Clinical trial NCT05850494
Conditions: Asthma
Keywords: Asthma, Bronchospasm
Sponsor: AstraZeneca
Start date: 2023-05-02; Completion date: 2023-08-21
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A study to assess bronchospasm potentially induced by HFO MDI as compared with HFA MDI in participants with well controlled or partially controlled asthma

Detailed description:
This is a phase 3b, multicentre, randomized, double-blind, single-dose crossover study comparing the safety and tolerability of HFO MDI with HFA MDI delivered in participants with well controlled or partially controlled asthma defined as an ACQ-5 score \< 1.5.Eligible participants are at least 18 years of age and no older than 45 years of age and are required to have asthma as defined by GINA guidelines (GINA 2022). Participants are required to be well controlled or partially controlled on their current treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as needed is used. The primary objective is to assess the potential change in FEV1 induced by HFO MDI as compared with HFA MDI in participants with asthma.

This study will be conducted at approximately 5 sites in the US and will randomize approximately 52 adult participants to achieve 46 completers.

The study will be conducted for a maximal 37 days and will comprise:

* A screening period approximately 14 (±2) days prior to first dosing
* Two treatment periods of 1 day each, with a 3 to 12-day washout period between the 2 treatment periods
* A final safety follow-up visit via telephone contact 3 to 7 days after the final dose administration in Treatment Period 2

Single dose study treatment will be administered via MDI device as 4 inhalations:

* Treatment A: HFO propellant only MDI; 4 inhalations per dose - test formulation
* Treatment B: HFA propellant only MDI; 4 inhalations per dose - reference formulation

Arms: arm 1: Test arm, 4 inhalations per dose arm 2: Reference arm, 4 inhalations per dose
Interventions: intervention 1: HFA MDI intervention 2: HFO MDI
Intervention descriptions: intervention 1: * Dose formulation: MDI
* Unit dose strength(s): Reference (propellant only)
* Dosage Level: 4 inhalations, single dose
* Route of administration: Oral inhalation
* Participants will receive treatment A in 1 or 2 possible sequences AB or BA intervention 2: * Dose formulation: MDI
* Unit dose strength(s): Experimental (propellant only)
* Dosage Level: 4 inhalations, single dose
* Route of administration: Oral inhalation
* Participants will receive treatment A in 1 or 2 possible sequences AB or BA

Protocol documents:
Prot_000.pdf: 
Clinical Study Report Appendix 16.1.1 
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Clinical Study Report Appendix 16.1.1 
Drug Substance Breztri PT010 
Study Code 
D5985C00007 
Appendix 16.1.1 
Protocol and Protocol Amendments 
 


Clinical Study Report Appendix 16.1.1 
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VERSION OF PROTOCOL OR PROTOCOL AMENDMENT 
Global Document Name 
Version No  
Version Date 
First final version of the protocol prior to any amendments 
1.0 
08 December 2022 
 


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Clinical Study Protocol 
Study 
Intervention
Breztri PT010
Study Code
D5985C00007
Version
1.0
Date
08Dec2022
A Randomized, Double-blind, Single Dose, 2-way Crossover Study 
to Assess Bronchospasm Potentially Induced by the 
Hydrofluoroolefin (HFO) Metered Dose Inhaler (MDI) Propellant 
as Compared with the Hydrofluoroalkane (HFA) MDI Propellant 
in Participants with Asthma, Well Controlled or Partially 
Controlled on Short-acting beta2-agonists (SABA) with or without 
Low-Dose Inhaled Corticosteroids (ICS) 
A multicenter, 2-way crossover, phase IIIb, double-blind study to assess bronchospasm 
potentially induced by HFO MDI as compared with HFA MDI in participants with asthma, well 
controlled or partially controlled, on SABA with or without low-dose ICS
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Manufacturer: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s)
Registry
ID
IND 
118313




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TABLE OF CONTENTS
TABLE OF CONTENTS ...................................................................................................... 3
LIST OF ABBREVIATIONS................................................................................................ 7
1
PROTOCOL SUMMARY .................................................................................. 9
1.1
Synopsis ............................................................................................................. 9
1.2
Schema............................................................................................................. 14
1.3
Schedule of Activities ....................................................................................... 15
2
INTRODUCTION............................................................................................ 17
2.1
Study Rationale ................................................................................................ 17
2.2
Background ...................................................................................................... 17
2.3
Benefit/Risk Assessment................................................................................... 19
2.3.1
Risk Assessment ............................................................................................... 19
2.3.2
Hydrofluoroolefin............................................................................................. 20
2.3.3
Risk Assessment for COVID-19 Pandemic ....................................................... 20
2.3.4
Benefit Assessment........................................................................................... 21
2.3.5
Overall Benefit/Risk Conclusion....................................................................... 21
3
OBJECTIVES AND ENDPOINTS................................................................... 22
4
STUDY DESIGN ............................................................................................. 23
4.1
Overall Design.................................................................................................. 23
4.2
Scientific Rationale for Study Design ............................................................... 24
4.2.1
Participant and Site Input Into Design............................................................... 25
4.3
Justification for Dose........................................................................................ 25
4.4
End-of-study Definition.................................................................................... 25
5
STUDY POPULATION.................................................................................... 26
5.1
Inclusion Criteria .............................................................................................. 26
5.2
Exclusion Criteria ............................................................................................. 28
5.3
Lifestyle Considerations ................................................................................... 29
5.3.1
Caffeine, Alcohol, and Tobacco......................................................................... 29
5.3.2
Activity............................................................................................................. 30
5.4
Screen Failures ................................................................................................. 30
5.5
Criteria for Temporarily Delaying Enrolment/Randomisation/Administration of 
Study Intervention ............................................................................................ 31
6
STUDY INTERVENTIONS AND CONCOMITANT THERAPY..................... 31
6.1
Study Intervention(s) Administered................................................................... 31
6.1.1
Medical Devices Including Combination Products with a Device Constituent... 32
6.2
Preparation, Handling, Storage, and Accountability .......................................... 32
6.3
Assignment to Study Intervention ..................................................................... 33
6.4
Blinding............................................................................................................ 33


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6.5
Study Intervention Compliance......................................................................... 34
6.6
Dose Modification ............................................................................................ 34
6.6.1
Retreatment Criteria.......................................................................................... 34
6.7
Continued Access to Study Intervention After the End of the Study .................. 35
6.8
Treatment of Overdose...................................................................................... 35
6.9
Prior and Concomitant Therapy ........................................................................ 35
6.9.1
Prior Medications ............................................................................................. 35
6.9.2
Concomitant Medications ................................................................................. 36
6.9.2.1
Vaccinations...................................................................................................... 37
6.9.3
Prohibited Medications ..................................................................................... 37
6.10
Discontinuation 
of 
Study 
Intervention 
and 
Participant 
Discontinuation/Withdrawal.............................................................................. 39
6.11
Discontinuation of Study Intervention............................................................... 39
6.12
Participant Discontinuation/Withdrawal from the Study.................................... 39
6.13
Lost to Follow-up ............................................................................................. 40
7
STUDY ASSESSMENTS AND PROCEDURES.............................................. 41
7.1
Administrative and General/Baseline Procedures.............................................. 41
7.1.1
Demographics and Medical/Surgical History .................................................... 41
7.1.2
Height and Weight ............................................................................................ 42
7.1.3
Physical Examinations...................................................................................... 42
7.1.4
Vital Signs ........................................................................................................ 42
7.1.5
Electrocardiograms........................................................................................... 42
7.1.6
Clinical Laboratory Tests .................................................................................. 43
7.2
Efficacy Assessments........................................................................................ 43
7.3
Safety Assessments........................................................................................... 43
7.3.1
Asthma Control Questionnaire 5....................................................................... 43
7.3.2
Spirometry........................................................................................................ 44
7.3.2.1
Monitoring for Bronchospasm .......................................................................... 45
7.3.3
Other Safety Assessments ................................................................................. 45
7.3.3.1
Pregnancy testing.............................................................................................. 45
7.4
AEs, SAEs, and Other Safety Reporting............................................................ 45
7.4.1
Time Period and Frequency for Collecting AE and SAE Information................ 46
7.4.2
Follow-up of AEs and SAEs ............................................................................. 47
7.4.3
Causality Collection.......................................................................................... 47
7.4.4
AEs Based on Examinations and Tests.............................................................. 47
7.4.5
AEs Based on Signs and Symptoms.................................................................. 48
7.4.6
Adverse Events of Special Interest.................................................................... 48
7.4.7
Reporting of SAEs............................................................................................ 49
7.4.8
Pregnancy......................................................................................................... 50
7.4.8.1
Maternal Exposure............................................................................................ 50
7.4.8.2
Paternal Exposure............................................................................................. 50
7.4.9
Medication Error, Drug Abuse, and Drug Misuse.............................................. 51
7.4.9.1
Timelines.......................................................................................................... 51


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7.4.9.2
Medication Error............................................................................................... 51
7.4.9.3
Drug Abuse....................................................................................................... 51
7.4.9.4
Drug Misuse ..................................................................................................... 51
7.4.10
Reporting of Overdose...................................................................................... 51
7.4.11
Medical Device Deficiencies............................................................................. 52
7.4.11.1
Time Period for Detecting Medical Device Deficiencies ................................... 52
7.4.11.2
Follow-up of Medical Device Deficiencies ....................................................... 53
7.4.11.3
Prompt Reporting of Medical Device Deficiencies to Sponsor .......................... 53
7.4.11.4
Regulatory Reporting Requirements for Device Deficiencies............................ 53
7.5
Pharmacokinetics.............................................................................................. 53
7.6
Pharmacodynamics ........................................................................................... 53
7.7
Optional Genomics Initiative ............................................................................ 53
7.8
Biomarkers ....................................................................................................... 54
7.9
Immunogenicity Assessments ........................................................................... 54
7.10
Health Economics OR Medical Resource Utilisation and Health Economics..... 54
7.11
Study Participant Feedback Questionnaire ........................................................ 54
8
STATISTICAL CONSIDERATIONS................................................................ 54
8.1
Statistical Hypotheses....................................................................................... 54
8.2
Sample Size Determination............................................................................... 54
8.3
Populations for Analyses................................................................................... 55
8.4
Statistical Analyses ........................................................................................... 55
8.4.1
General Considerations..................................................................................... 55
8.4.1.1
Intercurrent Events............................................................................................ 56
8.4.1.2
Strategy for Intercurrent Events ........................................................................ 56
8.4.2
Safety ............................................................................................................... 56
8.4.2.1
Primary Endpoint.............................................................................................. 56
8.4.2.2
Secondary Endpoints ........................................................................................ 57
8.4.3
Other Analyses.................................................................................................. 58
8.4.3.1
Physical Examinations...................................................................................... 58
8.4.3.2
Vital Signs ........................................................................................................ 58
8.4.3.3
Electrocardiogram............................................................................................. 58
8.5
Interim Analyses............................................................................................... 58
8.6
Data Monitoring/Other Committee.................................................................... 58
9
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 58
10
REFERENCES................................................................................................. 78
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 14
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LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 15
Table 2
Risk Assessment...................................................................................... 19
Table 3
Objectives and Endpoints......................................................................... 22
Table 4
Low Daily Metered Dose of ICS (Monotherapy or in Combination with 
LABA) .................................................................................................... 36
Table 5
Allowed Medications with Defined Stable Dosing Period Prior to Visit 1 36
Table 6
Prohibited Medications Throughout the Study and Prior to Visit 1........... 37
Table 7
Prohibited Asthma and Allergy Medications During the Study Conduct 
and Required Washout Period Prior to Visit 2.......................................... 38
Table 8
Laboratory Variables ............................................................................... 43
Table 9
Populations for Analysis .......................................................................... 55
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 59
Appendix B
AEs: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting .......................................................................................... 65
Appendix C
Handling of Human Biological Samples .................................................. 71
Appendix D
Medical Device AEs, ADEs, SAEs, SADEs, USADEs, and Medical 
Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...................................................... 73


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LIST OF ABBREVIATIONS 
Abbreviation or special 
term
Explanation
ACQ
Asthma Control Questionnaire
ADE
Adverse device effect
AE
Adverse event
AUC
Area under the curve
AUC0-15 min
Area under the curve from 0 to 15 minutes
BGF
Budesonide, glycopyrronium, and formoterol fumarate
CFR
Code of Federal Regulations
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CRO
Contract research organisation
CSR
Clinical study report
DPI
Dry powder inhaler
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EU
European Union
FEV1
Forced expiratory volume in 1 second
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GWP
Global warming potential
HBS
Human biological sample(s)
HFA
Hydrofluoroalkane
HFO
Hydrofluoroolefin
IATA
International Air Transport Association
IB
Investigator’s Brochure
ICE
Intercurrent event
ICF
Informed consent form
ICH
International Council for Harmonisation
ICS
Inhaled corticosteroid
IMP
Investigational medicinal product
IND
Investigational New Drug
IRB
Institutional review board


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Abbreviation or special 
term
Explanation
IRT
Interactive Response Technology
LABA
Long-acting beta2-agonist
MDI
Metered dose inhaler
NI
Non-inferiority
NIMP
Non-investigational medicinal product 
RTSM
Randomisation and Trial Supply Management
SADE
Serious adverse device effect
SAE
Serious adverse event 
SABA
Short-acting beta2-agonists
SAP
Statistical Analysis Plan
SoA
Schedule of activities
USADE
Unanticipated serious adverse device effect






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needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as 
needed is used, through the study. 
 
 
 
 
 
 
 
 
  
 
 
Brief Summary:
The purpose of this study is to assess bronchospasm potentially induced by hydrofluoroolefin 
(HFO) metered dose inhaler (MDI) as compared with hydrofluoroalkane (HFA) MDI in
participants with asthma, well controlled or partially controlled on treatment for asthma, 
including, low-dose inhaled corticosteroid (ICS) daily or low-dose ICS/formoterol as needed 
(not approved in the US), or short-acting beta2-agonists (SABA) as needed, or low-dose ICS 
whenever SABA as needed is used.  
Study details include:
!
Disclosure Statement: This is a 2-way crossover study with 2 treatment arms that is 
participant, sponsor, and investigator blinded.
Number of Participants:
It is estimated that approximately 52 participants with well controlled or partially controlled 
asthma will be randomized to achieve 46 completers, with 26 participants in each treatment 
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sequence. This assumes a 10% dropout rate.
Study Arms and Duration:
 
 
Study treatment will be administered via MDI device as 4 inhalations:
!
Treatment A: HFO propellant only MDI; 4 inhalations per dose – test formulation
!
Treatment B: HFA propellant only MDI; 4 inhalations per dose – reference 
formulation
Participants will be randomized in a ratio of 1:1 to receive treatments in one of two possible 
treatment sequences: A followed by B, or B followed by A. 
Data Monitoring/Other Committee: No
Statistical Methods
The null hypothesis tested in this study for the primary objective is that HFO MDI (test arm) 
is inferior to HFA MDI (reference arm) in terms of the change from baseline in FEV1 AUC0-15 
min, versus the alternative hypothesis that the test arm is non-inferior to the reference arm. The 
non-inferiority (NI) margin is set at –200 mL.  If the lower limit of the 2-sided 95% 
confidence interval (CI) for the difference in the mean change from baseline of HFO MDI 
minus HFA MDI  is > −200 mL, then NI will be demonstrated. 
 
 
 
 
.
The following populations are defined:
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Population/Analysis set
Description
Enrolled 
All participants who sign the ICF. The Enrolled Analysis Set will be used to 
summarise disposition.
Randomised
All enrolled participants who are randomised to one of the study treatment 
sequences. The Randomised Analysis Set will be used to summarise 
baseline characteristics.
Safety
All participants who are randomised to one of the study treatment sequences 
and have received any amount of the study treatment (ie, at least 1 puff). 
Participants will be analysed according to the actual treatment received. 
Abbreviations: ICF = informed consent form.
For secondary safety endpoints and other safety assesssments, no formal statistical analyses 
will be performed. Descriptive summaries will be produced and any clinically relevant 
differences will be noted and discussed.
Demographic and baseline characteristics data will be summarised by treatment sequence. 
Categorical variables will be summarised using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population unless otherwise 
specified. Continuous variables will be summarised with descriptive statistics using number of 
available observations, mean, standard deviation, median, minimum, and maximum, and 
quartiles where appropriate.
The primary endpoint is defined as change from baseline in FEV1 AUC0-15 min post-dose. The 
analysis will be performed based on the Safety Analysis Set using a Principal Stratum 
estimand.
Change in FEV1 AUC0-15 min post-dose will be calculated from FEV1 change from baseline at 
5 and 15 minutes post-dose using the trapezoidal rule, divided by the actual observation time 
from the first to the last non-missing value, for each treatment period. Baseline is the FEV1
value obtained within 30 minutes prior to study intervention administration in each treatment 
period.
For the primary endpoint, a Mixed Model Repeated Measures analysis with treatment
sequence, period, average baseline FEV1, and treatment as fixed effects, and participant within 
sequence as the random effect will be used. Average baseline (period-specific baseline FEV1
averaged over the treatment periods) is included to account for cross-level bias.
Adjusted mean change from baseline estimates per treatment group and corresponding 2-sided 
95% CIs along with an overall estimate of the treatment difference (HFO MDI minus HFA 
MDI) will be presented. If the lower limit of the 2-sided 95% CI for the difference in mean 
change from baseline of HFO MDI minus HFA MDI is > −200 mL, the null hypothesis of 




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1.3
Schedule of Activities
Table 1
Schedule of Activities
Details in protocol section or 
appendix
Informed consent d
X
Section 5.1
Inclusion/exclusion criteria
X
X
Sections 5.1 and 5.2
Verify continued eligibility
X
X
Sections 5.1 and 5.2
ACQ-5
X e
Section 7.3.1
Randomisation
X
Section 6.3
Routine clinical procedures
Demographics and medical/surgical 
history
X
Sections 5.1, 5.2, and 7.1.1
Prior/concomitant medication review 
X
X
X
X
X
X
Section 6.9
Spirometry f
X
X g
X g
X
X
Section 7.3.2
Routine safety measurements
AE
X
X
X
X
X
X
Section 7.4 and
Appendix B
Pregnancy testing h
X
X
X
Sections 5.1
and 7.3.3.1
FSH h
X
Section 7.3.3.1
(Local) Clinical laboratory tests (blood and 
urine)
X
Section 7.1.6
Physical examination
X
X i
X i
X
Section 7.1.3
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Table 1
Schedule of Activities
Details in protocol section or 
appendix
Height and weight
X
Section 7.1.2
Vital signs
X
X i
X i
X
Section 7.1.4
12-lead ECG
X
Section 7.1.5
Study intervention administration
Inhalation technique verification
X
X
X
Section 6
Administer blinded study intervention in 
clinic
X
X
Sections 4.1 and 6
a
All participants should remain on their current treatment for asthma through the study, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not approved in 
the US), or SABA as needed, or low-dose ICS whenever SABA as needed is used.
b
Assessments done at unscheduled visits are at the discretion of the Investigator.
c
 sites should call participants 1 to 2 days before each scheduled in-clinic visit to remind them of the upcoming visit and related 
restrictions/requirements, including withholding morning dose of asthma medications on the day of on-site study visit.
d
ICF could be signed up to 7 days prior to 
 
e
Whether the participant has an ACQ-5 score < 1.5 and a pre-dose FEV1 > 60% will be assessed at 
 for study participation.
f
Albuterol/salbutamol must be withheld for at least 8 hours prior to FEV1 measurements. All LABAs, formoterol included and combinations there-of, must be withheld for 48 
hours prior to spirometry.
g
Pre-dose spirometry will be performed at 30 minutes prior to dosing and post-dose spirometry will be performed at 5, 15, and 30 minutes after dosing. During both Treatment 
Periods, if FEV1 drops > 15% from baseline, measurements should be repeated at Investigator’s discretion until FEV1 values are within 10% of baseline performed that day.
h
A serum pregnancy test 
 and urine pregnancy tests at following visits will be performed for women of childbearing potential. A serum FSH test will be conducted at 
only, for women who have been amenorrhoeic for 12 months without an alternative medical cause, to confirm postmenopausal status.
i
Assessments will be performed prior to dosing. Brief physical examinations will be performed at 
 
Abbreviations: ACQ-5 = Asthma Control Questionnaire 5; AE = adverse event; ECG = electrocardiogram; FEV1 = forced expiratory volume in 1 second; FSH = follicle-
stimulating hormone; ICF = informed consent form; ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; TC = telephone contact; WD = withdrawal.
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2
INTRODUCTION
The sponsor, AstraZeneca, has developed orally inhaled drug products containing budesonide 
(an inhaled corticosteroid; ICS), glycopyrronium (a long-acting muscarinic antagonist), and 
formoterol fumarate (a long-acting beta2-agonist) (BGF metered dose inhaler [MDI]) for the 
treatment of asthma. These drug products are formulated as a suspension with micronized 
active pharmaceutical ingredients and Co-Suspension™ Delivery Technology in MDIs. The 
Co-Suspension Delivery Technology of spray-dried porous particles comprised of the 
phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine and calcium chloride suspended in a 
hydrofluoroalkane (HFA) propellant. Hydrofluoroolefin (HFO) has been identified by sponsor 
as a novel propellant potentially suitable for replacement of HFA-134a in the BGF MDI HFA 
product for the purpose of lowering global warming potential (GWP).
The test and reference formulation used in this study is an MDI with a desiccated flow path 
containing HFA or HFO propellant only.
2.1
Study Rationale
The current HFA (HFA-134a) propellant in AstraZeneca’s MDI type treatments is known to 
have a relatively high GWP compared to some new alternative propellants, and contributes 
substantially to AstraZeneca’s carbon footprint. In order to address this issue, AstraZeneca is 
evaluating an MDI reformulated with a next generation propellant HFO (HFO-1234ze), which 
has a near zero GWP and will allow patients to continue to use MDI type treatments, while 
contributing to AstraZeneca’s sustainability efforts. 
As part of the clinical development program for gaining regulatory approval for BGF MDI 
HFO for the treatment of asthma and chronic obstructive pulmonary disease (COPD), and for 
supporting other potential products, this study is being conducted to assess if HFO MDI 
induces a potential change in FEV1 as compared to HFA MDI in participants with well 
controlled or partially controlled asthma, as primarily evaluated by change from baseline in 
forced expiratory volume in 1 second (FEV1) area under curve from 0 to 15 minutes (AUC0-15 
min) post-dose .
2.2
Background
Asthma is a heterogeneous disease that is characterized by chronic airway inflammation and 
bronchial hyperreactivity. It is defined by a history of respiratory symptoms such as wheeze, 
shortness of breath, chest tightness, and cough that vary over time and in intensity, together 
with variable expiratory airflow obstruction [Global Initiative for Asthma (GINA) Guidance
2022].
The long-term goals of asthma management are risk reduction and symptom control. The aim 
is to reduce the patient burden and risk of asthma-related death, exacerbations, airway 
damage, and medication side effects. The patient’s own goals regarding their asthma and its 


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treatment should also be identified [GINA 2022]. This concept encompasses 2 components: 
(1) patient’s recent clinical status and current disease impact which includes assessment of 
symptoms, night awakenings, use of rescue medication, and lung function and (2) patient 
assessment for future risk of exacerbations, decline in lung function, or treatment-related side 
effects. 
AstraZeneca has developed MDI products with HFA for the treatment of asthma. Their 
formulations are generally comprised of a therapeutic material, a propellant, co-solvents, and 
surfactants. The HFA MDI products are formulated with HFA-134a propellant, a liquefied 
compressed gas, in which the active pharmaceutical ingredients are suspended. HFA-134a is a 
common propellant in pharmaceutical MDI products that provides the force to generate an 
aerosol to deliver a product inhalation or dose. More information on the HFA MDI drug 
product is provided in the BGF MDI Investigator’s Brochure (IB). 
The current HFA (HFA-134a) propellant in AstraZeneca’s MDI type treatments is known to 
have a relatively high GWP compared to some alternative propellants, and contributes 
substantially to AstraZeneca’s carbon footprint. HFO-1234ze, which is available for industrial 
uses such as refrigeration, has been further purified by the manufacturer through fractional 
distillation to provide a propellant of suitable grade for clinical studies. HFO-1234ze has a 
near-zero GWP and very low photochemical reactivity. In addition, it has very similar physical 
properties to HFA-134a, which are expected to have comparable performance of the HFA 
MDI product. The sponsor has identified HFO-1234ze as a novel propellant potentially 
suitable for replacement of HFA-134a in the BGF MDI HFA product. 
Study D5985C00001 assessed the safety and tolerability of a combination of BGF when 
administered as single doses in 3 different propellant formulations: BGF MDI HFO, BGF 
MDI hydrofluorocarbon, and BGF MDI HFA in 47 healthy volunteers. The combination of 
BGF when administered as single doses in 3 different propellant formulations demonstrated a 
similar and acceptable safety profile among 3 formulations and was well tolerated in healthy 
volunteers. The development of BGF MDI HFO products including non-clinical toxicology 
results and study D5985C00001 results is specified in IB Section 3.2.3, Section 5.2.5, and 
Appendix A.
To further support HFO-1234ze regulatory applications, this study will assess the safety and 
tolerability of HFO-1234ze (HFO MDI; propellant only) compared with HFA-134a (HFA 
MDI; propellant only) delivered in participants with well controlled or partially controlled on 
treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed 
(not approved in the US), or short-acting beta2-agonists (SABA) as needed, or low-dose ICS 
whenever SABA as needed is used, defined as an Asthma Control Questionnaire 5 (ACQ-5) 
score < 1.5. 


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2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of HFO 
MDI and HFA MDI may be found in the IB.
2.3.1
Risk Assessment
Table 2
Risk Assessment
Potential risk of clinical 
significance
Summary of data/rationale for 
risk 
Mitigation strategy
Study intervention
Safety (ie, risk of bronchospasm)
Study intervention is a pMDI 
containing HFA or HFO 
propellant only.
Participants will be well controlled 
or partially controlled on 
treatments for asthma, including,  
low-dose ICS daily or low-dose 
ICS/formoterol as needed (not 
approved in the US), or SABA as 
needed, or low-dose ICS whenever 
SABA as needed is used.
Study procedures
Risk of bronchospasm
Handling of bronchospasm events
by site staff in case such event 
happens
Sites will be equipped with well 
trained site staff to deal with 
bronchospasm events. Sites will 
also provide appropriate 
medications for bronchospasm 
treatment. 
In the event of a bronchospasm, 
participants could be discharged 
should FEV1 values be within 10% 
of the baseline FEV1 performed 
that day, or at investigator 
discretion.
Trial integrity
Improper blinding leading to bias
Participants should not be able to 
distinguish the propellants by 
colour or smell since they are 
similar. There are few participants 
and only 2 products that need to be 
blinded.
Study population
Safety
1. Asthma stability is related to 
seasonality.
2. Excessive hyperreactivity may 
happen because some patients that 
are perceived as having mild 
1. For inclusion criteria, 
participants with asthma ACQ-5 
score < 1.5 will be enrolled, which 
is also an indication of the stability 
of asthma.




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
Participants will be closely monitored for any signs and symptoms of COVID-19, 
including fever, dry cough, dyspnea, sore throat, and fatigue throughout the study. Once 
clinical signs of infection are reported by participants, the investigator needs to determine 
whether samples can be collected, and safety data can be recorded on site. If not, adverse 
events (AEs) and concomitant medications will be obtained via phone calls. Daily body 
temperature measurements during outpatient visits will be implemented.

The investigator will not dose participants upon identification of any signs of COVID-19 
infection.

The probability of virus transmission will be controlled as much as possible by:

Advising the participant to adhere to local requirements for reduction of the public 
exposure while ambulatory.

If applicable, all participants will be contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs and are asked not to attend the site in case 
of suspected reports. In addition, participants are asked for any contact with a person 
who has tested positive for severe acute respiratory syndrome coronavirus 2. If 
applicable, participants will be referred to the local health care system for further 
follow-up and treatment.

Physical distancing and person-to-person contact restrictions will be applied during 
site visits.

Where physical distancing is not possible, personal protective equipment will be used 
by participants (surgical face masks, gloves) and staff (for example, but not limited to 
masks, gloves, protectors, medical suits) if deemed appropriate by the investigator 
and site staff and guided by local requirements.

Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing.
2.3.4 Benefit Assessment
No direct benefit for individuals in this study is expected. Indirect benefits include assisting 
with clinical development of MDI products with a lower GWP.
2.3.5 Overall Benefit/Risk Conclusion
Considering the measures taken to minimize risk to participants participating in this study, the 
potential risks identified in association with HFO MDI are justified by the anticipated indirect 
benefits that may be afforded with regard to a reduced carbon footprint of MDI products.




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4
STUDY DESIGN
4.1
Overall Design
This is a phase 3b, multicentre, randomized, double-blind, single-dose crossover study 
comparing the safety and tolerability of HFO MDI with HFA MDI delivered in participants 
with well controlled or partially controlled asthma defined as an ACQ-5 score < 1.5.Eligible 
participants are at least 18 years of age and no older than 45 years of age and are required to 
have asthma as defined by GINA guidelines (GINA 2022). Participants are required to be well 
controlled or partially controlled on their current treatment for asthma, including, low-dose
ICS daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as 
needed, or low-dose ICS whenever SABA as needed is used. The primary objective is to 
assess the potential change in FEV1 induced by HFO MDI as compared with HFA MDI in 
participants with asthma.
This study will be conducted at approximately 5 sites in the US and will randomize 
approximately 52 adult participants to achieve 46 completers.
 
 
Single dose study treatment will be administered via MDI device as 4 inhalations:
!
Treatment A: HFO propellant only MDI; 4 inhalations per dose – test formulation
!
Treatment B: HFA propellant only MDI; 4 inhalations per dose – reference 
formulation
Participants will be randomized in a ratio of 1:1 to receive treatments in one of two possible 
treatment sequences: A followed by B, or B followed by A. 
All participants will remain on their current treatment for asthma, including, low-dose ICS 
daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as needed, or 
low-dose ICS whenever SABA as needed is used, during the screening, treatment, and 
washout periods.
Note: Albuterol/salbutamol must be withheld for at least 8 hours prior to FEV1 measurements.
 participants’ eligibility will be verified, and whether the participant has an ACQ-5 
score < 1.5 and a pre-dose FEV1 > 60% will be assessed. Participants will remain on their 
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current treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as 
needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as 
needed is used, through the study. 
 
 
 
 
 
 
 
 
 
 
Note: An event of bronchospasm is defined as a reduction in FEV1 of > 15% from baseline (ie, 
the FEV1 value obtained within 30 minutes prior to study intervention administration) at 5 or 
15 minutes post-dose with associated symptoms of wheezing, shortness of breath, or cough.
For details on study interventions given during the study, see Section 6.1. The study schematic 
with flow of events for all treatments, depending on the participant’s assigned randomization 
is presented in Figure 1. The schedule of activities (SoA) displaying assessments/tasks and 
timepoints is presented in Table 1.
4.2
Scientific Rationale for Study Design
The primary objective is to assess the potential change in FEV1 induced by HFO MDI as 
compared with HFA MDI in participants with asthma. As such, the primary endpoint is the 
change from baseline in FEV1 AUC0-15 min post-dose. The secondary objectives of the study 
are to assess the potential of bronchospasm induced by HFO MDI as compared to HFA MDI 
in participants with asthma, measured as the cumulative incidence of bronchospasm events, 
and to assess the safety and tolerability of HFO MDI as compared to HFA MDI in participants 
with asthma, evaluated in terms of AEs. An event of bronchospasm is defined as a reduction in 
FEV1 of > 15% from baseline (ie, the FEV1 value obtained within 30 minutes prior to study 
intervention administration) at 5 or 15 minutes post-dose.
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The study is double blinded to minimize any bias from the participants, investigators, or 
sponsor that may affect study results. Participants will be randomised to prevent bias in 
allocation of treatments in each treatment period, with each participant serving as his/her own 
matched control.
This study will enroll participants with well controlled or partially controlled asthma defined 
by ACQ-5 score < 1.5 who are on current treatment with low-dose ICS daily or low-dose
ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS 
whenever SABA as needed is used. As patients with asthma have hyperreactive airways and 
could be more prone to develop a bronchospasm as compared with patients with COPD, 
asthma patients were chosen for this study even though the MDI products are intended to be 
used in both populations. Participants in the study will be maintained on their current 
treatment, open-label, at study entry.. This would allow an effective assessment of potential 
events of bronchospasm should they be induced by HFO propellant in comparison to the HFA 
propellant in the study. 
4.2.1 Participant and Site Input Into Design
Gathering input on study design from both investigators and aimed study population has been 
part of the preparations for this study and development of this Clinical Study Protocol. This 
aims to provide opportunities for informing study design, improving operational aspects of the 
study, reducing patient/site burden and retaining interest, enthusiasm, and engagement in a 
study. Investigator input has been provided by potential sites as part of the study feasibility 
evaluation. Participant input has been obtained from similar programs/studies where 
interviews have been held with asthma patients.
4.3
Justification for Dose
The dose of BGF MDI HFA is 2 inhalations per dose for a total of 4 inhalations per day. As 
there is no regulatory or company precedent for dosing in this type of study, a single dose of 
4 inhalations of HFA/HFO propellant will be administered, which is the same dose as the 
maximum daily dose of propellant administered with BGF MDI HFA. This dose is well within 
the safety margin of the non-clinical exposure data.
4.4
End-of-study Definition
For the purpose of clinical trial transparency, the definition of the end of the study differs 
under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for 
any protocol-related activity.
Food and Drug Administration requirements defines 2 completion dates:


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Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated.
A participant is considered to have completed the study if they have completed all phases of 
the study including the last scheduled treatment period shown in the SoA (Table 1).
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment 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
Male and female participant must be 18 to 45 years of age inclusive, at the time of 
signing the informed consent form (ICF).
Type of Participant and Disease Characteristics
2
Participants who have a documented history of physician-diagnosed asthma 
≥12 months prior to Visit 1, according to GINA guidelines (GINA 2022).
3
Participants who are well controlled or partially controlled on their current treatment for 
asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not 
approved in the US), or SABA as needed, or low-dose ICS whenever SABA as needed
is used (low-dose ICS as defined by GINA 2022 in Table 4), for 4 weeks prior to 
screening.
4
ACQ-5 total score < 1.5 at 
5
A pre-bronchodilator FEV1 > 60% predicted normal value at 
6
Demonstrate acceptable MDI administration technique.
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Sex and Contraceptive/Barrier Requirements
7
Females must be not of childbearing potential, or should be using a form of highly 
effective birth control as defined below: 
!
Female participants: Women not of childbearing potential are defined as women 
who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy), or who are postmenopausal. Women included in this 
study will be considered postmenopausal if they have been amenorrhoeic for 
12 months or more following cessation of exogenous hormonal treatment and 
follicle-stimulating hormone levels in the postmenopausal range. 
!
Female participants of childbearing potential must use one highly effective form 
of birth control. A highly effective method of contraception is defined as one that 
can achieve a failure rate of less than 1% per year when used consistently and 
correctly. At enrolment, women of childbearing potential who are sexually active 
with a non-sterilised male partner should be stable on their chosen method of 
highly effective birth control, as defined below, and willing to remain on the birth 
control until at least 14 days after last dose of study intervention. Cessation of 
contraception after this point should be discussed with a responsible physician. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception. Female condom and male 
condom should not be used together. All women of childbearing potential must 
have a negative serum pregnancy test result 
!
Highly effective birth control methods are listed below:
o
Total sexual abstinence is an acceptable method provided it is the usual 
lifestyle of the participant (defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 
treatments). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of 
exposure to study intervention, and withdrawal are not acceptable methods 
of contraception.
o
Contraceptive subdermal implant
o
Intrauterine device or intrauterine system
o
Oral contraceptive (combined or progesterone only)
o
Injectable progestogen
o
Contraceptive vaginal ring
o
Percutaneous contraceptive patches
o
Male partner sterilisation with documentation of azoospermia prior to the 
female participant’s entry into the study, and this male is the sole partner for 
that participant. The documentation on male sterility can come from the site 
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personnel’s review of participant’s medical records, medical examination 
and/or semen analysis or medical history interview provided by her or her 
partner.
o
Bilateral tubal ligation
Informed Consent
8
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Life-threatening asthma defined as a history of significant asthma episode(s) requiring 
intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma 
related syncopal episode(s).
2
Current smokers, former smokers with > 10 pack-years history, or former smokers who 
stopped smoking < 6 months prior to Visit 1 (including all forms of tobacco, e-cigarettes 
or other vaping devices, and marijuana).
3
Historical or current evidence of a clinically significant disease including, but not limited 
to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, 
or pulmonary (e.g., active tuberculosis, bronchiectasis, pulmonary eosinophilic 
syndromes, COPD, and uncontrolled severe asthma). Significant is defined as any disease 
that, in the opinion of the investigator, would put the safety of the participant at risk 
through participation, or that could affect the safety/tolerability analysis.
4
Any respiratory infection or asthma exacerbation treated with systemic corticosteroids 
and/or additional ICS treatment in the 8 weeks prior to Visit 1 and throughout the 
screening period.
5
Hospitalization for asthma within 1 year prior to Visit 1.
6
Admission to intensive care unit or mechanical ventilation due to asthma exacerbation.
7
Known history of drug or alcohol abuse within 12 months of Visit 1.
Prior/Concomitant Therapy
8
Do not meet the stable dosing period prior to Visit 1 (see Table 5) or unable to abstain 
from protocol-defined prohibited medications during screening and treatment periods (see 
Table 6 and Table 7).
9
Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, e.g., vector, lipid 
nanoparticle) ≤ 7 days prior to Visit 1 (from last vaccination or booster dose).


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Prior/Concurrent Clinical Study Experience
10 Participation in another clinical study with an investigational product administered within 
30 days or 5 half-lives (whichever is longer).
11 Participants with a known hypersensitivity to HFO or HFA or any of the excipients of the 
product.
12 Previously randomised into a study with an HFO-containing MDI.
Diagnostic Assessments
13 Any clinically relevant abnormal findings in physical examination, clinical chemistry, 
hematology, urinalysis, vital signs, or electrocardiogram (ECG), which in the opinion of 
the investigator, may put the participant at risk because of his/her participation in the 
study.
Note: Participants with ECG QT interval corrected for heart rate using Fridericia’s 
formula (QTcF) > 480 msec will be excluded. Participants with high degree 
atrioventricular block II or III, or with sinus node dysfunction with clinically significant 
pauses who are not treated with pacemaker will also be excluded. 
Other Exclusions
14 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
15 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.
16 Previous enrolment or randomisation in the present study. 
17 For women only – currently pregnant (confirmed with positive pregnancy test), breast 
feeding, or planned pregnancy during the study or women of childbearing potential not 
using acceptable contraception measures.
18 Study investigators, sub-investigators, coordinators, and their employees or immediate 
family members.
5.3 Lifestyle Considerations
5.3.1
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 6 hours 
before and for the duration of each in-clinic study visit.

Use of tobacco products or vaping will not be allowed from 6 months prior to Visit 1 until 
after the final follow-up visit.


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!
Participants will abstain from consuming any intoxicants (eg, alcohol) within 24 hours 
before spirometry testing.
5.3.2
Activity
Participants will abstain from strenuous exercise for 24 hours before each spirometry testing 
and each blood collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (eg, watching television, reading).
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 intervention. 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 publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious AE (SAE).
Rescreening is allowed for screen failure reason(s) that are transient (including, but not 
limited to, pre-defined time period requirements, respiratory tract infection not treated with 
systemic corticosteroids, equipment/procedure failure, required study documentation, or 
unforeseen personal reasons).
Participants may not be rescreened due to failure to meet the study requirements of 
pre-bronchodilator FEV1 (including stability) during the screening period.
Participants on SABA alone therapy who have failed screening due to an ACQ-5 score >1.5 
could be rescreened if they have subsequently received treatment with low-dose ICS for a 
period of 4 weeks as prescribed by their treating physician (i.e. healthcare provider). If they 
failed screening for a second time, they must be considered screen-failures. 
Albuterol/salbutamol must be withheld for at least 8 hours prior to FEV1 measurements. If 
repeat spirometry failed, then participant must be screen-failed.
Only one rescreening is allowed in the study. Rescreened participants should be assigned the 
same participant number as for the initial screening. Rescreened participants will sign a new 
ICF. All procedures required for the screening periods, starting 
 should be repeated. 
Rescreening should be documented so that its effect on the study results, if any, can be 
assessed.
For all participants who are screen failures, an AE assessment and highly sensitive urine 
pregnancy test (for women of childbearing potential) must be performed within 7 days of the 
screen failure date.
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5.5
Criteria for Temporarily Delaying 
Enrolment/Randomisation/Administration of Study Intervention
Should there be an emergency situation (eg, COVID-19 pandemic), a risk assessment will be 
performed to determine if temporary delaying of enrolment/randomisation/administration of 
study intervention is allowed. 
6
STUDY INTERVENTIONS AND CONCOMITANT THERAPY
Study interventions are all pre-specified investigational medicinal products (IMPs) and non-
investigational medicinal products (NIMPs), medical devices, and other interventions (eg, 
surgical and behavioral) intended to be administered to the study participants during the study 
conduct.
6.1
Study Intervention(s) Administered
Arm name
Treatment A HFO MDI
Treatment B HFA MDI
Intervention name
Pressurized inhalation 
propellant, HFO
Pressurized inhalation 
propellant, HFA
Type 
Combination product
Combination product
Dose formulation
MDI
MDI
Unit dose strength(s)
Experimental (propellant only)
Reference (propellant only)
Dosage level(s)
4 inhalations, single dose
4 inhalations, single dose
Route of administration
Oral inhalation
Oral inhalation
Use
Experimental
Comparator
IMP and NIMP
IMP   
IMP
Sourcing
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor 
Packaging and labelling
Study intervention will be 
provided in an MDI. Each MDI 
will be labelled as required per 
US requirement.
Study intervention will be 
provided in an MDI. Each MDI 
will be labelled as required per 
US requirement.
Abbreviations: HFA = hydrofluoroalkane; HFO = hydrofluoroolefin; IMP = investigational medicinal product; 
MDI = metered dose inhaler; NIMP = non-investigational medicinal product. 
Dosing instructions and dispensing details will be provided by AstraZeneca.
The HFO MDI and HFA MDI are combination products (propellant + device).
Details of the batch numbers will be included in the Trial Master File and the final clinical 
study report (CSR).


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Study participants will be trained on the correct inhalation technique of the MDI (supplied by 
AstraZeneca) and other inhalers under study. Per inclusion criteria, participants must 
demonstrate the proper inhalation technique and have the ability to properly use an MDI 
device after training.
6.1.1
Medical Devices Including Combination Products with a Device 
Constituent
The AstraZeneca manufactured combination products with a device constituent provided for 
use in this study are:

HFO MDI

HFA MDI
Instructions for MDIs use are provided in instructions for use.
All medical device deficiencies and device constituent deficiencies (including malfunction, 
use error and inadequate labelling), hereafter referred to as medical device deficiencies, shall 
be documented and reported by the investigator throughout the clinical investigation (see 
Section 7.4.11) and appropriately managed by the sponsor.
6.2
Preparation, Handling, Storage, and Accountability
The HFO MDIs and HFA MDIs will be supplied by AstraZeneca as individual participant kits. 
A technical agreement or Item Requirement Schedule between the investigator and 
AstraZeneca will be in place to cover all pharmacy-related activities, detailing roles, and 
responsibilities prior to receipt of the study interventions at the clinical unit.
A release document signed by a pharmacist at the clinical unit will be placed in the 
appropriate section of the Trial Master File to document labelling and dispensing of the study 
interventions to the participant.

The investigator or designee (eg, unblinded pharmacist) must confirm appropriate 
conditions (eg, temperature) have been maintained during transit for all study 
intervention received at the site and throughout the entire study until authorisation is 
provided for on-site destruction or removal of the study interventions, reflecting 
completion of the study. In the event of a temperature excursion detected at any time 
during the study, sites will follow the reporting procedures for notifying AstraZeneca 
(or designated party); release of study interventions for clinical use can only occur 
once the event has been reviewed and approval is provided by AstraZeneca (or 
designated party).

Only participants enrolled in the study may receive study intervention and only 
authorised site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 


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(manual or automated) area in accordance with the labelled storage conditions with 
access limited to the investigator and authorised site staff.
∀
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).
∀
Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual.
6.3
Assignment to Study Intervention
 participants meeting all inclusion criteria and none of the exclusion criteria will be 
randomized before study intervention administration. 
Single dose study treatment will be administered via MDI device as 4 inhalations:
!
Treatment A: HFO propellant only MDI; 4 inhalations per dose – test formulation
!
Treatment B: HFA propellant only MDI; 4 inhalations per dose – reference 
formulation
Participants will be randomized in a ratio of 1:1 to receive treatments in one of two possible 
treatment sequences: A followed by B, or B followed by A. The single-dose treatment periods 
will be separated by a 3 to 12-day washout period.
All participants will be centrally assigned to one of two randomized study interventions using 
an Interactive Response Technology (IRT) system. Before the study is initiated, the log-in 
information and directions for the IRT system will be provided to each site.
The IRT will provide to the investigator(s) or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit (as summarized in the SoA, Table 1).
Routines for this will be described in the IRT user manual that will be provided to each centre.
6.4
Blinding
This study is double blinded with regard to treatment (MDI administered with 2 different 
propellants [Treatment A or B]), ie, the sponsor, the investigator, all clinical staff involved in 
the clinical study, the participants, and the study monitor will remain blinded, unless safety 
concerns or a regulatory requirement necessitate unblinding.
The following personnel will have access to the randomization lists from study start:
!
The AstraZeneca staff carrying out the labelling and packaging of participant specific 
treatments
The randomisation code should not be broken except in medical emergencies when the 
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appropriate management of the participant requires knowledge of the treatment randomisation.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. A copy of the report, identifying the participant’s 
intervention assignment, may be sent to investigators in accordance with local regulations 
and/or sponsor policy. Randomisation 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.
The IRT will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment is 
warranted. Participant safety must always be the first consideration in making such a 
determination. If a participant’s intervention assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The investigator documents and reports the 
action to AstraZeneca, without revealing the treatment given to participant to the AstraZeneca 
staff.
6.5
Study Intervention Compliance
When participants are dosed at the site, they will self-administer study intervention directly 
under medical supervision by the investigator or designee. The date, and time if applicable, of 
dose administered in the clinic will be recorded in the source documents and recorded in the 
electronic case report form (eCRF). The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person preparing the study intervention for administration.
A record of the number of actuations from HFO/HFA MDIs taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the eCRF.
6.6
Dose Modification
Not applicable.
6.6.1
Retreatment Criteria 
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6.7
Continued Access to Study Intervention After the End of the 
Study
Not applicable.
6.8
Treatment of Overdose
For this study, any dose of HFO MDI or HFA MDI greater than 4 inhalations once daily, is
considered an overdose.
Sponsor does not have treatment for an overdose. Single dosing of HFO or HFA propellant at 
Treatment Period 1 and Treatment Period 2 will be closely monitored at clinic to avoid any 
overdose.  In the event of an overdose, the investigator/treating physician should:

Evaluate the participant to determine, in consultation with the Study Clinical Lead, if 
possible, whether study intervention should be interrupted. 

Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. Refer to 
Section 7.4.10 for details of AE/SAE reporting related to overdose.

Document the quantity of the excess dose as well as the duration of the overdose.
6.9
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the participant is 
receiving at the time of enrolment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose, frequency, and route
The Study Clinical Lead should be contacted if there are any questions regarding concomitant 
or prior therapy.
6.9.1
Prior Medications
Participants eligible for this study are required to be on low-dose ICS daily or low-dose
ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS 
whenever SABA as needed is used (low-dose ICS as defined by GINA 2022 in below Table 4) 
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Table 4
Low Daily Metered Dose of ICS (Monotherapy or in Combination with 
LABA)
ICS
Total Daily Dose (µg/day)
Beclomethasone dipropionate (pMDI, DPI, standard particle HFA)
200-500
Beclomethasone dipropionate (pMDI, extrafine particle HFA)
100-200
Budesonide (DPI or pMDI, standard particle HFA)
200-400
Ciclesonide (pMDI, extrafine particle HFA)
80-160
Fluticasone furoate (DPI)
100
Fluticasone propionate (DPI or pMDI, standard particle HFA)
100-250
Mometasone furoate (DPI) a
200
Mometasone furoate (pMDI, standard particle HFA)
200-400
Abbreviations: DPI = dry powder inhaler; HFA = hydrofluoroalkane; ICS = inhaled corticosteroid; LABA = long-acting 
beta2-agonist; pMDI = pressurized metered dose inhaler.
a
Dose depends on DPI device – see product information for more detail. Mometasone furoate 80 µg 
delivered via the Breezhaler® has been shown to be non-inferior to mometasone furoate Twisthaler® 200 µg 
[Buhl 2020] and can therefore be used as a permitted low-dose of ICS in this study.
6.9.2
Concomitant Medications
Any current ongoing medications, including over-the-counter medications, herbal 
supplements, and vaccinations, will be allowed provided they are not explicitly prohibited by 
the protocol. Participants should also be instructed to contact the investigator if they develop 
any illnesses, especially those requiring medicinal interventions.
Medications meeting the stable dosing period prior to Visit 1 are allowed during the study and 
listed in Table 5.
Table 5
Allowed Medications with Defined Stable Dosing Period Prior to Visit 1
Medication
Minimum Stable Dosing Period 
Selective serotonin reuptake inhibitors/serotonin and 
norepinephrine reuptake inhibitors a
4 weeks
Tricyclic antidepressants
2 weeks
Antipsychotics
4 weeks
Anticonvulsants
52 weeks for seizure disorders b
12 weeks for other conditions
Intranasal corticosteroids
4 weeks
Intranasal antihistamines or combination products of 
intranasal antihistamines/corticosteroids
4 weeks
Intranasal ipratropium bromide c
4 weeks
a
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b
Must be free of seizures for 1 year prior to Visit 1.
c
Intranasal ipratropium bromide should be withheld for at least 6 hours prior to each visit.
6.9.2.1
Vaccinations
All participants are recommended to be vaccinated with annual influenza vaccine [GINA 
2022] or any other inactive/killed vaccines per local policies, availability, and affordability. If 
a participant has egg intolerance or refuses to be vaccinated, the vaccination may be omitted. 
The annual influenza vaccine can be given at 
 or at any other visit throughout the study 
at the discretion of the investigator; however, administration should occur after obtaining all 
requisite spirometry assessments for that specific test day. There should be at least 7 days 
between vaccination and subsequent spirometry assessments.
If a participant is being considered for enrolment into the study and also being considered for 
COVID-19 vaccination, the participant must not be randomised until at least 7 days after the 
last dose of vaccine or booster. If COVID-19 vaccination is in the best interest of the 
participant and the participant is vaccinated during the study, there should be at least 7 days 
between vaccination and subsequent spirometry assessments.
Live attenuated vaccines are not allowed within 30 days prior to Visit 1 or during the study.
6.9.3
Prohibited Medications
Participants requiring medications presented in Table 6 are prohibited from participating in 
this study. Participants who recently discontinued use of these medications may be considered 
for study enrolment provided they have met the minimum cessation period prior to Visit 2. 
These medications are prohibited throughout the course of the study. If participants require 
any of the prohibited medications listed in Table 6, the investigator should discuss with the
medical monitor the suitability of the participant continuing study intervention.
Table 6
Prohibited Medications Throughout the Study and Prior to Visit 1
Medication
Minimum Cessation Period Prior to Visit 1
LABA including formoterol a
48 hours
LAMA
4 weeks
Leukotriene antagonists/modifiers (eg, Zileuton®)
2 weeks (ie, 14 days)
Oral beta2-agonist
3 months
Theophylline
3 months
Oral and intravenous corticosteroids b
12 months
Injectable systemic corticosteroids (e.g., depot 
formulation, intra-articular, intraocular, intradermal, 
intramuscular)
12 months
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Table 6
Prohibited Medications Throughout the Study and Prior to Visit 1
Medication
Minimum Cessation Period Prior to Visit 1
Any marketed (e.g., omalizumab, mepolizumab, 
benralizumab, reslizumab, tezepelumab) or investigational 
biological therapy for asthma or any other condition
12 months
Any immunomodulators or immunosuppressants c
3 months or 5 half-lives, whichever is longer
Medications not currently licensed for use in the treatment 
of asthma and not part of current standard of care
30 days
Any drug with potential to significantly prolong the QT 
interval d
14 days or 5 half-lives, whichever is longer
Other investigational drugs
30 days or 5 half-lives, whichever is longer
Live attenuated vaccines
30 days
Non-selective non-ocular β-blocking agents (except 
carvedilol)
7 days
Monoamine oxidase inhibitors
14 days
Systemic treatment with strong CYP3A4-inhibitors (e.g., 
ketoconazole, itraconazole, and ritonavir)
30 days
Systemic anticholinergics e
7 days
Herbal remedies for the treatment of allergic, 
inflammatory, or respiratory diseases (e.g., Chinese 
complementary and alternative bronchodilatory medicines)
10 days
Abbreviations: ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; LAMA = long-acting 
muscarinic antagonist.
a
Participants using ICS/LABA as needed (not approved in the US) must withhold it for 48 hours prior to 
each study visit for spirometry purposes.
b
Use of systemic corticosteroids for any other reason except for the acute treatment of a severe asthma 
exacerbation is prohibited for the duration of the study.
c
Topical administration of immunosuppressive medication may be allowed at the discretion of the 
investigator after discussion with the study physician.
d
Participants who are on medications that have the potential to prolong the QTc interval may be enrolled 
provided the dose has remained stable for at least 3 months prior to Visit 1, the participant meets all of the 
electrocardiogram inclusion criteria and none of the electrocardiogram exclusion criteria, and if, in the 
opinion of the investigator, there are not safety concerns for the participant to participate in the study.
e
If systemic anticholinergics are used for the treatment of irritable bowel syndrome or overactive bladder and 
the treatment has been constant for at least 1 month, they are allowed.
Specific prohibited asthma and allergy medications and their required washout periods prior to 
Visit 2 are displayed in Table 7.
Table 7
Prohibited Asthma and Allergy Medications During the Study Conduct 
and Required Washout Period Prior to Visit 2
Medication
Minimum Washout Period Prior to Visit 2
SABAa
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Table 7
Prohibited Asthma and Allergy Medications During the Study Conduct 
and Required Washout Period Prior to Visit 2
Medication
Minimum Washout Period Prior to Visit 2
LABA and LABA containing medications, including 
formoterol b
48 hours
Non-sedating long- and short-acting antihistamines for 
systemic administration, i.e., pills (topical use of eye drops 
or nasal spray is allowed).
7 days
Cromoglycate c
7 days
Nedocromil c
7 days
Ketotifen c
7 days
SAMA and SABA fixed combination
7 days
Abbreviations: ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; SABA = short-acting beta2-
agonists; SAMA = short-acting muscarinic antagonists.
a
SABA (eg, albuterol/salbutamol) must be withheld for 8 hours before spirometry 
 and 
unscheduled visits (if applicable).  
b
Participants using ICS/LABA as needed (not approved in the US) must withhold it for 48 hours prior to 
each study visit for spirometry purposes. 
c
Cromoglycate, nedocromil, and ketotifen eye drops are allowed for allergic conjunctivitis; no washout 
period.
6.10
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
6.11
Discontinuation of Study Intervention
Note that discontinuation from study intervention is not the same thing as a discontinuation or 
withdrawal from the study (see Section 6.12).
If study intervention is permanently discontinued, the participant should, if at all possible, 
remain in the study. See the SoA (Table 1) for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need 
to be completed.
If a participant experiences any of the changes listed below, the study intervention must be 
discontinued:
!
Development of exclusion criteria or other safety reasons as judged by the investigator
during the treatment periods
!
Pregnancy (Section 7.4.8)
6.12
Participant Discontinuation/Withdrawal from the Study
Discontinuation of the participant from the study by the investigator:
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
A participant may be discontinued from the study at any time at the discretion of the 
investigator for safety, behavioural, compliance, or administrative reasons.

At the time of discontinuing from the study, if the participant has not been discontinued 
from the study intervention, see Section 6.11. 
Voluntary withdrawal from the study by the participant:

A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason).

A participant who wishes to withdraw from the study must be informed by the 
investigator about modified follow-up options. A participant should be advised to follow 
his/her usual maintenance therapy prescribed by his/her physician and a withdrawal visit 
or a follow-up call should be scheduled. 

If the participant withdraws consent for disclosure of future information, AstraZeneca 
may retain and continue to use any data collected before such a withdrawal of consent.

If the participant withdraws from the study, AstraZeneca may retain and continue to use 
any samples collected before such a withdrawal of consent for the purposes the 
participant originally consented unless the participant withdraws consent for use of 
samples already collected. If the participant specifically withdraws consent for any use of 
samples, it must be documented in the site study records by the investigator and the 
investigator must inform the local and global study teams. Destruction of any samples 
taken and not yet tested should be carried out in line with documented sample withdrawal 
wishes in conjunction with what was stated in the informed consent and local regulation.
6.13
Lost to Follow-up
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the study site for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. The participant should be counseled on the importance of maintaining the 
assigned visit schedule. At this time ascertain whether the participant should or wishes to 
or continue in the study.

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, telephone calls, texts, 
emails, and if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.


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!
Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 
7
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarised in Section 1.3, SoA (Table 1). Protocol
waivers or exemptions are not allowed.
!
Spirometry SHOULD be performed in accordance with the specified timing as 
indicated in the SoA (Table 1).
!
Urgent safety concerns should be discussed with AstraZeneca immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the SoA 
(Table 1), is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 1).
!
Instructions for the collection and handling of human biological samples (HBS) will be 
provided in the study-specific laboratory manual. Samples should be stored in a secure 
storage space with adequate measures to protect confidentiality. For further details on 
handling of HBS, see Appendix C.
!
In the event of a significant study continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by AstraZeneca or the investigator, as per local health authority/ethics 
requirements.  
!
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 50 mL or 
will be in adherence to local laboratory standards. Repeat or unscheduled samples may be 
taken for safety reasons or for technical issues with the samples.
7.1
Administrative and General/Baseline Procedures
7.1.1
Demographics and Medical/Surgical History
Demographics and medical/surgical history will be collected 
 and updated during the 
screening period, if necessary. 
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7.1.2
Height and Weight
Height and weight will be measured as specified in the SoA (Table 1). Body mass index will 
be automatically calculated in the eCRF.
7.1.3
Physical Examinations
A complete physical examination will be performed on all participants at screening and 
withdrawal (if applicable). A brief physical examination will be performed on all participants 
 prior to dose (Section 1.3, SoA).
!
A complete physical examination will be performed and include assessments of the 
following; general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal (including 
spine and extremities), and neurological systems. 
!
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
7.1.4
Vital Signs
Vital signs will be performed at timelines as specified in Section 1.3, SoA.
The following variables will be collected after the participant has rested in the supine position 
for at least 5 minutes:
!
Systolic blood pressure (mmHg)
!
Diastolic blood pressure (mmHg)
!
Pulse rate (beats per minute)
!
Body temperature (°C)
!
Respiratory rate (breaths per minute)
The measurement of vital signs will be carried out according to the relevant site standard 
operating procedures.
7.1.5
Electrocardiograms
12-lead ECG will be performed at timepoints as specified in Section 1.3, SoA.
The 12-lead ECG will be taken in supine position after 10 minutes of rest. The investigator or 
authorized delegate will be responsible for the overall interpretation and determination of 
clinical significance of any potential ECG findings. In case of discrepancy between the 
investigator’s interpretation and that provided by the ECG machine (if applicable), the 
investigator’s interpretation will take precedence and should be noted on the printout and 
recorded in the eCRF. A copy of the ECG will be produced and quality checked and kept in 
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case of further need for re-evaluation.
7.1.6
Clinical Laboratory Tests
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the visits indicated in the SoA.
Additional samples may be collected if clinically indicated at the discretion of the investigator. 
The clinical chemistry, haematology, and urinalysis will be performed at local laboratory. 
The following laboratory variables will be measured (see Table 8). 
Table 8
Laboratory Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatase (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
Urinalysis (dipstick)
S/P-Albumin
U-Hb/Erythrocytes/Blood 
S/P-Potassium
U-Protein/Albumin 
S/P-Calcium, total
U-Glucose 
S/P-Sodium
S/P-Creatine kinase (CK)
7.2
Efficacy Assessments
Not applicable.
7.3
Safety Assessments
Planned time points for all safety assessments are provided in Section 1.3, SoA.
7.3.1
Asthma Control Questionnaire 5
Asthma Control Questionnaire 5 will only be assessed during screening (Visit 1) for 
participants’ eligibility.


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The ACQ [Juniper 1999a] was developed to measure asthma control and has been fully 
validated for use in adults (18 years and older) and children 6 to 17 years of age. International 
guidelines for the treatment of asthma have identified that the primary clinical goal of asthma 
management is to optimize asthma control (minimization of symptoms, activity limitation, 
bronchoconstriction, and rescue bronchodilator use) and thus reduce the risk of life-
threatening exacerbations and long-term morbidity. The ACQ was developed to meet these 
criteria by measuring both the adequacy of asthma control and change in asthma control, 
which occurs either spontaneously or as a result of treatment.
The ACQ-5 scores are supported entirely by patient-reported symptoms. Participants are asked 
5 symptom questions. Questions are weighted equally and scored from 0 (totally controlled) to 
6 (severely uncontrolled). The mean ACQ-5 score is the mean of the responses to items 1 to 5. 
A mean score of ≤0.75 indicates well-controlled asthma, scores between 0.75 and < 1.5 
indicate partly controlled asthma, and a score ≥1.5 indicates not well-controlled asthma 
[Juniper 2006]. Individual changes of at least 0.5 are considered clinically meaningful. 
7.3.2
Spirometry
Spirometry will be performed at the following timepoints (see SoA Table 1):
!
 
 
 
Spirometry will be performed by a technologist or a qualified designee to ensure participants 
achieve optimal lung function and using standardized equipment that meets or exceeds the 
American Thoracic Society/European Respiratory Society joint recommendations 
[Miller 2005].
If FEV1 drops > 15% from baseline, measurements should be repeated at Investigator’s 
discretion until FEV1 values are within 10% of baseline performed that day.
The participant will be in a seated position during spirometry. The following variables will be 
recorded:
!
FEV1
!
FEV1 percentage of predicted value
Spirometry must meet both acceptability and repeatability criteria according to American 
Thoracic Society/European Respiratory Society 2019 recommendations [Graham 2019]. 
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Calculated predicted spirometry results will be obtained using the Global Lung Initiative 
equations [Quanjer 2012].
7.3.2.1
Monitoring for Bronchospasm
 
  
 
 
Note: FEV1 measurement at post-dose 30 minutes is for exploratory safety assessment, but not 
as part of the bronchospasm definition.
7.3.3
Other Safety Assessments
7.3.3.1
Pregnancy testing
A serum pregnancy test (β-human chorionic gonadotropin) will be conducted at 
 and 
urine β-human chorionic gonadotropin tests at the following visits for women of childbearing 
potential, as specified in the SoA (Table 1).
A serum follicle-stimulating hormone test will be conducted at 
 only, for women who 
have been amenorrhoeic for 12 months without an alternative medical cause, to confirm 
postmenopausal status.
For all participants who are screen failures, a highly sensitive urine pregnancy test (for women 
of childbearing potential) must be performed within 7 days of the screen failure date.
7.4
AEs, SAEs, and Other Safety Reporting
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.
The definitions of medical device-related safety events (medical device AEs and adverse 
device effects [ADEs], medical device SAEs, serious adverse device effects [SADEs], 
unanticipated serious adverse device effects [USADEs], and medical device deficiencies), can 
be found in Appendix D. Medical device deficiencies are covered in Section 7.4.11.
Participants (or, when appropriate, a caregiver, surrogate, or the participant’s legally 
authorised representative) will notify the investigator or designees of symptoms. These must 
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then be assessed by the investigator and if considered an AE it will be reported by the 
investigator.
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
AE variables
The following variables will be collected for each AE:

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the study interventions (yes or no)

Action taken with regard to study interventions

AE caused participant’s withdrawal from the study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE description

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
7.4.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from time of signature of the ICF throughout the treatment 
period and including the follow-up period.
If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP 
that occurs after the end of the clinical study in a treated participant, the investigator shall, 


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without undue delay, report the SAE to AstraZeneca.
7.4.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
7.4.3 Causality Collection
The investigator should assess causal relationship between study intervention and/or 
investigational medical devices 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 and/or medical devices. 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. For medical 
devices, a guide to the interpretation of the causality question can be found in Appendix D.
7.4.4 AEs Based on Examinations and Tests
Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs should only be reported as AEs if they meet any of the following:

fulfil any of the SAE criteria

are the reason for discontinuation of the study interventions

are clinically relevant as judged by the investigator (which may include but is not limited 
to consideration as to whether intervention or non-planned visits were required or other 
action was taken with the IMP, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia vs low haemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 


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as compared with the baseline assessment will be reported as an AE.
The results from the protocol mandated laboratory tests and vital signs will be summarised in 
the CSR. 
7.4.5 AEs Based on Signs and Symptoms
All signs or symptoms spontaneously reported by the participant 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.
7.4.6
Adverse Events of Special Interest
Adverse events of special interest in this study are respiratory events such as dysphonia, 
cough, dyspnoea, wheezing, bronchospasm, and asthma exacerbations. 
For the purpose of this study, an event of bronchospasm is defined as a reduction in FEV1 of 
> 15% from baseline (ie, the FEV1 value obtained within 30 minutes prior to study 
intervention administration) at 5 or 15 minutes post-dose with associated symptoms of 
wheezing, shortness of breath, or cough.
An asthma exacerbation is defined as worsening of asthma that requires a medical 
intervention. 
A moderate asthma exacerbation is defined as worsening of asthma symptoms (shortness of 
breath, wheezing, chest tightness, cough) that result in additional ICS treatment for at least 
3 days.
The worsening of asthma includes deterioration in at least one of the following:

asthma symptoms (eg, shortness of breath, wheezing, chest tightness, cough)

night-time awakening due to asthma

physical exam finding consistent with deterioration of asthma
An asthma exacerbation will be considered severe if it results in at least one of the following:

A short course of systemic corticosteroids for at least 3 consecutive days to treat
symptoms of asthma worsening


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
An emergency room or urgent care visit (defined as evaluation and treatment for 
< 24 hours in an emergency department or urgent care centre) due to asthma that 
required treatment with systemic corticosteroids

An in-patient hospitalization (defined as admission to an in-patient facility and/or
evaluation and treatment in a health care facility for ≥ 24 hours) due to asthma

Death related to asthma
7.4.7
Reporting of SAEs
All SAEs must be reported, whether or not considered causally related to the study 
interventions. All SAEs will be recorded in the eCRF.
If any SAE occurs during the study, investigators or other site personnel will inform the 
appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 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 
AstraZeneca 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 electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the EDC system is not available, then the investigator or other study site staff reports the 
SAE via secure method to the appropriate AstraZeneca representative.
When the EDC is temporarily not accessible, the AstraZeneca study representative should 
confirm that the investigator/site staff enters the SAE in the AstraZeneca EDC when access 
resumes.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
study interventions. For HFO MDI and HFA MDI, no serious adverse reactions (SARs) are 


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considered expected by the sponsor for the purpose of expedited reporting of suspected 
unexpected serious adverse reactions (SUSARs). Any AE that is deemed to be related to the 
study drug by the investigator or the company, which is also serious will be treated as a 
SUSAR and appropriately expedited.
7.4.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except:

If the pregnancy is discovered before the study participant has received any study 
intervention

Pregnancies in the partner of male participants
7.4.8.1
Maternal Exposure
If a participant becomes pregnant during the study, study intervention should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
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 during the study, then the investigator or other site personnel informs 
the appropriate AstraZeneca representatives immediately but no later than 24 hours after he or 
she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for pregnancies associated with SAEs (see Section 7.4.7) and within 30 days
for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
7.4.8.2
Paternal Exposure 
There is no restriction on fathering children or donating sperm during the study.


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7.4.9
Medication Error, Drug Abuse, and Drug Misuse
7.4.9.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
1 calendar day, ie, immediately but no later than 24 hours of when they become aware of it. 
The designated AstraZeneca representative works 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 event of medication error, drug abuse, or misuse (see Section 7.4.7) 
and within 30 days for all other events.
7.4.9.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix B 4.
7.4.9.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
7.4.9.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B 4.
7.4.10
Reporting of Overdose
Refer to Section 6.8 for definition and treatment of overdose.

An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.


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If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 7.4.7) and within 30 days
for all other overdoses.
7.4.11
Medical Device Deficiencies
Combination products with a device constituent (MDIs and DPIs) are being provided for use 
in this study. In order to fulfil regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of events meeting the definition of a medical 
device deficiency that occur during the study with the combination products.
Medical device deficiencies from this study will be collected and monitored to ensure the 
safety of participants and improve the safety and performance of the device.
Medical device deficiencies will not be presented in the CSR, but where required by local 
regulations, deficiencies will be summarised in the relevant periodic report.
The definition of a medical device deficiency is an inadequacy of a medical device/device 
constituent with respect to its identity, quality, durability, reliability, safety, or performance. 
Medical device deficiencies include malfunctions, use errors, and information supplied by the 
manufacturer.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Appendix D.
The AstraZeneca Clinical Study Medical Device/Device Constituent Report Form and/or 
Product Complaint Intake Form will be used to collect the deficiency.
7.4.11.1
Time Period for Detecting Medical Device Deficiencies

Medical device incidents or malfunctions of the medical device will be detected, 
documented, and reported during all periods of the study in which the medical device is 
used.

If the investigator learns of any medical device deficiency at any time after a participant 
has been discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the investigator will promptly notify 
AstraZeneca.
The method of documenting medical device deficiencies is provided in Appendix D.


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7.4.11.2
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.

New or updated information will be recorded on the original form used to report the 
deficiency, with all changes signed and dated by the investigator.
7.4.11.3
Prompt Reporting of Medical Device Deficiencies to Sponsor

Medical device deficiencies will be reported to AstraZeneca within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency.

The AstraZeneca Clinical Study Medical Device/Device Constituent Report Form and/or 
Product Complaint Intake Form will be sent to AstraZeneca by email. If email is 
unavailable, then fax should be utilised.

Where an SAE has occurred in addition to the malfunction, the SAE will be recorded in 
the eCRF as detailed in Section 7.4.7.

AstraZeneca will be the contact for the receipt of medical device deficiency reports.
7.4.11.4
Regulatory Reporting Requirements for Device Deficiencies

The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for AstraZeneca to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of medical device deficiencies to the institutional review board 
(IRB).

For further guidance on the definition of an SAE, see Appendix D.
7.5
Pharmacokinetics
Not applicable.
7.6
Pharmacodynamics
Not applicable.
7.7
Optional Genomics Initiative
Optional Genomics Initiative research is not applicable in this study. 






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Analyses will be performed by the sponsor or its representatives. Demographic and baseline 
characteristics data will be summarised by treatment sequence. Categorical variables will be 
summarised using frequency and percentages, where the denominator for calculation is the 
underlying analysis set population unless otherwise specified. Continuous variables will be 
summarised with descriptive statistics using number of available observations, mean, standard 
deviation, median, minimum, and maximum, and quartiles where appropriate.
Specific details regarding the statistical analyses will be provided in the SAP.
8.4.1.1
Intercurrent Events
Relevant intercurrent events (ICEs) include use of any leukotriene receptor antagonists 
(LTRA’s) or any inhaled bronchodilator within the restricted time window prior to a clinic 
visit that would directly affect airway calibre and the primary and exploratory endpoints. 
8.4.1.2
Strategy for Intercurrent Events
If use of an LTRA or any inhaled bronchodilator occurs prior to a scheduled clinic visit, 
optimally, the FEV1 assessment should be delayed (time permitting) or rescheduled.  
However, if a spirometry assessment is performed and it’s later discovered and confirmed that 
an LTRA or any inhaled bronchodilator was used within the restricted window prior to the 
clinical visit, the resulting data from that visit will not be included in the primary and 
exploratory analysis, and will be considered an important protocol deviation.  
8.4.2
Safety
Safety data will be presented using descriptive statistics unless otherwise specified.
8.4.2.1
Primary Endpoint
The primary endpoint is defined as change from baseline in FEV1 AUC0-15 min post-dose. The 
analysis will be performed based on the Safety Analysis Set using a Principal Stratum 
estimand.
Change in FEV1 AUC0-15 min post-dose will be calculated from FEV1 change from baseline at 5 
and 15 minutes post-dose using the trapezoidal rule, divided by the actual observation time 
from the first to the last non-missing value, for each treatment period. Baseline is the FEV1
value obtained within 30 minutes prior to study intervention administration in each treatment 
period.
A Mixed Model Repeated Measures analysis with treatment sequence, period, average 
baseline FEV1, and treatment as fixed effects, and participant within sequence as the random 
effect will be used. Average baseline (period-specific baseline FEV1 averaged over the 
treatment periods) is included to account for cross-level bias. Adjusted mean change from 
baseline estimates per treatment group and corresponding 2-sided 95% CIs along with an 
overall estimate of the treatment difference (HFO MDI minus HFA MDI) will be presented. If 


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the lower limit of the 2-sided 95% CI for the difference in mean change from baseline of HFO 
MDI minus HFA MDI is > −200 mL, the null hypothesis of inferiority will be rejected and NI 
will be demonstrated.
Descriptive summaries for FEV1 at 30 minutes pre-dose, 5 and 15 minutes post-dose, and 
change in FEV1 AUC0-15 min post-dose, will be reported by treatment and period.
8.4.2.2
Secondary Endpoints
8.4.2.2.1
Cumulative Incidence of Bronchospasm
An event of bronchospasm is defined as a reduction in FEV1 of > 15% from baseline (ie, the 
FEV1 value obtained within 30 minutes prior to study intervention administration) at 5 or 
15 minutes post-dose with associated symptoms of wheezing, shortness of breath, or cough.
The secondary endpoint is defined as cumulative incidence of bronchospasm events. The 
analysis will be performed based on the Safety Analysis Set. McNemar’s test for the 
bronchospasm event rate analysis will be applied given the crossover design. For each 
treatment, the proportion of participants who experience an event along with the 2-sided 95% 
CI (if applicable) will be reported. The difference in proportions along with the 2-sided 95% 
CI (if applicable) will also be reported.  
8.4.2.2.2
Adverse Events
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities that will have been released for execution at AstraZeneca/designee. All 
AE summaries will be performed based on Safety Analysis Set. 
Adverse events will be presented for each treatment and for each treatment period by system 
organ class, and/or preferred term covering number and percentage of participants reporting at 
least one event and number of events where appropriate. The number and rate of AEs will be 
summarized for each treatment.
An overview of treatment-emergent AEs will be presented for each treatment group 
summarizing the number and percentage of participants with any AE, AEs with outcome of 
death, serious AEs, and AEs leading to discontinuation of IP as well as the number of 
individual occurrences in those categories.
Separate AE tables will be provided taken into consideration relationship as assessed by the 
investigator, maximum intensity, seriousness, death, and events leading to discontinuation of 
IP as well as other action taken related to IP.
An additional table will be presented summarizing the number and percentage of participants 
with most common AEs.


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Full details of AE analyses will be provided in the SAP.
 
8.4.3
Other Analyses 
8.4.3.1
Physical Examinations
Physical examination data will be presented in a data listing.
8.4.3.2
Vital Signs
Vital signs data will be presented in a data listing.
8.4.3.3
Electrocardiogram
Electrocardiogram data will be presented in a data listing.
8.5
Interim Analyses 
No interim analysis is planned.
8.6
Data Monitoring/Other Committee
Not applicable. 
9
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
CCI


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

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 as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013 and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines

Applicable laws and regulations

The protocol, revised protocol, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB by the investigator and reviewed and 
approved by the IRB before the study is initiated.

Any revised protocol will require IRB and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca.

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) 312.120, 
ICH guidelines, the IRB, 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

Prompt notification by the investigator to AstraZeneca of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

AstraZeneca has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB, and investigators.

For all studies except those utilising medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.


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
Adherence to European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and will notify the IRB, if appropriate according 
to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB, and investigators. If EU 
Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter details 
of serious breaches into the European Medicines Agency Clinical Trial Information 
System. It is important to note that redacted versions of serious breach reports will be 
available to the public via Clinical Trial Information System.

The investigator should have a process in place to ensure that:
o
The site staff or service providers delegated by the investigator/institution are 
able to identify the occurrence of a (potential) serious breach

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca 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 study 
and for 1 year after completion of the study.


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A 3
Informed Consent Process

The investigator or their representative will explain the nature of the study to the 
participant or their legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, 
and the IRB or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

If new information requires changes to the ICF, consider if participants must be 
re-consented and if so, this must be to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
A 4
Data Protection

Participants will be assigned a unique identifier by AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that their personal study-related data will be used by 
AstraZeneca 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 informed consent. 

The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by AstraZeneca, by 
appropriate IRB members, and by inspectors from regulatory authorities.

The participant must be informed that data will be collected only for the business needs. 
We will only collect and use the minimum amount of personal data to support our 
business activities and will not make personal data available to anyone (including internal 
staff) who is not authorised or does not have a business need to know the information. 

The participant must be informed that in some cases their data may be pseudonymised. 
The General data Protection Regulation defines pseudonymisation as the processing of 


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personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional 
information is kept separately and protected by technical and organisational measures to 
ensure that the personal data are not attributed to an identified or identifiable natural 
person.
A 5
Committees Structure
Not applicable. 
A 6
Dissemination of Clinical Study Data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant.
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents.

Monitoring details describing strategy, including definition of study-critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are included in the 
Monitoring Plan.

AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan.


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
AstraZeneca or designee is responsible for the data management of this study, including 
quality checking of the data.

AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
CROs).

Study monitors will perform ongoing source data verification as per the 
Monitoring Plan(s) to confirm that data entered into the eCRF by authorised site 
personnel are accurate, complete, and verifiable from source 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.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca Global Retention and 
Disposal (GRAD) schedule. No records may be destroyed during the retention period 
without the written approval of AstraZeneca. No records may be transferred to another 
location or party without written notification to AstraZeneca.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.

Definition of what constitutes source data and its origin can be found in Source Data 
Identification Form provided by Labcorp.
A 9
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.
AstraZeneca designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of AstraZeneca. Study sites will be closed upon study 
completion. 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.


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Reasons for the early closure of a study site by AstraZeneca or the investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, AstraZeneca’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform the 
investigators, the 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.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments.

AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of multicentre studies only in their entirety and not as individual site 
data. In this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
AEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of AEs
An AE 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 unfavourable 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 it’s 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 intervention has been administered.
B 2
Definition of SAEs
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:

Results in death.

Is immediately life-threatening.

Requires in-patient hospitalisation or prolongation of existing hospitalisation. 

Results in persistent or significant disability or incapacity. 

Is a congenital anomaly or birth defect.

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events for malignant tumours reported during a study should generally be assessed 
as SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should 
be used. In certain situations, however, medical judgement on an individual event basis should 
be applied to clarify that the malignant tumour event should be assessed and reported as a 
non-SAE. For example, if the tumour is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, 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 medicinal 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).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). 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 judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise 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 
judgement must be used.
Examples include:

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
Intensity Rating Scale

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 


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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 an 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 an SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When assessing causality consider the following factors when deciding if there is a 
‘reasonable possibility’ that an AE may have been caused by the medicinal product.

Time course. Exposure to suspect drug. Has the participant received the suspect drug? 
Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host, or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 


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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 disease under study has deteriorated due to lack of 
effect should be classified as ‘no reasonable possibility’.
B 4
Medication Error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP 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: 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the refrigerators when it should be at room 
temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which led to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s), eg, forgot to take medication


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
Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the data entry site using the Drug Abuse Report Form. This form should be used both if the 
drug abuse happened in a study participant or if the drug abuse involves a person not enrolled 
in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant 
or a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the data entry site using the Drug Misuse Report Form. This form should be used both if the 
drug misuse happened in a study participant or if the drug misuse regards a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes 

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route


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
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that he/she is feeling 
better when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at the site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment, and keeps record of receipt of arrival and 
onward shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca team for the 
remainder of the sample life cycle.
All appropriately consented samples will be retained for maximum 15 years from last subject 
last visit.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures the participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant HBS from that participant, if stored at the study site, are 
immediately identified, disposed of as appropriate, and the action documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.


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AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented, and study site is notified.
C 3
International Air Transport Association Guidance Document 62nd
edition
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
The International Air Transport Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B, or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

Are to be packed in accordance with UN 3373 and IATA 650
Exempt Substances are substances which do not contain infectious substances, or substances 
which are unlikely to cause disease in humans or animals, are not subject to these regulations 
unless they meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations.

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/contentassets/b08040a138dc4442a4f066e6fb99fe2a/dgr-62-en-
pi650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content.


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Appendix D
Medical Device AEs, ADEs, SAEs, SADEs, USADEs, and 
Medical Device Deficiencies: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting

The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization 14155 and European Medical Device 
Regulation 2017/745 for clinical device research (if applicable). 

Both the investigator and AstraZeneca will comply with all local reporting requirements 
for medical devices.

The detection and documentation procedures described in this protocol apply to all 
sponsor combination products provided for use in the study. See Section 6.1.1 for the list 
of sponsor combination products.
D 1
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition

A medical device AE is any untoward medical occurrence in a clinical study participant, 
users, or other persons, temporally associated with the use of study intervention, whether 
or not considered related to the medical device. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
(new or exacerbated) temporally associated with the use of a medical device. This 
definition includes events related to the medical device or comparator and events related 
to the procedures involved except for events in users or other persons, which only include 
events related to medical devices.

ADE is defined as an AE related to the use of a medical device. This definition includes 
any AE resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the medical device as well 
as any event resulting from use error or from intentional misuse of the medical device.
D 2
Definition of Medical Device SAE, SADE, and USADE
A Medical Device SAE is an any AE that:
a.
Led to death.
b.
Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury. The term ‘life-threatening’ in the definition of 
‘serious’ refers to an event in which the participant was at risk of death at the time of the 
event. It does not refer to an event, which hypothetically might have caused death if it 
were more severe.

A permanent impairment of a body structure or a body function.


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
Inpatient or prolonged hospitalisation. Planned hospitalisation for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in health, 
is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function.

Chronic disease (European Medical Device Regulation 2017/745).
c.
Led to foetal distress, foetal death, or a congenital anomaly or birth defect.
A Medical Device SADE is:

Any ADE that has resulted in any of the consequences characteristic of an SAE.

Any medical device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less fortunate.
USADE Definition:

A USADE (also identified as UADE in the US Regulation 21 CFR 812.3) is defined as a 
SADE that by its nature, incidence, severity, or outcome has not been identified in the 
current version of the risk analysis report (see Section 2.3).
D 3
Definition of Medical Device Deficiency
Medical Device Deficiency Definition

A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequacy of the information supplied by the manufacturer.
D 4
Recording and Follow-up of Medical Device AE and/or SAE and
Medical Device Deficiencies
AE, SAE, and Medical Device Deficiency Recording

When an AE/SAE/medical device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/medical device deficiency 
information in the participant’s medical records, in accordance with the investigator’s 
normal clinical practice and on the appropriate form.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designated CRO in lieu of completion of the AE/SAE/medical 
device deficiency form.

There may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this case, all participant identifiers, except for the participant number, will 
be redacted on the copies of the medical records before submission to the sponsor.


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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.

For medical device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.
o A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a medical 
device deficiency. This includes any protocol revision to the medical device design to 
prevent recurrence.
Assessment of Intensity
The investigator will assess intensity for each AE/SAE/medical device deficiency reported 
during the study and assign it to one of the following categories: 

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
Other measures to evaluate AEs and SAEs may be used (eg, National Cancer Institute 
Common Terminology Criteria for Adverse Events).
Assessment of Causality

The investigator is obligated to assess the causal relationship between study intervention 
and each occurrence of AE/SAE/medical device deficiency.

A ‘reasonable possibility’ of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB and/or Investigational Directions for Use (IDFU) 
or Product Information, for marketed products in their assessment.

For each AE/SAE/medical device deficiency, the investigator must document in the 
medical notes that they have reviewed the AE/SAE/medical device deficiency and have 
provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor.


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
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed 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’.
Follow-up of AE/SAE/Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE/SAE/medical device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognised follow-up 
period, the investigator will provide the sponsor with a copy of any post-mortem findings 
including histopathology.

New or updated information will be recorded in the original form used to report the 
deficiency.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
D 5
Reporting of Medical Device SAEs and SADEs

All medical device SAEs will be reported in accordance with Section 7.4.7.
NOTE: There are additional reporting obligations for SADEs that must fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.

Any medical device deficiency that is associated with an SAE must be reported to 
AstraZeneca within 24 hours after the investigator determines that the event meets the 
definition of a medical device deficiency.

In addition to the reporting process described in Section 7.4.7, the AstraZeneca Clinical 
Study Medical Device/Device Constituent Report Form will be used to capture details of 
the device and related deficiency.


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
Facsimile transmission of the AstraZeneca Clinical Study Medical Device/Device 
Constituent Report Form is the preferred method to transmit this information to the Study 
Clinical Lead/SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the AstraZeneca Clinical Study Medical Device/Device 
Constituent Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the AstraZeneca Clinical Study Medical Device/Device Constituent Report Form 
within the designated reporting time frames.

AstraZeneca will review all medical device deficiencies and determine and document in 
writing whether they could have led to an SAE. These medical device deficiencies will be 
reported to the regulatory authorities and IRBs as required by national regulations.

Contacts for SAE reporting can be found in the Safety Handling Plan.


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10
REFERENCES
Buhl R, Tanase AM, Hosoe M, Cao W, Demin I, Bartels C, et al. A randomized, double-blind 
study to compare the efficacy and safety of two doses of mometasone furoate delivered via 
Breezhaler® or Twisthaler® in patients with asthma. Pulm Pharmacol Ther. 2020;62:101919.
Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention, 2022. http://ginasthma.org.
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
Standardization of Spirometry 2019 Update. An Official American Thoracic Society and 
European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019 Oct
15;200(8):e70-e88.
Investigator’s Brochure - Budesonide, Glycopyrronium and Formoterol Fumarate Inhalation 
Aerosol (BGF MDI); Budesonide and Formoterol Fumarate Inhalation Aerosol (BFF MDI); 
Budesonide Inhalation Aerosol (BD MDI); Glycopyrronium Inhalation Aerosol (GP MDI) 
(Also known as PT010 [BGF MDI], PT009 [BFF MDI], PT008 (BD MDI); PT001 (GP MDI); 
Edition Number 9.0, 16 September 2022.
Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘well-controlled’ and ‘not 
well-controlled’ asthma using the Asthma Control Questionnaire. Resp Med. 2006 
Apr;100:616-21.
Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J. 1999a;14(4):902-7.
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005;26(2):319-38.
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al; ERS Global Lung 
Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the 
global lung function 2012 equations. Eur Respir J. 2012 Dec;40(6):1324-43.
Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes 
and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, 
European Community for Steel and Coal. Official Statement of the European Respiratory 
Society. Eur Respir J. 1993;6: Suppl. 16 S5–S40.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5985c00007-csp-v1
Document Title:
D5985C00007 Clinical Study Protocol version 1
Document ID:
Doc ID-004953675
Version Label:
1.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
22-Dec-2022 16:38 UTC
Content Approval
24-Dec-2022 00:48 UTC
Author Approval
27-Dec-2022 10:55 UTC
Content Approval
22-Dec-2022 16:43 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD
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SAP_001.pdf: 
Clinical Study Report Appendix 16.1.9 
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Clinical Study Report Appendix 16.1.9 
Drug Substance Breztri PT010 
Study Code 
D5985C00007 
Appendix 16.1.9 
Documentation of Statistical Methods and Supporting Statistical 
Analysis 
 
 
 


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Statistical Analysis Plan Number 
Date 
Page Number 
Statistical Analysis Plan Edition 
Number 2.0 External 
04 October 2023 
33 


STATISTICAL ANALYSIS PLAN 
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STATISTICAL ANALYSIS PLAN 
 
Study Code 
D5985C00007 
 
Edition Number 
2.0 External 
 
Date 
4-Oct-2023 
 
 
 
 
 
 
 
A Randomized, Double-blind, Single Dose, 2-way Crossover 
Study to Assess Bronchospasm Potentially Induced by the 
Hydrofluoroolefin (HFO) Metered Dose Inhaler (MDI) 
Propellant as Compared with the Hydrofluoroalkane (HFA) 
MDI Propellant in Participants with Asthma, Well Controlled or 
Partially Controlled on Short-acting beta2-agonists (SABA) with 
or without Low-Dose Inhaled Corticosteroids (ICS) 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................. 2 
LIST OF ABBREVIATIONS .......................................................................................... 5 
AMENDMENT HISTORY .............................................................................................. 7 
1 
INTRODUCTION ......................................................................................... 9 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES .............................. 9 
3 
DATA ANALYSIS CONSIDERATIONS .................................................... 9 
3.1 
Timing of Analyses ........................................................................................ 9 
3.2 
Analysis Populations ..................................................................................... 9 
3.3 
General Considerations ................................................................................ 10 
3.3.1 
General Study Level Definitions ................................................................. 11 
3.3.1.1 
Screening/Baseline ...................................................................................... 12 
3.3.1.2 
Analysis periods ........................................................................................... 12 
3.3.1.3 
Handling of missing dates ........................................................................... 13 
3.3.1.4 
Handling of Missing Data ............................................................................ 14 
3.3.2 
Visit Window ............................................................................................... 14 
3.3.3 
Handling of Unscheduled Visits .................................................................. 15 
3.3.4 
Multiplicity/Multiple Comparisons ............................................................. 15 
3.3.5 
Handling of Protocol Deviations in Study Analysis .................................... 16 
4 
STATISTICAL ANALYSIS ....................................................................... 16 
4.1 
Study Population .......................................................................................... 16 
4.1.1 
Subject Disposition and Completion Status ................................................ 17 
4.1.1.1 
Definitions and Derivations ......................................................................... 17 
4.1.1.2 
Presentation .................................................................................................. 17 
4.1.2 
Analysis Sets ................................................................................................ 18 
4.1.2.1 
Definitions and Derivations ......................................................................... 18 
4.1.2.2 
Presentation .................................................................................................. 18 
4.1.3 
Protocol Deviations ..................................................................................... 18 
4.1.3.1 
Definitions and Derivations ......................................................................... 18 
4.1.3.2 
Presentation .................................................................................................. 18 
4.1.4 
Demographics .............................................................................................. 18 
4.1.4.1 
Definitions and Derivations ......................................................................... 18 
4.1.4.2 
Presentation .................................................................................................. 19 
4.1.5 
Baseline Characteristics ............................................................................... 19 
4.1.5.1 
Definitions and Derivations ......................................................................... 19 
4.1.5.2 
Presentation .................................................................................................. 19 
4.1.6 
Disease Characteristics ................................................................................ 19 
4.1.6.1 
Definitions and Derivations ......................................................................... 19 
4.1.6.2 
Presentation .................................................................................................. 19 
4.1.7 
Medical History and Concomitant Disease ................................................. 19 
4.1.7.1 
Definitions and Derivations ......................................................................... 19 


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4.1.7.2 
Presentation .................................................................................................. 19 
4.1.8 
Prior and Concomitant Medications ............................................................ 20 
4.1.8.1 
Definitions and Derivations ......................................................................... 20 
4.1.8.2 
Presentation .................................................................................................. 20 
4.1.9 
Study Drug Compliance .............................................................................. 20 
4.1.9.1 
Definitions and Derivations ......................................................................... 20 
4.1.9.2 
Presentation .................................................................................................. 21 
4.2 
Endpoint Analyses ....................................................................................... 21 
4.2.1 
Primary Endpoint ......................................................................................... 24 
4.2.1.1 
Definition ..................................................................................................... 24 
4.2.1.2 
Derivations ................................................................................................... 24 
 
 
 
 
4.2.1.5 
Sensitivity Analyses of the Primary Endpoint ............................................. 26 
4.2.1.6 
Supplementary Analyses of the Primary Endpoint ...................................... 26 
4.2.1.7 
Subgroup Analyses ...................................................................................... 26 
4.2.2 
Secondary Endpoint ..................................................................................... 26 
4.2.2.1 
Definition ..................................................................................................... 26 
4.2.2.2 
Derivations ................................................................................................... 26 
4.2.2.3 
Handling of Dropouts and Missing Data ..................................................... 27 
4.2.2.4 
Primary Analysis of Secondary Endpoint .................................................... 27 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 27 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint .................................. 27 
4.2.2.7 
Subgroup Analyses ...................................................................................... 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3 
Pharmacodynamic Endpoint(s) .................................................................... 28 
4.4 
Pharmacokinetics ......................................................................................... 28 
4.5 
Immunogenicity ........................................................................................... 29 
4.6 
Safety Analyses ........................................................................................... 29 
4.6.1 
Exposure ...................................................................................................... 29 
4.6.1.1 
Definitions and Derivations ......................................................................... 29 
4.6.1.2 
Presentation .................................................................................................. 29 
4.6.2 
Adverse Events ............................................................................................ 29 
4.6.2.1 
Definitions and Derivations ......................................................................... 29 
4.6.2.2 
Presentation .................................................................................................. 30 
4.6.3 
Clinical Laboratory ...................................................................................... 32 
4.6.3.1 
Definitions and Derivations ......................................................................... 32 
4.6.3.2 
Presentations ................................................................................................ 32 
4.6.4 
Other Laboratory Evaluations ...................................................................... 32 
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4.6.4.1 
Definitions and Derivations ......................................................................... 32 
4.6.4.2 
Presentations ................................................................................................ 32 
4.6.5 
Vital Signs ................................................................................................... 32 
4.6.5.1 
Definitions and Derivations ......................................................................... 32 
4.6.5.2 
Presentations ................................................................................................ 32 
4.6.6 
Electrocardiogram ........................................................................................ 32 
4.6.6.1 
Definitions and Derivations ......................................................................... 32 
4.6.6.2 
Presentations ................................................................................................ 32 
4.6.7 
Other Safety Assessments ............................................................................ 32 
4.6.7.1 
Definitions and Derivations ......................................................................... 32 
4.6.7.2 
Presentations ................................................................................................ 33 
5 
INTERIM ANALYSIS ................................................................................ 33 
6 
REFERENCES ............................................................................................ 33 
7 
APPENDIX.................................................................................................. 33 


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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialised 
Term 
Definition 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUC0-15 min 
Area under the curve from 0 to 15 minutes 
BID 
Twice daily 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced Vital Capacity 
HFA 
Hydrofluoroalkane 
HFO 
Hydrofluoroolefin 
ICE 
Intercurrent events 
ICF 
Informed Consent Form 
IPD 
Important Protocol Deviation 
ITT 
Intent-to-Treat 
IV 
intravenous 
ICH 
International Council for Harmonization 
IP 
Investigational product 
IPD 
Important Protocol Deviations 
IRT 
Interactive Response Technology 
LRTA 
Leukotriene Receptor Antagonists 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDI 
Metered Dose Inhaler 
NI 
Non-inferiority 


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Abbreviation or 
Specialised 
Term 
Definition 
PI 
Principal Investigator 
Q3 
Third quartile 
QRS 
ECG interval measured from the onset of the QRS complex to the J point 
QT 
ECG interval measured from the onset of the QST complex to the end of the T wave 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RR 
The time between corresponding point on 2 consecutive R waves on ECG 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment emergent adverse event 
TFL 
Table, Figure and Listing 
 


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AMENDMENT HISTORY 
CATEGORY 
Change refers to: 
Date 
Description of change 
In line with 
CSP? 
Rationale 
N/A 
03-Jul-2023 
Initial approved SAP 
Yes 
N/A 
Other - Safety 
endpoints 
4-Oct-2023 
Update to add details of analyses of safety section, including 
the analysis of adverse events of special interest and removal 
of presentation by treatment period. 
Treatment emergent AEs definition simplified (3.3.1). 
Study drug compliance definition (section 4.1.9.1) has been 
changed to use the number of puffs used, instead of 
dispensed and returned. 
Clarification on laboratory data to be included for listings 
(4.6.3). 
Yes 
Review by safety leads 
noted updates required. 
Other - Visit 
windows 
4-Oct-2023 
Additional detail in Visit Window (3.3.2) section for 
spirometry assessment inclusion.  
No 
Clarification of timepoint 
windowing rules and 
handling situations where 
multiple measurements are 
in-window. 
Primary or 
secondary 
endpoints 
4-Oct-2023 
Definition of primary analysis set amended - condition 
regarding missing FEV1 measurements has been removed 
and instead included in definitions of the relevant endpoints. 
No 
Missing data issue separated 
from estimand definition in 
line with ICH E9 R1 for 
primary analysis set. 
Data presentations 
4-Oct-2023 
Concomitant medications (section 4.1.8.2) will be 
summarised by treatment sequence instead of by analysis 
period and treatment received, for consistency with prior 
medications. 
ATC medication summaries (section 4.1.8.2) will be 
summarised differently, in adherence with AZ standards. 
Lab data inclusion (sec 4.6.3.2) 
Yes 
Review by safety leads 
noted updates required. 
 


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CATEGORY 
Change refers to: 
Date 
Description of change 
In line with 
CSP? 
Rationale 
Primary or 
secondary 
endpoints 
Date 
Primary endpoint intercurrent event strategy (section 
4.2.1.1) amended - updated to add condition that participants 
who do not receive complete treatment in both periods will 
be excluded, consistent with primary analysis set definition. 
Amended condition of missing FEV1 measurements. 
Supplementary analysis of the primary endpoint - Removed 
specification of participants missing an FEV1 measurement 
at 5 minutes, due to change in primary analysis, which 
would now include these. Removed imputation of FEV1 at 
15 minutes. 
No 
Missing data issue separated 
from estimand definition in 
line with ICH E9 R1 for 
primary endpoint. 
Revised handling of missing 
data for primary endpoint. 
Supplementary analysis 
revised due to updates to 
analysis set definitions. 
Derivation of 
primary or 
endpoints 
Date 
Primary endpoint derivation amended (section 4.2.1.2) - 
participants included if baseline and at least one post-dose 
measurement included. Multiple observations per participant 
may be included. 
Yes 
Derivation updated to align 
with CSP text that actual 
observation time to be used. 
Statistical analysis 
method for the 
primary or 
secondary 
endpoints 
Date 
Primary analysis of primary endpoint (4.2.1.4) model 
amended to change random intercept per participant to 
participant within treatment sequence as a random effect, to 
align with the CSP. 
Yes 
Model text updated to align 
with CSP text of a 
participant within sequence 
random effect. 
 
 
 
 
 
 
 
Other – Statistical 
analysis method for 
the exploratory 
endpoint 
Date 
Primary analysis of exploratory endpoint amended to use 
separate models per timepoint. 
Yes 
Model adjusted as the 
number of subjects with 
measurements in both 
periods will vary by 
timepoint. 
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1 
INTRODUCTION 
The purpose of this document is to give details for the statistical analysis of study 
D5985C00007 supporting the clinical study report. The reader is referred to the Clinical 
Study Protocol (CSP) and the Case Report Form (CRF) for the details of the study conduct 
and data collection. 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES 
The Primary Analysis Set was added to support the principal stratum estimand described in 
the protocol, and to be used as the population for the primary estimand of the primary 
endpoint, and for the exploratory endpoint. 
The acceptable windowing for the start time of spirometry assessments has been added to 
section 3.3.2 of the Statistical Analysis Plan (SAP) and is not specified in the CSP. 
The protocol states that a mixed model repeated measures analysis will be used for the 
analysis of the primary endpoint. This has been updated to describe the analysis model as a 
linear mixed model. 
The protocol states that the study day of treatment period 1 is day 0. Following the 
principles of CDISC this has been updated in the SAP to be study day 1 and study day 0 is 
not defined. 
The protocol states that physical examination results will be presented in a data listing. 
New or aggravated findings, as compared with baseline, on the physical examinations are 
to be reported as Adverse Events (AE) so will be summarised in the relevant AE 
summaries. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
Timing of Analyses 
A final analysis will be conducted when all randomised participants have completed the 
follow-up/early termination visit, data cleaning has been completed and the database has 
been locked for analysis. 
3.2 
Analysis Populations 
This study will include the following analysis populations: 
Enrolled
Randomised


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 Primary Analysis Set 
 Safety. 
Enrolled 
All participants who signed the Informed Consent Form (ICF). The Enrolled Analysis Set 
will be used to summarise disposition. 
Randomised 
All enrolled participants who are randomised to one of the study treatment sequences. The 
Randomised Analysis Set will be used to summarise baseline characteristics. 
Primary Analysis Set 
All participants who are randomised to one of the study treatment sequences. Participants 
who use any Leukotriene receptor antagonists (LTRA) or any inhaled bronchodilator within 
the restricted window prior to the clinical visit will be excluded from the analysis. 
Participants who do not receive complete treatment in both periods will be excluded from 
the analysis (Principal Stratum Strategy). Period level data will be analysed according to 
the actual treatment received. 
Safety 
All participants who are randomised to one of the study treatment sequences and have 
received any amount of the study treatment (i.e. at least 1 puff). Participants will be 
analysed according to the actual treatment received. 
3.3 
General Considerations 
All  analyses outlined in this Statistical Analysis Plan will be conducted by Fortrea, in 
accordance with the contract with AstraZeneca (UK) and following the SOLIS description 
of services. 
The general principles below will be followed for analyses: 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables will 
be summarised by the number of observations, mean, standard deviation (SD), median, first 
quartile (Q1), third quartile (Q3), minimum and maximum. For log transformed data it is 
more appropriate to present geometric mean, coefficient of variation (CV), median, 
minimum and maximum. Categorical variables will be summarised by frequency counts 
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For qualitative variables, the number (n) and percentage (%) of participants with non-
missing data per category will be the default summary presentation, and where appropriate 
and present, the number of missing values as a “Missing” category. Number of participants 
in the analysis population will be used as denominator for percentages calculation, unless 
stated otherwise in Tables, Figures and Listings (TFLs) mock shell(s). 
For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional 
decimal places compared to the original data. Minimum and maximum will be displayed 
with the same accuracy as the original data. For derived continuous data, the decimal places 
displayed will follow the rules provided, using the precision of the variable included in the 
calculation with the greatest number of decimal places. 
For categorical data, percentages will be rounded to 1 decimal place. 
SAS® version 9.4 or higher will be used for all analyses. 
It is acceptable to present large numerical values in more appropriate units. For example, an 
Area Under Curve (AUC) value of 123,000 ng h/mL may be reported as 123 μg h/mL 
instead. It is however, important to keep the units consistent within the report and the 
precision consistent with that prior to conversion. 
3.3.1 
General Study Level Definitions 
The date and time of randomisation will be as recorded in the Interactive Response 
Technology (IRT) system. The date of the last dose of MDI HFA/MDI HFO will be taken 
from the Discontinuation of Investigational Product (IP) eCRF page. If the date in this 
eCRF page is missing, alternatively the date of the last visit will be used. 
Study treatment will be administered via MDI device as 4 inhalations at visit 2 and visit 3 
respectively. 
• Treatment A: HFO MDI; 4 inhalations per dose – test formulation 
• Treatment B: HFA MDI; 4 inhalations per dose – reference formulation 
 
 
 
 
 
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Treatment emergent AE (TEAE) will be defined as an AE with the start date on or after the 
date of treatment during treatment period 1 up to (and including) 7 days after the last dose 
date.  
3.3.1.1 
Screening/Baseline 
For all participants, the screening period is defined as the period from informed consent to 
the date of IP dispensation. For some variables, data from more than one assessment within 
the screening period may be collected prior to the first dose of IP. 
The baseline value for a variable is therefore defined as the last non-missing value prior to 
the start date of treatment during each treatment period and, for treatment period 2, after the 
end date of treatment during treatment period 1. The start date of treatment for each 
participant will be taken from the exposure as collected eCRF page. For assessments on the 
day of first dose, where time is not captured, a nominal pre-dose indicator, if available, will 
serve as sufficient evidence that the assessment occurred prior to first dose. Any 
observation made after the first dose of study treatment will be considered post-baseline for 
that treatment period and will be assigned to the nominal visit recorded. For FEV1 
measurements the baseline value will be considered to be the best measurement nominally 
recorded as pre-dose. 
Assessments on the dispensation date of IP during each treatment period, when neither time 
nor a nominal pre-dose indicator are captured will be considered prior to the first dose if 
such procedures are required by the protocol to be conducted before first dose. 
In all quantitative summaries from baseline, absolute changes from baseline will be 
calculated at the post-baseline value minus the value at baseline. The percentage change 
from baseline will be calculated as [(post-baseline value – baseline value) / baseline value] 
x 100. 
3.3.1.2 
Analysis periods 
Analysis periods do not precisely align with the treatment periods described in the CSP. 
The analysis period of treatment period i describes the period which adverse events should 
be attributable to rather than the period where IP is dispensed. 
Screening Period 
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The screening period is defined as the period from informed consent to the first 
dispensation of IP.  
Treatment Period 1 
Treatment period 1 is defined as the day of Visit 2 (Day 1) to the earliest of the end of 
treatment washout period (i.e. day of Visit 3 (Day 1)) or the date of withdrawal visit (if 
applicable). 
Treatment Period 2 
Treatment period 2 is defined as the period from the day of Visit 3 (Day 1) to the latest of 
the day of completion of safety follow-up visit or the date of withdrawal visit (if 
applicable). 
3.3.1.3 
Handling of missing dates 
Incomplete dates (partial or missing dates where a full date is permissible) will be presented 
in the data listings as recorded on the eCRF. Every effort will be made to ensure complete 
information for these dates are available. Missing/incomplete (partial) AE start and end 
dates will not be imputed for data listings. However, if an AE is missing or has a partial 
start date then it will be considered to be treatment-emergent during treatment period i as 
follows: 
 If AE start date is completely missing, then the AE is considered as treatment-
emergent during treatment period 1. 
 If AE start date month and day are missing and a participant’s treatment periods 
start in different years then the AE is considered as treatment-emergent during the 
matching year of the partial start date, otherwise the AE is considered as treatment-
emergent during treatment period 1. 
 If AE start date day is missing and a participant’s treatment periods start in different 
months then the AE is considered as treatment-emergent during the matching month 
of the partial start date, Otherwise, if the AE occurs during the month after the 
second treatment start date it is considered as treatment-emergent during treatment 
period 2, or otherwise the AE is considered as treatment-emergent during treatment 
period 1. 
Missing start and stop dates will be imputed for prior and concomitant medications as 
follows: 


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3.3.1.3.1 
Partial start dates 
If the year is unknown, then the date will not be imputed, and will be assigned a missing 
value. If the month is unknown, then if the year matches the year of the first dose date in 
treatment period 1, then impute the month and day of the first dose date. Otherwise, assign 
the month as July. 
 If the day is unknown, then if the month and year match the month and year of the first 
dose date in treatment period 1, then impute the day of the first dose date. Otherwise, assign 
the day as mid-month (14th for February, 15th for all other months). 
3.3.1.3.2 
Partial end dates 
If the year is unknown, then the date will not be imputed and will be assigned a missing 
value. 
If the month is unknown, then assign July. 
If the day is unknown, then assign the day as mid-month (14th for February, 15th for all 
other months). 
If the above rules for end dates result in an illogical date (i.e. end date < start date or end 
date > participant’s date of completion/discontinuation) with regards to the dates the 
participant was in the study, then the end date will be replaced with the participant’s date of 
completion/discontinuation. 
3.3.1.4 
Handling of Missing Data 
3.3.1.4.1 
Handling of Missing Efficacy Data 
Missing FEV1 measurements will not be imputed for the primary efficacy analysis but will 
be imputed for supplementary analyses. Imputation details are described in section 4.2.1.6.  
 
3.3.1.4.2 
Handling of Missing Safety Data 
In general, missing clinical laboratory data, vital signs and electrocardiogram (ECG) data 
will not be imputed. Adverse event imputations for missing intensity or relationship are 
given in section 4.6.2.1. Unknown or partial medication date imputations are given in 
section 3.3.1.4 and are to be used only for the assessment of prior / concomitant status for 
medications. 
3.3.2 
Visit Window 
For all populations, assessments will be assigned to visits based on the nominal visit 
recorded on the eCRF form. Visit windowing will not be applied for this study. 


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Spirometry assessments will be considered as in-window providing the start time of the 
repeated assessments at each scheduled assessment time point (e.g. 4 attempts at 5 minutes 
post-dose) is performed per the following table. Only results flagged as being a best result 
will be considered for analysis. These assessments can be considered as in-window for a 
different assessment time from that targeted (e.g. an assessment recorded as being at the 5-
minute post-dose timepoint can be included in the 15 minute post-dose timepoint if it 
occurred during the 15-minute window). If more than one assessment qualifies as in-
window for a given timepoint, the following rules will apply to select one: 
 30 minutes pre-dose: use the latest assessment 
 5, 15 and 30 minutes post-dose: use the assessment closest to the planned time. If 
two or more assessments are equidistant from the planned time, the earliest will be 
used.  
This is with the exception of area under the curve (AUC) calculations, where multiple post-
dose assessments may be included as in-window.  
Spirometry assessments performed out of window will be considered to be unscheduled. 
Out of window assessments will not be included in efficacy analyses and will be listed 
only.  
Table 1: Time windows for spirometry assignments 
Scheduled Spirometry Assessment Time 
Allowed Start Time Window 
30 minutes pre-dose 
< first dose time of IP on the same 
day 
5 minutes post-dose 
3 to 9 minutes 
15 minutes post-dose 
10 to 19 minutes 
30 minutes post-dose 
20 to 59 minutes 
 
3.3.3 
Handling of Unscheduled Visits  
All unscheduled visits will be included in listings. Unscheduled visits will not be 
considered for by-visit presentations. 
3.3.4 
Multiplicity/Multiple Comparisons 
No procedures will be applied to handle multiplicity or multiple comparisons. 


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3.3.5 
Handling of Protocol Deviations in Study Analysis 
Protocol deviations are defined as any change, divergence, or departure from the study 
design of procedures defined in the CSP. 
Important protocol deviations will be defined by AstraZeneca before database lock 
following the process described in the protocol deviation management plan and the project 
specific protocol deviations list. Important protocol deviations are a subset of protocol 
deviations which may significantly impact the correctness, accuracy, and / or reliability of 
the study data or that may significantly affect a participant’s rights, safety or well-being. 
The following criteria may be considered as important protocol deviations which may have 
a major effect on efficacy or that could potentially affect the interpretability of the study 
results. 
1. Informed Consent, such as ICF not signed before project specific assessments or 
procedures. 
2. Study Conduct/Procedures, such as failure to complete or comply with 
inclusion/exclusion criteria, including discrepancy within source documentation and 
/ or raw data, non-compliance with protocol requirements (Note: this does not 
include ICF issues), use of prohibited medication or prohibited treatment therapy or 
a participant’s first dose date prior to baseline evaluations.  
3. Investigational Product, such as inadequate supply of materials/IP (includes issues 
with regard to expiration date e.g. participant takes IP which has expired). 
4. Safety, such as non-recording of AEs and SAEs by PIs (e.g. recording on time, etc.). 
5. Use of LRTA or any inhaled bronchodilator within the restricted window prior to 
the clinical visit. 
4 
STATISTICAL ANALYSIS 
This section provides information on definitions, derivation and analysis/data presentation 
per domain. 
4.1 
Study Population 
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics, medical history, prior and concomitant medication 
and study drug compliance.  


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4.1.1 
Subject Disposition and Completion Status 
4.1.1.1 
Definitions and Derivations 
Participants are defined as completing study treatment if the eCRF page “Discontinuation 
of Investigational Product” has a main reason for IP discontinuation as “Completed”. Any 
other reasons for discontinuation of IP will be presented as “Subjects discontinued 
treatment”. Participants are defined as completing the study if the eCRF page “Disposition” 
has a participant status of “Completed”. Any other reason for discontinuation will be 
presented as “Withdrawn from Study”. 
4.1.1.2 
Presentation 
Participant disposition will be listed and summarised by assigned treatment sequence and in 
total. The number and percentage of participants in the following categories will be 
summarised for participants in the enrolled set: 
 Subjects screened; 
 Subjects who were screen failures; 
 Subjects randomised; 
 Subjects randomised, not treated and associated reasons; 
 Subjects who started treatment; 
 Subjects who completed treatment period 1; 
 Subjects who completed treatment period 2; 
 Subjects who completed both treatment periods; 
 Subjects who discontinued treatment and associated reasons; 
 Subjects who completed the study; 
 Subjects withdrawn from the study and associated reasons. 
The denominator used for percentages will be calculated as follows. No percentages will be 
presented for the number of participants who were screened, screen failures, randomised 
and were not randomised. The denominator for participants who started treatment, 
completed treatment, discontinued treatment, completed the study and withdrew from the 
study will be calculated using the number of randomised participants per assigned treatment 
sequence and in total respectively. 


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Additionally, a summary of recruitment by region, country will be produced for each 
analysis set. The denominator for the percentages in this summary will be based on the 
number of participants within each of the analysis sets. 
Furthermore, a summary of randomised participants by treatment sequence will present 
participants who discontinued treatment and withdrew from the study by whether the 
discontinuation/withdrawal was related to a global/country situation. Another summary of 
randomised participants by treatment sequence will present the number of participants who 
had any disruption during the study related to a global/country situation. Participants who 
discontinued treatment or withdrew from the study will also be listed.  
4.1.2 
Analysis Sets 
4.1.2.1 
Definitions and Derivations 
The definitions for analysis sets are described in section 3.2. 
4.1.2.2 
Presentation 
The number of participants in each of the analysis sets and the reasons for exclusion from 
each will be summarised for participants in the enrolled set by assigned treatment sequence 
and in total. Exclusions from analysis sets will also be listed. 
4.1.3 
Protocol Deviations 
4.1.3.1 
Definitions and Derivations 
Important protocol deviations will be defined according to section 3.3.5, and determined 
prior to database lock as outlined in the protocol deviation management plan. 
4.1.3.2 
Presentation 
All important protocol deviations will be listed and summarised by treatment sequence and 
in total for the randomised analysis set. 
4.1.4 
Demographics 
4.1.4.1 
Definitions and Derivations 
The demographic and baseline characteristics include the following: 
 
Age (years); 
 
Age group (18-45); 
 
Sex (male, female); 
 
Race category (White, Black or African American, Asian, Native Hawaiian or Other 
Pacific Islander, American Indian or Alaskan Native, Other, Not reported); 
 
Ethnic group (Hispanic or Latino, Not Hispanic or Latino); 
 
Participant recruitment country. 


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4.1.4.2 
Presentation 
The demographic characteristics will be listed and summarised by treatment sequence and 
in total for the randomised analysis set. No formal tests of statistical significance will be 
performed on the demographic and baseline data.  
4.1.5 
Baseline Characteristics 
4.1.5.1 
Definitions and Derivations 
Baseline body mass index (BMI; kg/m2) will be calculated as baseline weight/baseline 
height2 where weight is in kg and height is in m. 
4.1.5.2 
Presentation 
The participant baseline characteristics will be listed and summarised by treatment 
sequence and in total for the randomised analysis set. They will include: 
 Baseline height (cm); 
 Baseline weight (kg); 
 BMI (kg/m2). 
4.1.6 
Disease Characteristics 
4.1.6.1 
Definitions and Derivations 
Not Applicable. 
4.1.6.2 
Presentation 
Not Applicable. 
4.1.7 
Medical History and Concomitant Disease 
4.1.7.1 
Definitions and Derivations 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) [Version 26.0 (or a later version if updated during the study)]. 
4.1.7.2 
Presentation 
The number and percentage of participants with any medical history will be summarised by 
treatment sequence and in total for the randomised analysis set. The number and percentage 
of participants with at least one medical history record within each primary system organ 
class (SOC) and preferred term (PT) will be presented. The summary will be sorted by 
international order for SOC and alphabetically by PT. A participant can have one or more 
PTs reported under a given SOC but will be reported once per PT and SOC. 


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4.1.8 
Prior and Concomitant Medications 
4.1.8.1 
Definitions and Derivations 
Medications received prior to or concomitantly with study treatment will be coded using 
the WHO Drug Dictionary [Version March 2023 (or a later version if updated during the 
study)] Anatomical Therapeutic Chemical (ATC) Classification codes. 
Prior medications and concomitant medications are defined as follows: 
Prior medications are those taken with a stop date prior to, or on the day of, the first dose 
date of either study treatment. 
Concomitant medications during the study are those with a start date after the first dose 
date of either study treatment, or those with a start date before, and either a stop date on or 
after the first dose date of either study treatment or those which are ongoing. 
If a medication cannot be classified as prior or concomitant after applying imputation rules 
for missing/incomplete dates, it will be classified as concomitant. 
Concomitant medications will be classified as allowed or disallowed by the Fortrea medical 
data review management team. Allowed and disallowed concomitant medications are 
described in sections 6.9.2 and 6.9.3 of the CSP respectively. Furthermore, the Fortrea 
medical data review management team will also classify LTRAs or any inhaled 
bronchodilator use as intercurrent events (ICEs). 
4.1.8.2 
Presentation 
Prior medications and concomitant medications will be listed separately. Prior medications, 
allowed concomitant medications and disallowed concomitant medications will be 
summarised separately, by treatment sequence and in total using the randomised analysis 
set.  
The number and percentages of participants using each medication will be displayed 
together with the number and percentage of participants using at least one medication 
within each ATC classification and generic drug name. The summaries will be sorted 
alphabetically by ATC classification and generic drug name.  
4.1.9 
Study Drug Compliance 
4.1.9.1 
Definitions and Derivations 
The percentage compliance for MDI HFO and MDI HFA will be calculated per participant 
in each treatment period as: 
	

  
 !"##
$
  










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During each treatment period the change from baseline in FEV1 AUC0-15min post-dose will 
be calculated using the trapezoidal rule: 
ℎ      −
=
∑() + ()× (−)
2


−() 
Where FEV1(i) and FEV1(i+1) are FEV1 at time i and i+1, FEV1(0) is the pre-dose 
measurement, Ti and Ti+1 are the observed times after the end time of dosing in minutes of 
the FEV1 measurement and TTotal is the total observed time for the measurement from T0 = 
0. Measurements at pre-dose (in this calculation, included as T0=0) and post-dose at 5 and 
15 minutes will be included in the calculation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
CCI


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4.2.1.5 
Sensitivity Analyses of the Primary Endpoint 
No sensitivity analysis will be conducted to evaluate missing data assumptions. 
4.2.1.6 
Supplementary Analyses of the Primary Endpoint 
As a supplementary analysis the following estimand will be applied: 
 
Population: Participants with asthma, well controlled or partially controlled on SABA 
with or without low-dose ICS who randomised to one of the study treatment sequences 
and have received any amount of the study treatment. 
 
Endpoint: Change from baseline in FEV1 AUC0-15 min  post-dose. 
 
Intercurrent event strategy: Participants who use LTRAs or any inhaled bronchodilator 
within the restricted time window prior to a clinic visit that would directly affect 
airway calibre will be considered an ICE and will be treated using a while on treatment 
strategy (i.e. observations after the ICE will be removed from the analysis). 
Participants missing FEV1 measurements at pre-dose or post-dose up to 15 minutes in 
either treatment period will be removed from the analysis using a principal stratum 
estimand. 
 
Population level summary (analysis): The difference in the adjusted mean FEV1 AUC0-
15 min estimates between treatment groups and corresponding 95% CI as determined 
using a linear mixed model analysis. 
The analysis method will be as specified in section 4.2.1.4. 
4.2.1.7 
Subgroup Analyses 
No subgroup analyses are planned for the primary endpoint. 
4.2.2 
Secondary Endpoint 
Cumulative incidence of bronchospasm events. 
4.2.2.1 
Definition 
Cumulative incidence of bronchospasm events in the safety analysis set. An event of 
bronchospasm is defined as a reduction in FEV1 of >15% from baseline (i.e. the FEV1 
value obtained within 30 minutes prior to study administration) at 5 or 15 minutes post-
dose with associated symptoms of wheezing, shortness of breath, or cough. The difference 
in the proportion of patients who experience a bronchospasm event between treatment 
groups will be summarised along with the 2-sided 95% CI. 
4.2.2.2 
Derivations 
An event of bronchospasm per treatment period will be detected using either (i) information 
from the Adverse Event form and a MedDRA narrow SMQ of “Asthma/bronchospasm”, 
(ii) a reduction in FEV1 of >15% from baseline (i.e. the FEV1 value obtained within 30 
minutes prior to study intervention administration) at 5 or 15 minutes post-dose with an 


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associated AE during the day of study intervention administration with a preferred term of 
either “Wheezing”, “Dyspnoea” or “Cough”. 
4.2.2.3 
Handling of Dropouts and Missing Data 
No adjustment for dropout or missing data will be applied. 
4.2.2.4 
Primary Analysis of Secondary Endpoint 
The proportion of participants with a bronchospasm event by treatment received will be 
analysed using McNemar’s test of marginal homogeneity. 95% CIs for the proportions will 
be calculated using a generalised linear mixed model with a binomial distribution and an 
identity link and with dependent variable of Bronchospasm event and independent variables 
of actual treatment received, treatment period and actual treatment sequence. A per 
participant random intercept effect will be included in the model. The least square mean 
estimates (proportion) and 95% CI per actual treatment received, and the difference in least 
square mean (proportions) with 95% CI will be presented. 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint 
No sensitivity analyses are planned for the secondary endpoint. 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint 
No supplementary analyses are planned for the secondary endpoint. 
4.2.2.7 
Subgroup Analyses 
No subgroup analyses are planned for the secondary endpoint. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.5 
Immunogenicity 
Not Applicable. 
4.6 
Safety Analyses 
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, and 
ECG.  
Tables are provided for the safety analysis set; listings are provided for all participants or 
the safety set depending on the availability of data. 
4.6.1 
Exposure 
4.6.1.1 
Definitions and Derivations 
Exposure (i.e. duration of treatment) will be defined per treatment period as follows: 
 
Total duration of exposure during treatment period i = last dose date during treatment 
period i where puff>0 – first dose date during treatment period i + 1 
Per protocol this should be 1 day per participant per treatment period. Interruption of 
treatment is not considered in the calculation of exposure. 
4.6.1.2 
Presentation 
Total duration of exposure (days) per treatment period i will be summarised and listed by 
actual treatment sequence for the safety analysis set by the following: mean, standard 
deviation, minimum, maximum, median and number of observations. The listing will 
include date of first exposure to treatment, total duration of exposure and, for each visit, the 
prescribed dose per administration and planned dose. 
4.6.2 
Adverse Events 
4.6.2.1 
Definitions and Derivations 
All Adverse events, non-serious and serious adverse events (SAEs), will be collected from 
time of signature of the informed consent form, throughout the treatment period including 
during the follow-up period. Treatment emergent adverse events are defined in section 
3.3.1. 
Adverse events of special interest (AESIs) in this study are respiratory events such as 
dysphonia, cough, dyspnoea, wheezing, bronchospasm, and asthma exacerbations. See 
section 7.4.6 of the CSP for details.  
Adverse events will be assigned to the respective treatment period based on the AE start 
date and time according to the treatment period definitions in section 3.3.1.2. Adverse 


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events which occur during treatment period i, will be assigned to the treatment received by 
that participant during that treatment period. 
MedDRA [Version 26.0 (or a later version if updated during the study)] will be used to 
classify AEs SOC and PT. 
Every effort should be made to collect the maximum intensity and relationship to treatment 
for all AEs. However, if the maximum intensity is missing for a TEAE then it will be 
considered as severe only in the overall category in the summary tables. If the relationship 
to treatment is missing, then the AE will be considered as possibly related to treatment. 
Deaths 
All adverse events leading to death, including those not related to an AE, will be collected 
until the end of the study. 
4.6.2.2 
Presentation 
4.6.2.2.1 
Overall AE Summary 
An overall summary table of the number of participants experiencing each category of AEs 
will be produced using the safety analysis set. Analyses will include all TEAEs and will be 
presented for each treatment group. 
Treatment emergent adverse events occurring prior to first dose of IP (i.e. before study day 
1) which subsequently worsen in severity following dosing will be presented in the 
summary tables. All other AEs occurring prior to first dose of IP (i.e. before study day 1) or 
more than 7 days after the discontinuation of IP will be noted in the listings of adverse 
events. 
An overview table will summarise the number and percentage of participants with at least 
one of the following AEs, where participants with more than one AE in a particular 
category are counted only once in that category, and the number of events. The summary 
table will be presented for each treatment group: 
 Any AE 
 Any SAE 
 Any SAE with outcome of death 
 Any AE leading to discontinuation of IP 
 Any possibly related AE 


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 Any possibly related SAE 
 Any AESI. 
4.6.2.2.2 
Number of subjects with AEs 
The number of participants reporting each AE will be summarised by SOC and PT. Tables 
will be sorted by international order for SOC and PTs will be sorted alphabetically. 
Summaries will be presented for each treatment group. The following summaries will be 
produced using the safety analysis set: 
 AEs 
 Possibly related AEs 
 AEs by maximum intensity 
 AEs leading to discontinuation of IP 
 Non-serious AEs occurring in more than 5% of subjects 
 SAEs 
 SAEs with outcome of death 
 Possibly related SAEs 
 AESIs 
 Possibly related AESIs 
 AESIs by maximum intensity. 
A summary table of AEs sorted by decreasing frequency of PT in the HFO treatment group 
will be presented. 
All AE data will be listed for all participants including information on AE duration, 
intensity, seriousness, action taken, outcome, relationship as assessed by the investigator, 
timing of onset of AE in relation to the date of study treatment, study treatment and 
treatment period at the time of event. Tables will present key subject information for all 
AEs leading to discontinuation of IP, SAEs with outcome of death and SAEs. 


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4.6.3 
Clinical Laboratory 
4.6.3.1 
Definitions and Derivations 
Clinical laboratory (serum and urine) assessments are scheduled to be conducted at 
screening only. 
4.6.3.2 
Presentations 
Clinical laboratory data will be listed where available for the Safety Analysis Set.  
4.6.4 
Other Laboratory Evaluations 
4.6.4.1 
Definitions and Derivations 
Not Applicable. 
4.6.4.2 
Presentations 
Not Applicable. 
4.6.5 
Vital Signs 
4.6.5.1 
Definitions and Derivations 
Vital signs will be evaluated and assessed at screening (visit 1), pre-dose in treatment 
period 1/day 1 (visit 2), pre-dose in treatment period 2/day 1 (visit 3) and at the withdrawal 
visit according to the SoA. Vital signs include systolic blood pressure (mmHg), diastolic 
blood pressure (mmHg), pulse rate (beats per minute), body temperature (ºC) and 
respiratory rate (breaths per minute). 
4.6.5.2 
Presentations 
Vital sign values will be listed only for the Safety Analysis Set. 
4.6.6 
Electrocardiogram 
4.6.6.1 
Definitions and Derivations 
Electrocardiogram (ECG) assessments will be performed at screening only according to the 
SoA. ECG parameters will include heart rate (beats/min), PR interval (msec), RR interval 
(msec), QRS duration (msec), QT interval (msec) and QTcF (msec). 
4.6.6.2 
Presentations 
ECG data will be listed for the Safety Analysis Set. 
4.6.7 
Other Safety Assessments 
4.6.7.1 
Definitions and Derivations 
The Asthma Control Questionnaire (ACQ) 5 will be assessed during screening (Visit 1) to 
confirm participant’s eligibility. Physical examination assessments will be performed 


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during screening (Visit 1), Treatment Period 1/Day 1 (Visit 2), Treatment Period 2/Day 1 
(Visit 3) and withdrawal visit as required according to the SoA. 
4.6.7.2 
Presentations 
ACQ-5 responses and total score will be listed. Physical examination results will not be 
listed as new or aggravated findings, as compared with baseline, are to be reported as AEs. 
5 
INTERIM ANALYSIS 
Not Applicable. 
6 
REFERENCES 
Not Applicable. 
7 
APPENDIX 
Not Applicable.