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)
Phase: PHASE3
Conditions: Asthma
Sponsor: Bond Avillion 2 Development LP

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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. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.

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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 
 
portal). 

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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 
removed via cone biopsy.

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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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11
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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Section
Changes to Protocol Amendment 2 (Version 3.0)
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 
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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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