weeks of the PCD and to complete an 
EOS.
The date of last IMP dose, the date of IMP discontinuation decision, and the reason(s) for 
discontinuation should be documented in eSource documentation and recorded in the eCRF.
7.1.2
Premature Discontinuation of IMP
All participants who prematurely discontinue study IMP should contact the study center and 
complete the procedures described in the EOS or Early Study/IMP Discontinuation visit as 
soon as possible from discontinuing the study IMP. See the SoA (Section 1.3) for data to be 
collected at the time of IMP discontinuation, follow-up and for any further evaluations that 
need to be completed. A participant who decides to prematurely discontinue IMP will always 
be asked about the reason(s) for discontinuation and the presence of any AEs. 
All participants who prematurely discontinued IMP will be asked to continue in the study until 
they complete the EOS visit or until the study completes. It is strongly recommended that all 
scheduled virtual study visits and procedures are continued until the EOS visit if possible. 
However, participants will be provided with the following follow-up options and will be asked 
to provide consent for their preferred follow-up schedule:
Option 1: Ideally the participant should continue with all the regular virtual study visits and 
continue to respond to the bi-weekly messages from the 
 
 app asking if they 
had a need to seek medical help as a result of their asthma worsening or had any 
asthma-related unscheduled healthcare contacts/visits as per the SoA (Section 1.3) until EOS 
at Week 52 or within 4 weeks if the PCD has been reached.
Option 2: (If the participant cannot comply or does not wish to comply with Option 1 above). 
The participant agrees to receive and respond to the bi-weekly messages from the 
 app and perform an unscheduled visit to collect follow-up details if 
applicable. The participant agrees to be contacted for an EOS visit at 52 weeks or within 4 
weeks if the PCD has been reached.


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Option 3: (If the participant cannot comply or does not wish to comply with Options 1 and 2 
above). The participant agrees to be contacted for an EOS visit at 52 weeks or within 4 weeks 
if the PCD has been reached.
Option 4: (If the participant cannot comply with Option 1, 2 or 3 above). The participant may 
withdraw consent for further follow-up and may proceed to perform the EOS visit prematurely 
upon withdrawal.
Unscheduled visits following a response of ‘YES’ to the bi-weekly 
 app 
message will be performed in accordance with the details recorded in Section 8.7.
If a participant becomes pregnant during the course of the study, IMP should be discontinued 
and a conversation between the Investigator, and, if needed, the participant’s regular treating 
physician and/or obstetrician should be arranged as soon as possible to determine whether 
continuation in the study is in the best interest of the participant and their unborn fetus. If a 
participant becomes pregnant during the study, they should be re-consented before continuing 
in the study.
In the event an ineligible participant was randomized in error, the Investigator together with 
the medical monitor should determine if it is safe for the participant to continue or if she/he 
needs to be withdrawn from study IMP. If the decision is made that the participant can 
continue on study treatment the rationale should be clearly documented.
7.2
Participant Withdrawal from the Study
x
Participants who withdraw will not be replaced.
x
A participant may withdraw from the study at any time at their own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. 
x
At the time of withdrawal from the study, if possible, an Early Study/IMP 
Discontinuation visit should be conducted (equivalent to the EOS visit), as shown in the 
SoA (Section 1.3). See SoA for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed.

The participant will discontinue the study IMP and be withdrawn from the study at 
that time.
x
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.


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7.3
Lost to Follow-up
A participant will be considered lost to follow-up if they repeatedly fail to attend the 
scheduled virtual visits and are unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required virtual study 
visit:
x
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
x
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known email or postal address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.
x
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
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8
STUDY ASSESSMENTS AND PROCEDURES
This study will be decentralized. All assessments and procedures for this study are performed 
virtually with no planned in-person contact between the participant and the Investigator or 
their staff. The following systems and procedures are used to enable this decentralized 
approach:
x
Media advertising including social media for participant recruitment
x
 website for study pre-screener
x
platform for the site and the participants enabling the eConsent 
process, telemedicine visits (virtual visits), eSource and collection of participant 
reported data related to their asthma, concomitant medications and questionnaire 
completion
x
Direct to participants shipment of IMP and device sensors
x
portal app for participants to register their device sensor for capture of 
actuation information
x
 will provide a patient concierge service (Patient Navigator) with end-
to-end participant and caregiver support to assist with any study related questions by 
telephone. Patient Navigator contact details can be accessed via the 
 
app and additional information on the service will be available within the 
 
app.
In general study procedures and their timing are summarized in the SoA (Section 1.3).
Protocol waivers or exemptions are not allowed.
x
The Investigator will ensure that the eSource information is captured in 
 
platform and the data are recorded in the eCRF. The Electronic Data Capture (EDC) 
system will be used for data collection and query handling.
x
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 Study 
Agreement. The Investigator will sign the completed eCRF. A copy of the completed 
eCRF will be archived at the study site.
x
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study IMP.
x
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
x
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. A list of participants screened is maintained 
within 
 
.


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x
Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of the eICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
8.1
Screening and Critical Baseline Assessments
Informed consent will be obtained using the eConsent tool provided by 
 
 app.
Medical/medication history will be assessed as related to the inclusion/exclusion criteria listed 
in Section 5. Relevant medical and surgical history will be captured at Screening, including all 
background asthma medications (eg, SABA, ICS and LTRAs) and all other medications taken 
for any reason in the 3 months prior to enrollment. Any concomitant medication(s) taken 
during the study must also be recorded in the eCRF. In addition, smoking history will also be 
collected as relevant medical history. Adverse events are captured from the signature of eICF. 
The following demographic parameters will be captured: year of birth, sex (genetically female 
or male), race and ethnicity.
Evaluation of the participant’s asthma at Screening includes:
x
Date of diagnosis and/or approximate duration since diagnosis
x
Requirement for therapy (eg, SABA and ICS or LTRA use) including requirement for 
OCS treatment for the management of asthma during the 12 months prior to Screening 
(Visit 1).
x
Number of participant-reported severe asthma exacerbations experienced during the 12 
months prior to Screening (Visit 1). Details of whether the severe asthma exacerbation 
required systemic steroids only, an emergency room / urgent care visit lasting <24 
hours requiring systemic steroids or in-patient hospitalization lasting ≥24 hours, will 
be captured.
Participants should be enrolled into the 
 
 portal (Section 8.6) and then complete 
the AIRQ (Section 8.2.2.1) in the 
 
 app on their smartphone.
Participants who meet all the inclusion criteria and none of the exclusion criteria and who are 
not females of child-bearing potential may progress directly to randomization (Visit 2). 
For females of child-bearing potential, a negative pregnancy test result must be received 
before proceeding to randomization (a picture of the negative test should be uploaded to the 
 
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At randomization, both the AIRQ and the EuroQol-5 Dimension 5 Level (EQ-5D-5L) 
questionnaire (Section 8.2.2.2) will be completed in the 
 
 app. Where 
Screening Visit 1/re-screen and randomization (Visit 2) occur on the same day, AIRQ will 
only be captured once and this will be considered the baseline assessment.
Participants will be trained on the correct MDI technique and management of the device and 
sensors in accordance with the IFU before administering the first dose at V3. The first dose 
will be taken during the telemedicine visit to enable site personnel to assess MDI inhalation 
technique and ensure the sensor is attached appropriately as part of participant training.
8.2
Efficacy Assessments
8.2.1
Asthma Exacerbation Definition
All protocol defined exacerbations need to fulfill the symptom criteria as defined in 
Section 8.2.1.1 or be supported by an Investigator justification (Section 8.2.1.2). The 
Investigator will inquire to the participant as to which of the worsening/onset of 
signs/symptoms listed in Section 8.2.1.1 they experienced prior to/during the exacerbation.
An asthma exacerbation is defined as deterioration of asthma which includes: 
x
worsening of asthma signs/symptoms (refer to Section 8.2.1.1)
x
increased use of ‘as needed’ reliever medication 
8.2.1.1
Definition of Worsening of Asthma Signs/Symptoms
The worsening/onset of signs/symptoms include at least one of the following:
x
shortness of breath
x
wheezing
x
chest tightness
x
cough
x
sputum 
x
night-time awakening due to asthma
x
activity limitation and tiredness due to asthma
Inquiries as to any signs of worsening or new symptoms of asthma will be made at each 
contact with the participant.
8.2.1.2
Investigator Justified Asthma Exacerbations
A vast majority of asthma exacerbations are associated with worsening of the signs and 
symptoms described in Section 8.2.1.1. Clinical presentations may, however, vary among 
patients. If in the Investigator’s opinion, a participant’s symptoms and overall clinical findings 
support the diagnosis of an asthma exacerbation, but the signs and symptoms do not meet the 


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definition in Section 8.2.1.1, the Investigator must justify the decision for defining the event 
as an exacerbation and document the reasoning in the eCRF.
8.2.1.3
Severe Asthma Exacerbations
All protocol defined asthma exacerbations will be classified as severe based on the following 
treatment criteria.
An asthma exacerbation will be considered severe if it results in at least 1 of the following:
x
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. 
x
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).
x
An in-patient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma.
x
Death 
Any of the events above will need to be supported through relevant documentation in the 
eSource records, eg, a copy of a record of a prescription for OCS for asthma, evidence from a 
hospital that the participant was treated for an asthma exacerbation etc. 
8.2.1.4
Onset and Duration of Asthma Exacerbations
For severe exacerbations, the duration is defined by the prescribed treatment:
x
The start date will be defined as the start date of prescribed treatment with a SCS. 
x
The stop date will be defined as the last day of prescribed treatment with a SCS.
x
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.
x
If multiple treatments are prescribed for the same exacerbation, the earliest start date and 
the latest stop date will be used.
x
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.
8.2.1.5
Approach for Capturing Asthma Exacerbations
All severe asthma exacerbations following randomization (including Investigator justified 
asthma exacerbations) must be captured using the Asthma Exacerbation eCRF. 
If an asthma exacerbation requires hospitalization, the exacerbation should be reported as a 
SAE as well as on the Asthma Exacerbation eCRF.


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Severe asthma exacerbations will be considered study efficacy endpoints and will not be 
reported as AEs unless considered a SAE.
Associated symptoms of asthma are considered as symptoms of disease under study (DUS) 
and will not be recorded as AEs unless considered an SAE.
All asthma-related SAEs will also be recorded on the SAE eCRF.
8.2.2
Patient-Reported Outcomes
8.2.2.1
Asthma Impairment and Risk Questionnaire (AIRQ)TM
The Asthma Impairment and Risk Questionnaire (AIRQ)™ is a patient-reported outcome 
(PRO) tool intended to identify patients 12 years and older whose health may be at risk 
because of uncontrolled asthma. It has 10 questions that ask about respiratory symptoms, 
activity limitation, sleep, rescue medication use, social activities, exercise, difficulty 
controlling asthma, and severe exacerbations. All items have a yes/no response option and the 
tool is scored by summing the total number of ‘yes’ responses. This sum score is used 
to assess level of asthma control where: 0-1 is well controlled, 2-4 is not well controlled, and 
5-10 is very poorly controlled. Thus, a higher score indicates worse control status 
(Appendix C). 
The AIRQTM items have 2 different recall periods: The first seven impairment items are 
evaluated over the past 2 weeks and the last three risk items either over the past 3 months or 
the past year. This study will use the version with a recall period for last three risk items over 
the past year at Screening, Randomization, Week 52 EOS visits and the version with last three 
risk items for the past 3 months recall for the remaining visits where it is collected.
The AIRQ™will be administered within the 
 
 app and completed on 
the participant’s smartphone by the participant as per the SoA. The AIRQ™is estimated to 
take approximately 3 minutes to complete.
8.2.2.2
EuroQol-5 Dimension 5 Level (EQ-5D-5L)
The EQ-5D-5L is a 5-level standardized instrument for use as a measure of health outcome. 
Applicable to a wide range of health conditions and treatment, it provides a simple descriptive 
profile and a single index value for health status. The EQ-5D-5L consists of 2 assessments, a 
descriptive system, and a Visual Analog Scale (VAS). The descriptive system comprises of the 
following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension has 5 severity levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. EQ-5D-5L index score can be 
calculated based upon participants’ responses to the 5 dimensions and using an appropriate 
value set. A value set provides values (weights) for each health state description according to 
the preferences of the general population of a country/region, which will be further described 


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in the SAP.
The EQ-5D VAS records the respondent’s self-rated health on a 0 to 100 vertical scale with 
endpoints labeled “the best health you can imagine” and “the worst health you can imagine”, 
with higher scores corresponding to a better health state. This information is used as a 
quantitative measure of health as judged by the individual respondents.
The EQ-5D-5L will be completed within the 
 
 app on the participant’s 
smartphone by the participant as per the SoA.
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.4
Adverse Events and Serious Adverse Events
In this study all AEs will be collected.
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
AEs will be collected from the signing of eICF throughout the treatment period and last 
contact.
SAEs will be recorded from the time of signing of the eICF.
If the Investigator becomes aware of a SAE with a suspected causal relationship to the IMP 
that occurs after the end of the clinical study in a participant treated by him or her, the 
Investigator shall immediately report the SAE to the Sponsor.
8.4.2
Follow-up of AEs and SAEs
Any AEs/SAEs that are unresolved at the participant’s last AE assessment in the study will be 
followed up by the Investigator for as long as medically indicated, but without further 
recording in the eCRF. The CRO and the Pharmacovigilance Department retains the right to 
request additional information for any participant with ongoing AE(s)/SAE(s) at the end of the 


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study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;
x
AE (verbatim)
x
The date when the AE started and stopped
x
Maximum intensity
x
Whether the AE is serious or not
x
Investigator causality rating against the IMPs (yes or no)
x
Action taken with regard to IMPs
x
AE caused participant’s withdrawal from study (yes or no)
x
Outcome
In addition, the following variables will be collected for SAEs:
x
Date AE met criteria for SAE
x
Date Investigator became aware of SAE
x
AE is serious due to
x
Date of hospitalization
x
Date of discharge
x
Probable cause of death
x
Date of death
x
Autopsy performed
x
Severity grade (mild, moderate, severe)
x
Causality assessment to other medication
8.4.3
Causality Collection
The Investigator should assess causal relationship between IMP and each AE and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the IMP?’
For SAEs causal relationship should 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 B to the Clinical 


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Study Protocol. 
8.4.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant (including those reported during the 
interactions with the Patient Navigator service) or reported in response to the open question 
from the study site staff: ‘Have you 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 diagnoses is preferred (when possible) to 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.
8.4.5
Adverse Events of Special Interest
There are no AEs of special interest for this product.
8.4.6
Disease Under Study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of daily or 
seasonal variations in asthma. Events which are unequivocally due to DUS should not be 
reported as an AE during the study unless they meet SAE criteria of the IMP.
8.4.7
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IMP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, Investigators or other site personnel will inform 
the appropriate CRO representatives within one day ie, immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated CRO representative will work with the Investigator to ensure that all the 
necessary information is provided to the CRO Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
CRO representatives of any follow-up information on a previously reported SAE within one 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated CRO representative.


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If the EDC system is not available, then the Investigator or other study site staff must 
complete the SAE form and submit it to the appropriate CRO representative via email or via 
fax. In the event that the site is unable to complete the SAE form to report the event within 24 
hours of their knowledge of the event, the Investigators may report the SAE over the 
telephone via SAE answering service, and then provide the completed SAE form via fax or 
email. 
The CRO representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
The reference document for definition of expectedness/listedness is the IB for BDA MDI and 
AS MDI. 
8.4.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to CRO except for:
x
If the pregnancy is discovered before the study participant has received any study IMP
8.4.8.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, IMP should be discontinued 
and a conversation between the Investigator, and, if needed, the participant’s regular treating 
physician and/or obstetrician should be arranged as soon as possible to determine whether 
continuation in the study is in the best interest of the participant and their unborn fetus. If a 
participant becomes pregnant during the study, they should be re-consented before continuing 
in the study.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/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 anomaly/birth defect) should be followed up and documented even if the 
participant 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 appropriate CRO representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated CRO representative will work with the Investigator to ensure that all relevant 
information is provided to the CRO Patient Safety data entry site within 1 or 5 calendar days 


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for SAEs (see Section 8.4.7) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The Pregnancy report in the eCRF is used to report the pregnancy and the Pregnancy form is 
used to report the outcome of the pregnancy.
8.4.9
Medication Error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate CRO representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated CRO representative will work with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow-up Fatal/Life-
Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE 
associated with the medication error (see Section 8.4.7) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B 4. 
8.5
Overdose
In the absence of a specific antidote, management of toxicities can be dealt with on the basis 
of the symptoms.
All overdoses will be recorded in the overdose eCRF.
An overdose with associated AEs is recorded if the AE is serious and the AE 
diagnosis/symptoms will be reported on the relevant AE modules in the eCRF.
For the purpose of this study, any accidental or deliberate intake of blinded treatment of more 
than 12 inhalations during 1 calendar day is defined as an overdose.
If an overdose of IMP resulting in a SAE occurs in the course of the study, the Investigator or 
other site personnel will inform appropriate Sponsor/CRO representatives immediately, but no 
later than 24 hours of when he or she becomes aware of it.
The designated Sponsor/CRO representative will work with the Investigator to ensure that all 
relevant information is provided to the Sponsor/CRO Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.4.7).


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8.6
Mobile Software Application
The 
 
 mobile software application, and associated website system, will provide 
digital support to participants and Investigators/site staff from screening through to study 
completion for eConsent, ePRO completion, telemedicine visits and eSource activities 
(eSource is defined in Appendix A 7). In addition, the system will provide participants and site 
staff with information and tools relevant to the conduct of the study in accordance with the 
protocol, including educational content related to asthma and the study medication. This will 
include messages at bi-weekly intervals to inquire as to whether during the previous 14 days 
the participant has needed to seek medical help as a result of their asthma worsening. If the 
participant replies yes, a message will be sent to the Investigator to indicate a Health Event 
has occurred. The Investigator/site staff should contact the participant to collect further 
information. The app will be used to administer and collect the participant’s responses to the 
AIRQ and EQ-5D-5L, at the relevant virtual visits, and will allow the participant to confirm if 
they received the study medication. In addition, the participants can contact the 
Investigators/site staff via the 
 
 app study contacts section at any time during 
the study including when they require an unscheduled visit.
After eConsent has been obtained, the Investigator/site staff will enter the participant’s ID 
number and user details into the 
 
portal. Once enrolled in 
 
app, 
the participant will receive an invitation e-mail and will need to download the 
 
app on their smartphone, setting their password and watching a short instructional video. The 
participant will then be able to complete the AIRQ to determine their eligibility for the study.
The Sponsor will own any system data collected which may be used after the trial to make 
improvements to 
 
app. System data collected will be retained for a period of 
15 years after trial closure.
8.7
Unscheduled Visits following ‘Yes’ Response to 
bi-weekly Message
Between scheduled visits, participants will receive a message via a smartphone app 
(
 
) bi-weekly to inquire as to whether they have needed to seek medical help as 
a result of their asthma worsening or any asthma-related unscheduled healthcare related 
contacts/ visits. If the participant replies yes, then the Investigator/site staff will receive an 
email notification to contact the participant to collect further information. Where a scheduled 
visit is within 2 weeks of the notification, sites may (at their discretion) wait for the scheduled 
visit to collect follow-up information from the participant; however, they are encouraged to 
contact the participants as soon as possible. Where the next scheduled visit is > 2 weeks 
following the notification, an unscheduled visit should be conducted as soon as possible to 
obtain the follow-up information below.


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During the next scheduled or unscheduled contact, the Investigator or site staff will review 
and query the participant regarding:
o
AEs and SAEs 
o
Any documentation available suggesting or supporting of a severe asthma exacerbations 
including:
x
Any medical review (primary care/ER/hospitalization)
x
Any SCS use
x
Whether any other medications were used for asthma (other than IMP) and 
whether their ICS dose was changed or their ICS or LTRA was stopped, or other 
asthma controllers were started 
x
The details of any asthma signs/symptoms experienced before the exacerbation 
o
Any change in concomitant medication(s)
o
Any issues using the inhalers/digital sensors or the study portal/app
o
Number of doses/inhalers used and whether new study inhalers are required by the 
participant 
o
Healthcare utilization related to asthma and absences from work/school due to asthma 
8.8
Sensor, Portal and App
Sensors which attach to the MDI devices will be provided to record each actuation of the 
device in order to monitor IMP usage. Sensors are manufactured by 
 and two 
sensors will be provided within the initial shipment of IMP to each participant following 
randomization. Replacement sensors in case of damage or loss can be provided if required. 
Sensors will be specific for each participant and who will activate the sensors by downloading 
the 
 app to their mobile device and pairing the app and the sensors. After initial 
download and pairing, the sensor and the app will remain connected and data transfers will be 
automatic, with no further action required by the participant. Instructions will be provided to 
the participant. Data from the sensors will be available to the sites and Sponsor within the 
 portal for real time data review as required and regular data transfers conducted to 
support the data analysis. 
8.9
Medical Resource Utilization and Health Economics
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the Investigator and study site personnel for all participants throughout the study. 


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Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
x
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)
x
Duration of hospitalization (total days or length of stay, including duration by wards 
[eg, intensive care unit])
x
Number and type of diagnostic and therapeutic tests and procedures
x
Outpatient medical encounters (including physician or emergency room visits, tests and 
procedures, and medications).


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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary objective of this study is to evaluate the efficacy of BDA MDI (used at a dose of 
budesonide/albuterol 160/180 μg) as needed compared with AS MDI as needed (used at a 
dose of 180 μg) on the risk of a severe asthma exacerbation in participants receiving SABA 
alone or with a background of low-dose ICS or a LTRA. This is a superiority study to 
demonstrate the benefit of adding budesonide in the combination BDA MDI when used as 
needed compared with AS MDI as needed. The primary efficacy endpoint is the time to first 
severe exacerbation from the start of the IMP period, up to the EOS, as a measure of risk of 
experiencing a severe asthma exacerbation. The primary and secondary analyses will be based 
on a two-sided hypothesis testing approach.
Formally, the null and alternative hypotheses for the primary and secondary analyses of time 
to first severe exacerbation are:
H0: Hazard ratio (BDA MDI versus AS MDI) = 1,
HA: Hazard ratio (BDA MDI versus AS MDI) ӆ 1.
For the secondary endpoint of annualized exacerbation rate, the null and alternative 
hypotheses are:
H0: Annualized rate ratio (Annualized rateBDA /Annualized rateAS) = 1
HA: Annualized rate ratio (Annualized rateBDA / Annualized rateAS) ≠ 1
All p-values will be reported as two-sided. 
See Section 9.4.2.3 for further statements on the hypotheses testing.
9.2
Sample Size Determination
In order to achieve 350 first severe asthma exacerbation events, it is planned that 
1910 participants (955 participants per arm) will be randomized. It is expected that most 
participants in the proposed US asthma population will be on SABA only. Randomization will 
be stratified by pre-study asthma therapy (SABA only, low-dose ICS + SABA, and LTRA 
+SABA and number of prior severe exacerbations (0, ≥1) in the 12 months prior to the 
Screening visit) to ensure treatment balance within each stratum. The target number of events 
required is estimated from the sample size determinations based on the analysis of the 
secondary endpoint time to first severe asthma exacerbation targeting an estimand utilizing a 
Treatment Policy strategy.


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The primary endpoint of time to first severe exacerbation that targets the estimand utilizing 
the While on Treatment strategy assumes a 30% reduction in the risk of first severe 
exacerbation with BDA MDI versus AS MDI and is supported by results from the 
MANDALA study where the reduction in the rate of severe asthma exacerbations was 27% in 
participants ≥12 years old receiving BDA MDI 160/180 μg compared to AS MDI 180 μg. 
Assuming a 1-year first severe exacerbation event rate in the AS MDI arm of 21%, 345 events 
are needed to achieve 90.8% power, with a 2-sided significance of 5%.
For the secondary endpoint of time to first severe asthma exacerbation that targets an estimand 
utilizing a Treatment Policy strategy, it is assumed that 10% of participants in the study will 
discontinue IMP or step-up maintenance therapy resulting in a null treatment effect in this 
group of participants, such that the estimated overall hazard ratio is increased by 0.025. 
Therefore assuming, a 27.5% reduction in the risk of a first severe exacerbation with BDA 
MDI compared to AS MDI and a 1 year first severe exacerbation event rate of 21% in the AS 
MDI arm, 350 first severe exacerbation events are required to achieve 85% power, with a 2-
sided significance of 5%.
The estimated total number of participants to be randomized to treatment is 1910 to achieve 
the overall target number of 350 events. However, if during the study the observed first severe 
exacerbation rate is higher than expected then the required number of events may be met with 
less participants and recruitment will be stopped prior to reaching 1910 participants 
randomized. Similarly, if during the study the observed blinded first exacerbation rate is lower 
than predicted, the number of participants randomized may be increased to approximately 
2500 to ensure the required number of first severe exacerbations is achieved. Any assessment 
of accumulating data will be performed on pooled, blinded data. The timing and procedure for 
blinded sample size assessment will be documented in the SAP.
An unblinded interim analysis for efficacy is planned once 50% of the events have been 
observed (172 first severe exacerbation events total, prior to treatment discontinuation or a 
step-up in maintenance therapy), based on the primary analysis of the primary endpoint. Alpha 
spending will be governed through the O’Brien-Fleming approach, where 0.003 will be spent 
at the interim to assess significance. If efficacy cannot be established at the 50% of target 
number of event threshold, the study will continue until 350 total first events are observed or 
approximately 2500 participants have been randomized and completed treatment and assessed 
at alpha=0.049. If more than 172 first events are available, the alpha will be adjusted 
accordingly (DeMets, 1994). The interim analysis, with unblinding firewalls, will be 
addressed in the Data Review Committee charter and administered by a separate unblinded 
analysis team.
If the study completes, ie, all participants are treated for one year, without reaching the 
required number of events then all planned analyses will be conducted with the number of 


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events that have occurred as of completion of the study.
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned/assigned in the study, are considered” screen failures”, unless 
otherwise specified by the protocol.
9.3
Populations for Analyses
The following populations are defined:
Table 6
Populations for Analysis
Population/Analysis sets
Description
Enrolled 
All participants who sign the electronic informed consent form (eICF).
Full analysis set
All participants who are randomized to treatment and receive any amount of 
study treatment (ie, at least 1 actuation). Participants will be analyzed 
according to the treatment they were assigned at randomization, regardless 
of the actual treatment received. 
Safety analysis set
All participants who are randomized to treatment and receive any amount of 
the study treatment (ie, at least 1 actuation). Participants will be analyzed
according to the actual treatment received rather than randomized.
9.4
Statistical Analyses
The SAP will be finalized prior to database lock and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. Additional analyses assessing the impact of coronavirus disease 
2019 (COVID-19) pandemic or any other natural event may be included in the SAP.
9.4.1
General Considerations
Demographic and baseline characteristics data will be summarized by treatment for the Full 
and Safety analysis sets.
No study time windows will be derived by visit and data will be presented according to the 
scheduled study visit. For endpoints with repeated measures values collected at premature 
discontinuation visits should be assigned to the next available visit.
Baseline is defined as the non-missing value recorded prior to the start of the IMP (treatment 
period). For all endpoints the start of the IMP (treatment) period is defined as Visit 3.


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9.4.2
Efficacy
9.4.2.1
Primary Endpoint
The primary endpoint is the time to first severe asthma exacerbation and is defined as the 
length in days from start of the IMP period until the first date when the event occurs, up to the 
EOS. The primary estimand will adopt a While on Treatment strategy in the FAS. The 
following five attributes describe the estimand that will be used to define the treatment effect 
of interest for the primary efficacy analysis: 
•
Treatment Condition = Randomized IMP alone or usual Maintenance therapy + 
randomized IMP 
•
Population = Adults and adolescents (≥12 years) with asthma who are taking SABA as 
needed alone or with low-dose ICS or LTRA. 
•
Participant-level outcome = Time to first severe asthma exacerbation from start of the 
IMP period until the first date when the event occurs, up to the EOS. 
•
IE handling =Two IEs are defined: a) a step-up in maintenance therapy and b) all-
cause discontinuation of study treatment. A While on Treatment strategy will be implemented 
for both IEs, such that the data will be censored at the time at which the IE occurred.
•
Summary measure = Adjusted hazard ratio comparing BDA MDI administered as 
needed versus AS MDI as needed. 
In order to ensure that the same event is not counted twice, concurrent severe asthma 
exacerbations with start and stop dates ≤ 7 days apart will be considered the same event.
Participants that do not experience a severe asthma exacerbation event or an IE and complete 
the study will be censored at the date of their EOS visit. 
Participants that discontinue from study will be censored at the date of withdrawal from study 
or in the case of lost to follow-up the date of last contact.
The primary analysis will be based on a two-sided hypothesis testing approach. The statistical 
null hypothesis for the primary efficacy summary measure is that the adjusted hazard ratio for 
the primary treatment comparison is equal to 1 versus the alternative hypothesis that it is not 
equal to 1. 
The time to first severe asthma exacerbation from start of IMP period up to the end of 
treatment will be analyzed using a Cox proportional hazards regression model. Treatment 
comparison will be performed using a model including treatment, pre-study asthma therapy 
(SABA only, low-dose ICS + SABA, LTRA + SABA) and the number of prior severe 
exacerbations (0, ≥1) in the 12 months prior to Screening visit. The estimated adjusted hazard 


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ratio for the treatment comparison will be displayed along with the associated Wald two-sided 
95% confidence interval and p-value. 
Kaplan-Meier plots of time to first severe asthma exacerbation will be presented by treatment 
group.
Censoring times will be assumed to be at random however, sensitivity analyses in which 
censored results will have event times imputed under an informative censoring assumption 
will be performed. Details will be provided in the SAP.
9.4.2.2
Multiplicity adjustments
Interim Analyses
An interim analysis is planned for assessing efficacy. Only the primary and first secondary 
endpoint of time to first severe exacerbation based on the estimands utilizing a While on 
Treatment strategy (participants ≥12 years) and a Treatment Policy strategy (participants ≥12 
years), respectively, will be tested. Please refer to Section 9.5 for the strategy for hypothesis 
testing of the primary and first secondary endpoint that are part of the interim decision criteria 
for stopping for efficacy and the methods to control the overall type-I error rate. 
Testing of the remaining secondary endpoints of time to first severe exacerbation (While on 
Treatment strategy, participants ≥18 years), annualized severe exacerbation rate (While on 
Treatment strategy) and total systemic glucocorticoid exposure (While on Treatment strategy),
that are not part of the interim decision criteria for stopping will be tested. Details of the 
hypothesis testing and alpha level for these endpoints will be provided in the SAP.
Final Analyses (decision is not to stop for efficacy at interim analyses)
In order to account for the multiple tests across multiple endpoints, a hierarchical testing 
strategy will be employed to control the Type-I error rate for the primary and secondary 
endpoints, testing the endpoints in the following pre-specified order: 
1) Time to first severe asthma exacerbation, participants ≥12 years (While on Treatment strategy); 
2) Time to first severe asthma exacerbation, participants ≥12 years (Treatment Policy strategy); 
3) Time to first severe asthma exacerbation, participants ≥18 years (While on Treatment strategy);
4) Time to first severe asthma exacerbation, participants ≥18 years (Treatment Policy strategy);
5) Annualized rate of severe asthma exacerbation rates, participants ≥12 years (While on Treatment 
strategy);
6) Annualized rate of severe asthma exacerbation rates, participants ≥18 years (While on Treatment 


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strategy);
7) Total amount (mg/year) per participant of SCS exposure, participants ≥12 years (While on 
Treatment strategy), and
8) Total amount (mg/year) per participant of SCS exposure, participants ≥18 years (While on 
Treatment strategy).
Testing will be conducted at the specified alpha for the final analyses. The hierarchical testing 
strategy will be applied whereby the full fraction of alpha will be passed down to endpoints 
tested per the pre-specified order. Inference for a test in the pre-specified hierarchy is 
dependent upon statistical significance having been achieved for the previous tests in the 
hierarchy. Once statistical significance is not achieved further inferential testing will not be 
performed. 
9.4.2.3
Secondary Endpoint(s)
The first secondary endpoint, time to first severe exacerbation in participants ≥ 12 years, will 
also be analyzed based on an estimand utilizing a Treatment Policy strategy in which all 
observed data while participants are in the study, regardless of whether or not they are on 
randomized study treatment, will be included in the analyses. This is a secondary analysis and 
will be included in the hierarchical testing strategy (Section 9.4.2.2). The estimand adopting a 
treatment policy handling of intercurrent events will be evaluated in the FAS. The following 
five attributes describe the estimand that will be used to define the treatment effect of interest 
for this secondary analysis of effectiveness:
•
Treatment Condition = Randomized IMP alone or usual Maintenance therapy at Day 1 
+ randomized IMP, including any other additional medication/therapy. 
•
Population = Adults and adolescents (≥12 years) with asthma who are taking SABA as 
needed alone or with a stable low-dose ICS or LTRA. 
•
Participant-level outcome = Time to first severe asthma exacerbation from start of the 
IMP period until the first date when the event occurs, or up to EOS. 
•
IE handling = An IE is defined as a step-up in maintenance therapy or discontinuation 
of study treatment. A treatment policy strategy will be implemented such that the value for the 
participant-level outcome will be used regardless of whether or not the IEs occurs.
•
Summary measure = Adjusted hazard ratio comparing BDA MDI administered as 
needed versus AS MDI as needed. 
Participants that do not experience a severe asthma exacerbation event or an IE and complete 
the study will be censored at the date of their EOS visit. Participants that discontinue from 


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study will be censored at the date of withdrawal from study or in the case of lost to follow-up 
the date of last contact.
The statistical model used to analyze the time to severe asthma exacerbation from start of the 
IMP period up to EOS and associated hypothesis test will be the same as specified for the 
primary efficacy analysis.
In order to ensure that the same event is not counted twice, concurrent severe asthma 
exacerbations with start and stop dates ≤ 7 days apart will be considered the same event and 
assigned the maximum severity between the two events.
The second secondary endpoint is the time to first severe exacerbation based on the estimand 
utilizing a While on Treatment strategy in the adult population, defined as participants aged 
≥18 years. The estimand attributes of treatment condition, participant-level outcome, IE 
handling, and summary measure are defined as per the primary estimand utilizing a While on 
Treatment strategy. The population attribute is adults (≥18 years) with asthma who are taking 
SABA as needed alone or with a stable low-dose ICS or LTRA. The statistical model used to 
analyze the time to severe asthma exacerbation from start of the IMP period up to EOS and 
associated hypothesis test will be the same as specified for the primary efficacy analysis.
The third secondary efficacy endpoint is the time to first severe exacerbation based on an 
estimand utilizing a Treatment Policy in the adult population, defined as participants aged ≥18 
years. The estimand attributes of treatment condition, participant-level outcome, IE handling, 
and summary measure are defined as per the estimand for time to first severe asthma 
exacerbation in the ≥12 years population. The population attribute is adults (≥18 years) with 
asthma who are taking SABA as needed alone or with a stable low-dose ICS or LTRA. The 
statistical model used to analyze the time to severe asthma exacerbation from start of the IMP 
period up to EOS and associated hypothesis test will be the same as specified for the primary 
efficacy analysis.
The fourth secondary efficacy endpoint is the annualized rate of severe asthma exacerbations, 
participants ≥12 years. Severe asthma exacerbations from the start of the IMP period up to the 
end of treatment will be used in the analysis. Intercurrent events will be defined as per the 
primary efficacy endpoint (While on Treatment strategy). Intercurrent events will be handled 
such that severe asthma exacerbations occurring post an IE will be excluded from the analysis 
and the time on study will be calculated up to the date at which the IE occurred. Time during a 
severe asthma exacerbation and the 7 days after a severe exacerbation will not be included in 
the calculation. As per the primary efficacy endpoint, exacerbations separated by less than 
7 days will be treated as a continuation of the same exacerbation. The annualized rate of 
severe asthma exacerbations will also be evaluated based on the estimand utilizing a 
Treatment Policy strategy, where all data collected from the start of the IMP period up to the 
EOS participation, regardless of the occurrence of IEs, will be used.


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The annualized exacerbation rate will be analyzed using a generalized linear model, assuming 
the number of exacerbations has a negative binomial probability distribution and that its mean 
is related to covariate variables with a ‘log link’ function. The logarithm of time on study 
(years) will be used as an offset variable. The model will include covariates for treatment, pre-
study asthma therapy (SABA only, low-dose ICS + SABA, LTRA + SABA) and the number 
of prior severe exacerbations (0, ≥1) in the 12 months prior to screening/enrollment. The 
treatment comparison will be as per the primary efficacy analysis. From the negative binomial 
model, the annualized severe asthma exacerbation rates will be estimated along with the 
associated 95% confidence intervals, for each treatment group. The summary measure for the 
comparison of BDA MDI versus AS MDI will be the estimated rate ratio which will be 
presented with the corresponding 95% confidence interval and two-sided p-value. The 
analysis of annualized exacerbation rate assessed under the While on Treatment strategy will 
be included in the type-I error controlled testing strategy. The analysis based on the estimand 
utilizing a Treatment Policy strategy will be considered a supplemental analysis. Details will 
be provided in the SAP.
The fifth secondary endpoint is the annualized rate of severe asthma exacerbations.  The 
analysis will target the estimand utilizing  a While on Treatment strategy in the adult 
population, defined as participants aged ≥18 years. This analysis will be the same as the 
analyses described for the fourth secondary endpoint except the population is adults (≥18 
years) with asthma who are taking SABA as needed alone or with a stable low-dose ICS or 
LTRA.
The sixth secondary endpoint is total SCS exposure (participants ≥12 years) will be expressed 
as the annualized total dose of SCS (mg/year). Intercurrent events will be handled such that 
only SCS doses related to severe asthma exacerbation events that occurred while on treatment 
during the IMP period will be included in the analysis (While on Treatment strategy). Total 
SCS exposure will also be evaluated based on an estimand utilizing a Treatment Policy 
strategy, where all data collected from the start of the IMP period up to the EOS participation, 
regardless of IE occurrence, will be used.
Total amount (mg/year) of SCS exposure (per participant) = {Total SCS dose (mg) received 
during IMP treatment period / (Date of treatment completion/discontinuation - Date of start of 
IMP period + 1)} × 365.25 
Annualized total dose of SCS will be presented descriptively by treatment group. A 
comparison of the treatment groups will be performed using a Wilcoxon rank sum test and 
associated p-values will be presented. For this endpoint, additional descriptive statistics of the 
difference between treatment arithmetic means, percentage reduction in the treatment 
arithmetic means, 2.5th, 5th, 75th, 80th, 95th, and 97.5th percentiles will be presented. Further 
details of these and other summary measures will be provided in the SAP.


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The analysis of total SCS exposure assessed under the While on Treatment strategy will be 
included in the type-I error controlled testing strategy. The analysis of total SCS exposure 
assessing the estimand utilizing a Treatment Policy strategy will be considered a supplemental 
analysis.
Additionally, the total SCS exposure will be expressed as the total number of days taking SCS 
treatment due to asthma and will be summarized descriptively. 
Further details will be provided in the SAP.
The seventh secondary endpoint is total SCS exposure, which will be expressed as the 
annualized total dose of SCS (mg/year), based on an estimand utilizing a While on Treatment 
strategy in the adult population, defined as participants aged ≥18 years. This analysis will be 
the same as the analyses described for the sixth secondary endpoint except the population is 
adults (≥18 years) with asthma who are taking SABA as needed alone or with a stable low-
dose ICS or LTRA.
9.4.2.4
Tertiary/Exploratory Endpoint(s)
Tertiary/Exploratory endpoint efficacy analyses will be conducted based on estimand utilizing 
a While on Treatment Policy strategy only. Further details for all analyses will be provided in 
the SAP.
9.4.3
Safety
All safety summarizes will be performed on the Safety analysis set and will include all data 
obtained before participants discontinue randomized treatment. Participants will be analyzed 
according to the actual treatment received.
9.4.3.1
Adverse Events 
Adverse events during the treatment period will be summarized by the number of participants 
experiencing the event. AEs will be tabulated at the level of the Medical Dictionary for 
Regulatory Activities (MedDRA) system organ class and preferred term. The version of the 
MedDRA current at the time of database lock will be used in the tabulations and listings. 
9.4.3.2
Other Safety Endpoint(s)
Not applicable.
9.4.4
Other Analyses 
Analyses of the primary, secondary, and tertiary endpoints may be performed by various 
subgroups. In addition to baseline and demographic subgroups, other factors will be used to 
create subgroups of interest. All subgroup analyses will be described fully in the SAP.


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9.5
Interim Analyses 
An unblinded interim analysis for efficacy is planned once 50% of the target number of first 
severe exacerbation events have been observed (172 first severe exacerbation events total, 
prior to treatment discontinuation or a step-up in maintenance therapy). Alpha spending will 
be governed through the O’Brien-Fleming approach, where 0.003 will be spent at the interim 
to assess statistical significance. 
Only the primary and first secondary analysis of time to first severe exacerbation evaluating 
the estimands utilizing a While on Treatment strategy (participants ≥12 years) and a Treatment 
Policy strategy in (participants ≥12 years), respectively, will be tested at the interim analysis. 
No minimum exposure time is required and all participants in the FAS will be analyzed. 
Participants who are on-going at the time of the interim analysis, who have not had a severe 
exacerbation event or IE will be censored at the date of their last known contact.
Members of the DMC (see Section 9.6) will review the primary and secondary analysis of 
time to first severe exacerbation at the interim and recommend to the Sponsor if the trial can 
be stopped due to overwhelming efficacy, corresponding to a rejection of both the primary and 
secondary null hypotheses each at alpha=0.003.
In the event that the DMC recommends to stop the study due to overwhelming efficacy, the 
Sponsor, once informed, will inform site personnel and participants that the study is closing 
due to overwhelming efficacy. If the study is still enrolling, enrollment will be immediately 
closed. All participants who have not completed 12 weeks of treatment will continue in the 
study and complete their EOS visit once they completed 12 weeks of treatment. All 
participants ongoing in the study who have completed 12 weeks of treatment will return for 
their EOS visit at their next scheduled visit or within 4 weeks of notification, whichever 
comes first.
If efficacy cannot be established at the 50% of target number of events threshold, the study 
will continue until 350 total first events are observed or approximately 2500 participants have 
been randomized and completed treatment. In this scenario, the primary and key secondary 
analyses will be assessed at alpha=0.049. 
If more than 172 first severe exacerbation events total, prior to treatment discontinuation or a 
step-up in maintenance therapy are available at the interim analysis, the alpha will be adjusted 
accordingly (DeMets, 1994). Similarly, the final analysis will take account of the number of 
observed events at that time to ensure that the type-I error rate is controlled at 5%.
9.6
Data Monitoring Committee 
An independent, external DMC will be set up to review safety data at three time points during 
the study. At a single time point (Interim Analysis) DMC will review the primary efficacy 


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endpoint and the first secondary endpoint to determine stopping early for overwhelming 
efficacy. One safety review will occur before the interim analysis, with a second safety review 
at the time of the interim analysis, and a third safety review will occur at a later timepoint 
following the interim analysis if the study was not closed early for efficacy. The committee 
will operate in accordance with a DMC Charter. The DMC will have access to the individual 
treatment codes and will be able to merge these with the collected study data while the study 
is ongoing as required. The personnel involved in the clinical study at the Sponsor and/or its 
designee will remain blinded to these analyses and will have no knowledge of the results 
presented to the DMC.
Members of the DMC will review efficacy data generated externally and independently from 
the Sponsor, unblinded, once 50% of the events have been observed. The number of events 
will be monitored by the Sponsor in a blinded manner and the DMC triggered once the
required 172 first events have been achieved. 


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
x
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations
x
The protocol, protocol amendments, eICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an Institutional Review Board (IRB) / Independent 
Ethics Committee (IEC) by the Investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.
x
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.
x
The Sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with the Sponsor.
x
The Investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European Regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations.
Regulatory Reporting Requirements for SAEs
x
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study IMP under clinical investigation are met.
x
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study IMP under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/IEC, and Investigators.


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x
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and Sponsor policy and forwarded to Investigators as necessary.

European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
x
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
A 2
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process (eConsent)
x
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.
x
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent/assent at any time and for any reason 
during the study. Participants or their legally authorized representative [defined as parent 
or legal guardian] will be required to sign a statement of informed consent and 
participants not at age of majority will be required to sign a statement of assent, that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study center.
x
The participants source record for the study must include a statement that informed 
consent was obtained electronically before any study related procedures are performed 
and the date the eConsent was obtained. The authorized person obtaining the informed 
eConsent must also electronically sign the eICF.
x
If any changes occur to the eICF that may affect participant ongoing participation, the 
changes to the eICF must be IRB/IEC-approved and participants must be re-consented to 
the most current version of the eICF(s) during their participation in the study.
x
A copy of the eICF(s) must be provided to the participant or the participant’s legally 
authorized representative.


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x
Participants who become pregnant who have discontinued IMP during the study and 
agree to remain in the study (following discussion with the Investigator, the Study 
Physician and their treating physician and/or obstetrician) will be required to be 
re-consented. 
x
Assent forms will be provided electronically to participants ≥12 years who have not 
reached the age of majority at the time of entry to the trial.
A 4
Data Protection
x
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.
x
The participant 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 and use 
of their data must also be explained to the participant in the eICF. 
x
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
x
The participant will have to provide personal information to the investigational site via 
the
e-source platform who will in turn share some of this information 
with the following vendors: the IMP vendor (
) for shipment of 
study materials (IMP devices, IMP sensors), 
who enable 
Support to 
create a password for the app, 
 to process participant’s payment, and Patient 
Navigator to support participants. This information will be kept confidential by all 
providers.
A 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://www.clinicaltrials.gov as will the 
summary of the study results when they are available. The clinical study and/or summary of 
study results may also be available on other websites according to the regulations of the 
countries in which the study is conducted.
A 6
Data Quality Assurance
x
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, 
actuation data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
x
The Investigator must maintain accurate documentation (eSource data) in the 
platform that supports the information entered in the eCRF.


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x
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to the eSource data documents.
x
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring plan.
x
CRO is responsible for the data management of this study including quality checking of 
the data.
x
The Sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs).
x
Study monitors will perform ongoing eSource data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from the eSource documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory requirements.
x
Records and documents, including a record of the electronically signed eICFs, pertaining 
to the conduct of this study must be retained by the Investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or party 
without written notification to the Sponsor.
A 7
Source Documents
x
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are stored in the 
portal and filed at the Investigator’s site.
x
Data entered in the eCRF that are transcribed from the eSource documents must be 
consistent with the eSource documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending 
on the study. 

AIRQ and EQ5D-5L questionnaires are available within the 
portal. 
Completion of the questionnaires will be entered directly into the 
portal by the participants and are considered eSource data with no transcription 
requirement.

Dosing data will be automatically captured using the sensor with no transcription 
requirement into the eCRF.


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
Pictures / uploads of medical records into the 
 
portal will be required 
eSource documents for information including pregnancy tests, asthma diagnosis, 
asthma medication and asthma exacerbations.

A full definition of what constitutes source data can be found in the source data 
agreements for each site.
A 8
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
The Sponsor reserves the right to close a study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion 
(or early if they are unable to comply with study procedures or meeting study objectives). A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:
x
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines
x
Inadequate recruitment of participants by the Investigator
x
Discontinuation of further study IMP development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study participant 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 (for example 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 
run-in or washout periods, even if no study IMP has been administered.
B 2
Definition of Serious Adverse Events
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfills one or more of the following criteria:
x
Results in death
x
Is immediately life-threatening
x
Requires in-participant hospitalization or prolongation of existing hospitalization 
x
Results in persistent or significant disability or incapacity. 
x
Is a congenital anomaly or birth defect
x
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events (AEs) for malignant tumors reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgment on an individual 
event basis should be applied to clarify that the malignant tumor event should be assessed and 
reported as a non-serious AE. For example, if the tumor is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumor, the AE may not fulfill the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumors, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
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Life-threatening
‘Life-threatening’ means that the participant 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 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a 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 participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment 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 participant or may 
require medical treatment to prevent one 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 
judgment must be used. Examples of important medical events include but are not limited to:
x
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment
x
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
x
Intensive treatment in an emergency room or at home for allergic bronchospasm
x
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization
x
Development of drug dependency or drug abuse
Intensity Rating Scale:
x
Mild (awareness of sign or symptom, but easily tolerated)
x
Moderate (discomfort sufficient to cause interference with normal activities)
x
Severe (incapacitating, with inability to perform normal activities)


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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 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 a SAE unless it meets the criteria 
shown in Appendix B 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 a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
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.
x
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
x
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?
x
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
x
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.
x
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.
x
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
x
Is this a recognized feature of overdose of the drug?
x
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.


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The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the DUS has deteriorated due to lack of effect should be 
classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for study IMP that either causes harm to the participant or has the 
potential to cause harm to the participant. 
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 participant.
Medication error includes situations where an error:
x
Occurred
x
Was identified and intercepted before the participant received the drug
x
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:
x
Drug name confusion
x
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
x
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
x
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 
x
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 
x
Wrong participant received the medication (excluding Interactive Response Technology 
(IRT)/RTSM errors)
x
Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:
x
Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error 


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x
Participant accidentally missed drug dose(s) eg, forgot to take medication
x
Accidental overdose (will be captured as an overdose)
x
Participant failed to return unused medication or empty packaging
x
Errors related to background and rescue medication, or standard of care medication in 
open label studies. 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Asthma Impairment and Risk Questionnaire (AIRQTM)


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Appendix D
Avillion Protocol Signature Page
Avillion Signature Form for the Clinical Study Protocol
We, the undersigned, to the best of our knowledge and ability attest to the accuracy and 
validity of the contents of the Clinical Study Protocol.
_____________________________________
Name: 
Title: Senior Global Medical Lead 
Company: Avillion LLP
___________________________________
Date
_____________________________________
Name: 
Title: Statistician 
Company: Avillion LLP
___________________________________
Date


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Appendix E
Primary Investigator Signature Page
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files and return a copy to your local study 
monitor.


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Appendix F
Instructions for Use 
Instructions for use for MDI
Handling and cleaning instructions for MDI devices
1. Use of Study Drug and MDI
x
The parts that make up the MDI are presented in Figure 2.
x
The actuation counter presents the number of puffs left in the MDI and is part of the MDI 
that is pressed to dispense an actuation of medication. Figure 3 presents the dial of the 
actuation counter.
x
The actuation counter has numbers for every 10 actuations and tick marks for every 5 
actuations, as shown in Figure 3. For a new MDI, the actuation counter will start with the 
pointer to the left of the “120” mark.
x
The actuation counter pointer will move with every actuation. For example, if the 
actuation counter pointer is pointing to 120 and 10 actuations are dispensed, the pointer of 
the actuation counter will move from 120 to 110. This means that there are 110 actuations
of medicine left.
x
When the pointer on the actuation counter approaches 20, the color behind the number 
changes to yellow, indicating that it is time to change to a new MDI. 
x
When the number on the actuation counter dial reaches 0 and the color behind the number 
is red, this means that the MDI should no longer be used, and it needs to be replaced with 
a new MDI.




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2. Preparation and first use priming of the MDI
x
Take the MDI out of the foil pouch. Safely throw away the desiccant packet that comes 
inside the pouch. Do not eat or inhale the content of the desiccant packet. Retain the 
pouch and any other packaging for return at the end of the study.
x
Take the cap off the MDI by gently squeezing the sides of the dust-cap and pulling off, as 
presented in Figure 4.
Figure 4
Instructions for Removing the Cap from the MDI
x
Inspect the front of the MDI and make sure there is nothing inside the mouthpiece of the 
MDI. Make sure the canister is fully and firmly inserted into the actuator.
x
The MDI must be primed before first use. First use priming involves releasing 4 sprays 
into the air before using the MDI; shaking is required prior to each priming spray. 
Shaking and priming the MDI fills a chamber inside the canister with the correct dose and 
mix of medication so that the MDI is ready to use.
x
For each priming spray of the MDI, gently shake the MDI for 5-10 seconds and then 
spray once into the air away from yourself and others.
x
NOTE: an audible “click” may be heard when the spray is released, which is 
advancement of the actuation counter and considered normal.
x
Wait approximately 5-10 seconds and then repeat three more times.
Using the MDI
x
The MDI can be used for 12 months once the foil pouch has been opened. 
x
The MDI should be held upright with the mouthpiece at the bottom and the actuation 
counter at the top as pictured in Figure 5.


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Figure 5
Ways to Hold the MDI for Use
x
Shake the MDI for 5 to 10 seconds.
x
Breathe out fully through your mouth, expelling as much air from your lungs as possible. 
Tilt your head back slightly, placing the mouthpiece into your mouth, holding the MDI 
with the mouthpiece down, and closing your lips around it, as presented in Figure 6. To 
allow the medication to enter your lungs, keep your tongue flat on the bottom of your 
mouth.
Figure 6
Diagram of How to Use the MDI
x
While breathing in deeply and slowly through your mouth, fully depress the top of the 
actuation counter with your index finger. Immediately after the spray is delivered, release 
your finger from the canister. When you have breathed in fully, remove the MDI from 
your mouth and close your mouth.
x
Hold your breath as long as possible, up to 10 seconds, and then breathe normally.
x
Repeat steps above for the second inhalation to complete the full dose.
x
After you finish taking 2 inhalations, rinse your mouth with water. Spit out the water. Do 
not swallow it. 
x
Place the dust-cap back onto the device.


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Using the MDI (Children)
x
Children should use the MDI with an adult’s help, as instructed by the child’s healthcare 
provider.
Cleaning the actuator
x
The actuator should be cleaned once per week if used in the last 7 days. The sensor 
should be removed from the MDI and the canister should be gently pulled from the top of 
the actuator. Do not clean the canister or let it get wet.
x
Pull the canister out of the actuator and set the canister aside where it will not get wet.
x
Take the dust cap off of the mouthpiece.
x
Rinse the actuator through the top with warm running water for 30 seconds, as shown in 
Figure 7.
Figure 7
Cleaning the Actuator
x
Shake all of the water droplets out of the actuator.
x
Then rinse the actuator again through the mouthpiece with warming running water for 30 
seconds.
x
Shake all of the water droplets out of the actuator.
x
Look in the actuator and mouthpiece and make sure it is clean and clear. Repeat steps 
above until the actuator and mouthpiece are clean and clear.
x
Let the actuator dry completely, such as overnight. Do not put the canister back into the 
actuator if the actuator or dust cap is still wet.


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Reassembling the MDI and instructions for use after
x
After the actuator and dust cap are completely dry, gently press the canister down in the 
actuator. It is not necessary to press down on the canister hard enough to cause a puff to 
be released.
x
The MDI must be re-primed after each cleaning. Re-priming involves releasing 2 sprays 
into the air. To do this, gently shake the MDI for 5-10 seconds and then spray once into 
the air away from yourself and others.
x
NOTE: an audible “click” may be heard when the spray is released, which is the 
advancement of the actuation counter and is considered normal.
x
Wait approximately 5-10 seconds and then repeat the above two steps, one more time.
x
After re-priming the MDI two times, the MDI is ready for use.
Re-priming the MDI after periods of non-use or when dropped
x
The MDI must be re-primed if it has not been used in more than 7 days or when it has 
been dropped.
x
Re-priming involves releasing 2 sprays into the air. To do this, gently shake the MDI for 
5-10 seconds and then spray once into the air away from yourself and others. 
x
NOTE: an audible “click” may be heard which is advancement of the actuation counter 
and is considered normal.
x
To complete re-priming, wait approximately 5-10 seconds and then release 2 more sprays 
into the air as before. 
x
After re-priming the MDI, the MDI is ready for use.








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Appendix G
Daily Metered doses of Inhaled Corticosteroids in 
Adults/Adolescents 12 years and older
Inhaled corticosteroid
Total daily ICS dose (mcg)
Low
Medium
High
Beclometasone dipropionate (pMDI, standard particle, 
HFA)
200-500
>500-1000
>1000
Beclometasone dipropionate (DPI or pMDI, extrafine
particle, HFA)
100–200
>200–400
>400
Budesonide (DPI, or pMDI, standard particle, HFA)
200–400
>400–800
>800
Ciclesonide (pMDI, extrafine particle, HFA)
80–160
>160–320
>320
Fluticasone furoate (DPI)
100
200
Fluticasone propionate (DPI)
100–250
>250–500
>500
Fluticasone propionate (pMDI, standard particle, 
HFA)
100–250
>250–500
>500
Mometasone furoate (DPI) 
Depends on DPI device – see product 
information
Mometasone furoate (pMDI, standard particle, HFA)
200-400
>400
DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; ICS: inhaled corticosteroid; pMDI: pressurized 
metered-dose inhaler.
ICS by pMDI should preferably be used with a spacer.
Source: GINA, 2022


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Appendix H
Abbreviations
Abbreviation or special 
term
Explanation
AE
Adverse event
AIRQ
Asthma Impairment and Risk Questionnaire 
AS
Albuterol Sulfate
BDA
Budesonide/albuterol
CFR
Code of Federal Regulations
CRO
Contract Research Organization
DUS
Disease Under Study
eCRF
electronic Case Report Form
EDC
Electronic Data Capture 
EOS
End of Study
EQ-5D-5L
EuroQol-5 Dimension 5 Level 
FAS
Full Analysis Set
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HCP
Healthcare professional
IB
Investigator’s Brochure
(e) ICF
(Electronic) informed consent form
ICH
International Council for Harmonisation
ICS
Inhaled Corticosteroid
IE
Intercurrent Event
IEC
Independent Ethics Committee
IFU
Instructions for Use
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long-acting ș2-agonist
LTRA
Leukotriene receptor agonist
MDI
Metered-dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
OCS
Oral Corticosteroids
PCD
Primary Completion Date
PI
Principal Investigator 


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Abbreviation or special 
term
Explanation
RTSM
Randomization and Trial Supply Management
SABA
Short/rapid-acting β2agonist
SAE
serious adverse event 
SAP
statistical analysis plan
SCS
Systemic corticosteroids
SoA
Schedule of Activities
US
United States
VAS
Visual Analog Scale


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SUMMARY OF CHANGES
11.1
Changes to Protocol Amendment 2 (Version 3.0)
The overall rationale for this amendment is to update the testing hierarchy to test each of the 
key endpoints also on adult participants (participants ≥18 years) in line with the approved 
product label. 
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).
Section
Changes to Protocol Amendment 2 (Version 3.0)
Version History
Date and version changed; brief summary of changes added 
as Section 11.
1.1 Synopsis
Objectives and Endpoints: 
Updated primary and secondary objectives for clarity to
specify where testing is performed in relation to participants
≥12 years or ≥18 years respectively.
The following secondary objectives were added: 
To evaluate the efficacy of BDA MDI as needed compared 
with AS MDI as needed on the risk of severe asthma 
exacerbations, participants ≥18 years (While on Treatment 
strategy and Treatment Policy strategy).
To evaluate the efficacy of BDA MDI as needed compared 
with AS MDI as needed on the rate of severe asthma 
exacerbations, participants ≥18 years (While on Treatment 
strategy).
To evaluate the effect of BDA MDI as needed compared with 
AS MDI as needed on systemic glucocorticoid exposure 
associated with asthma management, participants ≥18 years 
(While on Treatment strategy).
Overall Design:
Flexibility was introduced to permit enrolment of 
‘approximately’ 2500 participants.


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3.0 Objectives and 
Endpoints
Changes were implemented in line with the changes made to 
section 1.1 for consistency.
9.2 Sample Size 
Determination
Flexibility was introduced to permit enrolment of 
‘approximately’ 2500 participants.
9.4.2.2 Multiplicity 
adjustments
In line with section 1.1. and 3.0, the testing hierarchy was 
updated to include the endpoints indicated in bold font below:
1) Time to first severe asthma exacerbation, participants ≥12 
years  (While on Treatment strategy); 
2) Time to first severe asthma exacerbation, participants ≥12 
years (Treatment Policy strategy); 
3) Time to first severe asthma exacerbation, participants 
≥18 years (While on Treatment strategy);
4) Time to first severe asthma exacerbation, participants 
≥18 years (Treatment Policy strategy);
5) Annualized rate of severe asthma exacerbation rates, 
participants ≥12 years (While on Treatment strategy);
6) Annualized rate of severe asthma exacerbation rates, 
participants ≥18 years (While on Treatment strategy);
7) Total amount (mg/year) per participant of SCS exposure, 
participants ≥12 years (While on Treatment strategy), and
8) Total amount (mg/year) per participant of SCS 
exposure, participants ≥18 years (While on Treatment 
strategy).
Additional details relating to the new endpoints were 
provided within the body text.
9.4.2.3 Secondary 
Endpoints 
Details provided for new secondary objectives.  Clarifications 
provided confirming when analyses will be performed for 
participants ≥12 years or ≥18 years respectively.


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9.5 Interim Analysis
Clarification provided that only the primary and first 
secondary endpoint will be tested at the interim analysis.
Throughout document
Minor administrative changes have been made.
11.2
Changes to Protocol Amendment 1 (Version 2.0)
The overall rationale for this amendment is to update the eligibility criteria based on label 
approval and experience to date. Further, the updates have been done to provide clarification 
in the protocol language. 
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).
Section
Changes to Protocol Amendment 1 (Version 2.0)
Version History
Date and version changed; brief summary of changes added 
as Section 11.
1.1 Synopsis
Objectives and Endpoints: 
Updated primary objective as “To evaluate the efficacy of 
as-needed BDA MDI compared with as-needed AS MDI on 
the risk of severe asthma exacerbations.”
Updated treatment as “Randomized Investigational Medicinal 
Product (IMP) alone or usual Maintenance therapy + 
randomized IMP.”
Investigational Medicinal Product (IMP) Groups and 
Duration: 
Updated that for females of child-bearing potential, following 
the initial screening assessment, a urine pregnancy test with 
high sensitivity is required.
Updated that the Treatment Initiation Visit (Visit 3) will occur 
once the participant is in receipt of the study medication 
(expected to be within 7 days following randomization).


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Removed digital training material from the additional training 
materials available.
Data Monitoring Committee
Deleted text “If needed, two other reviews will occur for 
safety review only” from the synopsis to briefly present in the 
synopsis and add further details on safety review in 
Section 9.6.
1.2 Schema
Number of participants for PT027 and PT007 in Figure 1 
updated as 955 instead of 959.
Note in Figure 1 updated as “Note: All visits conducted 
remotely/virtually with no in-person clinic visits”
1.3 Schedule of activities
Updated in the header of Table 1 that IMP will be delivered 
within 7 days instead of 3-5 days and the same change is 
reflected in the footnote b.
Medical and surgical row updated in Table 1 to include any 
smoking history.
Inclusion/exclusion criteria added at Visit 2 in Table 1 and 
the respective footnote f was updated to recheck eligibility 
status before randomization and/or before IMP is dispensed.
Footnote j updated as “AIRQ version with 12-month recall 
period will be used at Screening, Randomization and EOS or 
Early Study/ IMP Discontinuation visits. AIRQ version with 
a 3-month recall will be used at other visits as indicated 
above. AIRQ is performed at both screening/re-screen and 
randomization, however, where screening/re-screen and 
randomization is performed on the same day, the AIRQ 
questionnaire will only be completed once.
Footnote p added “The interval between screening and 
randomization may be up to 28 days. The screening 
period may be extended to collect documentation to 
confirm the asthma diagnosis only in the event that 
information has not been received within 28 days of 


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consent. The screening period cannot be extended >56 
days for any reason. See Section 5.1 for details.”
Footnote q added “Participants who initially screen failed 
due to failure to receive confirmatory medical records 
within the original 28-day screening period, use of 
corticosteroids within 6 weeks of Screening visit 1 or who 
were hospitalized for asthma within 3 months of screening 
Visit 1 may re-screen once. Participants who re-screen 
must complete all Visit 1 procedures during re-screening 
and satisfy eligibility criteria before being permitted to 
randomize into the study. Participants who fail to satisfy 
eligibility criteria during re-screening cannot be re-
screened for a second time.”
2 Introduction
Updated to include that the study will be conducted in 
patients with asthma, in partnership with AstraZeneca.
Updated to add “BDA MDI was approved by the Food and 
Drug Administration on 10 Jan 2023 for the as-needed 
treatment or prevention of bronchoconstriction and to 
reduce the risk of exacerbations in patients with asthma 
18 years of age and older (NDA 214070); AstraZeneca 
Pharmaceuticals LP is the NDA holder.”
2.3.1 Risk Assessment
Updated that the participants using >12 inhalations daily may 
potentially be at an increased risk of local or systemic 
corticosteroids side effects including adrenal suppression and, 
in adolescent participants, growth retardation.
3. Objectives and endpoints
Updated primary objective as “To evaluate the efficacy of 
as-needed BDA MDI compared with as-needed AS MDI on 
the risk of severe asthma exacerbations.”
Updated treatment as “Randomized IMP alone or usual
Maintenance therapy + randomized IMP. ”
4.1 Overall Design
Updated that for females of child-bearing potential, following 
the initial screening assessment, a urine pregnancy test with 


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high sensitivity is required.
Updated that the interval between screening and 
randomization may be up to 28 days.
Added “screening period may be extended to collect 
documentation to confirm the asthma diagnosis only in 
the event that information has not been received within 28 
days of consent. The screening period cannot be extended 
> 56 days for any reason. See Section 5.1 and Schedule of 
Activities (SoA) (Table 1) for details.”
Updated that the Treatment Initiation Visit (Visit 3) will occur 
once the participant is in receipt of the study medication 
(expected to be within 7 days following randomization).
Removed digital training material, including a training video 
from the additional training materials available.
4.2 Scientific Rationale for 
Study Design
Updated that the Phase III MANDALA study demonstrated 
that BDA MDI as needed significantly reduced the risk of a 
severe asthma exacerbation compared with albuterol alone by 
27%.
4.3 Justification for Dose
Updated the text as “The MANDALA Phase III study 
demonstrated that BDA MDI, taken as needed at the now 
approved dose of budesonide/albuterol 160/180 μg, was both 
efficacious and well-tolerated in a population with moderate 
to severe asthma.”
5.1 Inclusion Criteria
Inclusion criteria 1
Note updated as “For participants from 12 years of age to 
age of majority, their parents/legal guardian must provide 
signed consent, as appropriate, and participants will sign an 
assent form.”
Inclusion criteria 2
Updated to included list of suitable documentation for 
confirmation on asthma diagnosis.


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Inclusion criteria 3
Point no. a updated to remove text “at least 70% of 
participants should be on SABA alone.”
Prescriptions to be considered instead of filled prescriptions.
Added that “Participants must present their medication 
including any inhaler(s) during Screening Visit 1 and a 
picture of the medication(s) are required to captured in 
the 
 
 platform. For participants on SABA 
alone, verbal confirmation by the participant that they 
have used at least one additional inhaler in the past 12 
months will be considered acceptable.”
Inclusion Criteria 5
Updated as “An AIRQ score of ≥2 at Screening 
(Visit1/re-screen) and Randomization (Visit2) where 
applicable. Note, where screening Visit1/re-screen and 
randomization occur on the same day, AIRQ will only be 
completed once.”
Inclusion criteria 6
Females of sexually active in heterosexual relationships 
removed and updated that females of child-bearing potential 
must have a negative pregnancy test prior to randomization 
and agree to follow 1 of the options listed under this criterion 
to prevent pregnancy.
Point number b (ii) updated as single-barrier birth control 
method instead of double-barrier.
Specific recommendations for participants 12 years and over 
has been separated from point c and updated as point d.
Inclusion criteria 7
Updated as “Male participants who are in heterosexual 
relationships must be surgically sterile or agree to use an 


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effective method of contraception (condom) if the female 
partner does not use contraception from the date the eICF 
is signed until 2 weeks after their last dose. Male participants 
must not donate sperm during their study participation 
period.”
Inclusion criteria 8 
Updated as “Capable of giving signed eICF (including assent 
with parental / legal guardian consent in 12 years of age to 
age of majority as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the 
eICF and in this protocol.”
5.2 Exclusion Criteria
Exclusion Criteria 1
Added “or any significant disease (like malignancies or 
severe chronic diseases) that by Investigator judgment 
would interfere with the participant being able to comply 
with study procedures or complete the study.”
Exclusion Criteria 2
Added “Participants who were screen-failed due to 
hospitalization within the 3 months prior to enrollment
may be re-screened once when the participant is more 
than 3 months post-hospitalization. Participants who 
reported an Intensive Care Unit admission with life 
threatening asthma may not be re-screened.”
Exclusion Criteria 3
Updated as inhaled LABA and inhaled anticholinergic agent.
Exclusion Criteria 4
Updated as “Self-reported use of SCS for the treatment of 
asthma and any other condition in the 6 weeks prior to 
enrollment. Participants screen failed for this reason may 


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be re-screened once, with their re-screening visit 
scheduled >6 weeks after last use of SCS.”
Exclusion Criteria 5
Updated as “Participants with a home supply of oral 
corticosteroids (OCS) to be used in the case of an asthma 
exacerbation or any other condition that could require a 
course of OCS, that are not willing to commit to the treating 
physician to stop using this medication for the duration of 
the study.”
Exclusion Criteria 6
Added Tezepelumab as an example.
Exclusion Criteria 14
Updated as “Previous screening enrollment or randomization 
in the present study, except where re-screening is permitted 
(see Section 5.5).”
5.4 Screen Failures
Updated that the Individuals who do not meet the criteria for 
participation in this study (screen failure) may only be re-
screened once for specific reasons as specified within 
Section 5.1, Section 5.2 and Section 5.5.
5.5 Re-screening
New section for re-screening added.
6.2 Preparation/Handling/
Storage/ Accountability
Point no. 2 added “Participants will be given information 
about the delivery of their IMP at Visit 2 including what is 
included in the delivery, expected timelines and IMP 
storage information.”
Point no. 3 (previously point no. 2) was updated to include 
that the Instructions for Use (IFU) is contained within a 
Home Study Guide.
6.2.1 Dose and Treatment 
Regimens
Updated that the handling instructions for the MDI device 
will be available for the site to train participants and also for 


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the participants to refer to throughout the study.
6.2.2 Labeling
Updated that additional kits will be ordered through the 
RTSM by the Investigator.
6.2.3 Storage
Updated that the participants will receive information on IMP 
storage in a Home Study Guide, and the label in the IMP 
carton also specifies the appropriate storage temperature.
6.2.4 Accountability
Updated that the central depot will be responsible for the 
destruction of IMP after the accountability and reconciliation 
has been performed by the Investigator.
6.2.5 Metered-dose Inhaler: 
Handling and Cleaning
Updated that an instructional video with details on the 
instructions for use and cleaning of the device will be shown 
to the participant at Visit 3.
6.3.1 Methods for 
Assigning Treatment 
Groups
Updated as participant’s ID number instead of 
enrollment/randomization code.
6.4 Study IMP Compliance
Updated that the number of MDIs sent to the participant and 
returned by the participant to the central depot will be 
documented and stored in the Investigator File instead of 
Investigator Site.
6.5.3 Allowed and 
Prohibited Medication
Table 5 was updated for the Background (maintenance) 
asthma medication, systemic corticosteroids, biologics for the 
treatment of asthma, and allergen immunotherapy.
Background (maintenance) asthma medication (Low-dose 
ICS or a LTRA) was updated to allow only for participants 
receiving maintenance therapy at baseline or if clinically 
indicated.
Background (maintenance) asthma medication (Inhaled 
LABA, theophylline, inhaled anticholinergic agent, cromone 


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or medium/high dose ICS daily) was updated to prohibit as 
per exclusion criterion 3.
Systemic corticosteroids were updated to prohibit unless to 
treat a severe asthma exacerbation or in an equivalent 
acute situation. Details regarding use of systemic 
corticosteroid were updated.
Biologics for the treatment of asthma was updated to add 
tezepelumab as an example to any marketed products.
Added Footnote a “Stable allergen immunotherapy is 
defined as when the participant has reached the target 
dose and is on regular maintenance dosing for at least 4 
weeks.”
7.1.1 Planned 
Discontinuation of Study 
IMP
The following statement was updated as “If the PCD is 
achieved before a participant reaches 52 weeks of treatment, 
provided they have received at least 12 weeks of 
treatment, the participant will be asked to discontinue IMP 
within 4 weeks of the PCD and to complete an EOS.”
7.1.2 Premature 
Discontinuation of IMP
Updated that the participants who prematurely discontinue 
study IMP should complete the procedures described in the 
EOS or Early Study/ IMP Discontinuation visit as soon as 
possible from discontinuing the study IMP.
Updated option 4: (If the participant cannot comply with 
Option 1, 2 or 3 above) “The participant may withdraw 
consent for further follow-up and may proceed to perform the 
EOS visit prematurely upon withdrawal.”
7.2 Participant Withdrawal 
from the Study
Updated that at the time of withdrawal from the study, if 
possible, Early Study/IMP Discontinuation visit should be 
conducted (equivalent to the EOS visit).
8 Study Assessments and 
Procedures
Updated that all assessments and procedures will be 
performed virtually with no planned in-person contact 
between the participant and the Investigator or their staff.
Updated that the 
 portal app will capture actuation 


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information instead of dose information.
Updated that the Patient Navigator contact details can be 
accessed via the 
 
 app and additional 
information on the service will be available within the 
 
 app.
Updated that the list of participants screen is maintained 
within 
 
 instead of a screening log maintained 
by the Investigator.
8.1 Screening and Critical 
Baseline Assessments
Updated that the relevant medical and surgical history will be 
captured at Screening, including all background asthma 
medications (eg, SABA, ICS and LTRAs) and all other 
medications taken for any reason in the 3 months prior to 
enrollment. Any concomitant medication(s) taken during 
the study must also be recorded in the eCRF. In addition, 
smoking history will also be collected as relevant medical 
history.
Updated that where Screening Visit 1/re-screen and 
randomization (Visit 2) occur on the same day, AIRQ will 
only be captured once and this will be considered the baseline 
assessment.
8.6 
 
Mobile 
Software Application
eCode updated as participant’s ID number.
Updated that the System data collected will be retained for a 
period of 15 years after trial closure instead of 10 years.
8.7 Unscheduled Visits 
following ‘Yes’ Response 
to 
 
bi-weekly Message
Updated that the Investigator/site staff will receive an email 
notification to contact the participant to collect further 
information.
Added “Where a scheduled visit is within 2 weeks of the 
notification, sites may (at their discretion) wait for the 
scheduled visit to collect follow-up information from the 
participant; however, they are encouraged to contact the 
participants as soon as possible. Where the next scheduled 
visit is > 2 weeks following the notification, an 


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unscheduled visit should be conducted as soon as possible 
to obtain the follow-up information below.”
Updated that during the next scheduled or unscheduled 
contact, the Investigator or site staff will review and query the 
participant regarding the items listed as bullet points in this 
section.
8.9 Medical Resource 
Utilization and Health 
Economics
Updated as “Outpatient medical encounters (including 
physician or emergency room visits, tests and procedures, and 
medications).”
9.4.2.1 Primary Endpoint
Updated as “Treatment condition= Randomized IMP alone or 
usual Maintenance therapy + randomized IMP”
9.4.2.3 Primary Endpoint
Updated as “Treatment Condition = Randomized IMP alone 
or usual Maintenance therapy at Day 1 + randomized IMP, 
including any other additional medication/therapy.”
9.6 Data Monitoring 
Committee
Updated that one safety review will occur before the interim 
analysis, with a second safety review at the time of the 
interim analysis, and a third safety review will occur at a 
later timepoint following the interim analysis if the study 
was not closed early for efficacy.
Updated that the members of the DMC will review efficacy 
data generated externally and independently from the 
Sponsor, unblinded, once 50% of the events have been 
observed.
10 Supporting 
Documentation and 
Operational Considerations
A 3 Informed Consent Process (eConsent)
Updated that the participants may withdraw their 
consent/assent at any time and for any reason during the 
study.
Added that the participants not at age of majority will be 
required to sign a statement of assent.
Updated that the participants source record for the study must 
include a statement that informed consent was obtained 


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electronically before any study related procedures are 
performed and the date the eConsent was obtained.
A 4 Data Protection
Updated that the participant will have to provide personal 
information to the investigational site via the 
 
e-source platform who in turn share some of this 
information with the following vendors: the IMP vendor 
(
) for shipment of study materials 
(IMP devices, IMP sensors), 
who enable 
Support to create a password for the app, 
to
process participant’s payment, and Patient Navigator to 
support participants. This information will be kept 
confidential by all providers.
A 6 Data Quality Assurance
Updated example in the first bullet point as
actuation
data instead of 
dosing data.
A 7 Source Documents
Deleted text “Also, current medical records must be 
available.”
A 8 Study and Site Start and Closure
Updated that the study sites will be closed upon study 
completion (or early if they are unable to comply with 
study procedures or meeting study objectives).
B 2 Definition of Serious Adverse Events
Under “Important Medical Event or Medical Treatment” 
added text “Examples of important medical events include 
but are not limited to:”
Appendix F Instructions for Use 
Updated the appendix with instructions for use for MDI and 


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 Sensor.
Appendix H
Updated Appendix with new abbreviation.
Throughout document
Updated as CRO instead of 
across the document.
Updated as early study/IMP discontinuation instead of early 
study IMP discontinuation or early discontinuation.
Updated as participants instead of patients in relevant places.


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M, Keen C, Alagappan VKT, Reddel HK. Effect of a single day of increased as-needed 
budesonide-formoterol use on short-term risk of severe exacerbations in patients with mild 
asthma: a post-hoc analysis of the SYGMA 1 study. Lancet Respir Med. 2021;9(2):149-58. 
Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, 
Morelli P, Nicolini G, Fabbri LM. Rescue use of beclomethasone and albuterol in a single 
inhaler for mild asthma. N Engl J Med 2007;356:2040-52.
Papi A, Chipps B. E, Beasley R, Panettieri R A Jr., Israel E, Cooper M et al. Albuterol-
Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med 2022. 
Available from: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2203163.
Partridge MR, van der Molen T, Myrseth SE, Busse WW. Attitudes and actions of asthma 
patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med. 2006;6:13. 
Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al. Adverse outcomes 


Clinical Study Protocol 
Bond Avillion 2 Development LP
Budesonide/Albuterol Sulfate (BDA), AV007, Version 3.0, Final 05 Jan 2024
CONFIDENTIAL AND PROPRIETARY
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from initiation of systemic corticosteroids for asthma: long-term observational study. J 
Asthma Allergy. 2018;11:193-204. 
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. 
Sastre J, Fabbri LM, Price D, Wahn HU, Bousquet J, Fish JE, Murphy K, Sears MR. Insights, 
attitudes, and perceptions about asthma and its treatment: a multinational survey of patients 
from Europe and Canada. World Allergy Organ J. 2016; 9:13.
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):594-9. 
Thomas M, Bateman E. Asthma attacks: how can we reduce the risks? NPJ Prim Care Respir 
Med. 2015;25:14105.
US National Asthma Education and Prevention Program (NAEPP) Expert Panel Report-4 
(EPR-4; 2020). Available from: https://doi.org/10.1016/j.jaci.2020.10.003 
Yawn BP. Factors accounting for asthma variability: achieving optimal symptom control for 
individual patients. Prim Care Respir J. 2008;17(3):138-47.

SAP_001.pdf: 
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Title: Statistical Analysis Plan for AV007: A Multicentre, Randomized, Double-blind, Parallel group, 
Event Driven, Decentralized, Phase IIIb Study Comparing PT027 with PT007 Administered As Needed 
in Participants 12 Years of Age and Older with Asthma (BATURA) 
Compound Name/Number: PT027 
Effective Date: 19 JAN 2024 
Title, and Functional Area: 
 Principal Statistician, PHASTAR 
NCT05505734




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SIGNATURE PAGES ........................................................................................................... 2 
ABBREVIATIONS 5 
TRADEMARK INFORMATION ............................................................................................. 7 
REVISION HISTORY ........................................................................................................... 7 
1. 
INTRODUCTION ....................................................................................................... 7 
2. 
STUDY OBJECTIVES AND ESTIMANDS ....................................................................... 8 
2.1 
Study objectives ....................................................................................................... 8 
2.1.1 
Primary objectives .................................................................................................... 8 
2.1.2 
Secondary objectives ............................................................................................... 8 
2.1.3 
Exploratory objectives ............................................................................................ 10 
2.1.4 
Safety objectives .................................................................................................... 10 
2.2 
Study estimands ..................................................................................................... 10 
3. 
STUDY DESIGN ....................................................................................................... 11 
4. 
SAMPLE SIZE CONSIDERATIONS ............................................................................. 12 
5. 
ANALYSIS POPULATIONS ........................................................................................ 13 
5.1 
All participants enrolled analysis set ...................................................................... 13 
5.2 
All participants randomized analysis set ................................................................ 13 
5.3 
Full analysis set....................................................................................................... 13 
5.4 
Safety analysis set .................................................................................................. 13 
6. 
PROTOCOL DEVIATIONS ......................................................................................... 14 
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES .................................................. 14 
7.1 
Treatment periods ................................................................................................. 14 
7.2 
Treatment initiation ............................................................................................... 15 
7.3 
Standard summary statistics .................................................................................. 15 
7.4 
Strata and covariates ............................................................................................. 16 
7.5 
Examination of subgroups ..................................................................................... 16 
7.5.1 
Efficacy subgroups ................................................................................................. 16 
7.5.2 
Safety subgroups .................................................................................................... 17 
8. 
DATA HANDLING CONVENTIONS ............................................................................ 17 


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8.1 
Study endpoints ..................................................................................................... 17 
8.1.1 
Primary endpoint ................................................................................................... 17 
8.1.2 
Secondary endpoints .............................................................................................. 18 
8.1.3 
Exploratory endpoints ............................................................................................ 21 
8.1.4 
Safety endpoints .................................................................................................... 26 
8.2 
Statistical hypotheses ............................................................................................ 27 
8.2.1 
Primary hypothesis................................................................................................. 27 
8.2.2 
Secondary hypotheses ........................................................................................... 28 
8.3 
Multiple testing strategy ........................................................................................ 28 
8.4 
Premature withdrawal and missing data ............................................................... 29 
8.4.1 
Date imputation rules ............................................................................................ 30 
8.4.2 
Sensitivity analyses ................................................................................................ 31 
8.5 
Study population .................................................................................................... 31 
8.5.1 
Demographics and baseline characteristics ........................................................... 31 
8.5.2 
Concomitant medications ...................................................................................... 32 
8.5.3 
Treatment compliance ........................................................................................... 33 
8.6 
Assessment time windows ..................................................................................... 33 
8.6.1 
Methods for handling out-of-window observations .............................................. 34 
9. 
STATISTICAL ANALYSES AND METHODOLOGY ........................................................ 34 
9.1 
Study population .................................................................................................... 34 
9.1.1 
Disposition of subjects ........................................................................................... 34 
9.1.2 
Protocol deviations ................................................................................................ 35 
9.1.3 
Demographic and baseline characteristics ............................................................ 35 
9.2 
Efficacy analyses ..................................................................................................... 36 
9.2.1 
Primary efficacy analysis ........................................................................................ 36 
9.2.2 
Secondary efficacy analysis .................................................................................... 37 
9.2.3 
Exploratory efficacy analysis .................................................................................. 39 
9.3 
Safety analyses ....................................................................................................... 41 
9.3.1 
Adverse events ....................................................................................................... 41 
9.4 
Supplementary and Sensitivity Analyses ............................................................... 43 
10. 
INTERIM ANALYSIS ................................................................................................ 45 


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11. 
BLINDED SAMPLE SIZE REASSESSMENT .................................................................. 46 
12. 
CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSIS ............................................ 47 
13. 
REFERENCES .......................................................................................................... 47 
14. 
APPENDIX A ........................................................................................................... 47 
14.1 
List of tables, listings and figures ........................................................................... 47 
15. 
APPENDIX B ........................................................................................................... 48 
15.1 
Schedule of assessments........................................................................................ 48 
16. 
APPENDIX C ........................................................................................................... 51 
16.1 
USA value set.......................................................................................................... 51 
17. 
APPENDIX D ........................................................................................................... 52 
17.1 
List of Preferred Terms Included for Assessment of Local and Systemic Steroid 
Class Effects, Potentially Associated with Inhaled Corticosteroids .................................................. 52 
 
ABBREVIATIONS 
AE 
Adverse Event 
ADaM
Analysis dataset model
AIRQTM
Asthma Impairment and Risk QuestionnaireTM
AS 
Albuterol Sulfate 
ATC
Anatomical Therapeutic Chemical 
BDA
Budesonide / albuterol 
CI 
Confidence interval
CM
Concomitant medications
d.p. 
Decimal place 
DMC 
Data monitoring committee 
DRC
Data review committee 
eCRF
Electronic case report form 
eICF 
Electronic Informed Consent form 
ED-5D-5L
EuroQol 5 dimensions 5 levels 




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SoA
Schedule of Activities
VAS
Visual Analog Scale 
TRADEMARK INFORMATION 
SAS 
SAS (Statistical Analysis Software) is a registered trademark of SAS Institute Inc. 
REVISION HISTORY 
Version 
Date 
Summary of revisions 
 
 
 
 
1. 
 
The purpose of this Phase IIIb study is to evaluate the efficacy and safety of PT027 
(budesonide/albuterol [BDA] 80/90 µg metered dose inhaler [MDI]), used as needed in participants 
aged 12 years and older with asthma previously receiving short-acting 2-agonists (SABA) alone or 
SABA on a background of either low-dose inhaled corticosteroids (ICS) or a leukotriene receptor 
antagonist (LTRA). 
With BDA MDI, albuterol provides rapid relief of asthma symptoms while budesonide simultaneously 
treats underlying inflammation. Use of BDA MDI will be driven by day-to-day symptom levels and 
will follow a participant
treatment for inflammation will be provided when needed most. Safety and efficacy of BDA MDI will 
be compared with albuterol (PT007; AS MDI) because albuterol is the standard of care rescue 
therapy in the United States (US). 
The study evaluates the efficacy of as-needed BDA MDI (administered at a dose of 
budesonide/albuterol 160/180 µg, administered as 2 inhalations of BDA MDI 80/90 µg) in reducing 
the risk of severe asthma exacerbations, as measured by time to first severe asthma exacerbation, 
compared with AS MDI as needed (administered at a dose of albuterol 180 µg; administered as 2 
inhalations of AS MDI 90 µg) either alone or on top of participants' usual low-dose ICS or LTRA 
maintenance therapy in approximately 1910 participants 12 years of age and older.  
The study also investigates the effect of BDA MDI on the rate of severe asthma exacerbations, total 
annualized systemic corticosteroid use, asthma-related healthcare resource utilization, asthma 
control, and health-related quality-of-life. Safety will be assessed through the collection of adverse 
events (AEs) and serious adverse events (SAEs).  
The study is fully decentralized for all participants, with no planned in-clinic visits, i.e., all study visits 
will be conducted virtually. By employing a decentralized study delivery model, it is anticipated to 
reach a broader population of asthmatic participants who typically might not consider participating 








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Treatment Condition = Randomized IMP or maintenance therapy + randomized IMP, 
Population = Participants 12 years of age and older with asthma who are taking SABA as 
needed alone or with a low-dose ICS or LTRA, 
ICE handling = Two ICEs are defined:  
o
A step-up in maintenance therapy 
o
All-cause discontinuation of study treatment 
A While on Treatment strategy will be implemented such that effects of randomized treatment will 
be analysed using data collected during the period that participants were on treatment, before 
treatment discontinuation or a step-up in maintenance therapy. For time to event endpoints, 
patients will be censored at the time in which the ICE occurred. Annualized severe exacerbation 
rates and annualized systemic steroid exposure will be calculated from the data collected between 
randomized treatment initiation and the earliest occurrence of the ICE. For other secondary and 
exploratory endpoints, data collected following the ICE will be considered missing at random and 
excluded from the summaries and analyses under this estimand strategy.  
To assess efficacy in the adult population, a secondary estimand defined is the While on Treatment 
strategy in the full analysis set (
8 years). The treatment condition and ICE handling attributes are 
the same as defined in the primary estimand. The population attribute is defined as participants 18 
years of age and older with asthma who are taking SABA as needed alone or with a low-dose ICS or 
LTRA. 
A secondary estimand utilising a Treatment Policy estimation strategy in the full analysis set (
2 
years). All observed data while participants are in the study, regardless of whether they are on 
randomized treatment or have a step-up in maintenance therapy, will be included in the estimation 
procedure. The Treatment Policy strategy will be evaluated in the Full analysis set. Apart from the 
secondary endpoint of time to first severe exacerbation, all analyses produced under the Treatment 
Policy strategy will be considered supplemental. A similar secondary estimand is defined in the full 
analysis set (
8 years).  The population attribute is defined as participants 18 years of age and older 
with asthma who are taking SABA as needed alone or with a low-dose ICS or LTRA.  
The attributable estimand is defined as the effect of treatment in participants attributable to the 
randomized treatment assuming that maintenance therapy is not increased. For this estimand, 
discontinuation from the study for tolerability or a step-up in maintenance therapy for lack of 
asthma control is considered a negative outcome. This estimand is a mixture of composite and 
hypothetical strategies as defined in the draft ICH E9 addendum. The primary endpoint of time to 
first severe asthma exacerbation will be analyzed under the attributable estimand. 
3. 
 
This is a Phase IIIb, US, multicentre, double-blind, randomized, parallel-group, event-driven, variable-
length, decentralized study to evaluate the efficacy and safety of BDA MDI (used at a dose of 
budesonide/albuterol 160/180 µg) compared with AS MDI (used at a dose of albuterol 180 µg), both 
taken as needed, for at least 12 weeks and up to 52 weeks. Participants 12 years of age and older 
with asthma will be recruited with all visits conducted virtually.  


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Eligible participants must be using as-needed SABA alone, or as-needed SABA on a background of 
either low-
for a low-dose ICS inhaler or a LTRA in the 12 months prior to enrolment. Participants continue their 
days, for the relief of asthma symptoms, in the previous 2 weeks prior to Visit 2 and have an Asthma 
Impairment and Risk Questionnaire (AIRQ)TM 
 
Participants from 40 to 50 centres located in the United States (US) will be randomized 1:1 to receive 
one of the following two treatments, to be used as needed: 
 
BDA MDI 160/180 µg (given as 2 inhalations of BDA 80/90 µg per actuation) up to a 
maximum of 12 inhalations per day      
 
AS MDI 180 µg (given as 2 inhalations of AS 90 µg per actuation) up to a maximum of 12 
inhalations per day 
Participants are stratified by pre-study asthma medication (3-factor): SABA only, low dose ICS + SABA 
or LTRA + SABA, and the number of documented prior severe exacerbations (0, >=1) in the 12 
months prior to the screening visit. 
The study is double-blind with BDA and AS MDI being identical in appearance. Participants also 
receive a 
 sensor attachment (referred to as an MDI sensor, or sensor) compatible with the 
study inhalers that will be used to capture each actuation of the inhaler throughout the study. 
The schedule of assessments is presented in Appendix B. 
4. 
 
To achieve 350 first severe asthma exacerbation events, it is planned that 1910 participants (955 
participants per arm) will be randomized. It is expected that most participants in the proposed US 
asthma population will be on SABA only. Randomization will be stratified by pre-study asthma 
therapy (SABA only; low-dose ICS + SABA or LTRA + SABA) and number of documented prior severe 
within each stratum. The target number of events required is estimated from the sample size 
determinations based on the analysis of the primary endpoint time to first severe asthma 
exacerbation.  
The treatment effect is assumed to be a hazard ratio (HR) of 0.7 which is a 30% reduction in the risk 
of a first severe exacerbation (BDA MDI versus AS MDI) and is supported by results from the 
MANDALA study where the HR = 0.73 
compared to AS MDI 180 µg. Assuming a 1-year first severe exacerbation event rate in the AS MDI 
arm of 21%, 345 events are needed to achieve 90% power, with a 2-sided significance of 5%.  
For the secondary endpoint of time to first severe asthma exacerbation targeting the Treatment 
Policy strategy, it is assumed that 10% of participants in the study will discontinue IMP or step-up 
maintenance therapy resulting in a null treatment effect in this group of participants, such that the 
estimated overall hazard ratio is increased by 0.025. Therefore assuming, a 27.5% reduction in the 


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risk of a first event with BDA MDI compared to AS MDI and a 1 year first event rate of 21% in the AS 
MDI arm, 350 first events are required to achieve 85% power, with a 2-sided significance of 5%.  
The estimated total number of participants to be randomized to treatment is 1910 to achieve the 
overall target number of 350 first severe asthma exacerbation events. However, if during the study 
the observed blinded overall first event rate is higher than expected then the required number of 
events may be met with less participants and recruitment will be stopped prior to reaching 1910 
participants randomized. Similarly, if during the study the observed blinded overall rate is lower than 
predicted, the number of participants randomized may be increased up to approximately 2500 to 
ensure the required number of first severe asthma exacerbations are achieved. Any assessment of 
accumulating data will be performed on pooled, blinded data. Blinded event rate monitoring will be 
conducted during the study to ensure that the required number of events will be observed. Refer to 
section 11 for further details on blinded sample size reassessment. 
5. 
 
5.1 
ALL PARTICIPANTS ENROLLED ANALYSIS SET 
The all participants enrolled population will be defined as all participants who provide informed 
consent through the electronic informed consent form (eICF). This population will be used for 
descriptive summaries of disposition. 
5.2 
ALL PARTICIPANTS RANDOMIZED ANALYSIS SET 
The all participants randomized population are all participants that are randomized regardless of 
amount of IMP taken. The population will be used for descriptive summaries of site and disposition.  
5.3 
FULL ANALYSIS SET 
The full analysis set is defined as all participants who are randomized to treatment and receive any 
amount (i.e., at least 1 actuation) of IMP. Participants will be analyzed according to the treatment 
they were assigned at randomization, regardless of the actual treatment received. 
The full analysis set includes all patients (aged 12 years). A subpopulation of the full analysis set, 
which only includes participants aged 18 years is also defined to facilitate secondary analysis in this 
age group. In the programmed outputs, the population will be clearly described in the titles and 
presented as: 
Full analysis set; >=12 years 
Full analysis set; >=18 years  
5.4 
SAFETY ANALYSIS SET 
The safety analysis set is defined as all participants who are randomized to treatment and receive 
any amount (i.e., at least 1 actuation) of IMP. Participants will be analyzed according to the actual 
treatment received rather than randomized. If a participant receives more than 1 IMP then they will 
be summarized according to the treatment they received the most.  
All safety summaries will be based on the safety analysis set. 


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6. 
 
Important protocol deviations (IPDs) will be listed and summarized by randomized treatment group. 
A per-protocol analysis is not planned for this study.  
All participants who failed any inclusion/exclusion criteria and were subsequently randomized into 
study will be listed along with details of the failed criteria. This information will also be summarized 
in terms of the number and percentage of participants failing any of the inclusion/exclusion criteria 
and will be based on the FAS. 
IPDs are defined as a subset of protocol deviations that may significantly affect the completeness, 
accuracy, and/or 
safety, or well-being. 
A prospective list of important protocol deviations will be identified by the Sponsor prior to the 
interim analysis and the collected listing of protocol deviations and their assignment of minor, major 
and important will be finalised prior to the unblinding of the study results. Another review by the 
Sponsor will be conducted to assign any new protocol deviations between the interim analysis and 
the final database lock. 
Any participants stratified incorrectly will be identified as important protocol deviations. All 
participants 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. 
Any additional protocol deviations will be defined both prior to the unblinding of data for the interim 
analysis and prior to the final database lock, in the protocol deviation specification.  
7. 
 
7.1 
TREATMENT PERIODS 
The randomized treatment period for each participant is defined from treatment initiation (Visit 3) 
until the earliest occurrence of study completion, study withdrawal, discontinuation of randomized 
treatment, a step-up in maintenance therapy, or in the case of the participant being lost to follow-
up, the date of last contact. For adverse events, the randomized treatment period will be defined 
from treatment initiation (Visit 3) until the earliest occurrence of study completion, withdrawal, date 
of last contact, or discontinuation of randomized treatment. This is regardless of a step-up in 
maintenance therapy. 
The study period for each participant is defined from treatment initiation (Visit 3) until the earliest 
occurrence of study completion or withdrawal. This is regardless of any ICEs. The study period 
encompasses any time that the participant provides visit information, including information on 
severe exacerbations, adverse events, concomitant medications and hospitalizations. 
Any severe exacerbations, adverse events, hospitalizations or systemic corticosteroids that start 
after randomization and before treatment initiation will not be included in the analyses over the 
treatment period, or study period.  


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7.2 
TREATMENT INITIATION 
The treatment initiation visit occurs once the participant is in receipt of the study medication (6 IMP 
inhalers are expected to be delivered to their home 3 to 5 days following randomization). Alongside 
study IMP, participants will also receive 2 
sensor attachments to capture each actuation of 
study inhaler use throughout the study, allowing more than 1 inhaler to be fully operational 
concurrently. Participants with asthma often have rescue inhalers stored in different places at once. 
The start date of the IMP treatment period is defined as the day of first dose of IMP treatment, 
whereby at Visit 3, once the participant is in possession of study medication, all participants are 
required to take one inhalation of treatment as part of the training on how to use the study inhaler 
and inhaler sensor attachment. This is recorded in the eCRF Exposure page as the date of first 
actuation of IMP.  
The exposure start date on the eCRF corresponds to the date of first dose of IMP. The eCRF exposure 
date of first dose of IMP is used as the official treatment initiation date. This date will be used to 
assign baseline results and the start of follow-up for severe exacerbation events, systemic 
corticosteroid exposure, concomitant medications, and treatment emergent adverse events.  
In the event that the 
app records a start date of IMP treatment inconsistent with the eCRF, 
this will be raised as a discrepancy by PHASTAR to 
 data management to be queried and 
resolved. Under this process, the eCRF exposure information will be used to define the first dose of 
randomized treatment in the statistical programming activities. Inconsistencies between the date of 
first dose of IMP and the date of first actuation per the 
 app may occur due to sensor 
malfunctions, errors in attaching the sensor device to the inhaler, issues with synchronization of the 
sensor with the user application, or other user general error or misuse of the device. Reasons for 
inconsistency between date of first dose (eCRF) and date of first actuation (
app) will be 
documented via data reconciliation orchestrated by the data management vendor. 
7.3 
STANDARD SUMMARY STATISTICS 
For continuous endpoints we will summarise by the number of evaluable participants in the analysis 
(n); Mean; Standard Deviation; Median; Minimum; Maximum.  
Summaries of categorical endpoints will include the absolute counts (n) and percentage, with the 
denominator used in the percentage calculation as the number of participants in the analysis set 
used for the descriptive summaries of counts and percentages, unless otherwise defined in section 
9. 
Percentages will be displayed with one decimal place (d.p.). If the number of participants in the 
analysis set is zero, then this will be displayed with no percentage. Unless otherwise stated in section 
9, the Mean and Median will be displayed with 1 d.p., the Standard Deviation with 2 d.p. and the 
Minimum and Maximum will be displayed with the same d.p. as the data that the table is 
summarising. 
Any summary statistics required in addition to the aforementioned will be detailed within section 9, 
for each relevant endpoint. 






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An asthma exacerbation is considered severe if it results in at least one of the following criteria: 
A temporary bolus/burst of systemic corticosteroids (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 centre) due to asthma that required SCS (as per 
the above) 
An in-subject hospitalization (defined as an admission to an in-subject facility and/or 
evaluation and treatment in a healthcare facility for 24 hours) due to asthma 
Results in death 
All post-randomization severe asthma exacerbations must be captured using the Asthma 
Exacerbation form in the electronic case report form. One entry corresponds to one severe 
exacerbation, which includes the start date and end date of the clinical event (last date of systemic 
corticosteroid use). 
The duration of a severe exacerbation will be defined as the number of days from the date of 
prescribed treatment including systemic corticosteroids until the last day of prescribed treatment 
with a systemic corticosteroid. 
Time to first severe asthma exacerbation will be calculated as the time (days) from the start of 
treatment initiation (Visit 3) until the start date of the first severe asthma exacerbation:  
[Start date of first severe asthma exacerbation]  [ Date of treatment initiation (Visit 3)] +1 
The primary endpoint will be derived in accordance with the While on Treatment strategy. 
Participants will be censored if they experience an ICE prior to their first severe exacerbation event 
(see section 2.2 for details on ICEs). Participants that do not experience a severe asthma 
exacerbation event or an ICE will be censored at the date of withdrawal from the study or, in the 
case of lost to follow-up, the date of last contact. 
If a participant has a severe asthma exacerbation after randomization and prior to receipt of IMP 
then the treatment initiation visit (Visit 3) will be delayed until the severe exacerbation is ended. The 
patient will be followed up and their first severe exacerbation event emerging post-Visit 3 will be 
used for analysis. 
The time at risk up to the first severe exacerbation will be calculated as the time to first severe 
exacerbation (in days, as defined above), divided by 365.25 and multiplied by 100, to provide the 
time at risk per 100 patients years, per patient. 
8.1.2 SECONDARY ENDPOINTS 
8.1.2.1 
TIME TO FIRST SEVERE EXACERBATION 
The time to first severe asthma exacerbation will also be derived in accordance with the Treatment 
Policy strategy (see section 2.2), in which all data collected during the study period, following 
treatment initiation (Visit 3), will be included in the analyses, regardless of whether they have 


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prematurely discontinued randomized study treatment or had a step-up in maintenance therapy. A 
severe asthma exacerbation is defined as in the primary endpoint (section 8.1.1). 
8.1.2.2 
ANNUALIZED RATE OF SEVERE ASTHMA EXACERBATIONS 
For the secondary analysis of annualized rate of severe asthma exacerbations, the While on 
Treatment strategy will be used. Under this estimand, severe asthma exacerbations that start during 
the treatment period, from treatment initiation (Visit 3) up to the end of treatment or a step-up in 
maintenance therapy, will be included in the analysis. Severe asthma exacerbations that start after 
an ICE will not be included in the analysis. Time during a severe asthma exacerbation and the 7 days 
after a severe exacerbation will not be included in the time at risk for a participant. As per the 
primary efficacy endpoint, exacerbations separated by less than or equal to 7 days will be treated as 
a continuation of the same exacerbation.  
To produce summary statistics, the crude annualized severe asthma exacerbation rate will be 
calculated according to the following formula: 
 
where the summation is over all participants within a treatment arm. 
The time at risk will primarily use the duration (days) from the date of the treatment initiation visit 
to the earliest occurrence of study completion/withdrawal, treatment discontinuation, or a step up 
in maintenance therapy.  
[MIN(Date of study completion, IMP discontinuation, step-up in maintenance therapy)]  [date of 
treatment initiation (Visit 3)]  cumulative duration of severe exacerbation(s)] +1 
The annualized severe asthma exacerbation rate will also be derived according to the Treatment 
Policy strategy. Under this estimand all severe asthma exacerbation events that start during the 
study period, defined from the treatment initiation visit up to study completion or withdrawal from 
study, regardless of treatment discontinuation or a step-up in maintenance therapy, will be included 
in the analyses. Therefore, there time at risk under the Treatment Policy strategy is calculated as: 
[MIN(Date of study completion, study withdrawal)]  [date of treatment initiation (Visit 3)]  
cumulative duration of severe exacerbation(s)] +1 
The cumulative duration of severe exacerbations is calculated as the total number of days that a 
participant has been prescribed a course of SCS: 
Cumulative duration of severe exacerbation(s) = (adjusted stop date of severe exacerbation  date 
of start of severe exacerbation) 
where the sum is over every severe exacerbation event a participant has.  
If a participant experiences an ICE during a severe exacerbation, then, for analyses under the While 
on Treatment strategy, the exacerbation will be excluded from the cumulative duration of events 


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endpoint. Since in this scenario the severe exacerbation started prior to the ICE occurrence, the 
severe exacerbation will contribute to the total number of severe exacerbations (numerator) for the 
secondary endpoint of annualized exacerbation rate. However, the adjusted stop date of the severe 
exacerbation will be adjusted to the date of the ICE occurrence when calculating the time at risk. 
8.1.2.3 
TOTAL SYSTEMIC CORTICOSTEROID EXPOSURE 
The secondary endpoint of total amount (mg/year) per participant of systemic glucocorticoid 
prescribed in response to severe asthma exacerbations will be expressed as the total annualized 
dose (mg/year) of SCS. ICEs will be handled such that only SCS doses related to severe exacerbation 
events that occurred during the treatment period and prior to a step-up in maintenance therapy will 
be included in the analysis (While on Treatment strategy).  
Total SCS exposure will be reported as the total annualized dose (mg/year) and is calculated for each 
participant as the sum of the total dose of systemic corticosteroid per severe asthma exacerbation 
divided by the time (years) the participant was in the study, from the treatment initiation and up to 
study completion, treatment discontinuation, or a step-up in maintenance therapy. Specifically, the 
annualized total systemic corticosteroid dose will be calculated as follows: 
Where total time at risk is defined from treatment initiation until the earliest occurrence of study 
completion, treatment discontinuation, or a step up in maintenance therapy. If an ICE occurs during 
a severe exacerbation, the prescribed SCS up to the ICE will be included in the numerator of the 
equation above, inclusive of the onset day of the ICE. 
Systemic corticosteroids to be considered for the total annualized dose of SCS will be identified with 
ATC codes of H02AB or H02BX, and being taken during a severe exacerbation, and is a specified field 
in the concomitant medications (CM) module. The list of ATC codes described in this analysis plan 
may not be exhaustive. As a result, a clinical review will be conducted on the CM blinded data, prior 
to database lock, to define an exhaustive list of ATC codes associated with systemic corticosteroids 
used to treat asthma exacerbations, for the study. 
Doses of SCS not collected in mg should be converted before being used in calculations. 
SCS medication will be normalized to the equipotent dose of prednisone (mg) before being used in 
the calculation of total corticosteroid exposure. This will be facilitated through a scientific review of 
steroid medication reported on the CM module and the conversions will be provided to PHASTAR.  
The total duration of systemic corticosteroid use will be calculated as the total number of days 
during the randomized treatment period for which participants were prescribed systemic 
corticosteroids. On-going systemic corticosteroids at participant discontinuation/completion of the 
study period will have systemic steroid end dates set to their last date of contact where concomitant 
medications were assessed. 


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As a supplemental endpoint, total SCS exposure will also be evaluated under a Treatment Policy 
strategy where all data collected from the treatment initiation visit up to the end of study, 
regardless of the occurrence of ICEs, will be included in the analyses.  
8.1.3 EXPLORATORY ENDPOINTS 
8.1.3.1 
ASTHMA RELATED HEALTHCARE RESOURCE UTILIZATIONS 
The number of asthma related HCRU per participant year will be described using the following 
categories collected in the eCRF: 
Any health-related event 
Number of hospital admissions or emergency department for more than 24 hours 
Hospitalizations (Number of days) 
o
Hospital intensive care unit (ICU)
o
Hospitalization general ward (GW)
o
Hospitalization coronary care
Emergency room visits 
Urgent care visits (defined as evaluation and treatment for <24 hours in an emergency 
department or urgent care centre) due to asthma that required systemic corticosteroids 
Number of ambulance transports  
Specialist visits 
Primary healthcare physician visits 
Other health care visits 
Home visits by: 
o
A physician
o
A nurse
o
Other healthcare
Telephone calls to: 
o
A physician
o
A nurse
o
A specialist
o
Other physician/healthcare provider
Number of following assessments: 
o
Spirometry
o
Advanced pulmonary function tests
o
Plain chest X-ray
o
Computed tomography
Oxygen initiated 
HCRU will be asthma-related only. The summary measure to describe this data is the number of 
utilizations per participant year, calculated by: 


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The total exposure time is the length of time in years from treatment initiation until study 
completion, discontinuation of IMP or a step up in maintenance therapy. The numerator and 
denominator will be the total across patients, within the respective treatment groups, in order to 
produce crude rates. 
8.1.3.2 
STEPPING UP MAINTENANCE TREATMENT 
The proportion of participants stepping up maintenance treatment is calculated for each treatment 
arm as: 
Proportion is calculated as number of participants since randomization that have increased the 
dosage of their maintenance therapy. 
A step-up in maintenance therapy will be reviewed in accordance with the GINA guidelines. All 
maintenance therapy will be documented in the CM module with the Therapy Reason field selected 
as Asthma Maintenance. Patients with any maintenance therapy concomitant medication initiated 
following the treatment initiation visit will undergo a clinical review to categorise the maintenance 
therapy change as a step-up a step-down, or neither. Multiple changes in maintenance therapy 
during the treatment period will be classified relative to their pre-study maintenance therapy 
classification. The process of classifying changes in maintenance therapy will be finalised prior to the 
unblinding of efficacy data for interim and final analyses. 
The following ATC codes will be used to identify maintenance therapy in the CM module: 
R03DC (LTRA) 
R03BA (ICS) 
All maintenance therapy captured in the CM module will also require the following field values: 
8.1.3.3 
STEPPING DOWN/STOPPING MAINTENANCE TREATMENT 
The proportion of participants stepping down/stopping maintenance treatment is calculated for 
each treatment arm as: 
Proportion is calculated as number of participants since randomization that have decreased or 
stopped the dosage of their maintenance therapy.  
Please see section 8.1.3.2 for details on the process of defining changes in maintenance therapy, 
post treatment initiation. 


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8.1.3.4 
RESCUE MEDICATION ACTUATIONS 
The frequency and timing of actuations of the study IMP will be automatically logged in the 
app via the participant
-fi connection. An actuation is equal to 1 
inhalation of IMP. Data is collected and transmitted via Bluetooth from the sensor attached to each 
MDI provided by 
. The usage data generated will be visible to the investigator via 
The total actuations as recorded in the 
 portal will be used to determine the mean number of 
rescue medication actuations per day per participant. 
Rescue medication usage will be calculated as a mean daily actuations per participant over the 
treatment period, from the treatment initiation visit up to treatment discontinuation or a step-up in 
maintenance therapy. The total daily actuations will be derived from 00:00 to 23:59 within each 
calendar day, per participant.  
Additionally, mean daily actuations will be calculated over 4-weekly (28 day) time intervals across 
the 52-week study period, if a patient prematurely discontinues or has a step-up in maintenance 
therapy during a 4-weekly interval, their mean daily actuations for that interval will be calculated 
using the days from the start of the 4-weekly interval and the start of the ICE, or withdrawal from 
the study.  
The sensor data will only record the dates and times in which a puff of treatment was taken. Hence, 
any days during the interval of treatment initiation, up to randomized treatment discontinuation 
that are not present in the sensor data app will be considered as a day in which 0 inhalations were 
taken.  
The mean daily number of actuations will be re-calculated with erroneous and/or nonsensical sensor 
data excluded as an additional endpoint. Identification of erroneous and/or nonsensical data will be 
performed on blinded data. A flag will be included in the 
 sensor data to indicate which 
actuations should be excluded from the supportive endpoint. Exclusion of identified actuation(s) 
assumes the actuation did not happen, rather than missing, on the date of recording. 
To further assess the reliability of the sensor data, the mean daily actuations per participant will be 
calculated using the dose counter data, available in the drug accountability eCRF module. The mean 
daily actuations using this data will be calculated as follows: 
The total number of doses shown on the counter(s) corresponds to the cumulative sum all inhalers 
the participant receives during the treatment period. The treatment period duration is defined as 
the time in days from the treatment initiation visit up to treatment discontinuation. 


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The percentage of days over the entire treatment period, in which participants dosed the following 
number of puffs between the times of 00:00 to 23:59 within any calendar day will be calculated for 
each participant: 
Exactly zero puffs 
 1 puff to  2 puffs 
 3 puff to  4 puffs 
 5 puff to  6 puffs 
 7 puff to  8 puffs 
 9 puff to  10 puffs 
 11 puff to  12 puffs 
 13 puffs 
8.1.3.5 
ABSENTEEISM  
Absenteeism is the time a participant takes off from work or school over the study period per 
participant year. The participant will be asked about work and school productivity loss in term of: 
Work absence due to asthma (days)  
School absence due to asthma (days) 
The summary measure to be included is Absenteeism per participant year and is calculated by: 
Per the While on Treatment strategy, total exposure time is the length of time from treatment 
initiation until the earliest of study completion, treatment discontinuation or a step up in 
maintenance therapy. 
8.1.3.6 
ASTHMA IMPAIRMENT AND RISK QUESTIONNAIRE (AIRQ)TM 
The Asthma Impairment and Risk Questionnaire (AIRQ)TM is a patient-reported outcome (PRO) tool 
intended to identify participants whose health may be at risk because of uncontrolled asthma. It has 
10 questions that ask about respiratory symptoms, activity limitation, sleep, rescue medication use, 
social activities, exercise, difficulty controlling asthma, and exacerbations. All items have a yes/no 
score is used to assess level of asthma control where: 
0-1 is well-controlled
2-4 is not well controlled
5-10 is very poorly controlled
Thus, a higher score indicates worse control status. 
The AIRQTM items have 2 different recall periods: the first seven impairment items are evaluated 
over the past 2 weeks and the last three risk items either over the past 3 months or the past year. 
This study will use the version with a recall period for the last three risk items over the past year at 
Screening, Randomization, Week 52 EOS visits and the version with last three risk items for the past 


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3 months recall for the remaining visits where it is collected. Since these two recall periods will 
overlap for different visits (i.e., the Week 52 EOS visit will recall the same period of time as assessed 
in a Week 40 visit) then these responses cannot be assumed independent and therefore only 
descriptive statistics will be presented for these data together. 
The AIRQTM will be administered within the 
 application and completed on the 
Appendix B). The 
AIRQTM is estimated to take approximately 3 minutes to complete. 
The total score will be defined as the sum of the 10 questions in which a participant answered YES.  
If an AIRQTM response is missing for a participant, then this is assumed missing at random. If 1 
individual answers in a questionnaire are missing, then the whole questionnaire is assumed missing. 
More information on missing values will be discussed in section 8.4. The total scores will be 
calculated in the PRO tool, PHASTAR will perform a programming check in the relevant ADaM 
dataset to validate the total score. 
Baseline is defined as the most recent non-missing value recorded prior to the start of the IMP 
(treatment period). For all endpoints the start of the IMP (treatment) period is defined as Visit 3. 
Absolute change from baseline outcome variables is computed as 
(post-randomization value - baseline value). 
Change from baseline will be calculated for every post-baseline visit, including the End of Study 
(EOS). If either the post-randomization value or the baseline value is missing, then the absolute 
change from baseline value will also be set to missing.  
8.1.3.7 
EQ-5D-5L SCORE 
The EQ-5D-5L is a 5 dimension, 5-level standardized instrument for use as a measure of health 
outcome from EuroQol. Applicable to a wide range of health conditions and treatment, it provides a 
simple descriptive profile and a single index value for health status. The EQ-5D-5L consists of 2 
assessments, a descriptive system, and a Visual Analog Scale (VAS) which will not be used in analysis. 
The descriptive system comprises of the following 5 dimensions:  
mobility  
self-care  
usual activities 
pain/discomfort 
anxiety/depression 
Each dimension has 5 severity levels: 
No problems 
Slight problems 


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Moderate problems 
Severe problems 
Extreme problems 
EQ-5D-
nd 
using an appropriate value set. A value set provides values (weights) for each health state 
description according to the preferences of the general population of a country/region. The SAS 
syntax for applying the EQ-5D-5L value set for the USA can be found in Appendix C. 
The index score, after adjustment from the value set, will be used in analysis.  
The EQ-5D-
by the participant as per the SoA (Appendix B). 
Baseline is defined as the non-missing value recorded prior to treatment initiation. For all endpoints 
the start of the IMP (treatment) period is defined as Visit 3. 
Absolute change from baseline outcome variables is computed as 
(post-randomization value - baseline value). 
Change from baseline will be calculated for every post-baseline visit, including the End of Study 
(EOS). If either the post-randomization value or the baseline value is missing, then the absolute 
change from baseline value will also be set to missing. No imputation will be made for missing data. 
8.1.4 SAFETY ENDPOINTS 
8.1.4.1 
ADVERSE EVENTS 
AEs and SAEs will be collected from time of signature of informed consent/assent through to the 
study completion and EOS visit. 
The following variables will be collected for each AE:  
AE (verbatim) 
The date when the AE started and stopped  
Maximum intensity  
Seriousness  
Investigator causality rating against the IP (yes or no)  
Action taken with regards to IP AE required treatment  
Outcome  
In addition, the following variables will be collected for SAEs:  
Date AE met criteria for serious AE  
Date investigator became aware of serious AE 
Reason why the AE is considered serious  
SAE resolution date  
SAE outcome  


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Maximum SAE intensity  
Treatment given for the SAE  
Date of hospitalization 
Date of discharge  
Primary and secondary 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 
and reported separately (in addition to being reported as general AEs). 
Other significant adverse events (OAEs) will be defined by an Avillion medically qualified expert as 
AEs that were not reported as SAEs or DAEs that have particular clinical importance. These will be 
considered OAEs after consultation with the Global Subject Safety Physician and reported as such in 
the Clinical Study Report. OAEs will be reported in a separate table (in addition to being reported as 
general AEs).  
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. AEs that occur between 
randomization and treatment initiation will be listed. 
Please refer to section 8.4.1 for the imputation rule to programmatically determine the classification 
of AEs when there are partial start and/or stop dates recorded. 
Adverse events that are associated with local and systemic steroid effects will be identified using the 
pre-specified preferred terms provided in Appendix D. Please note that these lists of preferred terms 
are not exhaustive, and a comprehensive list of terms associated with local/systemic ICS effects will 
be confirmed at database lock and before unblinding of the clinical trial. 
8.2 
STATISTICAL HYPOTHESES 
8.2.1 PRIMARY HYPOTHESIS 
The primary objective of this study is to evaluate the efficacy of BDA MDI 160/180 µg administered 
as needed compared with AS MDI 180 µg administered as needed on the risk of a severe asthma 
exacerbation in participants receiving SABA alone or with a background of low-dose ICS or a LTRA 
over a variable length of 12 52-week treatment period. This is a superiority study to demonstrate 
the benefit of adding budesonide to albuterol in the fixed-dose combination BDA MDI used as 
needed compared to AS MDI. The primary efficacy endpoint is the time to first severe asthma 
exacerbation (While on Treatment strategy), from the treatment initiation visit to a step-up in 


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maintenance therapy or the end of treatment, as a measure of risk of experiencing a severe asthma 
exacerbation. 
Formally the null and alternative hypotheses for the primary and secondary analyses of time to first 
severe exacerbation are: 
H0: Hazard ratio (BDA MDI versus AS MDI) = 1, 
HA: Hazard ratio (BDA MDI versus AS MDI)  1. 
The primary objective and all secondary objectives will be tested at =0.05, two-sided. 
8.2.2 SECONDARY HYPOTHESES 
For the secondary endpoint of time to first severe asthma exacerbation, evaluating the Treatment 
Policy strategy, the null and alternative hypotheses are the same as in the primary analysis. 
For the secondary endpoint of annualized severe asthma exacerbation rate, the null and alternative 
hypotheses are: 
H0: Annualized rate ratio (Annualized rateBDA / Annualized rateAS) = 1, 
HA: Annualized rate ratio (Annualized rateBDA / Annualized rateAS)  1. 
The annualized severe exacerbation rate ratio will be analysed using a negative binomial model. 
Analysis will be repeated under the Treatment Policy strategy. 
The secondary endpoints of total (amount, mg/year) systemic corticosteroid (SCS) exposure, and 
total (days) SCS exposure will be analysed using a Wilcoxon Rank Sum test Formally, the null and 
alternative hypotheses are: 
H0: DBDA= DAS, 
HA:  DBDA  DAS. 
Where DT is the distribution of values in treatment group T. 
8.3 
MULTIPLE TESTING STRATEGY 
A hierarchical testing strategy will be employed to control the two-sided Type I error rate for the 
primary and secondary endpoints, testing the endpoints in the following pre-specified order:  
1)
Time to first severe asthma exacerbation (While on Treatment strategy in the full analysis 
set; 
2 years);  
2)
Time to first severe asthma exacerbation (Treatment Policy strategy in the full analysis set; 
2 years);  
3)
Time to first severe asthma exacerbation (While on Treatment strategy in the full analysis 
set; 
8 years);  
4)
Time to first severe asthma exacerbation (Treatment Policy strategy in the full analysis set; 
8 years); 


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5)
Annualized severe asthma exacerbation rate (While on Treatment strategy in the full 
analysis set; 
2 years); 
6)
Annualized severe asthma exacerbation rate (While on Treatment strategy in the full 
analysis set; 
8 years); 
7)
Total systemic glucocorticoid exposure (While on Treatment strategy in the full analysis set; 
2 years); and  
8)
Total systemic glucocorticoid exposure (While on Treatment strategy in the full analysis set; 
8 years). 
Testing will be conducted at the specified alpha for the final analyses. The hierarchical testing 
strategy will be applied whereby the full fraction of alpha will be passed down to endpoints tested 
per the pre-specified order. Inference for a test in the pre-specified hierarchy is dependent upon 
statistical significance having been achieved for the previous tests in the hierarchy. Once statistical 
significance is not achieved further inferential testing will not be performed. Further discussion 
about alpha spending and interim analyses will be in section 10. 
8.4 
PREMATURE WITHDRAWAL AND MISSING DATA 
If the sponsor, investigator, study monitor, IDMC, or regulatory officials discover conditions arising 
quality of the IPs have been compromised, the study may be halted, or the study 
 
participation may be terminated. Ongoing participants will be discontinued from the study and 
assigned to receive treatment as per local standard of care. 
Participants who withdraw will not be replaced on the study. A participant may withdraw from the 
study at any time at their own request or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons.  
Reasons for withdrawal will be recorded on the Disposition CRF (study completion) with the 
following reasons for discontinuation: 
Participant decision 
Adverse event 
Severe non-compliance to protocol 
Condition under investigation worsened 
Lack of therapeutic response 
Lost to Follow-up 
Completed 
Physician decision 
Study terminated by sponsor 
Site terminated by sponsor 
Death 
Withdrawal by parent/guardian 
Pregnancy 
Other 


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For all analyses under the While on Treatment strategy and Treatment Policy strategy, all missing 
data will be considered non-informatively missing and therefore missing at random. For the 
sensitivity analysis of the primary endpoint and for the analyses conducted under the attributable 
estimand, a subset of missing data will be considered missing not at random. Please see section 9.4 
for the handling of missing data under these specific analyses and estimands. 
If a participant chooses to prematurely discontinue randomized treatment, then they will be 
assigned to receive treatment as per local standard of care. The participant may choose to remain on 
the study and complete any subsequent visits up to the end of the study, including providing 
instances of severe asthma exacerbation, SCS exposure, hospitalizations, absences from work or 
school, and completing study questionnaires up to their EOS visit. 
If a participant chooses to prematurely discontinue randomized treatment and subsequently 
withdraw from the study completely, then an Early Study IMP Discontinuation visit should be 
conducted. The schedule of assessments (Appendix B) should be referred to for data to be collected 
at the time of study withdrawal and follow-up and for any further evaluations that need to be 
completed. If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of consent. Further 
information on premature withdrawal from the study is outlined in section 7 of the CSP. 
All missing AIRQTM and EQ-5D-5L responses will be assumed to be missing at random and excluded 
from analysis. No imputation will be made for any missing data in either questionnaire.  
8.4.1 DATE IMPUTATION RULES 
In the instance that the eCRF records partial dates for a severe exacerbation, SCS prescription, 
concomitant medication or adverse event then a conservative imputation rule is applied. 
If an event has a missing onset date, then, unless the stop date of the event indicates otherwise, this 
will be considered as starting during the randomized treatment period. Similarly, if the event 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 treatment period. 
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).  
3. If completely missing then impute as date of treatment discontinuation.  
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 the treatment 
initiation date then impute as the treatment initiation date;  


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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 treatment initiation; 
End date of medication/ event (after partial date handling has been applied). 
The treatment discontinuation/completion date will be as recorded on the discontinuation of 
investigational product eCRF page. The raw, original dates will be presented in listings produced. The 
intention for date imputation is to facilitate a programmatical decision making process to classify on-
treatment observations. 
8.4.2 SENSITIVITY ANALYSES 
Sensitivity analyses in which censored results will have event times imputed under an informative 
censoring assumption will be performed. Sensitivity analysis will only be performed on missing data 
from the primary endpoint of time to severe exacerbation and must meet missing data assumptions. 
In these analyses, the following primary reasons for discontinuation, as collected on the eCRF will 
correspond to missing not at random data: 
Participant decision, with a specific reason of: 
o
Participant perceives the investigational product to be ineffective 
Adverse event, indicated as treatment related 
Condition under investigation worsened 
Lack of therapeutic response 
Investigator decision 
Death 
Further details on the imputation procedure will be presented in section 9.4. 
8.5 
STUDY POPULATION 
Participants must be 12 years of age, at the time of signing the eICF.  
Participants must be actively using SABA alone or SABA on a background of either low dose ICS or 
LTRA, and have self-reported use of a SABA in response to symptoms on 2 occasions in the previous 
2 weeks prior to enrolment. Participants must also have an AIRQTM score of 2 at Screening. 
See sections 5.1 and 5.2 of the CSP for further details on inclusion and exclusion criteria, 
respectively, for this study. 
8.5.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 


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Sex, ethnicity, and race will be collected at screening. Age (years) collected at screening will be 
summarised as a continuous variable. Additionally, age group strata will be summarised under the 
following groupings: 
Age group 1 
Adolescents: 12 - <18 years 
Adults: 18 - <65 years 
Elderly: 65 years 
Age group 2 
Adolescents: <18 years 
Adults: 18 years 
Medical (including surgical), asthma (including exacerbations) and smoking history are recorded on 
the eCRF at Visit 1. 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 
date of randomization.  
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.  
The day of most recent severe asthma exacerbation, relative to randomization, will be calculated as  
Date of randomization (Visit 2) - Date of most recent severe exacerbation prior to screening +1. 
Partial dates for the above calculations will be handled as per section 8.4.1. 
The number of severe exacerbations (0, 1) in the last 12 months prior to randomization will be 
collected on the eCRF. 
8.5.2 CONCOMITANT MEDICATIONS 
All prior and concomitant medication recorded during the study are entered onto the CM module.  
A medication which has a start date on the day of, or after the treatment initiation visit will be 
concomitant. Additionally, all medication starting prior to treatment initiation and continuing after 
treatment initiation will also be considered concomitant. All medication recorded for which the stop 
date is prior to treatment initiation will be classified as a prior medication.  
If a concomitant medication is recorded with missing or 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 8.4.1 will be considered. The raw dates will be used in listings. 


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Prohibited medication will be identified following a clinical review of WHO drug dictionary terms 
prior to unblinding.  
8.5.3 TREATMENT COMPLIANCE 
As the study medication is being taken as needed, no assessment of compliance will be made. 
However, the Investigator / authorized delegate will check overall inhaler usage at each contact with 
the participant to ensure that the participant has a sufficient number of inhalers. The number of 
MDIs sent to the participant, as well as the number of inhalers returned by the participant to the 
central depot at the end of the trial will be captured in the RTSM as well as documented and stored 
at the Investigator Site.  
Adherence to asthma maintenance medications for those currently receiving will not be assessed. 
8.6 
ASSESSMENT TIME WINDOWS 
For endpoints with repeated measures values collected at premature discontinuation visits should 
be assigned to the next available visit. The schedule of assessments (presented in Appendix B) has 
further detail on the visit window intervals. 
Enrolment, screening assessments and randomization may occur on the same day or on separate 
days within a 28-day period. 
IMP delivery is expected to take 3-5 days, but Day 1, or Visit 3, can be up to 14 days after 
randomization (Visit 2). 
Visit windowing for analysis will consider the midpoint between two scheduled assessments. If two 
visits occur in the same window, then the closest to the target will be used for analysis. If the two 
visits are equidistant from the target day, then we choose the earliest occurrence. Please see table 
below for the visit windows. The early termination visit will be considered in the visit windowing 
rules. In a situation where two scheduled visits (as labelled in the eCRF), including the early 
termination visit, occur in the same window as the early termination visit, then the visit closest to 
the target day will be used in analysis. 
Unscheduled visits will not be used in the visit windowing algorithm. 
Table 2 Visit Windows 
Visit number / Visit label 
Target day (window) 
Visit 3 / Day 1 
Day 1 
Visit 4 / Week 4 
Day 28 (day 2 - 70) 
Visit 5 / Week 16 
Day 112 (day 71  154)  
Visit 6 / Week 28 
Day 196 (day 155  238) 
Visit 7 / Week 40 
Day 280 (day 239  322) 
Visit 8 / Week 52  
Day 364 (day 323+) 


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Week 52 will be the End of Study (EOS) visit for participants who complete the full treatment period. 
If a participant prematurely discontinues from the study, then the early study IMP discontinuation 
visit will be conducted as soon as possible. 
8.6.1 METHODS FOR HANDLING OUT-OF-WINDOW OBSERVATIONS 
Telephone/televisit contact to be performed if confirmation received from the participant through 
the bi-weekly messages within the 
 app that there was any systemic corticosteroid use 
and/or unscheduled asthma related healthcare visits. This data will not be summarised and will be 
mapped to SDTM datasets only. Unscheduled visits and unmapped visits that are not assigned a visit 
number will be listed. 
Participants who prematurely withdraw from the study will undergo an early study 
IMP/discontinuation visit. Participants who do not withdraw consent for follow-up will be 
encouraged to continue with all study assessments as scheduled until withdrawal from study or 
completing at 12 months. When reaching the Primary Completion Date (i.e., when 350 events have 
been reached), participants who have had at least 12 weeks of treatment but not completed the 
entire 52 weeks treatment period, will have their end of study visit scheduled within 4 weeks. The 
end of study and IMP/discontinuation visits will be mapped to a scheduled visit according to the 
rules defined above (section 8.6). 
9. 
 
9.1 
STUDY POPULATION 
9.1.1 DISPOSITION OF SUBJECTS 
Subject disposition will be summarised for all enrolled participants. The number of participants who 
were enrolled (provided informed consent) will be summarised. The number and percentage of 
participants randomized and not randomized (and reasons) will be presented, with percentages 
calculated from the total number of participants enrolled. The number and percentage of 
participants who were: randomized and received randomized treatment, randomized and did not 
receive randomized treatment (and reasons), completed (broken down by on-treatment and off-
treatment completion), discontinued IMP (reasons) and discontinued the study (reasons) will also be 
presented with percentages calculated from the total number of participants randomized.  
A separate table will present the number and percentage of participants randomized to each 
treatment group, by site. This table will be based on the full analysis set ( 12 years) and repeated on 
the full analysis set ( 18 years). 
The number and percentage of participants included in the full analysis set ( 12 years), full analysis 
set ( 18 years) and in the safety analysis set, along with the corresponding number of participants 
excluded from each analysis set will be summarised by treatment group and overall. Additionally, 
listings of enrolled patients who were excluded from the randomized full- and safety analysis sets 
will be listed separately, the listing will provide the treatment group (if applicable) basic 
demographic information (age, sex, race) and the reason for exclusion. Those who have not met 
eligibility criteria for randomization will also be listed. 


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9.1.2 PROTOCOL DEVIATIONS 
Important deviations will be summarized by the number and percentage of participants meeting the 
pre-defined protocol deviation coded term. These will be identified by the sponsor prior to the 
primary completion date and unblinding of the study results. All protocol deviations, major and 
minor, will be listed, along with a flag to indicate whether the deviation was considered important. 
Listings of protocol deviations will additionally include the date of the deviation occurrence, the 
protocol deviation verbatim term and the coded term. 
9.1.3 DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Age (years), sex, race and ethnic group will be summarised by treatment group and overall for the 
full analysis set ( 12 years). Percentages for demographics characteristics will be based on number 
of participants with non-missing data. Baseline characteristics will be summarised by treatment 
group and overall for the full analysis set ( 12 years). These include previous disease-related 
treatments, medical and surgical histories, and asthma history variables collected on the CRF. 
Asthma history will be summarised descriptively for participants in the full analysis set ( 12 years). 
exacerbation will be presented by descriptive statistics of median, 25th percentile, 75th percentile, 
minimum and maximum. The number of severe exacerbations in the previous 12 months will be 
summarized by treatment group and overall as a discrete outcome, presenting the number (%) of 
participants with 0 exacerbations, 1 exacerbation, 2 exacerbations, and >2 exacerbations, and 
further broken down for SEEs that resulted in emergency room treatment or hospitalization. 
Associated conditions, triggers or allergies will also be summarised by treatment group and overall. 
Additional asthma history information will be listed for each participant in the full analysis set ( 12 
years).  
A separate table will present the number and percentage of participants randomized to each 
treatment group, by stratification factor allocated at randomization. This table will be based on the 
full analysis set ( 12 years). 
Medical and surgical histories will be summarized by treatment group by MedDRA preferred term 
within MedDRA system organ class for participants in the full analysis set ( 12 years). 
Smoking status will be summarized categorically as the number of participants who currently smoke, 
have never smoked or are former smokers and grouped by randomized treatment group. Nicotine 
pack years of cigarette usage and duration of e-cigarette use (years) will be summarized as a 
continuous endpoint by randomized treatment group. Smoking status summaries will be based on 
the full analysis set ( 12 years). 
The number and percentage of participants in the full analysis set ( 12 years) who take allowed 
concomitant medications, and those who take prohibited medications during the study, will be 
presented by treatment group and ATC classification and generic term. A review of the CM data will 
be conducted by the clinical team to identify an exhaustive list of concomitant medication ATC 
terms, and doses (where applicable) according to the clinical study protocol, prior to database lock 
and unblinding of study results at each milestone of interim and final analysis. 


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Summaries will be grouped by prior medication, concomitant medication occurring during the 
randomized treatment period. Concomitant medication will be presented under both the While on 
Treatment strategy Maintenance medication will not contribute to these summaries and will be 
presented in a separate table. Concomitant medication prescribed following an ICE (step-up in 
maintenance therapy or premature discontinuation of randomized treatment) will be summarized 
separately. 
Exposure to study medication will be summarised descriptively for the safety analysis set as the total 
duration (days) from the first dose at treatment initiation, up to treatment discontinuation. 
Summary of exposure will also be displayed as the total daily number of actuations of the IMP. 
Please refer to section 9.2.3.2 for further details. 
Demographics and baseline characteristics will also be summarized by the pre-specified subgroups, 
as described in Section 7.5.1. 
9.2 
EFFICACY ANALYSES 
All efficacy analyses will be conducted in the full analysis set ( 12 years). 
9.2.1 PRIMARY EFFICACY ANALYSIS 
The primary efficacy analysis is the time to first severe asthma exacerbation based on the While on 
Treatment strategy, as defined in section 8.1.1. 
The time to first severe asthma exacerbation from the treatment initiation visit up to the end of the 
treatment period will be analysed fitting a Cox proportional hazards regression model including 
terms for treatment, pre-study asthma therapy (SABA only, SABA + low-dose ICS or LTRA) and the 
summary measure to compare treatments is the estimated hazard ratio which will be presented 
with the associated Wald two-sided 95% confidence interval and two-sided p-value.  In addition, the 
number and percentage of participants with a severe exacerbation event will be presented. Ties in 
the data will be handled using the Breslow method.  
The assumption of proportionality will be assessed. Proportionality will be tested firstly by examining 
plots of complementary log-log (event times) versus log (time). If these raise concerns, a time 
dependent covariate would be fitted (adding a treatment-by-time interaction term) to assess the 
extent to which this represents random variation. If a lack of proportionality is evident, the variation 
in treatment effect can be described by presenting piecewise HR calculated over distinct time-
periods as supportive estimates. Time-event plots for first severe exacerbations will be produced 
from the full analysis set ( 12 years) and will be grouped by randomized treatment. 
Kaplan-Meier (KM) plots of time to first severe asthma exacerbation will be presented by treatment 
group with final KM estimate presented.   
Severe asthma exacerbations will be summarised descriptively as the frequency and percentage of 
participants with at least 1 severe exacerbation, the number of severe exacerbations prior to IMP 
discontinuation or a step up in maintenance therapy and the total number of severe exacerbations 


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per treatment-year. Number of severe exacerbations per treatment-year will be calculated as 
described in section 8.1.2.2.  
The number of participants who have been censored along with the reason for censoring (completed 
study prior to first severe exacerbation; discontinued treatment due to asthma; change in 
maintenance therapy; death; other).  
The descriptive statistics for first severe exacerbations will be further broken down into: Severe 
exacerbations requiring systemic corticosteroid use; severe exacerbations requiring hospitalization; 
severe exacerbations requiring emergency room visit/ urgent care visit. This summary will be 
repeated for all severe exacerbations.  
Sensitivity analyses in which censored results will have event times imputed under an informative 
censoring assumption will be performed. Please refer to section 9.4.1.1 for the detail on imputing 
event times. A Cox proportional hazards regression model will be performed including treatment, 
pre-study asthma therapy and the number of documented severe exacerbations in the 12 months 
prior to randomization as stratification factors. The estimated adjusted hazard ratio for the 
treatment comparison will be displayed along with the associated Wald two-sided 95% confidence 
interval (CI) and two-sided p-value.  
A forest plot will be produced to show the changing hazard ratio and two-sided 95% CIs for different 
values of delta assigned in the tipping point analysis. These delta values presented in the forest plot 
are as follows:  
1.
Integer delta from 0 to 10 
2.
In the event that the tipping point occurs between two integer values of delta, the range of 
this unit of delta will be presented in 0.1 increments 
Finally, the Cox regression and forest plots will be repeated under the attributable estimand in which 
censored results will have event times imputed under an informative censoring assumption. Further 
details are provided section 9.4.1.1. 
As a supportive descriptive measure, the cumulative (across-participant sum) time at risk per 100 
participant years up to first severe exacerbation will be summarized by treatment group under the 
While on Treatment strategy, Treatment Policy strategy and Attributable estimand. Refer to section 
9.2.1 for a description of this endpoint calculation. 
9.2.2 SECONDARY EFFICACY ANALYSIS 
Unless specified otherwise in the relevant subsection, secondary analyses described below will be 
based on the full analysis set ( 12 years) population and repeated on the full analysis set 18 years 
population, in accordance with the multiple testing strategy (section 8.3). 
9.2.2.1 
TIME TO FIRST SEVERE EXACERBATION, TREATMENT POLICY 
STRATEGY 
The secondary efficacy analysis of time to first severe exacerbation under the Treatment Policy 
strategy (
2 years) will be analysed using a Cox proportional hazards model as defined for the 


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primary analysis. The descriptive summaries of severe exacerbations defined under section 9.2.1 will 
be repeated under the Treatment Policy strategy; severe exacerbations occurring from treatment 
initiation and up to study completion/withdrawal. 
These secondary analyses will be repeated on the full analysis set (
8 years). 
9.2.2.2 
TIME TO FIRST SEVERE EXACERBATION, WHILE ON TREATMENT  
ESTIMAND 
 YEARS) 
The primary analysis under the While on Treatment strategy includes all participants in the full 
analysis set ( 12 years). The analyses described in section 9.2.1 will be repeated on the full analysis 
set 18 years population.  
9.2.2.3 
ANNUALIZED SEVERE EXACERBATION RATE 
The annualized severe asthma exacerbation rate will be analyzed using a generalized linear model, 
assuming the number of exacerbations has a negative binomial probability distribution and that its 
nction. The logarithm of time at risk (years) 
will be used as an offset variable. The model will include covariates for treatment, pre-study asthma 
therapy (SABA only,  SABA + low-dose ICS or LTRA) and the number of prior severe exacerbations (0, 
e 12 months prior to screening/enrolment (Visit 1/2). From the negative binomial model, 
the annual severe asthma exacerbation rates will be estimated for each treatment group, and the 
summary measure for the comparison of treatments will be the estimated annualised rate ratio 
which will be presented with the corresponding two-sided 95% confidence interval and 
corresponding 2-sided p-value. In addition, the model-adjusted annualised severe asthma 
exacerbation rate and the overdispersion parameter estimated from the negative binomial model 
will be presented. 
An overall summary of severe asthma exacerbations during the treatment period will be summarized 
descriptively, presenting the frequency and percentage of participants who had at least one severe 
exacerbation during the study (Yes/No); The number of exacerbations per participant, 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 participant will be summarized as a continuous endpoint.  
The analysis of annualized exacerbation rate assessed under the While on Treatment strategy will be 
considered a secondary analysis and included in the type-I error controlled testing strategy. The 
annualized rate of severe exacerbations will also be evaluated under a Treatment Policy strategy, 
where all data collected from treatment initiation up to the end of study participation, regardless of 
ICE occurrence, will be used. The analysis of annualized exacerbation rate assessed under the 
Treatment Policy strategy will be considered a supplemental analysis. 
These secondary analyses will be repeated on the full analysis set (
8 years). 
9.2.2.4 
TOTAL SYSTEMIC CORTICOSTEROID EXPOSURE 
Annualized dose of systemic corticosteroid exposure prescribed in response to severe exacerbations 
will be summarized as a continuous measure descriptively for patients in the full analysis set ( 12 
years). For this endpoint, additional descriptive statistics will include the treatment difference in 


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arithmetic means, percentage reduction in the treatment arithmetic means, 2.5th, 5th, 75th, 80th, 95th 
and 97.5th percentiles will be presented in the summary of annualized SCS dose.  
A comparison in total annualized SCS dose between BDA MDI 160/180 versus AS MDI 180 will be 
analyzed using a Wilcoxon rank sum test, comparing the distribution of exposure. The p-value from 
the Wilcoxon rank sum test will be presented alongside the percentage difference in arithmetic 
means, and the difference in predicted means (mg) estimated from a log-normal hurdle model 
adjusted for randomized treatment. Additionally, the total SCS exposure will be summarised 
descriptively as the total number of days with SCS treatment due to asthma for all participants.   
The analysis of total systemic corticosteroid exposure assessed under the While on Treatment 
strategy is a secondary analysis and included in the type-I error controlled testing strategy. SCS 
exposure analyses will be repeated under the Treatment Policy strategy and will be considered a 
supplemental analysis. 
Exposure will also be summarised for each treatment group and overall under the following 
categories: average duration (days) of course of SCS prescribed per exacerbation; average daily dose 
of SCS prescribed for a severe exacerbation; total number of courses prescribed per participant per 
year; total SCS (mg); total duration (days) of SCS use. 
These secondary analyses will be repeated on the full analysis set (
8 years). 
9.2.3 EXPLORATORY EFFICACY ANALYSIS 
Unless stated otherwise in the relevant endpoint section, exploratory efficacy analyses will be 
conducted in the full analysis set ( 12 years). 
9.2.3.1 
CHANGE IN MAINTENANCE THERAPY 
The time to a step up in maintenance therapy will be summarized descriptively along with the time 
to a step down or stop in maintenance therapy. The proportion of participants changing their 
maintenance therapy will be summarized for each treatment group. Step up and step-down analyses 
will be under the While on Treatment strategy (
2 years).  
9.2.3.2 
RESCUE MEDICATION ACTUATIONS 
Rescue medication actuations (number of as-needed inhalations per day) will be summarised 
descriptively by randomized treatment group as a continuous endpoint. Reliever use will be 
summarized under the While on Treatment strategy (
2 years), which includes reliever use from 
treatment initiation and up to randomized treatment discontinuation or a step-up in maintenance 
therapy. 
Summaries of rescue medication will be repeated based on the supportive endpoints which 1) 
exclude erroneous and/or nonsensical data; 2) where mean daily dose is calculated from the dose 
counter data. Refer to section 9.2.3.2 for a description of these supportive endpoints. 
The percentage of days in which participants dosed exactly zero, 1 to  2 puffs, 3 to  
1 to  12 puffs and  13 puffs will be summarized as a continuous measure by randomized 
treatment group. A supportive bar chart plotting the mean percentage of days under the pre-


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specified categories of puffs will also be produced and grouped by randomized treatment. 
Percentage days of reliever use will be summarized under the While on Treatment strategy (
2 
years). 
9.2.3.3 
THE EXPLORATORY ANALYSES OF RESCUE MEDICATION USE WILL BE 
REPEATED ON THE FULL ANALYSIS SET (
8 YEARS).HEALTHCARE 
RESOURCE UTILIZATION 
Descriptive statistics will be presented for each health care resource item described in section 
8.1.3.1, by treatment group. Summary measures to be included are total number of each HRU event 
(visits) and/or days of events, number and percentage of participants experiencing at least one HRU 
event, and the total number of each HRU event or days of event divided by participant treatment 
years (annualized event rate).  Healthcare resource utilization will be summarized under the While 
on Treatment strategy (
2 years) and include HCRU from treatment initiation up to randomized 
treatment discontinuation or a step-up in maintenance therapy. 
9.2.3.4 
WORK AND SCHOOL ABSENCE 
Descriptive statistics will be presented for work and school absence, by treatment group. Summary 
measures to be included are total number of days, number and percentage of participants 
experiencing at least one absence day, and mean number of days absent per participant per year. 
Work and school absence will be summarized under the While on Treatment strategy (
2 years) 
and include absence data from treatment initiation up to randomized treatment discontinuation or a 
step-up in maintenance therapy. 
9.2.3.5 
AIRQTM 
Analysis of change from baseline in AIRQTM at Week 52 will target the While on Treatment strategy 
(
2 years). The overall AIRQTM score and the change from baseline, will be descriptively summarised 
by treatment and visit. Boxplots of change from baseline AIRQTM over time will be presented. 
Boxplots will also be produced to show the absolute values at baseline and each visit.  
Baseline will be defined as the most recent score prior to treatment initiation. Only Week 16, Week 
28, Week 40, and Week 52 will be assessed alongside the baseline assessment. 
An ANCOVA model for the change in AIRQTM scores at each visit from baseline will be analysed with 
stratification factors of randomized treatment group, pre-study asthma therapy [SABA only,  SABA + 
low-dose ICS or LTRA
screening/randomisation. Least squared means by randomized treatment group and differences in 
least squared means between each treatment group along with corresponding 95% confidence 
intervals and two-sided p-values will be estimated. 
Additionally, a figure showing the least squares means estimates over time from the ANCOVA 
analyses, along with 95% confidence intervals will be presented. The least squares means will not be 
joined together for this visualisation. 
AIRQ descriptive summaries and analyses will be repeated under the Treatment Policy strategy (
2 
years), which will include all collected AIRQ total scores regardless of step-up in maintenance 
therapy or premature treatment discontinuation. 


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9.2.3.6 
EQ-5D-5L 
Summary statistics by treatment will be provided for absolute and change from baseline values by 
treatment and visit and will target the While on Treatment strategy (
2 years). Boxplots will be 
produced to show the absolute values at baseline and each visit, and the change from baseline over 
time.  
Baseline will be defined as the most recent score prior to treatment initiation.  
The treatment effect for change from baseline in EQ-5D-5L index value will be estimated using a 
repeated measures model analysis. All scheduled visits up to and including Week 52 where EQ-5D-5L 
is completed will be included in the model, with terms for treatment, visit, treatment*visit, and 
baseline EQ-5D-5L. The model will also be adjusted for the randomization stratification factors (pre-
study asthma therapy [SABA only,  SABA + low-dose ICS or LTRA] and the number of prior severe 
 The variance-covariance 
matrix will be assumed to be unstructured. Kenward-Roger denominator degrees of freedom will be 
used (Kenward and Roger 1997). If the procedure does not converge, then a compound symmetric 
variance-covariance matrix will be used instead. This model will be used to give an overall 
assessment of the treatment effect as well as 95% confidence intervals and associated 2-sided p-
values. 
Only index values provided at weeks 4, 28 and 52 will be used in EQ-5D-5L analysis alongside the 
baseline response.  
9.3 
SAFETY ANALYSES 
9.3.1 ADVERSE EVENTS 
AEs 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:  
AEs in any category, which will include the number of participants with: any AE; any AE that 
is related to IP; any AE with an outcome of death; any serious AE (SAE); and any AE leading 
to discontinuation of investigational product; any OAE 
Number of participants with adverse events and incidence rate during the randomized 
treatment period 
Number of participants with most frequently occurring AEs (at least 2% participants in any 
treatment group), by preferred term  
Number of AEs and event rate during the randomized treatment period, by system organ 
class and preferred term  
Number of participants with AEs with an outcome of death, by system organ class and 
preferred term 
Number of participants with AEs during the randomized treatment period by maximum 
reported intensity, system organ class and preferred term  
Number of participants with AEs during the randomized treatment period, by preferred term 
and relationship to IP, as assessed by the investigator  


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Number of participants with AEs during the randomized treatment period by preferred term 
and outcome 
Number of participants with SAE during the randomized treatment period, by system organ 
class and preferred term 
Number of SAEs during the randomized treatment period, by system organ class and 
preferred term 
Number of participants with AEs during the randomized treatment period leading to 
discontinuation of randomized treatment, by system organ class and preferred term  
AEs during the randomized treatment period assessed by the sponsor to be significant, by 
system organ class and preferred term  
Non-serious AEs (frequency >= 2%) during the randomized treatment period by preferred 
term  
Number of participants with AEs during the study period by system organ class and 
preferred term 
Number of AEs during the study period by system organ class and preferred term 
Treatment emergent adverse events summarized during the randomized treatment period are 
identified as any AE where the onset date is on or after the date of treatment initiation, up until the 
participant discontinues randomized treatment, regardless of a step-up in maintenance therapy. 
AEs occurring during the randomized treatment period will include the incidence rate. The incidence 
rate is defined as the number of participants who have experienced the event per 100 participant 
treatment years. Number 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 participants in the treatment group per 
100 participant treatment years. The number of participants with adverse events occurring post-
randomized treatment discontinuation will be summarised separately. 
In the overall summary table of AEs in any category, and the summary of most frequent AEs ( 2% 
total incidence) by preferred term, risk differences between treatment groups will be presented 
along with associated 95% CIs. Agresti-Caffo CIs will be computed for risk differences, which can 
accommodate zero events in one of the two treatment groups. 
AEs that start after randomization and before the treatment initiation visit will be listed. These AEs 
will not be included in the descriptive summary tables.  
All AEs will also be listed for each participant and will include age/sex/race; AE reported term and 
preferred term; start of AE relative to randomization and duration of event (days); maximum 
intensity; serious (Y/N); action taken with randomized treatment; causality with randomized 
treatment; outcome of AE. 
A summary of the number of participants with adverse events, by system organ class and preferred 
term will be produced and grouped within background maintenance therapy (SABA, SABA + low-
dose ICS, SABA + LTRA).  
Additionally, the number (%) of participants with adverse events associated with local ICS (as 
defined in section 8.1.4.1) will be presented overall (at least 1 local ICS-related AE) and by preferred 


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term for participants in the safety analysis set. Additionally, these AEs will be summarised within 
pre-study asthma therapy category (SABA, SABA + low-dose ICS, SABA + LTRA).  
A similar output will be produced displaying the number (%) of participants with adverse events that 
are associated with systemic ICS effects (as defined in section 8.1.4.1). The number of participants 
with pneumonia during the randomized treatment period will also be summarised by pre-study 
asthma therapy.  
For AEs leading to death, AEs leading to discontinuation of randomized treatment, and all SAEs will 
be listed by participant and treatment group, and will include the following key participant 
information: Sex; Age at study entry; AE term as reported by the investigator; AE preferred term; 
time from start of treatment to onset of AE (days); time from start of treatment to becoming serious 
(days); outcome; Action taken with randomized treatment; Causality to randomized treatment. 
9.4 
SUPPLEMENTARY AND SENSITIVITY ANALYSES 
Multiple imputation tipping point analysis under an informative censoring assumption (Censored not 
at random; CNAR) will be conducted for the primary endpoint of time to first severe exacerbation 
using. For subjects in the BDA MDI treatment group, this method will impute unobserved event 
times post early IP discontinuation for lack of asthma control/ step-up in maintenance therapy, 
assuming they were more likely to have a severe asthma exacerbation event than was implied under 
the censoring at random (CAR) assumption. For subjects in the AS MDI treatment group, event times 
will be imputed using multiple imputation but will assume non-informative CAR. The tipping point 
analysis will be conducted on the While on Treatment strategy and the Treatment Policy strategy. 
For a breakdown of treatment discontinuation criteria which are indicative of a lack of asthma 
control/informative censoring, please refer to section 8.4. 
All supplemental and sensitivity analyses will be conducted on the full analysis set ( 12 years) and 
repeated using the full analysis set 18 years population. 
9.4.1.1 
APPLYING THE INFORMATIVE CENSORING ASSUMPTION  
Consider the Cox proportional hazards model for observed events of severe exacerbations: 
 
 
[1] 
for participant  and covariates as specified for the primary analysis 
, 
is the baseline hazard 
function for the Cox model and   are the parameter estimates from the regression model. For a 
participant censored at time 
, we can impute the event time based on the hazard function  
 
 
[2] 
Where a penalty  will be applied and corresponds to the increased log-hazard of a severe 
exacerbation. For participants in the AS MDI treatment group, 
 will be applied and this will 
correspond to imputing under a CAR assumption. For participants in the BDA MDI group, 
 will 
be assigned if they have discontinued IMP and/or had a step up in maintenance therapy due to a 
lack of asthma control. Otherwise 
 will be applied as with the AS MDI treatment group. This 
will correspond to an increased hazard and consequentially a reduced time to event to what would 
be assumed under a CAR assumption (Jackson et al 2014). 


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The tipping point analysis will initialize with a 
 for imputing the event time for all participants 
who are censored. For participants in the BDA MDI treatment group who discontinue the study 
and/or step-up maintenance therapy, the penalty will be subsequently incremented with a step of 
0.1 until either null hypothesis is not rejected or 
 is reached. An applied penalty of 
 
would correspond to imputing event times immediately after the observed censoring date. 
The multiple imputation process will be conducted using bootstrapped samples with replacement 
within each treatment group to create 100 bootstrap samples, one for each imputed dataset. 
To impute an event time for a subject who has been censored at time 
, the following hazard 
function will be used to propose 
, a time-to-event from censoring; where 
 is the origin of follow 
up. The following hazard function can be used: 
 
 
[3] 
 
Where 
 and   are the estimated baseline hazard function and parameter estimates from the 
Cox regression model for a single bootstrap sample. 
Bender et al (2005) propose a method to simulate even times from the hazard function given in [3] 
which requires the cumulative baseline hazard function. For the event time 
, the cumulative 
baseline hazard function is 
 
 
[4] 
Where 
 denotes the cumulative baseline hazard function from the Cox regression model of a 
single bootstrap sample. The following formula proposed by Bender et al (2005) can be used to 
propose an event time: 
 
 
[5] 
Where 
 denotes the inverse of the cumulative baseline hazard function for 
 and 
. The inverse cumulative hazard 
can be calculated as 
 
 
[6] 
 
Once we have 
, the overall event time can be calculated as 
. 
If a random number 
is generated such that 
; the event time to would 
be greater than the last event observed in the study, and in such cases the participant will be 
imputed as being censored at the end of the study at 52 weeks. 
Each fully imputed dataset will be individually analysed using a Cox proportional hazards model as 
specified in the primary analysis. The estimates of the treatment effect, confidence intervals and 


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p-value (Rubin, 1987). As the time to event data are not normally distributed, results will be
combined on the log-scale and will be back-transformed for reporting in displays.
9.4.1.2 
ATTRIBUTABLE ESTIMAND 
The supplementary analysis of the attributable estimand will be conducted for the primary endpoint 
time to first severe exacerbation using data obtained before participants discontinue randomized 
treatment and/or before a step-up in maintenance therapy and will use the FAS. However, the data 
that is censored due to study withdrawal will have the event time imputed on the basis of the 
percentile of the AS MDI as needed distribution if the reason is reasonably attributable to tolerability 
or lack of control. For all other participants who do not experience a severe exacerbation during the 
treatment period, event times will be imputed using multiple imputation but will assume non-
informative CAR. 
Imputation methods specified in section 9.4.1.1 will be implemented, using the 5th percentile of the 
AS MDI treatment group time to first severe exacerbation instead of a delta-adjustment. i.e., when 
imputing the BDA MDI or AS MDI treatment groups under the informative censoring assumption, we 
will impute the time from censoring as 
. The multiple imputed datasets will 
be analysed with a Cox proportional hazards model as in the primary analysis and results will be 
 (Rubin, 1987). As the time to event data are not normally distributed, 
results will be combined on the log-scale and will be back-transformed for reporting in displays. 
10. 
An unblinded interim analysis for efficacy is planned once 50% of the target number of first severe 
exacerbation events according to the While on Treatment strategy in the full analysis set (
2 years) 
have been observed (172 first severe exacerbation events total, prior to treatment discontinuation 
or a step-up in maintenance therapy). Alpha spending will 
-Fleming 
approach, where 0.003 will be spent at the interim to assess statistical significance of the primary 
endpoint, and the first secondary endpoint of time to first severe exacerbation under the Treatment 
Policy strategy in the full analysis set (
2 years).  
No minimum exposure time is required and all patients in the full analysis set ( 12 years) will be 
analyzed. Patients who are on-going at the time of the interim analysis, who have not had a severe 
exacerbation event or ICE will be censored at the date of the interim data cut.  
Formally, the stopping criteria for overwhelming efficacy are: 
1.
Reject the null hypothesis for the primary endpoint, time to first severe asthma exacerbation
under the While on Treatment strategy in the full analysis set (
2 years) at 2-sided alpha =
0.003
AND 
2.
Reject the null hypothesis for the secondary endpoint, time to first severe asthma
exacerbation under the Treatment Policy strategy in the full analysis set (
2 years) at 2-
sided alpha = 0.003 


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Members of the data monitoring committee will review the primary and secondary analysis of time 
to first severe exacerbation at the interim and recommend to the Sponsor if the trial can be stopped 
due to overwhelming efficacy.  
No evaluation of superiority will be conducted on the remaining secondary endpoints detailed in 
Section 8.3 at the interim analysis. 
In the event that the DMC recommends stopping the study due to overwhelming efficacy per the 
above stopping criteria, the sponsor, once informed, will inform site personnel and participants that 
the study is closing due to overwhelming efficacy. If the study is still enrolling, enrolment will be 
immediately closed. All participants who have not completed 12 weeks of treatment will continue in 
the study and complete their EOS visit once they completed 12 weeks of treatment. All participants 
ongoing in the study who have completed 12 weeks of treatment will return for their EOS visit at 
their next scheduled visit or within 4 weeks of notification, whichever comes first. 
Type-I error control for remaining secondary endpoints 
In the event of stopping the clinical trial following a recommendation due to overwhelming efficacy 
from the DMC, the remaining untested secondary endpoints detailed in Section 8.3 will be analysed 
following database lock and formal unblinding of the study once all participants have completed 
their EOS visits following a minimum of 12 weeks on treatment. These remaining secondary 
endpoints will be evaluated at an alpha= 0.05 (2-sided).  
If the DMC recommends that the trial continues until the earliest occurrence of 350 first severe 
exacerbation events, or all patients have been randomized and followed up for 12 months, then the 
remaining secondary endpoints will be tested at the same alpha threshold used for the primary 
endpoint of time to first severe exacerbation at the final analysis, i.e. alpha=0.049 (2-sided). 
If the final number of first severe exacerbations is above or below the expected pre-specified total, 
then the generalized Haybittle-Peto method will be used to correct the alpha to ensure the overall 
type-I error is controlled at 5% for the final analysis. 
11. 
 
A reassessment of the sample size will be expected to ensure that the required number of events 
will be observed once all participants have completed the study or discontinued or had a step up in 
maintenance therapy, with the aim of preserving 90% power.  
A BSSR will be performed, the timing of which will be dictated by there being a sufficient number of 
severe asthma exacerbation events and exposure time on study to provide good precision and a 
meaningful event rate prediction. 
A blinded estimate of the annualized first severe exacerbation rate will be calculated on the accrued 
data at the point triggering the formal sample size review. 
If the observed blinded first exacerbation rate is lower than predicted, the number of randomized 
participants may be increased to a maximum of 2,500. 


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Due to the nature of the criteria triggering the blinded sample size reassessment, care must be taken 
when evaluating the estimated annualised first severe exacerbation rate. Seasonal trends and total 
cumulative exposure might impact the under- or over-estimation of the annualized event rate. As 
such, supportive data presentations of cumulative exposure and enrolment will be considered when 
making decisions on changes to the number of participants required to meet the expected 350 first 
severe exacerbation events.  
Any changes to the number of patients randomized following the sample size reassessment will be 
documented in a protocol amendment. 
12. 
 
1)
The multiple testing strategy has been updated to include repeats of the primary and 
secondary analyses in an 18 years sub-population of the full analysis set. Note: as of SAP 
V1.0, this is a change from the protocol-specified analyses. However, a protocol amendment 
is planned to detail this change. For clarity, the following text has been added to the SAP 
with respect to this change: 
a.
Clarified the additional objectives and endpoints in section 2.1 
b.
The description of the sub population full analysis set ( 18 years) has been defined 
in section 5.3 
c.
Repeats of all primary and secondary analyses are to be performed on this sub-
population of the full analysis set ( 18 years). Clarification on which age group will 
be used for all analyses on the full analysis set has been added to the relevant sub-
section within section 9 
d.
The multiple testing strategy has been updated to include the repeat primary and 
secondary analyses on the full analysis set ( 18 years) in section 8.3. 
 
13. 
 
1.
Jackson D., White I. R., Seaman S., Evans H., Baisley K., and Carpenter J. (2014), Relaxing the 
independent censoring assumption in the Cox proportional hazards model using multiple 
imputation, Statist. Med., 27, 4681 4694. DOI: 10.1002/sim.6274 
2.
 
3.
Bender, R., Augustin, T. and Blettner, M. (2005), Generating survival times to simulate Cox 
proportional hazards models. Statist. Med., 24: 1713-1723. doi:10.1002/sim.2059 
 
14. 
 
14.1 LIST OF TABLES, LISTINGS AND FIGURES 
The list of tables, listings of figures are provided in a separate supporting mock shells document. 


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15. 
 
15.1 SCHEDULE OF ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 


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16. 
 
16.1 USA VALUE SET 
 
Computing EQ-5D-5L index values with SAS using the United States (US) Pickard value set 
Version 1.2 (Updated 31/01/2022) 
 
The variables for the 5 dimensions of the EQ-5D-5L descriptive system should be named 
'mobility', 'selfcare', 'activity', 'pain', and 'anxiety'.  
If they are given different names the syntax code below will not work properly. The 5 
variables should contain the values for the different dimensions 
in the EQ-5D health profile (i.e. 1, 2, 3, 4 or 5). The variable 'EQindex' contains the 
values of the  
EQ-5D-5L index values on the basis of the US set of weights.  
 
You can copy and paste the syntax below directly into a SAS syntax window. 
 
****************************************************************** 
*SAS syntax code for the computation of index* 
*values with the US TTO value set* 
****************************************************************** 
 
data WORK.CAT; 
set WORK.CAT; 
 
 
if mobility eq 1 then disut_mo=0; 
else if mobility eq 2 then disut_mo=0.096; 
else if mobility eq 3 then disut_mo=0.122; 
else if mobility eq 4 then disut_mo=0.237; 
else if mobility eq 5 then disut_mo=0.322; 
 
if selfcare eq 1 then disut_sc=0; 
else if selfcare eq 2 then disut_sc=0.089; 
else if selfcare eq 3 then disut_sc=0.107; 
else if selfcare eq 4 then disut_sc=0.220; 
else if selfcare eq 5 then disut_sc=0.261; 
 
if activity eq 1 then disut_ua=0; 
else if activity eq 2 then disut_ua=0.068; 
else if activity eq 3 then disut_ua=0.101; 
else if activity eq 4 then disut_ua=0.255; 
else if activity eq 5 then disut_ua=0.255; 
 
if pain  eq 1 then disut_pd=0; 
else if pain  eq 2 then disut_pd=0.060; 
else if pain  eq 3 then disut_pd=0.098; 
else if pain  eq 4 then disut_pd=0.318; 
else if pain  eq 5 then disut_pd=0.414; 
 
if anxiety eq 1 then disut_ad=0; 
else if anxiety eq 2 then disut_ad=0.057; 
else if anxiety eq 3 then disut_ad=0.123; 
else if anxiety eq 4 then disut_ad=0.299; 
else if anxiety eq 5 then disut_ad=0.321; 
 
disut_total=disut_mo+disut_sc+disut_ua+disut_pd+disut_ad; 
EQindex=1-disut_total; 
run; 
 
https://euroqol.org/wp-content/uploads/2020/12/US_valueset_SAS.txt 


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17. 
 
17.1 LIST OF PREFERRED TERMS INCLUDED FOR ASSESSMENT OF LOCAL AND SYSTEMIC 
STEROID CLASS EFFECTS, POTENTIALLY ASSOCIATED WITH INHALED 
CORTICOSTEROIDS 
Location 
Medical Concept 
MedDRA (Version 24) Preferred Term 
Local steroid effects 
Candidiasis 
Candida infection  
Oral candidiasis 
Oropharyngeal candidiasis 
Oesophageal candidiasis  
Oral fungal infection 
Infection 
Voice effects 
Aphonia 
Dysphonia 
Bronchospasm 
Paradoxical bronchospasm 
Systemic steroid effects 
Adrenal suppression 
Addison´s disease 
Adrenal insufficiency 
Adrenal suppression 
Adrenocortical insufficiency acute 
Blood cortisol decreased 
Cortisol free urine decreased 
Secondary adrenocortical insufficiency 
Urine cortisol/creatinine ratio decreased  
Cortisol level impact 
Hypercorticism 
Systemic steroid effects 
Diabetes control 
Diabetes mellitus 
Diabetes mellitus inadequate control 
Diabetic metabolic decompensation  
Type 2 diabetes mellitus  
Hyperglycaemia  
Blood glucose increased  
Glucose tolerance impaired  
Systemic steroid effects 
Fractures  
Ankle fracture 
Compression fracture 
Femoral neck fracture 
Femur fracture 
Fibula fracture 


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Location 
Medical Concept 
MedDRA (Version 24) Preferred Term 
Foot fracture 
Fracture 
Hand fracture 
Hip fracture 
Osteoporotic fracture 
Radius fracture 
Rib fracture 
Scapula fracture  
Spinal compression fracture 
Spinal fracture 
Stress fracture  
Tibia fracture 
Ulna fracture 
Wrist fracture 
Cervical vertebral fracture 
Lumbar vertebral fracture 
Thoracic vertebral fracture 
Upper limb fracture 
Lower limb fracture 
Systemic steroid effects 
Growth retardation 
Growth retardation 
Body height below normal 
Body height decreased 
Systemic steroid effects 
Metabolic bone effects
Osteoporosis 
Osteoporosis postmenopausal 
Osteopaenia  
Bone density decreased 
Osteocalcin decreased 
Systemic steroid effects 
Ocular effects 
Cataract 
Cataract cortical 
Cataract diabetic 
Cataract nuclear 
Cataract subcapsular 
Glaucoma 
Intraocular pressure increased 


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Location 
Medical Concept 
MedDRA (Version 24) Preferred Term 
Lenticular opacities 
Ocular hypertension 
Glaucomatous optic disc atrophy 
Intraocular pressure test abnormal 
Systemic steroid effects 
Psychiatric effects 
Depressed mood 
Adjustment disorder with depressed mood  
Depressive symptom 
Depression  
Mixed anxiety and depressive disorder  
Dysphoria 
Euphoric mood 
Insomnia 
Initial insomnia  
Psychotic disorder 
Restlessness 
Systemic steroid effects 
Skin effects 
Contusion  
Ecchymosis 
Increased tendency to bruise 
Petechiae 
Purpura 
Skin atrophy 
Systemic steroid effects 
Taste effects 
Dysgeusia