A Randomized, Double-Blind, Parallel Group, Multicenter 24 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler and Open-Label Symbicort® Turbuhaler® in Participants With Inadequately Controlled Asthma (VATHOS).
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

Clinical Study Protocol - 4.0
AstraZeneca
Budesonide and Formoterol Fumarate - D5982C00006
CONFIDENTIAL AND PROPRIETARY
1 of 130
Clinical Study Protocol
Study Intervention
Budesonide and Formoterol 
Fumarate
Study Code
D5982C00006
Version
4.0
Date
07 Nov 2024
A Randomized, Double-Blind, Parallel Group, Multicenter 
24 Week Study to Assess the Efficacy and Safety of Budesonide 
and Formoterol Fumarate Metered Dose Inhaler Relative to 
Budesonide Metered Dose Inhaler and Open-Label Symbicort®
Turbuhaler® in Participants with Inadequately Controlled Asthma 
(VATHOS)
Sponsor Name:
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s)
IND Number: 122166
EudraCT Number/EU CT Number: 2021-002026-24/2024-513568-24-00
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D5982C00006
Amendment Number: 3
Redacted for Public Disclosure
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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
5 of 130 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
SUMMARY OF CHANGES TABLE ....................................................................................... 3 
TABLE OF CONTENTS .......................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................. 10 
1 
PROTOCOL SUMMARY.................................................................................... 12 
1.1 
Synopsis ................................................................................................................ 12 
1.2 
Schema .................................................................................................................. 20 
1.3 
Schedule of Activities ........................................................................................... 21 
2 
INTRODUCTION ................................................................................................ 26 
2.1 
Study Rationale ..................................................................................................... 26 
2.2 
Background ........................................................................................................... 26 
2.3 
Benefit/Risk Assessment ...................................................................................... 27 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 29 
4 
STUDY DESIGN ................................................................................................. 39 
4.1 
Overall Design ...................................................................................................... 39 
4.2 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 41 
4.2.1 
Completing Participant Numbers to Maintain Study Integrity ............................. 42 
4.3 
Scientific Rationale for Study Design .................................................................. 42 
4.3.1 
Participant Input into Design ................................................................................ 42 
4.3.1.1 
Coordinator Input.................................................................................................. 42 
4.3.1.2 
Participant Input.................................................................................................... 43 
4.4 
Justification for Dose ............................................................................................ 43 
4.5 
End of Study Definition ........................................................................................ 44 
5 
STUDY POPULATION ....................................................................................... 44 
5.1 
Inclusion Criteria .................................................................................................. 45 
5.2 
Exclusion Criteria ................................................................................................. 47 
5.3 
Lifestyle Considerations ....................................................................................... 49 
5.3.1 
Caffeine, Tobacco, and Alcohol ........................................................................... 49 
5.3.2 
Illicit Drugs or Drugs of Abuse ............................................................................ 49 
5.4 
Screen Failures...................................................................................................... 49 
6 
STUDY INTERVENTION .................................................................................. 50 
6.1 
Study Intervention(s) Administered ..................................................................... 51 
6.1.1 
Investigational Products........................................................................................ 51 
6.1.2 
Medical Devices Including Combination Products with Device Constituent ...... 53 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 53 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 53 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
6 of 130 
6.4 
Study Intervention Compliance ............................................................................ 54 
6.5 
Concomitant Therapy ........................................................................................... 54 
6.5.1 
Rescue Medicine ................................................................................................... 55 
6.5.2 
Prior Medications.................................................................................................. 55 
6.5.3 
Concomitant Medications ..................................................................................... 56 
6.5.3.1 
Vaccinations ......................................................................................................... 57 
6.5.4 
Prohibited Medications ......................................................................................... 57 
6.6 
Dose Modification ................................................................................................ 60 
6.7 
Intervention After the End of the Study ............................................................... 60 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................ 60 
7.1 
Discontinuation of Study Intervention ................................................................. 60 
7.2 
Participant Withdrawal from the Study ................................................................ 61 
7.3 
Lost to Follow-up ................................................................................................. 62 
8 
STUDY ASSESSMENTS AND PROCEDURES................................................ 62 
8.1 
Efficacy Assessments ........................................................................................... 63 
8.1.1 
Pulmonary Function Tests .................................................................................... 63 
8.1.1.1 
Spirometry Standardization .................................................................................. 63 
8.1.1.2 
Spirometry Schedule ............................................................................................. 63 
8.1.1.3 
Reversibility to Albuterol ..................................................................................... 65 
8.1.2 
Participant’s eDiary Data Collection .................................................................... 66 
8.1.2.1 
eDiary Compliance Requirement ......................................................................... 67 
8.1.2.2 
Daily eDiary Reporting......................................................................................... 67 
8.1.2.3 
Asthma Symptoms ................................................................................................ 67 
8.1.2.4 
Rescue Medication Use ........................................................................................ 68 
8.1.2.5 
Peak Expiratory Flow ........................................................................................... 68 
8.1.2.6 
Inhaled Asthma Maintenance Use ........................................................................ 68 
8.1.2.7 
Study Visit eDiary Data Collection ...................................................................... 69 
8.1.2.8 
Symptom Worsening Assessment and eDiary Alert System ................................ 72 
8.2 
Safety Assessments ............................................................................................... 72 
8.2.1 
Medical/Surgical History ...................................................................................... 72 
8.2.2 
Physical Exam ...................................................................................................... 72 
8.2.3 
Height and Weight ................................................................................................ 73 
8.2.4 
Vital Signs ............................................................................................................ 73 
8.2.5 
Electrocardiograms ............................................................................................... 73 
8.2.6 
Clinical Safety Laboratory Assessments .............................................................. 73 
8.2.7 
Asthma Exacerbations .......................................................................................... 74 
8.2.7.1 
Definition of Worsening of Asthma Signs/Symptoms ......................................... 74 
8.2.7.2 
Investigator Justified Asthma Exacerbations........................................................ 75 
8.2.7.3 
Severity of Asthma Exacerbation ......................................................................... 75 
8.2.7.4 
Treatment for Asthma Exacerbations ................................................................... 75 
8.2.7.5 
Onset and Duration of Asthma Exacerbations...................................................... 76 
8.2.7.6 
Approach for Capturing Asthma Exacerbations ................................................... 77 
8.2.8 
Other Safety Assessments..................................................................................... 77 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
9 of 130 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ........................ 103 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................... 111 
Appendix C 
Optional Genomics Initiative Research .................................................... 117 
Appendix D 
Protocol Amendment History ................................................................... 120 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
11 of 130 
Abbreviation or special 
term 
Explanation 
HFA 
hydrofluoroalkane 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Conference of Harmonisation 
ICS 
inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IPD 
important protocol deviation 
IRB 
Institutional Review Board 
IV 
intravenous 
IRT 
Interactive Response Technology 
LABA 
long-acting beta2-agonist 
LAMA 
long-acting muscarinic antagonist 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
NI 
non-inferiority 
NIMP 
Non-Investigational Medicinal Product 
PEF 
peak expiratory flow  
pMDI 
Pressurized Metered Dose Inhaler 
PP 
Per Protocol 
PRO 
patient reported outcome 
QTcF 
Fridericia-corrected QT interval 
RoW 
Rest of World 
RR 
rate ratio 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SD 
standard deviation 
SoA 
Schedule of Activities 
TBH 
Turbuhaler 
US 
United States 
VAS 
visual analogue scale 
 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
12 of 130 
1 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title: A Randomized, Double-Blind, Parallel Group, Multicenter 24 Week Study to 
Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler 
Relative to Budesonide Metered Dose Inhaler and Open-Label Symbicort® Turbuhaler® in 
Participants with Inadequately Controlled Asthma (VATHOS) 
Short Title: A 24-Week Efficacy and Safety Study to Assess Budesonide and Formoterol 
Fumarate Metered Dose Inhaler in Adult and Adolescent Participants with Inadequately 
Controlled Asthma (VATHOS) 
Rationale: This study will evaluate the efficacy and safety of Budesonide and Formoterol 
Fumarate Metered Dose Inhaler (BFF MDI) 320/9.6 μg BID compared with Budesonide MDI 
320 μg, hereinafter referred to as BD MDI, and open-label Symbicort TBH 320/9 μg over 
24 weeks. BFF MDI 160/9.6 μg BID is included to evaluate dose response by comparing to 
BFF MDI 320/9.6 μg BID. The study population will consist of adult and adolescent 
participants with asthma who remain inadequately controlled, as demonstrated by an ACQ-7 
total score ≥ 1.5, despite treatment with medium dose ICS or ICS/LABA. This study is to 
assess the benefits and safety of BFF MDI on lung function and asthma health-related quality 
of life. 
 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
21 of 130 
1.3 
Schedule of Activities  
Table 1 
Schedule of Activities  
 
Screening 
Treatment Period 
Study 
Intervention 
Discontinuation 
or Study 
Withdrawal 
F/U TC 
Details in CSP 
Section or 
Appendix 
Visita,b 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
2 weeks 
(± 2 days) 
after last 
dose 
Week 
-3  
-2 
-1 
Rand 
4 
8 
12 
16 
20 
24 
Study Dayc 
-21  
-14 (+ 2)  -7 (± 2) 
1 
29 (± 2) 57 (± 5) 85 (± 5) 
113 
(±5) 
141 
(±5) 
169 
(±5) 
Telemedicine Visit (telephone 
or video) 
 
 
 
 
 
X 
 
X 
 
 
Informed consent/assentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 4.1, 
Section 5.1, 
Appendix A 3 
Inclusion/exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Section 5.1, 
Section 5.2 
Verify continuing eligibility 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Section 7.1 
Calculate FEV1 stability limit 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Calculate PEF stability limit 
 
 
 
X 
 
 
 
 
 
 
 
 
Section 8.1.2.5 
Routine clinical procedures 
Demography and 
medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1 
Prior/concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 6.5 
Dispense and collect eDiary 
Xe 
 
 
 
 
 
 
 
 
X 
X 
 
Section 8.1.2 
eDiary/peak flow meter training 
and review 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Section 8.1.2, 
Section 8.1.2.5 
Peak flow meter 
dispensed/collected 
Xe 
 
 
 
 
 
 
 
 
X 
X 
 
Section 8.1.2.5 
Dispense/collect albuterol (as 
needed) 
Xe 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Section 4.1, 
Section 6, 
Section 6.5.1 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
22 of 130 
Table 1 
Schedule of Activities  
 
Screening 
Treatment Period 
Study 
Intervention 
Discontinuation 
or Study 
Withdrawal 
F/U TC 
Details in CSP 
Section or 
Appendix 
Visita,b 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
2 weeks 
(± 2 days) 
after last 
dose 
Week 
-3  
-2 
-1 
Rand 
4 
8 
12 
16 
20 
24 
Study Dayc 
-21  
-14 (+ 2)  -7 (± 2) 
1 
29 (± 2) 57 (± 5) 85 (± 5) 
113 
(±5) 
141 
(±5) 
169 
(±5) 
Telemedicine Visit (telephone 
or video) 
 
 
 
 
 
X 
 
X 
 
 
Reversibility to albuterol 
 
Xf 
Xf 
 
 
 
 
 
 
 
 
 
Table 2, 
Section 8.1.1.3 
Discontinue ICS or ICS/LABA 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Section 4.1, 
Section 6 
Dispense/collect Run-in BD 
MDI 
Xe 
 
 
X 
 
 
 
 
 
 
 
 
Section 4.1, 
Section 6 
Dispense/collect blinded/open-
label study intervention 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
Section 4.1, 
Section 6 
Routine safety measurements (pre-dose) 
Adverse event assessmentsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.3, 
Appendix B 
Asthma exacerbations 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.2.1, 
Section 8.2.7  
Pregnancy testingg 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Section 5.1, 
Section 8.3.10 
Safety laboratory assessments 
(blood) 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Section 8.2.6 
Physical examination 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Section 8.2.2 
Height and weight 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Section 8.2.3 
Vital signs (blood pressure and 
pulse) 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
Section 8.2.4 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.5 
Genomics Initiative, optional 
exploratory genetic sample 
 
 
 
X 
 
 
 
 
 
 
 
 
Section 8.7, 
Appendix C 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
23 of 130 
Table 1 
Schedule of Activities  
 
Screening 
Treatment Period 
Study 
Intervention 
Discontinuation 
or Study 
Withdrawal 
F/U TC 
Details in CSP 
Section or 
Appendix 
Visita,b 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
2 weeks 
(± 2 days) 
after last 
dose 
Week 
-3  
-2 
-1 
Rand 
4 
8 
12 
16 
20 
24 
Study Dayc 
-21  
-14 (+ 2)  -7 (± 2) 
1 
29 (± 2) 57 (± 5) 85 (± 5) 
113 
(±5) 
141 
(±5) 
169 
(±5) 
Telemedicine Visit (telephone 
or video) 
 
 
 
 
 
X 
 
X 
 
 
Efficacy measurementsh 
Serial spirometryi 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Table 2, 
Section 8.1.1 
Pre-dose spirometryi 
Xj 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Table 2, 
Section 8.1.1 
ACQ (pre-dose) 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
Section 8.1.2.7 
AQLQ(s)+12 (pre-dose) 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
Section 8.1.2.7 
EQ-5D (pre-dose) 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
Section 8.1.2.7 
AIRQ (pre-dose) 
X 
 
 
X 
 
 
X 
 
 
X 
X  
 
Section 8.1.2.7 
Healthcare resource utilization 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Section 8.8 
Study intervention administration 
Check of inhalation device 
technique and training 
Xe 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Section 6 
Administer Run-in BD MDI in 
clinicj 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Section 4.1, 
Section 6 
Administer blinded/open-label 
study intervention in clinick 
 
 
 
X 
Xl 
 
Xl 
 
X 
X 
 
 
Section 4.1, 
Section 6 
a 
Risk assessments for the SARS-CoV-2 pandemic must be made prior to every in-clinic visit in line with the Study Disruption Mitigation Instructions. 
b 
Sites should call participants one to 2 days before each scheduled visit to remind the participant of the visit and the required medication washouts (6 hours 
for short-acting bronchodilators and 12 hours for run-in BD MDI and blinded/open-label study intervention). Participants will be required to return to the 
clinic at approximately the same time ± 1 hour as Visit 1 throughout the study for all in-clinic visits. For all visits after Visit 1, if albuterol and study 
intervention have not been withheld for the specified timeframes, the visit should be rescheduled and conducted within the specified visit window. 
c 
Site should make every effort to maintain participants within the scheduled visit windows. Participants who fall outside the visit window should be placed 
in the protocol-defined window at the next scheduled visit. 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
24 of 130 
d 
Informed consent form may be signed at or prior to Visit 1. 
e 
At Visit 1, issue/train participants on eDiary/peak flow meter use, discontinue ICS or ICS/LABA, and dispense albuterol and run-in BD MDI only after the 
participant has been found eligible to proceed to Visit 2. Should there be any concern that the ICS or ICS/LABA was taken prior to Visit 1, this visit can be 
rescheduled within 2  days. 
f 
If reversibility criterion is not met at Visit 2, participants may continue to Visit 3. Reversibility criterion must be met either in the 12 months prior to Visit 1 
or at Visit 2 or Visit 3, otherwise the participant will be screen failed. 
g 
For all screen failures, an assessment of AEs and highly sensitive urine pregnancy testing (for women of childbearing potential) must be performed within 7 
days of the screen failure date. 
h 
The suggested order of assessments is vital signs, AE/SAE assessments, -60-minute spirometry, PRO questionnaires, -30-minute spirometry, ECG, blood 
draw, and then study intervention administration. Spirometry MUST be performed in accordance with the specified timing. 
i 
All pre-dose (trough) spirometry will be required to be collected in the morning (0800 ± 2 hours). 
j 
Participants who have not withheld asthma medications prior to Visit 1 and failed spirometry inclusion criteria at Visit 1 should return to the clinic to repeat 
spirometry testing (or have the spirometry postponed if it is known in advance that the participant has not washed out) within 2 days. If repeat spirometry 
fails to meet the inclusion criteria, then the participant must be screen failed. 
k 
All dosing occurring during study visits must occur prior to 1000 (+ 1 hour allowance). 
l 
Sufficient blinded/open-label study intervention should be provided to account for next physical visit. 
Abbreviations: ACQ=Asthma Control Questionnaire; AEs=adverse events; AIRQ=Asthma Impairment and Risk Questionnaire; AQLQ(s)+12=Asthma Quality 
of Life Questionnaire for 12 years and older; BD=budesonide; CSP=Clinical Study Protocol; ECG=electrocardiogram; eDiary=electronic diary; EQ-
5D=European Quality of Life-5 Dimensions; F/U=follow-up; ICS/LABA=inhaled corticosteroid/long-acting beta2-agonist; MDI=metered dose inhaler; 
PEF=peak expiratory flow; PRO=Patient Reported Outcome; Rand=randomization; SAE=serious adverse event; TC=telephone call 
 
Table 2 provides timing of specific assessments. Ensure pre-dose spirometry assessments are conducted as close to the specified 
timepoints as possible. All study procedures will be conducted prior to dosing, with the exception of post-dose spirometry. 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
25 of 130 
Table 2 
Timing of Spirometry Measurements  
Visits 
Pre-dose 
Post-dose 
Minutes 
Minutes 
Hours 
-60 (±10) 
-30 (±10) 
5 (±2) 
15 (±5) 
30 (±5) 
1 (±10 min) 
2 (±10 min) 
3 (±10 min) 
1, 5, and 9 
X 
X 
 
 
 
 
 
 
2 (reversibility to albuterol) 
and 3 (reversibility to 
albuterol, if needed) 
X 
X 
 
 
X 
Xa 
 
 
4 
X 
X 
X 
X 
X 
X 
X 
X 
7 and 10, or Study 
Intervention 
Discontinuation/Withdrawal 
X 
X 
 
X 
X 
X 
X 
X 
a 
For reversibility, 1-hour post-dose spirometry may be assessed if not reversible at 30 minutes post-dose 
 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
27 of 130 
obstruction are often triggered by factors such as exercise, allergen or irritant exposure, 
changes in weather, noxious fumes, or viral respiratory infections. These responses are more 
likely when asthma is uncontrolled and, in this scenario, deteriorations can be associated with 
significant risk [GINA 2020]. 
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 
treatment should also be identified [GINA 2020]. 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. 
The GINA guidelines specify 5 treatment steps for asthma, each step outlining options for 
higher levels of treatment for controlling asthma in patients 12 years of age and older [GINA 
2020]. Within this stepwise approach, GINA proposes a classification of asthma severity 
based on the type and intensity of controller medication required for the control of the disease 
(Steps 1 to 5). This classification of asthma severity is then assessed retrospectively once the 
patient is on regular controller treatment for several months. 
Dual combinations of ICS (low or medium dose) and a LABA can provide important 
treatment options in asthma, as described in Section 2.1. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of BD MDI and 
BFF MDI can be found in the Budesonide, Glycopyrronium, and Formoterol Fumarate (BGF) 
Investigator’s Brochure and for Symbicort TBH can be found in the Symbicort TBH 
Investigator’s Brochure. Note: Information pertaining to Glycopyrronium in the BGF 
Investigator’s Brochure is not relevant for this study. 
2.3 
Benefit/Risk Assessment  
Budesonide and formoterol fumarate are approved in many countries worldwide in multiple 
formulations for different indications, such as the treatment of COPD and asthma. 
In order to evaluate the clinical benefit/risk balance, efficacy and safety data are available 
from Phase I, II, and III studies (AstraZeneca COPD/asthma programs) evaluating data with 
budesonide and formoterol fumarate as single agents or in dual combinations. Budesonide and 
formoterol have been well tolerated with favorable safety profiles identified in studies to date. 
Potential risks with BFF MDI will be mitigated by the selected inclusion/exclusion criteria 
and continuous monitoring of safety data during the study. Benefits of BFF MDI over BD 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
28 of 130 
MDI in this study are expected to include an improvement in lung function and asthma 
symptoms. 
More detailed information about the known and expected benefits and potential risks of BFF 
MDI, BD MDI, and Symbicort TBH are provided in the Investigator’s Brochures, as detailed 
above. 
This global study may be initiated or conducted during the SARS-CoV-2 pandemic, another 
civil crisis, natural disaster, or public health crisis; the regional and/or country level risk may 
vary during the conduct of the study. Guidance will be ratified with local regulations, health 
authority and relevant professional bodies to minimize the expected direct risks to site 
personnel and study participants. Alternative measures and procedures may be implemented 
during the conduct of the study as described in Section 4.2. Risk assessments for the SARS-
CoV-2 pandemic per local standards must be made prior to every in-clinic visit in line with 
the current Study Disruptions Mitigation Instructions. 
 

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Table 3 
Objectives and Endpoints  
Tertiary/Exploratory 
 
 
To further assess the 
effect of BFF MDI 
320/9.6 μg relative to BD 
MDI on lung function, 
symptoms, PROs, and 
asthma exacerbations. 
Participants with 
inadequately 
controlled asthma 
(symptomatic on 
medium dose ICS or 
ICS/LABA) 
Percentage of rescue-free days 
(24-hour period without rescue 
medication use) 
Difference in mean 
percentage 
While on Treatment  
- Data after any ICE will 
not be used 
Percentage of symptom-free days 
(24-hour period without 
symptoms) 
Difference in mean 
percentage 
While on Treatment 
- Data after any ICE will 
not be used 
Peak change from baseline in 
FEV1 at each visit 
Mean difference 
While on Treatment 
- Data after any ICE will 
not be used 
Time to peak FEV1 on Day 1 
Mean difference 
While on Treatment 
- Data after any ICE will 
not be used 
FVC, PEF, and FEF25-75 evaluated 
using AUC0-3 
Difference in mean 
change from baseline 
While on Treatment  
- Data after any ICE will 
not be used 
Change from baseline in morning 
pre-dose trough PEF 
Difference in mean 
change from baseline 
While on Treatment 
- Data after any ICE will 
not be used 
Change from baseline in evening 
pre-dose PEF 
Difference in mean 
change from baseline 
While on Treatment 
- Data after any ICE will 
not be used 
Percentage of responders in ACQ-
6 (≥ 0.5 decrease equals response) 
Odds Ratio 
Primary approach for 
handling of ICEs: As for 
ACQ-7 

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Table 3 
Objectives and Endpoints  
Change from baseline in EQ-5D 
Questionnaire index score and 
VAS Questionnaire score  
Difference in mean 
change from baseline 
While on Treatment 
- Data after any ICE will 
not be used 
The percentage of participant’s 
categorical responses to each of 
the 5-dimensions in EQ-5D 
Percentage  
While on Treatment 
- Data after any ICE will 
not be used 
AIRQ 
Mean value and mean 
change from baseline 
While on Treatment 
- Data after any ICE will 
not be used 
AIRQ percentage of participants 
that are well-controlled, not-well 
controlled, and very poorly 
controlled 
Percentage 
While on Treatment 
- Data after any ICE will 
not be used 
Percentage of peak FEV1 
improvement achieved at 5 
minutes on Day 1 
Percentage 
While on Treatment 
- Data after any ICE will 
not be used 
To evaluate dose 
response by comparing 
BFF MDI 320/9.6 μg to 
BFF MDI 160/9.6 μg on 
lung function, 
exacerbations symptoms, 
and PROs. 
Participants with 
inadequately 
controlled asthma 
(symptomatic on 
medium dose ICS or 
ICS/LABA) 
Same estimands as for the comparison of BFF MDI 320/9.6 μg vs BD MDI for primary, 
secondary, tertiary endpoints. 

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Table 3 
Objectives and Endpoints  
Healthcare Resource Utilization Objective 
 
 
To assess the overall and 
asthma-specific 
Healthcare Resource 
Utilization of BFF MDI 
relative to BD MDI. 
Participants with 
inadequately 
controlled asthma 
(symptomatic on 
medium dose ICS or 
ICS/LABA) 
Percentage of participants with 
ER visits 
Percentage 
While on Treatment 
- Data after any ICE will 
not be used 
Number of visits to ERs per 
patient-year 
Mean Annualized 
Rate 
While on Treatment 
- Data after any ICE will 
not be used 
Percentage of participants 
hospitalized 
Percentage 
While on Treatment 
- Data after any ICE will 
not be used 
Number of participant 
hospitalizations per patient-year 
Mean Annualized 
Rate 
While on Treatment 
- Data after any ICE will 
not be used 
Number of days in the hospital per 
patient-year 
Mean Annualized 
Rate 
While on Treatment 
- Data after any ICE will 
not be used 
a 
Refers to submission strategy with respect to Health Authority responsible for reviewing marketing authorization, not the recruitment location/nationality of 
the participants. 
b 
As defined in the SAP. 
 
Intercurrent Events 
• 
Discontinuation from randomized study intervention (may be further broken down for lack of efficacy or for tolerability/other as 
well as reasons related to global/country situation). 
• 
Prolonged exposure to systemic corticosteroids or increased ICS for more than 14 days or having received depot corticosteroid 
injection. Furthermore, use of systemic corticosteroids or increased ICS for 14 days or less will also be considered as an ICE for 
lung function assessments during this temporary additional use. 

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• 
Initiation of any new asthma therapy or administration of prohibited medications thought to impact efficacy, including biological 
therapy/monoclonal antibodies, LABA, LAMA, or LTRA (further details provided in the SAP). 
• 
For the Principal Stratum strategy, in addition to the above ICEs, any IPD that impacts efficacy. 
 

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4 
STUDY DESIGN  
4.1 
Overall Design  
This is a Phase III randomized, double-blind, active comparator, parallel group, multicenter 
study comparing BFF MDI 320/9.6 μg to BD MDI 320 µg and open-label Symbicort TBH 
320/9 μg in adult and adolescent participants who have asthma which remains inadequately 
controlled (ACQ-7 total score ≥ 1.5) despite treatment with medium dose ICS or ICS/LABA. 
Budesonide and Formoterol Fumarate MDI 160/9.6 μg is included in this study to evaluate 
dose response by comparing to BFF MDI 320/9.6 μg. Symbicort TBH is included as a 
marketed comparator for regions that require this. All study interventions will be administered 
as 2 actuations BID for 24 weeks. 
For an overview of the study design see Figure 1. For details on-study interventions given 
during the study, see Section 6.1 Study Intervention(s) Administered. 
This study will be conducted at approximately 125 sites worldwide and will randomize 
approximately 630 adult and adolescent participants. 
At Visit 1, participants (or the parents or legal guardians of participants 12 to < 18 years of 
age) will sign an ICF and participants 12 to < 18 years of age will sign an assent form. All 
participants must be taking a stable daily medium dose ICS or a combination of ICS/LABA 
(see Table 5) for at least 8 weeks prior to Visit 1. Participants who have not withheld asthma 
medications prior to Visit 1 and failed spirometry inclusion criteria at Visit 1 should return to 
the clinic to repeat spirometry testing within 2 days. If the repeat spirometry again fails to 
meet the inclusion criteria, the participant must be screen failed. After meeting all eligibility 
criteria, participants will discontinue their medium dose ICS or ICS/LABA at Visit 1 and 
initiate run-in BD MDI 320 µg taken BID until the evening prior to Visit 4 (randomization), 
when run-in BD MDI will be discontinued. All participants will receive albuterol sulfate 
inhalation aerosol or salbutamol sulfate inhalation aerosol, hereinafter referred to as albuterol, 
at Visit 1 for rescue use during the study (see Section 6.5.1). 
Participants will return for Visit 2 after adequate washout of prohibited asthma medications. 
There will be a minimum of 7 days between Visit 1 and Visit 2. Participants must demonstrate 
a pre-bronchodilator FEV1 of ≤ 90% of predicted normal value at Visits 1, 2, and 3, a pre-dose 
FEV1 of 50% to 90% at Visit 4 (pre-randomization), and an ACQ-7 total score of ≥ 1.5 at 
Visit 1 and Visit 4 (pre-randomization). All participants must be assessed for reversibility to 
albuterol at Visit 2 (and Visit 3 if reversibility is not demonstrated at Visit 2; see Section 5.1 
and Section 8.1.1.3) to provide reversibility baseline data for characterization. However, 
participants who have historically documented reversibility within 12 months of Visit 1 can 
still be randomized to the study even if they fail reversibility testing at Visits 2 and 3. 

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4.2 
Study Conduct Mitigation During Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis  
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 virus or a similar 
pandemic infection) which would prevent the conduct of study-related activities at study sites, 
thereby compromising the study site staff or the participant’s ability to conduct the study. The 
Investigator or designee should contact AstraZeneca to discuss whether the mitigation plans in 
the Study Disruption Mitigation Instructions should be implemented. 
In the scenario of a civil crisis, natural disaster, or public health crisis, changes may be 
implemented to ensure the safety of study participants, maintain compliance with GCP and 
minimize risks to trial integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies), or local government, if study participants cannot attend the visits at the 
study site due to significant regional disruption, evolving global pandemic or similar natural 
disaster, telemedicine sessions (video conference or telephone call) will be implemented for 
all participants currently randomized in the study and study intervention supply maintained for 
the participant given this comprises their asthma controller medications. These sessions 
should include all SoA (Table 1) assessments which can be performed virtually, to collect 
safety information as a minimum requirement. Assessments in the SoA (Table 1) which 
cannot be performed virtually should be captured at the next opportunity for an in-clinic visit, 
provided the Investigator assesses the participant to be safe to continue in the study. 
Alternatively, if the Investigator considers it appropriate for the participant to stop study 
intervention and have alternative asthma controller medications, arrangements for this will 
need to be made by the study staff, in accordance with local regulatory requirements and 
guidance. All participants who stop study intervention and are prescribed alternative asthma 
controller medications will require follow-up with a telephone call 2 weeks following the 
cessation of study intervention to assess safety. 
If an emergent event results in centralized laboratory testing of samples not being available, 
AstraZeneca may decide to use local laboratories. 
Visits 1 through 4 must be conducted at the study site. If mitigation practices are implemented 
at a site, until agreed otherwise with AstraZeneca, no further participants can be enrolled and 
all participants who are currently in Screening (Visits 1 through 4), must be screen failed (see 
Section 5.4). 

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4.2.1 
Completing Participant Numbers to Maintain Study Integrity  
In the event of a natural disaster or civil or public health crisis that prevents participants from 
attending on-site visits (as described in Section 4.2), participants will be followed remotely to 
collect symptomatic, PRO, and safety assessments for the event's duration; however, it will 
not be possible to collect spirometry assessments for the primary endpoint during this time. 
Additionally, owing to the likelihood of some participant drop-out during the event and to 
maintain study integrity which requires sufficient lung function data at Week 24 by 
completing participants, more participants may be required and subsequently enrolled. 
Additional analytic and operational approaches may be considered to address data limitations 
caused by the crisis. If this occurs, additional details may be included in the SAP. 
4.3 
Scientific Rationale for Study Design  
The product being tested in this study, BFF MDI 320/9.6 μg BID, are being compared with 
BD MDI 320 μg BID and open-label Symbicort TBH 320/9 μg BID. BFF MDI 160/9.6 μg 
BID is included to evaluate dose response by comparing to BFF MDI 320/9.6 μg BID. Per 
GINA guidelines, the goal of the stepwise approach to treatment in asthma is to optimize lung 
function and improve control of asthma symptoms [GINA 2020]. Therapy with an ICS for 
asthma is well established in clinical practice and the inclusion of a LABA has demonstrated 
additional benefit in managing patients with poorly controlled asthma [GINA 2020]. The 
addition of a LABA is expected to improve lung function and health-related quality of life in 
this population. Inclusion of 2 doses of BFF MDI may demonstrate a dose ordering effect of 
BD when added to formoterol fumarate. The development of a dual combination product also 
provides the convenience of a single inhaler for patients, increasing the likelihood of 
adherence. The length of this study will allow safety to be captured and provide adequate time 
to observe lung function changes after 24 weeks of treatment. 
4.3.1 Participant Input into Design  
Obtaining coordinator and participant insight early has provided opportunities for informing 
study design, improving operational feasibility, reducing patient/site burden, and retaining 
interest, enthusiasm, and engagement in a study. 
4.3.1.1 
Coordinator Input  
Four face-to-face coordinator meetings involving 25 coordinators from 17 countries were 
conducted. Coordinator perspectives and insights were collected around consenting, 
eligibility, requesting medical records, screening, randomization, safety/efficacy measures, 
study intervention, technology, retention, and data. The following changes to the protocol 
were made based on coordinator input: 
• 
Reduced the number of serial spirometry assessments and added telemedicine visits to 
limit number of in-clinic visits required 

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• 
Broadened the window for performing morning assessments 
• 
Added vaping to smoking history eligibility criteria 
• 
Refined corticosteroid eligibility criteria to include oral and IV use 
 
Explaining the “why” behind a study and activities in the SoA (Table 1) and improving 
training materials to support geographical challenges will be incorporated into Investigator 
and site training. 
4.3.1.2 
Participant Input  
Two virtual meetings were conducted with 7 asthma patients from 4 countries. Insights were 
collected around exacerbations and the ability to collect medical records to support eligibility 
and/or an on-study event, eDiary burden, and virtual study visits. Patients indicated that 
ensuring direct lines of communication with site staff, allowing “in-clinic” assessments to be 
done at home, utilizing a personal device to collect data, and explaining why PROs are needed 
and how PRO data will be used, is important to them. These insights will be considered and 
when possible, incorporated into the protocol, Investigator, site and PRO eDiary training. 
4.4 
Justification for Dose  
The budesonide doses of 320 µg and 160 μg administered as 2 puffs BID (total daily doses of 
640 µg and 320 μg, respectively) being evaluated as part of BFF MDI are considered medium 
and low ICS doses within ICS/LABA combinations by GINA. The GINA treatment guidelines 
advocate the addition of a LABA to ICS, such as BFF MDI, as a step-up therapy to asthma 
patients who are inadequately controlled on a low or medium dose ICS alone [GINA 2020]. 
The efficacy and safety profile of BD, as part of BFF MDI 320/9.6 µg and BGF MDI 
320/14.4/9.6 µg, has been established in the Phase III COPD program and is part of the 
approved BGF MDI dose submitted globally. The BD doses included in this study are the 
same doses, and the formoterol fumarate dose very similar, to those in Symbicort, a 
combination ICS/LABA containing the same molecules, that has been approved globally in 
asthma at an equivalent dose of 160/9 µg and 320/9 µg (both administered as 2 inhalations) 
BID. Subsequently, there is a wealth of safety and efficacy data to support the doses included 
in this study. 
The formoterol fumarate dose of 9.6 µg administered as 2 puffs BID (total daily dose of 
19.2 µg) is being evaluated as part of the current BGF MDI Phase III program in asthma. The 
efficacy and safety profile of formoterol fumarate, as part of Glycopyrronium and Formoterol 
Fumarate MDI 14.4/9.6 µg and BGF MDI 320/14.4/9.6 µg, has been established in the Phase 
III COPD programs and is part of the approved doses of Bevespi Aerosphere and 
Breztri/Trixeo Aerosphere. The formoterol fumarate dose of 9 µg in Symbicort TBH has a 
well-established safety and efficacy profile and is comparable to the formoterol fumarate dose 

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of 9.6 µg in the BGF MDI and BFF MDI treatment arms included in the BGF asthma Phase 
III program. 
4.5 
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 study 
participant for any protocol related activity. 
Food and Drug Administration requirements define 2 completion dates: 
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 when he/she has completed his/her 
last scheduled procedure shown in the SoA (Table 1). 
Participants who discontinue study intervention will be encouraged to continue in the study 
and complete all remaining study visits and procedures. 
5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 

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5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 12 to 80 years of age inclusive, at the time of signing the ICF. 
Note: For participants 12 to < 18 years of age, their parents or legal guardians must give 
their signed written informed consent, as appropriate, and participants will sign an assent 
form. 
 
Type of Participant and Disease Characteristics 
2. Participants who have a documented history of physician-diagnosed asthma ≥ 6 months 
prior to Visit 1, according to GINA guidelines [GINA 2020]. Healthcare records for 
one year prior to Visit 1 must be provided for adolescent participants (12 to < 18 years of 
age) to ensure consistent evaluation and follow-up of treatment in those participants. 
3. Participants who have been regularly using a stable daily ICS or an ICS/LABA regimen 
(including a stable ICS dose), with the ICS doses allowed in Table 5, for at least 8 weeks 
prior to Visit 1. 
4. ACQ-7 total score ≥ 1.5 at Visits 1 and 4. 
5. Pre-bronchodilator/pre-dose FEV1 < 90% predicted normal value at Visits 1, 2 and 3, and 
a pre-dose FEV1 of 50% to 90% at Visit 4 (pre-randomization). 
Note: Participants who have not withheld asthma medications prior to Visit 1 and failed 
spirometry testing at Visit 1 should return to the clinic to repeat spirometry testing within 
2 days. If repeat spirometry fails, then participants must be screen failed. 
6. Reversibility to albuterol, defined as a post-albuterol increase in FEV1 of ≥ 12% and 
≥ 200 mL for participants ≥ 18 years of age OR a post-albuterol increase in FEV1 of 
≥ 12% for participants 12 to < 18 years of age, either in the 12 months prior to Visit 1 or at 
Visit 2 or Visit 3. 
Note: Even if there is documented history of reversibility, all participants must be assessed 
for reversibility at Visit 2 (and Visit 3, if reversibility is not demonstrated at Visit 2) to 
evaluate presence of reversibility during screening. 
7. A pre-bronchodilator/pre-dose FEV1 at Visits 2, 3, and 4 that has not changed 20% or 
more (increase or decrease) from the pre-bronchodilator/pre-dose FEV1 recorded at the 
previous visit. 
8. Asthma stability during run-in based on Investigator discretion using the symptom 
worsening assessment defined in Section 8.1.2.8 as a guideline. 
9. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as 
required by the protocol. 

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10. Demonstrate acceptable MDI administration technique. 
Note: Historical use of a spacer device within the 8 weeks prior to and/or during the 
Screening and Randomized Treatment Periods is not permitted. 
11. eDiary compliance ≥ 70% during screening, defined as completing the daily eDiary and 
answering “Yes” to taking 2 puffs of run-in BD MDI for any 10 mornings and 10 evenings 
in the last 14 days prior to randomization. 
 
Weight 
12. Body mass index < 40 kg/m2. 
 
Sex 
13. Male or female. 
Females must be not of childbearing potential or 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 sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered postmenopausal 
if they have been amenorrhoeic for 12 months prior to the planned date of randomization 
without an alternative medical cause. The following age-specific requirements apply: 
− 
Women < 50 years old would 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. 
− 
Women ≥ 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment. 
• Female participants of childbearing potential must use a 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. Women of 
childbearing potential who are sexually active with a non-sterilized male partner must 
agree to use a highly effective method of birth control, as defined below, from enrollment 
throughout the study and until at least 16 weeks after last dose of study intervention. 
Cessation of contraception after this point should be discussed with a responsible 
physician. All women of childbearing potential must have a negative highly sensitive urine 
(at all clinic visits). Adolescent participants should be counselled appropriately by the 
Investigator. 
• Highly effective birth control methods are listed below: 
− 
Sexual abstinence defined as complete abstinence from intercourse when it is the 
preferred and usual lifestyle of the participant (however, periodic abstinence eg, 

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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) 
− 
Contraceptive subdermal implant 
− 
Intrauterine device or intrauterine system 
− 
Oral contraceptive (combined or progesterone only) 
− 
Injectable progestogen [Hatcher et al 2011] 
− 
Contraceptive vaginal ring [Hatcher et al 2011] 
− 
Percutaneous contraceptive patches [Hatcher et al 2011] 
− 
Male partner sterilization with documentation of azoospermia prior to the female 
participant’s entry into the study, and this male is the sole partner for that participant 
[Hatcher et al 2011]. The documentation on male sterility can come from the site 
personnel’s review of participant’s medical records, medical examination and/or 
semen analysis or medical history interview provided by her or her partner. 
− 
Bilateral tubal ligation 
 
Informed Consent 
14. 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. 
15. Provision of signed and dated written Optional Genomics Initiative Research Information 
consent form prior to collection of samples for Optional Genomics Initiative Research that 
supports Genomic Initiative. 
 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Life-threatening asthma as 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. 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. 
3. Hospitalization for asthma within 8 weeks of Visit 1. 
4. Historical or current evidence of a clinically significant disease including, but not limited 
to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, 
or pulmonary (eg, active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes, 

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and COPD). 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 
efficacy or safety analysis. 
5. Known history of drug or alcohol abuse within 12 months of Visit 1. 
6. Unresectable cancer that has not been in complete remission for at least 5 years prior to 
Visit 1. 
Note: Squamous cell and basal cell carcinomas of the skin are not exclusionary. 
 
Prior/Concomitant Therapy 
7. Participation in another clinical study with a study intervention administered in the last 
30 days or 5 half-lives, whichever is longer. Any other study intervention that is not 
identified in this protocol is prohibited for use during study duration. 
8. Previous or current randomization into studies within the AEROSPHERE program 
including KALOS, LOGOS, VATHOS, LITHOS, or any glycopyrronium studies (PT001). 
9. Use of a nebulizer or a home nebulizer for receiving asthma medications. 
Note: Acute use of a nebulizer for an asthma exacerbation during hospitalization is 
allowed as long as there is no occurrence within 8 weeks of Visit 1. 
10. Do not meet the stable dosing period prior to Visit 1 (see Table 6) or unable to abstain 
from protocol-defined prohibited medications during Screening and Treatment Periods 
(see Table 7 and Table 8). 
11. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, eg, vector, lipid 
nanoparticle) < 7 days prior to Visit 1 (from last vaccination or booster dose). 
12. Participants with known hypersensitivity to beta2-agonists, corticosteroids, or any 
component of the MDI. 
 
Diagnostic Assessments 
13. Any clinically relevant abnormal findings in physical examination, clinical chemistry, 
hematology, vital signs, or 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 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 do not have a pacemaker will also be excluded. 
 
Other Exclusions 
14. 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). 

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15. Planned hospitalization during the study. 
16. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site). 
17. Study Investigators, sub-Investigators, coordinators, and their employees or immediate 
family members. 
18. Judgment by the Investigator that the participant is unlikely to comply with study 
procedures, restrictions, and requirements. 
19. For women only – currently pregnant (confirmed with positive highly sensitive urine 
pregnancy test), breast-feeding, or planned pregnancy during the study or not using 
acceptable contraception measures, as judged by the Investigator. 
 
5.3 
Lifestyle Considerations  
5.3.1 
Caffeine, Tobacco, and Alcohol  
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. Participants will abstain from consuming any intoxicants 
within 24 hours before spirometry testing. 
5.3.2 
Illicit Drugs or Drugs of Abuse  
Illicit drugs or drugs of abuse will not be allowed from Visit 1 to the end of the follow-up 
telephone call or to whenever the participant withdraws from the study. If any illicit drugs or 
drugs of abuse are used by the participant during the study, the dates of use and the amount 
will be documented, and the participant will be discontinued from randomized study 
intervention and will be withdrawn from the study at the discretion of the Investigator. 
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 AEs. 
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 [eg, problems with the eDiary 
impacting availability of data], required study documentation, or unforeseen personal 
reasons). 

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Each participant will have a maximum of 2 rescreening opportunities during the recruitment 
period. 
Participants may not be rescreened due to failure to meet the study requirements of pre-
bronchodilator FEV1 (including stability) and ACQ score during the Screening Period. 
Rescreened participants will be assigned the same participant number as for the initial 
screening. Rescreened participants will sign a new ICF. All procedures required for the 
screening/run-in periods, starting at Visit 1, should be repeated. Rescreening should be 
documented so that its effect on the study results, if any, can be assessed. 
If a participant is rescreened and fails for any reason other than pre-bronchodilator FEV1 and 
ACQ score, another rescreening is allowed after a 3-month period. 
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. 
6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to, or medical device(s) utilized by a study participant 
according to the study protocol. 
Placebo MDI will be dispensed at Visit 1 and empty TBH devices will be dispensed at Visit 4 
for in-clinic training purposes. Run-in BD MDI will be provided during the Screening Period. 
Instructions for use of Investigational Products will be provided. 
 

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6.1.2 
Medical Devices Including Combination Products with Device 
Constituent  
1. The AstraZeneca manufactured combination product with a device constituent provided 
for use in this study are the MDI (Approved) and pMDI (Approved). 
2. Instructions for combination products with a device constituent use are provided in the 
Investigator Brochure and Combination Products section of the Summary of Medical 
Product Characteristics. 
3. All device constituent deficiencies (including malfunction, use error and inadequate 
labeling) shall be documented and reported by the Investigator throughout the clinical 
investigation (see Section 8.3.12) and appropriately managed by AstraZeneca. 
 
6.2 
Preparation/Handling/Storage/Accountability  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized 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). 
All handling instructions and further guidance and information for the final disposition of 
unused study interventions are provided separately outside of the protocol. 
6.3 
Measures to Minimize Bias: Randomization and Blinding  
All participants will be centrally assigned to one of 4 randomized study interventions using an 
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 system will provide to the Investigators 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 system user manual that will be provided to each 
center. 

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For blinded study intervention, the randomization code should not be broken except in 
medical emergencies when the appropriate management of the participant requires knowledge 
of the treatment randomization. The Investigator documents and reports the action to 
AstraZeneca, without revealing the blinded treatment that was given to the participant to the 
AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study intervention and that potentially require expedited 
reporting to regulatory authorities. Randomization codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented. 
The IRT system 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, 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, AstraZeneca 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. 
6.4 
Study Intervention Compliance  
When participants are dosed during a study visit, they will take study intervention under 
medical supervision from the Investigator or designee. The date, and time if applicable, of 
dose administered during the study visit will be recorded in the source documents and 
recorded in the eCRF. 
Compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by reviewing the daily eDiary recording and the remaining doses of the dose counter 
during the site visits. The dose counter reading should be documented in the source 
documents. 
A record of the number of MDIs and TBHs dispensed to and used by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates will also be recorded in the eCRF. 
6.5 
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 

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receiving from up to 3 months prior to Visit 1 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 and frequency 
 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 Rescue Medicine  
Albuterol for participants to use as rescue medication and for reversibility testing at Visits 2 
and 3 (if needed) is not regarded as study intervention but will be provided/reimbursed by 
AstraZeneca according to local regulations in order to maintain appropriate oversight and 
access to this concomitant medication. The only rescue medication allowed in this study is 
albuterol; all other medications for rescue use are prohibited. 
Although the use of albuterol is allowable at any time during the study, the use of rescue 
medications should be withheld, if possible, for at least 6 hours prior to the start and during 
each clinic visit. If albuterol is used within 6 hours from the start of a clinic visit, then the visit 
will need to be rescheduled within the allowed visit window. The number of puffs of rescue 
medication will be recorded by the participant daily in the eDiary. 
6.5.2 
Prior Medications  
Participants eligible for this study are required to be on a stable regimen, including fixed daily 
dosing, of an inhaled asthma maintenance therapy defined as an ICS or ICS/LABA for at least 
8 weeks prior to Visit 1. The permitted total daily ICS dosage to qualify for the study is 
defined in Table 5. Any ICS not listed in the GINA 2020 guidelines or considerations outside 
this list should be discussed with the Medical Monitor prior to entry of the participant. 

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Table 5 
Required ICS Dosages (Monotherapy or in Combination with LABA) 
Prior to Visit 1  
Inhaled Corticosteroid 
Total Daily Dose (µg/day)a 
Beclomethasone dipropionate (pMDI, standard particle, HFA) 
> 500-1000 
Beclomethasone dipropionate (pMDI, extrafine particle, HFA) 
> 200-400 
Budesonide (DPI or pMDI, standard particle, HFA)b 
> 400-800 
Ciclesonide (pMDI, extrafine particle, HFA) 
> 160-320 
Fluticasone furoate (DPI) 
100 
Fluticasone propionate (DPI or pMDI, standard particle, HFA) 
> 250-500 
Mometasone furoate (DPI) 
Due to complexity around 
dosing in different 
devices/formulations, please 
discuss with the Study 
Physician 
Mometasone furoate (pMDI, standard particle, HFA) 
200-400 
a 
Daily doses in this table are shown as metered doses. 
b 
The total daily dose of budesonide in Symbicort 160/4.5 μg pMDI, taken as 2 puffs BID equals a total 
delivered dose of 640 μg, which is equivalent to 800 μg metered dose. 
DPI=Dry Powder Inhaler; HFA=hydrofluoroalkane; pMDI=Pressurized Metered Dose Inhaler 
 
6.5.3 
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 6. 

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Table 6 
Allowed Medications with Defined Stable Dosing Period Prior to 
Visit 1  
Medication 
Minimum Stable Dosing Period Prior to 
Visit 1 
Selective serotonin reuptake inhibitors/serotonin and 
norepinephrine reuptake inhibitorsa 
4 weeks 
Tricyclic antidepressants 
2 weeks 
Antipsychotics 
4 weeks 
Anticonvulsants 
52 weeks for seizure disordersb 
12 weeks for other conditions 
Non-sedating long- and short-acting antihistamines 
4 weeks 
Intranasal corticosteroids 
4 weeks 
Intranasal antihistamines or combination products of 
intranasal antihistamines/corticosteroids 
4 weeks 
Intranasal ipratropium bromidec 
4 weeks 
a 
Must be on a stable dose for at least 4 weeks prior to Visit 1 and not altered during the Screening Period. 
b 
Must be free of seizures for one year prior to Visit 1. 
c 
Intranasal ipratropium bromide should be withheld for at least 6 hours prior to each visit. 
 
6.5.3.1 
Vaccinations  
All participants should be vaccinated with annual influenza vaccine [GINA 2020] 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 Visit 1 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 enrollment into the study and also being considered for 
COVID-19 vaccination, the participant must not be randomized 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. 
6.5.4 
Prohibited Medications  
Participants requiring medications presented in Table 7 are prohibited from participating in 
this study. Participants who recently discontinued use of these medications may be considered 

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for study enrollment provided they have met the minimum cessation period prior to Visit 1. 
These medications are prohibited throughout the course of the study. If participants require 
any of the prohibited medications listed in Table 7, the Investigator should discuss with the 
Medical Monitor the suitability of the participant continuing study intervention. 

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Table 7 
Prohibited Medications Throughout the Study and Required Cessation 
Period Prior to Visit 1  
Medication 
Minimum Cessation Period Prior to 
Visit 1 
Long-acting beta2-agonist as reliever 
8 weeks 
Long-acting muscarinic antagonist 
12 weeks 
Leukotriene antagonists/modifiers (eg, Zileuton®) 
3 months 
Oral beta2-agonist 
3 months 
Theophylline 
7 days 
Oral and IV corticosteroidsa 
8 weeks 
Injectable systemic corticosteroids (eg, depot formulation, intra-
articular, intradermal, intramuscular) 
3 months 
Any marketed (eg, omalizumab, mepolizumab, benralizumab, 
reslizumab) or investigational biological therapy for asthma or 
any other condition 
6 months or 5 half-lives, whichever is 
longer 
Prophylactic antibiotics 
8 weeks 
Roflumilast 
30 days 
Any immunomodulators or immunosuppressivesb 
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 intervalc 
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 (eg, 
ketoconazole, itraconazole, and ritonavir) 
30 days 
Systemic anticholinergicsd 
7 days 
Herbal remedies for the treatment of allergic, inflammatory, or 
respiratory diseases (eg, Chinese complementary and alternative 
bronchodilatory medicines) 
10 days 
a 
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. 
b 
Topical administration of immunosuppressive medication maybe allowed at the discretion of the 
Investigator after discussion with the Study Physician. 

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c 
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 ECG inclusion criteria and none of the ECG exclusion criteria, and if, in the opinion of the 
Investigator, there are not safety concerns for the participant to participate in the study. 
d 
If systemic anticholinergics are used for the treatment of irritable bowel syndrome or overactive bladder 
and the treatment has been constant for at least one month, they are allowed. 
 
Specific prohibited asthma and allergy medications and their required washout periods prior to 
Visit 2 are displayed in Table 8. 
Table 8 
Prohibited Asthma and Allergy Medications from Visit 1 Onwards  
Medication 
Minimum Washout Period Prior to 
Visit 2 
ICS other than sponsor-provideda 
7 days 
ICS/LABA other than sponsor-provideda 
7 days 
Cromoglycateb 
7 days 
Nedocromilb 
7 days 
Ketotifenb 
7 days 
Short-acting muscarinic antagonists and/or short-
acting beta2-agonists alone, loose, or fixed 
combination other than sponsor-provided albuterol 
7 days 
a 
Administration as fixed or loose combinations. 
b 
Cromoglycate, nedocromil, and ketotifen eye drops are allowed for allergic conjunctivitis; no washout 
period. 
 
6.6 
Dose Modification  
Not applicable for this study. 
6.7 
Intervention After the End of the Study  
At the end of the Randomized Treatment Period, the Investigator or treating physician of the 
participant will prescribe alternative asthma therapy for the participant. There will be no 
provisions to supply BFF MDI, BD MDI, or Symbicort after the end of the treatment period. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue study intervention. If study 
intervention is permanently discontinued, the participant will be encouraged to remain in the 
study and complete the remainder of the study visits and procedures. 

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Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. 
If a participant experiences any of the below, the study intervention MUST be discontinued: 
• 
Development of exclusion criteria or other safety reasons as judged by the Investigator 
during the treatment period 
• 
Pregnancy (see Section 8.3.10) 
• 
An asthma exacerbation requiring in-patient hospitalization 
• 
More than 2 severe asthma exacerbations requiring oral corticosteroid treatment 
 
See the SoA (Table 1) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.2 
Participant Withdrawal from the Study  
• 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
If a participant is unwilling/unable to attend the scheduled clinic visits, he/she will be 
informed by the Investigator about modified follow-up options (eg, telephone contact, a 
contact with a relative or treating physician, or information from medical records). 
• 
At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA (Table 1). See SoA for 
data to be collected at the time of study withdrawal and follow-up for any further 
evaluations that need to be completed. 
− 
The participant will discontinue the study intervention and be withdrawn from the 
study at that time. 
• 
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 a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
Investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team. 
 

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7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she 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 clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
8 
STUDY ASSESSMENTS AND PROCEDURES  
• 
Study procedures and their timing are summarized in the SoA (Table 1). Protocol waivers 
or exemptions are not allowed. 
• 
The suggested order of assessments is vital signs, AE/SAE assessments, -60-minute 
spirometry, PRO questionnaires, -30-minute spirometry, ECG, blood draw, and then 
study intervention administration. Spirometry MUST be performed in accordance 
with the specified timing. 
• 
Immediate 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. 
 

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8.1 
Efficacy Assessments  
8.1.1 
Pulmonary Function Tests  
8.1.1.1 
Spirometry Standardization  
All spirometry including FEV1, FVC, and FEF25-75 as defined in ATS/ERS guidelines will be 
performed in accordance with ATS/ERS acceptability and repeatability criteria [Miller et al 
2005] and will be assessed using a spirometer that meets or exceeds minimum performance 
recommendations. Calculated predicted spirometry results will be obtained using the Global 
Lung Initiative equations [Quanjer et al 2012]. 
The central spirometry vendor is responsible for assuring that the spirometer meets ATS/ERS 
recommendations [Miller et al 2005] and that the study site personnel who will be performing 
the testing are properly certified. Additional details will be provided in a Spirometry 
Procedures Manual. 
As spirometry results are primary and secondary efficacy endpoints for this study, it is 
important for the medication withholding conventions and timing of spirometry to be 
consistently managed throughout the study (see Section 8.1.1.2). 
8.1.1.2 
Spirometry Schedule  
Spirometry collection is briefly outlined below. For exact spirometry collection and 
specifications, please refer to the SoA (Table 1) and Timing of Spirometry Measurements 
(Table 2). 
Important requirements to support consistent spirometry assessments during study: 
• 
Participants will be required to return to the clinic at approximately the same time of the 
day ± 1 hr as Visit 1 throughout study. 
• 
All pre-dose (trough) spirometry will be required to be conducted in the morning 
(0800 ± 2 hours). 
• 
During the Screening and Treatment Periods, sites should call 24 to 48 hours prior to each 
visit to remind participants that the evening dose of study intervention (run-in BD MDI or 
study intervention) should be 12 ± 1 hr prior to the expected dosing time at the next 
morning visit, having considered the time at which assessments prior to dosing will be 
completed. 
Note: If the site morning dose time is going to be > 13 hours from the prior evening dose 
time, then the visit should be rescheduled within the allowed visit window. 
• 
All in-clinic dosing should occur prior to 1000 (+ 1 hour allowance) in the morning and 
visits must be planned accordingly. Participants will be dispensed and administered new 
study intervention at each clinic visit during the treatment period. 

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• 
The morning dose on the day of the clinic visit must be withheld until after all pre-dose 
assessments are completed at the clinic. 
Note: Albuterol must be withheld at least 6 hours prior to the start time of the morning 
visit. If these requirements are not met, then the visit will need to be rescheduled within 
visit windows. 
• 
Participants will be required to remain at the clinic until completion of all protocol-
defined assessments and procedures. 
 
Screening Period (Visit 1 through Visit 4): 
• 
The average of the 2 pre-bronchodilator FEV1 values (-60 and -30 minutes) will be 
calculated to determine if the participant meets the inclusion criteria. If a participant does 
not meet this criterion at any one of the screening visits, the participant will be screen 
failed at that visit. 
• 
Participants who have not withheld asthma medications prior to Visit 1 and failed 
spirometry testing per criterion at Visit 1 should return to the clinic to repeat spirometry 
testing within 2 days. Participants whose repeat spirometry testing fails to meet the 
criterion will be screen failed. 
Note: Run-in BD MDI and albuterol will only be dispensed to participants after meeting 
eligibility criteria to proceed to Visit 2 
 
Visit 1: 
• 
Spirometry will be conducted 60 and 30 minutes prior to run-in BD MDI administration. 
 
Visit 2: 
• 
Spirometry will be conducted at 60 and 30 minutes prior to albuterol administration and 
30 minutes post-albuterol (see Section 8.1.1.3). 
• 
Albuterol reversibility testing should be conducted for all participants at Visit 2; 
participants who fail to meet the reversibility criterion at Visit 2 should still proceed to 
Visit 3 for further reversibility testing (including those with documented historical 
reversibility). 
• 
If participants are not reversible to albuterol at 30 minutes post-dose, the post-dose 
spirometry can be repeated at 60 minutes post-dose. 
• 
Administer run-in BD MDI after completion of reversibility test. 
 
Visit 3: 
• 
For participants who did meet the albuterol reversibility criterion at Visit 2, spirometry 
will be conducted 60 and 30 minutes prior to run-in BD MDI administration. 

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• 
For participants who did not meet albuterol reversibility criterion at Visit 2 (including 
those with documented historical reversibility to albuterol within 12 months prior to 
Visit 1), albuterol reversibility testing must be repeated at Visit 3. The albuterol 
reversibility testing at Visit 2 (and Visit 3 if reversibility is not demonstrated at Visit 2) is 
required to evaluate presence of reversibility during screening. 
• 
Participants who fail to meet the albuterol reversibility criterion at both Visit 2 and Visit 3 
can still proceed to Visit 4 if they meet all other study criteria, provided they have a 
documented history of reversibility in the 12 months prior to Visit 1. 
• 
Participants who have not met historical reversibility in the 12 months prior to Visit 1 and 
do not meet the reversibility criterion at Visit 2 or Visit 3 will be screen failed. 
• 
Administer run-in BD MDI after completion of reversibility test. 
 
Visit 4 (Randomization): 
• 
Serial spirometry will be conducted 60 minutes and 30 minutes prior to the first dose of 
study intervention and 5, 15, and 30 minutes, and 1-, 2-, and 3-hours post-dose. 
 
Visits 5 and 9: 
• 
Spirometry will be conducted 60 minutes and 30 minutes prior to study intervention 
administration. 
 
Visits 7 and 10 or the Treatment Discontinuation/Study Withdrawal Visit: 
• 
Serial spirometry will be conducted 60 minutes and 30 minutes prior to study intervention 
administration and 15 and 30 minutes, and 1-, 2-, and 3-hours post-dose. 
 
8.1.1.3 
Reversibility to Albuterol  
Reversibility to albuterol will be evaluated for participant qualification purposes and baseline 
data characterization. For participants without historically documented reversibility, the 
reversibility criterion must be met at Visit 2 or Visit 3 (see Section 5.1), otherwise the 
participant will be screen failed. For participants who meet reversibility at Visit 2, reversibility 
testing will not be repeated at Visit 3. Participants with historically documented reversibility 
who fail to meet reversibility at Visit 2 and Visit 3 can still proceed to Visit 4 if they meet all 
other criteria. 
All participants must demonstrate reversibility either through historically documented 
reversibility in the 12 months prior to Visit 1 or through demonstrating reversibility at 
Visit 2 or Visit 3. 
The procedures for testing reversibility to albuterol are as follows: 

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1. Confirm run-in BD MDI was taken the prior evening 12 hours (± 1 hour) before the 
expected dosing time of the next morning visit. The morning dose must not have been 
taken and albuterol withheld at least 6 hours prior to the start time of the visit. 
2. Perform pre-bronchodilator spirometry at 60 and 30 minutes prior to administration of 
bronchodilator. 
3. Administer 4 puffs of albuterol. 
4. Perform post-bronchodilator spirometry 30 minutes after the administration of albuterol. If 
participants are not reversible to albuterol at 30 minutes, the post-dose spirometry can be 
repeated at 60 minutes post-dose. 
 
Reversibility will be a comparison of the average best FEV1 effort obtained at 60- and 30-
minutes pre-bronchodilator to the best FEV1 effort obtained at 30 minutes (or up to 
60 minutes, if repeated) post-bronchodilator following administration of albuterol. A 
participant ≥ 18 years of age is considered reversible if the improvement in FEV1 at 
30 minutes (or at 60 minutes) post-dose is ≥ 12% and ≥ 200 mL. A participant 12 to < 18 
years of age is considered reversible if the improvement in FEV1 at 30 minutes (or at 
60 minutes) post-dose is ≥ 12%. 
Please note, reversibility testing is still required at Visit 2 and/or Visit 3, even if the 
participant has documented historical reversibility reported in the 12 months prior to Visit 1. 
8.1.2 
Participant’s eDiary Data Collection  
Participants will be supplied with a hand-held eDiary device at Visit 1 to take home and enter 
data electronically at home in the morning and in the evening of each day. Participants will 
also be trained on the device at Visit 1. Prior to issuing the eDiary to the participant, site 
personnel will receive eDiary training. The site staff are responsible for setting up the eDiary 
for each participant’s use and for ensuring each participant is trained to complete the 
questionnaires on the eDiary according to the SoA (Table 1). 
Important reminders regarding eDiary use prior to study visits: 
• 
On the evening prior to the visit, participants will complete their eDiary before dosing. 
Dosing should be 12 hours (± 1 hour) prior to the expected dosing time at the next 
morning visit. 
• 
On the morning of a visit, participants will not complete their eDiary before the visit, but 
will instead wait to fill out the eDiary during the visit. 
 

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8.1.2.1 
eDiary Compliance Requirement  
Compliance with eDiary is required throughout the study. Participants must have an eDiary 
compliance of ≥ 70% during Screening to be eligible for randomization (defined as 
completing the daily eDiary and answering “Yes” to taking 2 puffs of run-in BD MDI for any 
10 mornings and any 10 evenings in the last 14 days prior to Visit 4). During the treatment 
period, daily eDiary compliance is critical for capturing worsening symptoms and use of study 
interventions. The Investigator/authorized delegate will check the participant’s adherence to 
the eDiary at each visit during the study. An alert will be generated when a participant is not 
consistently completing the eDiary and/or confirming on the eDiary that they have taken their 
study intervention. Sites will respond to the alert as per Section 8.1.2.8. 
8.1.2.2 
Daily eDiary Reporting  
The eDiary will include the following daily recordings: morning and evening home PEF data 
(obtained from the home peak flow meter), asthma symptoms, inhalations of rescue 
medication use, nights with awakenings due to asthma symptoms, and background 
(maintenance) medication use. 
The eDiary will alert the participant with an alarm when it is time to fill out the questions and 
will also prompt the participant to collect PEF. Reporting via the eDiary will occur before 
administration of run-in BD MDI during the Screening Period and study intervention or 
asthma maintenance medication during the Treatment Period. 
Participants will record the following in their eDiary each day (pre-dose): 
• 
Respond to eDiary alerts, as applicable (Section 8.1.2.1 and Section 8.1.2.8) 
• 
Daily asthma symptoms, activity limitations, and night-time awakening questions 
(Section 8.1.2.3) 
• 
Number of puffs of rescue medication (albuterol) (Section 8.1.2.4) 
• 
Ensure collection of PEF (Section 8.1.2.5) 
• 
Daily use of inhaled asthma maintenance treatment including run-in BD MDI and study 
interventions (Section 8.1.2.6) 
 
8.1.2.3 
Asthma Symptoms  
The participant will record their symptoms in the eDiary before dosing each morning 
(reflecting nighttime symptoms) and each evening (reflecting daytime symptoms). 
The daily eDiary questions will ask participants about severity of nighttime and daytime 
symptoms of asthma; limitations on activities, albuterol use, and prompt the participant to 
electronically record PEF. Daytime is defined as the time period between the morning peak 
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function assessment. Night-time is defined as the time period between the evening peak 
flow/lung function assessment (at bedtime) and the morning peak flow/lung function 
assessment. 
Nocturnal awakenings due to asthma symptoms will be recorded by the participant in the daily 
eDiary each morning by answering the questions whether he/she woke up during the night due 
to asthma symptoms by a “yes” or “no” response. 
8.1.2.4 
Rescue Medication Use  
Use of rescue medication (albuterol) will be recorded in the eDiary each morning (reflecting 
night-time albuterol use) and each evening (reflecting daytime albuterol use). The participant 
will record the total number of “puffs” of albuterol used over the time period. For example, 
when rescue medication is required, and 2 actuations are inhaled, this should be recorded as 
2 “puffs”. If the participant requires 4 actuations, this should be recorded as 4 “puffs”. 
8.1.2.5 
Peak Expiratory Flow  
The PEF is to be assessed using the Sponsor-provided PEF meter that is linked to the eDiary 
device. Participants will be dispensed and trained on the device at Visit 1. The eDiary will 
prompt the participant to obtain 3 peak flow assessments every morning and 3 every evening. 
Once the participant has completed the peak flow assessment, the data will be automatically 
transmitted from the PEF to the eDiary. The best (highest) of 3 PEF efforts BID will be 
captured in the eDiary. 
Participants will complete the PEF maneuver at home in the morning and in the evening after 
recording asthma symptoms and before dosing with run-in BD MDI during the Screening 
Period or study intervention during the Treatment Period. In addition, PEF will be measured 
before use of rescue albuterol. 
At Visit 4, a PEF baseline will be calculated to define a stability limit. The stability limit is 
defined as the average of the available morning PEF eDiary recordings during the last 7 days 
before Visit 4 (ie, the baseline PEF), multiplied by 0.8. The PEF stability limit will be used to 
define a threshold for an eDiary alert. 
8.1.2.6 
Inhaled Asthma Maintenance Use  
Inhaled asthma maintenance use includes run-in BD MDI, study intervention or asthma 
maintenance medication (for participants who discontinue study intervention). The eDiary will 
ask participants about daily inhaled asthma maintenance use each morning and each evening. 
Participants will record the prior evening dose in the morning eDiary entry, and the morning 
dose will be recorded in the evening eDiary entry. 
Rescue inhaler use will be collected in a separate eDiary question. 

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8.1.2.7 
Study Visit eDiary Data Collection  
Participants will also fill out PRO questionnaires electronically on the eDiary at study visits 
according to the SoA (Table 1). On the morning of a visit day, participants will wait until the 
visit before filling out the eDiary. Participants will complete all required eDiary questions 
prior to dosing during the visit; all PROs should be completed after the -60-minute spirometry 
assessment. Participants will bring their eDiary to every clinic visit after Visit 1. 
Table 9 describes the number of items and an estimate of the time to complete the PROs 
administered at visits; however, not every questionnaire is administered at every visit and the 
completion time varies by participant. The eDiary device will be programmed to administer 
the appropriate questionnaires in the correct order in accordance with the SoA (Table 1). Site 
personnel must trigger a study visit for the PROs to appear on the eDiary device. Training on 
the eDiary device will be provided prior to study start up. 
The estimated timeframe for completion of all the PROs during a visit is about 20 minutes. 
Table 9 
Patient Reported Outcomes Administered at the Clinic Visit  
 
Number of Questions 
Estimated Minutes to Complete 
eDiary – morning (pre-dose) 
10 
3 
ACQ (pre-dose) 
6 
2 
AQLQ(s)+12 (pre-dose) 
32 
8 
EQ-5D (pre-dose) 
6 
2 
AIRQ (pre-dose) 
10 
3 
Asthma Control Questionnaire (ACQ), Asthma Impairment and Risk Questionnaire (AIRQ), Asthma Quality of 
Life Questionnaire 12 Years of Age and Older (AQLQ(s)+12), European Quality of Life-5 Dimensions (EQ-5D) 
 
Asthma Control Questionnaire 
The ACQ [Juniper et al 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. 
There are 3 ways to score the ACQ that are being analyzed in this study to support the 
endpoints: ACQ-5, ACQ-6, and ACQ-7. The ACQ-5 and ACQ-6 scores are supported entirely 
by patient-reported symptom and reliver use data. The ACQ-7 scoring includes both the ACQ-

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6 PRO items and a clinician reported pre-bronchodilator FEV1 percent predicted normal value 
in the scoring algorithm. 
The ACQ-6 will be administered to participants. Participants are asked 6 questions to recall 
how their asthma has been during the previous week by responding to one bronchodilator use 
question and 5 symptom questions. Questions are weighted equally and scored from 0 (totally 
controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is the mean of the responses 
to items 1-6, and the mean ACQ-5 score is the mean of the responses to items 1-5. 
The score for the ACQ-7 includes the ACQ-6 PRO items and FEV1 reported by the clinician. 
The mean ACQ-7 score is the mean of responses to the ACQ-6 PRO items and the 
one clinician reported FEV1 item. 
Control categories based on the ACQ-5, ACQ-6, and ACQ-7 scores are the same. 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 et al 2006]. 
Individual changes of at least 0.5 are considered clinically meaningful. 
The Investigator/authorized delegate will check participant’s adherence to the ACQ at each 
visit per the SoA (Table 1). 
Asthma Quality of Life Questionnaire 12 Years of Age and Older 
The AQLQ(s)+12 is a 32-item questionnaire that measures health-related quality of life 
experienced by patients with asthma who are 12 years or older in age [Juniper et al 2005, 
Juniper et al 1999b, Juniper et al 1994, Juniper et al 1993, Juniper et al 1992]. 
The AQLQ(s)+12 comprises 4 separate domains (symptoms, activity limitation, emotional 
function, and environmental stimuli) and a global score. 
Participants are asked to recall the previous 2 weeks and score each of the questions on a 
7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The overall score is 
calculated as the mean response to all questions. The individual domain scores (symptoms, 
activity limitation, emotional function, and environmental stimuli) are the means of the 
responses to the questions in each of the domains. Individual AQLQ(s)+12 total or domain 
score changes ≥ 0.5 are considered clinically meaningful. 
The questionnaire will be completed according to the SoA, starting at randomization. 
The Investigator/authorized delegate will check participant adherence to the AQLQ(s)+12 at 
each visit per the SoA (Table 1). 

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European Quality of Life-5 Dimensions 
The EQ-5D [EuroQol Group 2020] is a standardized instrument for use as a measure of health 
outcome. Applicable to a wide range of health conditions and treatments, it provides a simple 
descriptive profile and a single index value for health status. The EQ-5D data will be collected 
using EQ-5D-Y for the participants age between 12 and 15 years old at randomization and 
EQ-5D-5L for the participants age 16 years and older [EQ-5D User Guides: EQ-5D-Y 2014, 
EQ-5D-5L 2019]. The participants will complete the same questionnaire used at 
randomization throughout the study. The EQ-5D-5L consists of 2 assessments, a descriptive 
system, and a VAS. The descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 
5 severity levels: no problems, slight problems, moderate problems, severe problems, and 
extreme problems. The EQ-5D-Y consists of 2 assessments, a descriptive system, and a VAS. 
The descriptive system comprises the same 5 dimensions as the EQ-5D-5L, but using a child-
friendly wording (mobility, looking after myself, doing usual activities, having pain or 
discomfort, feeling worried, sad, or unhappy). Each dimension has 3 levels: no problems, 
some problems, a lot of problems. 
EQ-5D-5L and EQ-5D-Y index score can be calculated based upon participants’ responses to 
the 5 dimensions and using an appropriate value set [Corren et al 2007, EQ-5D User Guides: 
EQ-5D-5L 2019, EQ-5D-Y 2014]. A value set provides values (weights) for each health state 
description according to the preferences of the general population of a country/region. 
The VAS records the respondent’s self-rated health on a 20 cm, 0 to 100 vertical scale with 
endpoints labeled “the best health you can imagine” and “the worst health you can imagine” 
with higher scores corresponding to a better health state. This information is used as a 
quantitative measure of health as judged by the individual respondents. 
The EQ-5D will be completed on the eDiary by the participant per the SoA (Table 1). The 
Investigator/authorized delegate will check participant’s adherence to the EQ-5D at each visit. 
Asthma Impairment and Risk Questionnaire 
The Asthma Impairment and Risk Questionnaire is a PRO tool intended to identify patients 
12 years and older whose health may be at risk because of uncontrolled asthma [Murphy et al 
2020]. It has 10 questions that ask about respiratory symptoms, activity limitation, sleep, 
rescue medication use, social activities, exercise, difficulty controlling asthma, and 
exacerbations. All items have a yes/no response option, and the tool is scored by summing the 
total number of ‘yes’ responses. This sum score is used to assess level of asthma control 
where: 0-1 is well-controlled, 2-4 is not well-controlled, and 5-10 is very poorly controlled. 
Thus, a higher score indicates worse control status. 
The AIRQ items have 2 different recall periods: The first 7 impairment items are evaluated 
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study will use the past 3 months recall. The AIRQ will be administered and completed on the 
eDiary by the participant as per SoA (Table 1). 
8.1.2.8 
Symptom Worsening Assessment and eDiary Alert System  
The eDiary will be programmed to alert both the participant and study site if any of the 
thresholds listed below are met on at least 2 consecutive days: 
• 
PEF: a decrease in morning PEF of ≥ 20% as compared with baseline average (baseline is 
defined in Section 9.5.1.3), and/or 
• 
Rescue albuterol use: an increase of ≥ 4 inhalations compared with baseline average use, 
and/or 
• 
Nighttime awakening: an increase of 2 or more nights with awakenings due to asthma 
requiring rescue medication use over a 7-day period compared with the average baseline 
and/or ≥ 6 out of the 7 previous nights with awakenings due to asthma requiring rescue 
medication, and/or 
• 
Asthma symptoms: an increase of total asthma symptom score (the sum of daytime plus 
nighttime) of at least 2 units above the average baseline or the highest possible score 
(daily score of 6) 
 
An eDiary alert is not an asthma exacerbation per se. Although the eDiary alert should initiate 
contact between the participant and the investigational site within 48 hours of the alert, the 
Investigator or designee will always assess the participant’s symptoms and determine whether 
to treat the participant for an asthma exacerbation. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.2.1 
Medical/Surgical History  
Medical history will be collected at Visit 1 and updated during the Screening Period, if 
necessary. The number of asthma exacerbations requiring systemic corticosteroids, ER visits, 
and/or hospitalizations within the previous 12 months will be collected at Visit 1. 
8.2.2 
Physical Exam  
A brief physical examination will be performed as specified in the SoA (Table 1). The brief 
physical examination will include the following: 
General appearance, respiratory, cardiovascular, and abdomen 

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8.2.3 
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. 
8.2.4 
Vital Signs  
Vital signs will be performed at timelines as specified in the SoA (Table 1). 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in either a supine or seated position in a quiet setting without distractions (eg, 
television, cell phones). 
8.2.5 
Electrocardiograms  
An ECG will be performed using the study-provided device at visit as specified in the SoA 
(Table 1). 
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, quality checked, and kept in case 
of further need for re-evaluation. 
8.2.6 
Clinical Safety Laboratory Assessments  
Blood and urine samples for determination of clinical chemistry and hematology will be taken 
pre-dose prior to 1000 + 1 hour at the visits indicated in the SoA (Table 1). 
Clinical safety laboratory tests will be analyzed by a central laboratory according to 
standardized, validated assays with the exception of highly sensitive urine pregnancy tests. 
The laboratory will supply detailed procedures for the preparation and collection of blood 
samples along with all containers needed for their collection. Urine pregnancy tests will be 
performed at the clinical site using a highly sensitive test product provided to the site. 
The Investigator should assess the available results with regard to clinically relevant 
abnormalities. The laboratory results should be signed and dated and retained at the center as 
source data for laboratory variables. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator at unscheduled visits. The date of collection will be recorded on the appropriate 
eCRF. 

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For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.6. 
The following laboratory variables will be measured (Table 10): 
Table 10 
Laboratory Variables  
Hematology (whole blood) 
Clinical Chemistry (serum or plasma) 
Hemoglobin 
Creatinine 
Leukocyte count (including differential count) 
Bilirubin, total 
Eosinophil count 
Alkaline phosphatase 
Platelet count 
Aspartate transaminase 
 
Alanine transaminase 
Other Tests 
Albumin 
Highly sensitive urine pregnancy test for women of 
childbearing potential 
Potassium 
Calcium, total 
Sodium 
Glucose 
 
8.2.7 
Asthma Exacerbations  
An asthma exacerbation is defined as worsening of asthma that requires a medical intervention 
as described in Section8.2.7.4. 
Worsening of asthma is defined as at least one of the following 3 elements of worsening listed 
below fulfilled for at least 2 consecutive days (see Section 8.1.2.8 for eDiary alerts): 
• 
worsening of asthma signs/symptoms (see Section 8.2.7.1) 
• 
increased use of ‘as-needed’ rescue/reliever medication (see Section 8.1.2.4) 
• 
deterioration of PEF (see Section 8.1.2.5) 
 
8.2.7.1 
Definition of Worsening of Asthma Signs/Symptoms  
The worsening/onset of signs/symptoms include deterioration in at least one of the following: 
• 
asthma symptoms (eg, shortness of breath, wheezing, chest tightness, cough) 
• 
night-time awakening due to asthma 
• 
activity limitation due to asthma 
• 
physical exam finding consistent with deterioration of asthma 
 

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8.2.7.2 
Investigator Justified Asthma Exacerbations  
The majority of asthma exacerbations should be associated with worsening of asthma 
signs/symptoms described in Section 8.2.7.1. However, clinical presentations may vary among 
participants and the associated asthma worsening signs/symptoms and/or duration may not 
meet the definition of a moderate or severe exacerbation. For moderate and severe 
exacerbations without an eDiary alert date recorded in the eCRF, the Investigator will record 
the worsening signs/symptoms with duration and provide the justification(s) for diagnosing 
the exacerbation (eg, rapid onset and/or severity of worsening asthma) in the eCRF. If an 
exacerbation is recorded in the setting of treatment with additional systemic corticosteroids for 
less than 3 days (Section 8.2.7.3), the Investigator will record whether it is considered severe 
or moderate and the justification(s) for diagnosis and treatment duration (eg, single 
administration of IV corticosteroid without follow-up oral corticosteroid prescribed) in the 
eCRF. 
8.2.7.3 
Severity of Asthma Exacerbation  
All protocol-defined asthma exacerbations will be classified as severe or moderate based on 
the following treatment criteria [Reddel et al 2009]. 
An asthma exacerbation will be considered severe if it results in at least one of the following: 
• 
A course of systemic corticosteroids for at least 3 consecutive days to treat symptoms of 
asthma worsening. 
• 
An ER or urgent care visit (defined as evaluation and treatment for < 24 hours in an 
emergency department or urgent care center) due to asthma that required treatment with 
systemic corticosteroids 
• 
An in-patient hospitalization (defined as admission to an in-patient facility and/or 
evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma 
• 
Death related to asthma 
 
A moderate asthma exacerbation is defined as a worsening of asthma symptoms (defined in 
Section 8.2.7.1) that results in an additional ICS for at least 3 days and did not meet any of the 
criteria for a severe asthma exacerbation. 
8.2.7.4 
Treatment for Asthma Exacerbations  
Asthma exacerbations should be treated at the discretion of the Investigator. If a participant 
experiences an asthma exacerbation, they should continue dosing with study intervention if 
Investigator or treating physician assess it is safe do so. 
In the instance a participant is hospitalized for a severe asthma exacerbation and study 
intervention is interrupted, the participant may be able to restart study intervention upon 
stopping the asthma medications. 

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The recommended treatment [GINA 2020] for a severe asthma exacerbation is prednisolone 
up to 50 mg/day (or equivalent) for adults once daily in the morning for 5 to 7 days. A 
prednisolone dose of 1 to 2 mg/kg/day up to a total of 50 mg/day may be considered 
appropriate in adolescents who may alternatively be treated in the same manner as adults. 
Tapering the prednisolone dose is not needed if the treatment has been given for less than 
2 weeks [GINA 2020]. A maximum duration for a short course of systemic corticosteroids is 
defined as 14 days. 
Use of depot corticosteroids in the treatment of asthma exacerbations is prohibited. 
The recommended treatment for a moderate asthma exacerbation is a short course of an 
additional ICS for 5 to 7 days if deemed clinically relevant. If a participant has not adequately 
improved at the end of 2 weeks of treatment with an additional ICS, a short course of systemic 
corticosteroids should be given, and the asthma exacerbation will be considered as a severe 
asthma exacerbation. 
8.2.7.5 
Onset and Duration of Asthma Exacerbations  
For moderate or severe asthma exacerbations, the duration is defined by the prescribed 
treatment. For severe asthma exacerbations, the duration of hospitalization or ER visit could 
replace the duration of prescribed systemic corticosteroids as described below. 
For severe asthma exacerbations: 
• 
The start date will be defined as the start date of prescribed treatment with a systemic 
corticosteroid, the hospital/ER admission date, or the date of death (if the exacerbation 
resulted in death), whichever is earlier. 
Note: The start date could be the start date of an additional ICS when treatment is 
switched to at least 3 days of systemic corticosteroids as described in Section 8.2.7.4. 
• 
The stop date is defined as the last day of prescribed systemic corticosteroids, hospital/ER 
discharge date or the date of death (from the exacerbation), whichever is later. 
• 
If multiple treatments are prescribed for the same exacerbation, the earliest start date and 
the latest stop date will be used. 
• 
For a severe asthma exacerbation requiring hospitalization with no documented systemic 
corticosteroid treatment, hospitalization admission/discharge dates will be used as 
start/stop dates as described in Section 8.2.7.3. 
 
For moderate asthma exacerbations: 
• 
The start date is defined as the first day of the additional dose of ICS treatment. 
• 
The end date is defined as the last day of the above treatment. 

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In order to ensure that the same event is not counted twice, consecutive exacerbations with 
start and stop days ≤ 7 days apart will be considered the same event of the highest severity. If 
there is a > 7-day time period between ICS or systemic corticosteroid treatments, then 
separate exacerbations should be recorded in the eCRF. 
8.2.7.6 
Approach for Capturing Asthma Exacerbations  
A copy of the medical records should be obtained for exacerbations evaluated and treated at a 
non-study center (eg, by the primary care Health Care Provider or at an emergency 
department/hospital) and details entered in the exacerbation eCRF in a timely fashion. 
Changes in concomitant medication due to the exacerbation must be recorded in the 
appropriate module of the eCRF. 
All moderate or severe asthma exacerbations (including Investigator justified asthma 
exacerbations) following Visit 1 must be captured using the Asthma Exacerbation eCRF. 
If there were eDiary alerts within the window of -7 to + 1 days of the initiation of 
exacerbation treatment, the exacerbation will be considered an eDiary supported exacerbation. 
One of the eDiary alert dates within the defined window should be captured on the 
exacerbation eCRF. If an exacerbation is not supported by an eDiary alert date in the defined 
window, then Investigators will provide justifications and record in the eCRF. 
If an asthma exacerbation meets the definition of an SAE, the exacerbation will be reported as 
an SAE as well as on the Asthma Exacerbation eCRF. 
Any symptoms of asthma or an asthma exacerbation of any severity will be considered the 
disease under study and will not be reported as AEs unless meeting the definition of an SAE 
or leads to discontinuation of study intervention. 
8.2.8 
Other Safety Assessments  
8.2.8.1 
Paradoxical Bronchospasm  
Monitoring for paradoxical bronchospasm will occur at each in-clinic visit in which there are 
post-dose spirometry assessment during the Treatment Period (Visits 4 and 7 or Treatment 
Discontinuation/Study Withdrawal Visit) at 15- and 30-minutes post-dose. In this study, 
paradoxical bronchospasm is defined as a reduction in FEV1 of > 20% from baseline (ie, the 
mean FEV1 values obtained 60 and 30 minutes prior to study intervention administration) that 
occurs within 30 minutes post-dosing with associated symptoms of wheezing, shortness of 
breath, or cough. If an event meets both the spirometry and the symptoms for a paradoxical 
bronchospasm, then it will be reported as an AE. 

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8.3 
Adverse Events and Serious Adverse Events  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
Adverse events will be collected from first intake of study intervention after Visit 1, during 
screening and throughout the treatment period and including the follow-up period. 
All SAEs will be recorded from the time of signing of the informed consent form. 
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 participant treated by him or her, the 
Investigator shall, without undue delay, report the SAE to AstraZeneca. 
8.3.2 
Follow-up of AEs and SAEs  
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate 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. 
Adverse event variables 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Maximum intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study intervention(s) (yes or no) 
• 
Action taken with regard to study intervention(s) 
• 
Outcome 
 

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In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
AE is serious due to 
• 
Date of hospitalization 
• 
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 
 
8.3.3 
Causality Collection  
The Investigator should assess causal relationship between study intervention 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 study intervention?’ 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 
Adverse Events Based on Signs and Symptoms  
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: ‘Have you/the child had any health problems since 
the previous visit/you were last asked?’, or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately. 
8.3.5 
Adverse Events Associated with Use of ICS and LABAs  
Certain AEs have been identified as associated to the class of drugs being studied. Known 
effects of LABAs include cardiovascular and tremor effects. Local corticosteroid effects 
include oral candidiasis, oropharyngeal candidiasis, dysphonia, and throat irritation. These 

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8.3.9 
Reporting of Serious Adverse Events  
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, Investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within one 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 DES within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
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 Investigator or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the eCRF is not available, then the Investigator or other study site staff reports an SAE to 
the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of an SAE, see Appendix B of the CSP. 
The reference document for definition of expectedness/listedness is the Investigator Brochures 
for AstraZeneca drugs and for the comparator products (including any AstraZeneca 
comparator). 
8.3.10 
Pregnancy  
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca from Visit 1 
except for: 
• 
If the pregnancy is discovered before the study participant has received any study 
intervention 
 

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8.3.10.1 
Maternal Exposure  
If a participant becomes pregnant during the course of 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 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital anomaly/birth defect) should be followed up and documented even 
if the participant was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within one day (ie, 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 DES within one or 
5 calendar days for SAEs (see Section 8.3.9) 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. 
8.3.11 
Medication Error, Drug Abuse, and Drug Misuse  
8.3.11.1 
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 one 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 medication error, drug abuse, or misuse (see Section 8.3.9) and 
within 30 days for all other events. 
8.3.11.2 
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. 

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The full definition and examples of a medication error can be found in Appendix B 4. 
8.3.11.3 
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. 
8.3.11.4 
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 authorized product information, or 
for unauthorized 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. 
8.3.12 
Device Constituent Deficiencies  
Combination products with a device constituent are being provided in this study. In order to 
fulfill regulatory reporting obligations worldwide, the Investigator is responsible for the 
detection and documentation or events meeting the definition of a device deficiency that occur 
during the study with the device constituent of the combination product. 
Device constituent deficiencies from this study will be collected and monitored to ensure the 
safety of participants and improve the safety and performance of the device. 
Device constituent deficiencies will not be presented in the CSR, but where required by local 
regulations, deficiencies will be summarized in the relevant periodic report. 
The definition of a device constituent deficiency is an inadequacy of a device constituent with 
respect to its identity, quality, durability, reliability, safety, or performance. Device constituent 
deficiencies include malfunctions, use errors, and information supplied by the manufacturer. 
The AstraZeneca Device Constituent Report Form and/or Product Complaint Intake Form will 
be used to collect the deficiency. 
8.3.12.1 
Time Period for Detecting Device Constituent Deficiencies  
Device constituent incidents or malfunctions will be detected, documented, and reported 
during all periods of the study in which the device constituent is used. 
If the Investigator learns of any device constituent deficiency at any time after a participant 
has been discharged from the study, and such incident is considered reasonably related to a 
device constituent provided for the study, the Investigator will promptly notify AstraZeneca. 

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8.3.12.2 
Follow-up of Device Constituent 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 originally completed form with all changes 
signed and dated by the Investigator. 
8.3.12.3 
Prompt Reporting of Device Constituent Deficiencies to AstraZeneca  
Device constituent deficiencies will be reported to AstraZeneca within 24 hours after the 
Investigator determines that the event meets the protocol definition of a device constituent 
deficiency. 
The AstraZeneca Device Constituent Deficiency Report Form and/or Product Complaint 
Intake Form will be sent to AstraZeneca by email to the AstraZeneca DES. If paper is 
unavailable, then Investigator or other study site staff reports a SAE to the appropriate 
AstraZeneca representative by telephone. AstraZeneca will be the contact for the receipt of 
device constituent deficiency reports. 
8.4 
Overdose  
For this study, any dosing of BFF MDI, BD MDI, or Symbicort TBH of more than 2 
inhalations BID will be considered an overdose. 
• An overdose with associated AEs is recorded as the AE diagnosis/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. 
 
If an overdose on an AstraZeneca study intervention 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 DES within one or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.9) and within 30 days 
for all other overdoses. 
8.5 
Human Biological Samples  
8.5.1 
Pharmacokinetics  
Pharmacokinetic parameters are not evaluated in this study. 

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8.5.2 
Immunogenicity Assessments  
Immunogenicity assessments are not evaluated in this study. 
8.5.3 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6 
Human Biological Sample Biomarkers  
Biomarkers are not evaluated in this study. 
8.7 
Optional Genomics Initiative Sample  
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA and is subject to agreement in the Optional Genomics Initiative Research 
Information of the ICF. 
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
See Appendix C for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection, shipment, and destruction of these samples can be found either in the 
appendices or in the Laboratory Manual. 
For storage and destruction of genetic samples see Appendix C. 
8.8 
Healthcare Resource Utilization Data  
Healthcare resource utilization data associated with medical encounters, will be collected in 
the eCRF by the Investigator and study site personnel for all participants throughout the study. 
During screening at Visit 3, HCRU information will be collected with a ‘one year’ recall 
period. All the subsequent visits after Visit 4, will collect HCRU information with a recall 
period of ‘since the last scheduled visit’. Protocol-mandated procedures, tests, and encounters 
are excluded. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical Hypotheses  
For the efficacy comparisons for the primary objective, the null hypothesis will be that the 
mean treatment difference (BFF MDI 320/9.6 μg vs BD MDI 320 μg) is zero (mean treatment 
effects are equal). The alternative hypothesis is that the mean treatment difference is not zero 
(mean treatment effects are not equal). All p-values will be reported as two-sided. 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
92 of 130 
Table 11 
Populations for Analyses  
Analysis set 
Description 
Safety set 
All participants who are randomized to study intervention and receive any 
amount of the study intervention. Participants will be analyzed according to 
the actual study intervention received rather than randomized. 
 
9.5 
Statistical Analyses  
The SAP will be finalized before the earliest of the following milestones: 90 days after first 
participant in, first Data Monitoring Committee or first Dry Run and will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and secondary endpoints. Additional analyses assessing the impact of 
SARS-CoV-2 pandemic, or any other natural event may be included in the SAP. 
9.5.1 
General Considerations  
9.5.1.1 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics data will be summarized by treatment for the 
Efficacy and Safety sets. 
9.5.1.2 
Visit Windows  
For post-randomization visit based analyses, the variables are summarized based on data from 
scheduled or repeat visits (including premature study intervention discontinuation visits) by 
mapping the visit date to an adjusted analysis-defined visit window irrespective of the visits’ 
label numbering. The adjusted analysis-defined windows will be specified in the SAP. For 
spirometry endpoints by timepoint pre- and post-dosing, the assessments will be allocated to 
derived nominal collection time windows of minutes from study intervention dosing. These 
will be specified in the SAP. Actual time will be used for the AUC calculations. 
9.5.1.3 
Baseline  
For FEV1 and onset of action on Day 1, baseline is defined as the mean of the pre-dose FEV1 
assessments on Visit 4 (Day 1). For the asthma PROs, baseline is defined as the last non-
missing value before first dose of randomized IP. For daily eDiary metrics (rescue medication, 
awakenings, PEF, and asthma symptoms scores), baseline is defined as the average of eDiary 
metrics measured during last 7 days before randomization. For severe asthma exacerbation 
history in the past 12 months before Visit 1, baseline is the number of severe asthma 
exacerbations reported on the Respiratory Disease History eCRF page. 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
94 of 130 
Rate of Severe Asthma Exacerbations 
The rates of severe asthma exacerbations will be analyzed using negative binomial regression 
in the D5982C00005 and D5982C00006 studies separately. The negative binomial model for 
each study will include treatment, baseline trough FEV1, percent albuterol reversibility, 
baseline severe asthma exacerbation history (0, ≥ 1), prior maintenance medication (ICS 
versus ICS/LABA), and region as covariates. Furthermore, the rates of severe asthma 
exacerbations will be analyzed for the pooled individual participant data from both studies 
(D5982C00006: BFF 320/9.6 μg, BFF 160/9.6 μg, BD 320 μg and D5982C00005: 
BFF 160/9.6 μg, BD 160 μg treatment arms. The Symbicort treatment arm in Study 
D5982C00006 will not be included in the pooled analysis.). The pooled analysis will use all 
available data (over the planned 12-week treatment period in D5982C00005 and over the 
24-week treatment period for study D5982C00006) to maximize the amount of data included. 
For the pooled analysis, a negative binomial additive model will be used with the same 
covariates, except it will also include study, budesonide (1 if the budesonide dose is 320 μg, 
and 0 if the budesonide dose is 160 μg), and formoterol (1 if the formoterol dose is 9.6 μg, and 
0 if no formoterol dose) instead of treatment as covariates. The comparison of interest is the 
formoterol effect. For the pooled analysis, one dispersion parameter will be estimated. Further 
details will be specified in the SAP. 
Under the primary strategy for handling ICEs, all available data will be utilized irrespectively 
of any ICE, except new medication in conjunction with premature IP discontinuation which 
will be considered an unfavourable outcome. In addition, a supportive analysis utilizing While 
on Treatment strategy will be performed. 
Asthma exacerbations will be considered separate events if more than 7 days are between the 
recorded stop date of the earlier event and start date of the later event. Time at risk of 
experiencing a severe exacerbation will be used as an offset variable in the model. Time 
during a severe exacerbation or in the 7 days following a severe exacerbation will not be 
included in the calculation of exposure. 
The number and percentage of participants with severe exacerbations in each treatment group 
will be tabulated for individual study and pooled studies. 
Change from Baseline in Mean Number of Puffs of Rescue Medication Use (puffs/day) 
The mean daily number of puffs of rescue medication use will be calculated overall and for 
each of the 4-week intervals during the Treatment Period. For every period of time for which 
the mean number of puffs of rescue medication will be calculated, missing values will be 
ignored in both the numerator and denominator. As such, the denominator will be adjusted 
based on the number of days (including half days) with non-missing values. Under the 
primary strategy for handling ICEs, all available data will be utilized irrespectively of any ICE 
except new medication in conjunction with premature IP discontinuation which will be 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
95 of 130 
considered an unfavourable outcome. A repeated measures ANCOVA model will be used to 
analyze change from baseline in average daily rescue albuterol use. The model will include 
treatment, the number of the relevant 4-week interval (interval 1 to 6), prior maintenance 
medication (ICS versus ICS/LABA), severe asthma exacerbation history (0, ≥ 1), and the 
treatment-by-4-week interval interaction as categorical covariates and baseline daily rescue 
albuterol use, baseline trough FEV1, and percent reversibility as continuous covariates. An 
unstructured variance-covariance matrix will be fit. If this model fails to converge, an 
alternative structure will be employed as pre-specified in the SAP. Contrasts will be used to 
obtain estimates of the treatment differences over 24 Weeks or over 12 to 24 Weeks. Two-
sided p-values and point estimates with two-sided 95% CIs will be produced for each 
treatment difference. 
Percentage of Responders in ACQ-7 and ACQ-5 (≥ 0.5 Decrease Equals Response) 
Responder analyses will be performed for ACQ-7 and ACQ-5 at Week 24, over 24 Weeks or 
over 12 to 24 Weeks. Responders are defined as participants with a decrease in total score of 
≥ 0.5 points from baseline. Under the primary strategy for handling ICE, all available data will 
be utilized to determine response irrespectively of any ICE except new medication in 
conjunction with premature IP discontinuation where a participant will be considered 
non-responder. For supportive analyses, participants who experience an ICE (except for 
discontinuation of study intervention for reasons related to global/country situation) will be 
classified as non-responders at visits subsequent to the ICE under the Composite estimand 
strategy approach to ICEs. Data following study intervention discontinuation for reasons 
related to global/country situation will be considered missing and will not be imputed. Those 
datapoints are considered to be missing completely at random and will be excluded from the 
analysis. Intermittently missing data will be classified as non-response. Logistic regression 
will be used to compare the treatment groups with treatment and prior maintenance 
medication (ICS versus ICS/LABA) as categorical covariates and baseline instrument score, 
baseline trough FEV1, and percent reversibility as continuous covariates. P-values and Odds 
Ratios with 95% CIs will be produced for each treatment comparison. 
Percentage of Responders in AQLQ(s)+12 (≥ 0.5 Increase Equals Response) 
Responder analyses will be performed for AQLQ(s)+12 at Week 24, over 24 Weeks or over 
12 to 24 Weeks for participants 12 years and older. Responders are defined as participants 
with an improvement of ≥ 0.5 points increase over baseline. The strategies for handling ICEs 
and missing data are similar to the ones used for percentage of responders in ACQ-5. Logistic 
regression will be used to compare the treatment groups, similar to the one used for 
percentage of responders in ACQ-5. P-values and Odds Ratios with 95% CIs will be produced 
for each treatment comparison. 

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Onset of Action on Day 1 
All spirometry attempts at Visit 4 (Day 1) that meet ATS/ERS acceptability criteria will be 
recorded along with the actual time. The onset of action for BFF MDI 320/9.6 μg will be 
evaluated on Day 1 by comparing BFF MDI 320/9.6 μg vs BD MDI in the mean change from 
baseline in FEV1 at the 5-minute post-dose timepoint. Comparisons will also be made at 
additional timepoints but will not be controlled for multiplicity. A repeated measures 
ANCOVA will be fit to the Day 1 post-baseline data. This model will include treatment, 
timepoint, prior maintenance medication (ICS versus ICS/LABA), and treatment-by-timepoint 
interaction as categorical covariates and baseline trough FEV1 and percent reversibility as 
continuous covariates. An unstructured variance-covariance matrix will be used to model the 
variance-covariance structure. If this model fails to converge, an alternative structure will be 
employed as pre-specified in the SAP. Contrasts will be used to obtain estimates of the 
treatment differences on Day 1 at the 5-minute post-dose timepoints. Two-sided p-values and 
point estimates with two-sided 95% CIs will be produced for each treatment difference of BFF 
MDI 320/9.6 μg vs BD MDI, and BFF MDI 320/9.6 μg vs BFF MDI 160/9.6 μg. Furthermore, 
descriptive statistics will be presented by treatment group. A supportive within-group T-test to 
demonstrate that the mean change from baseline in FEV1 at 5 minutes post-dose is statistically 
greater than 100 mL will also be provided with corresponding p-value and 95% CI. 
9.5.2.3 
Tertiary/Exploratory Endpoint(s)  
The following tertiary/exploratory endpoint efficacy analyses will be conducted for the While 
on Treatment estimand strategy for ICEs except for ACQ and AQLQ(s)+12 endpoints which 
will use the primary strategy for handling of ICEs. Results from tertiary/exploratory analyses 
may be reported outside of the CSR. 
Percentage of Rescue-Free and Symptom-Free Days 
The percentages of rescue-free days and symptom-free days will each be analyzed over 
24 Weeks and over 12 to 24 Weeks. Additionally, analyses will be conducted over each 
4-week interval in the study. A repeated measures analysis of covariance model will be used 
with treatment, the number of the relevant 4-week interval (interval 1 to 6), prior maintenance 
medication (ICS versus ICS/LABA), severe asthma exacerbation history (0, ≥ 1), and the 
treatment-by-4-week interval interaction as categorical covariates. Baseline percentage of 
endpoint days (where endpoint is rescue-free or symptom-free), baseline trough FEV1, and 
percent reversibility will be continuous covariates. 
Peak Change from Baseline in FEV1 
Peak change from baseline in FEV1 will be analyzed using a repeated measures ANCOVA 
model. The model will be similar as the one used for the primary analyses. Contrasts for 
treatment comparisons over 24 Weeks and for each visit will be derived from the model. 

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Time to Peak FEV1 on Day 1 
Time to peak FEV1 on Day 1 will be analyzed with ANCOVA model to compare the 
treatment groups, adjusted for prior maintenance medication (ICS versus ICS/LABA), 
baseline trough FEV1, and percent reversibility. The time to peak will be based on the actual 
rather than nominal assessment time. If necessary, non-parametric or semi-parametric 
methods may be used. Details will be provided in the SAP. 
Percentage of Peak FEV1 Improvement Achieved at 5 Minutes Post-dose on Day of 
Randomization 
Descriptive statistics will be presented by treatment group for the percentage of peak FEV1 
improvement achieved at 5 minutes post-dose on the day of randomization. 
Supportive analyses of the proportion of participants meeting improvement thresholds on 
Day 1 will also be conducted to compare the speed of onset between treatments. The 
percentage of participants with ≥ 12% improvement over baseline in FEV1 at 5 minutes post-
dose and at other timepoints on Day 1 will be compared between treatment groups using 
logistic regression adjusted for prior maintenance medication (ICS versus ICS/LABA), 
percent reversibility, and baseline trough FEV1. Details will be given in the SAP, where 
alternative thresholds and timepoints may be defined. 
Change from Baseline in FVC, PEF, and FEF25-75 Evaluated Using AUC0-3 
Change from baseline in FVC, PEF, and FEF25-75 evaluated using AUC0-3 will be analyzed 
using a repeated measures ANCOVA model. The model will be similar as the one used for the 
primary analyses. Contrasts for treatment comparisons over 12 Weeks and for each visit will 
be derived from the model. 
Change from Baseline in Morning Pre-Dose Trough PEF 
Change from baseline in morning pre-dose trough PEF will be analyzed using a repeated 
measures ANCOVA model. The model will include treatment, 4-week interval (interval 1 to 
6), prior maintenance medication (ICS versus ICS/LABA), and treatment-by 4-week interval 
interaction as categorical covariates and baseline morning pre-dose trough PEF, baseline 
trough FEV1, and percent reversibility as continuous covariates. An unstructured variance-
covariance matrix will be used to model the variance-covariance structure. If this model fails 
to converge, an alternative structure will be employed as pre-specified in the SAP. Contrasts 
will be used to obtain estimates of the treatment differences over 24 weeks, over 12 to 24 
Weeks, and for each 4-week interval. Two-sided p-values and point estimates with two-sided 
95% CIs will be produced for each treatment difference. 
Change from Baseline in Evening Pre-Dose PEF 
Change from baseline in evening pre-dose PEF will be analyzed over 24 Weeks, 12 to 24 
Weeks, and over each 4-week interval using a repeated measures ANCOVA model. The 
model will be similar as the one used for the change from baseline in morning pre-dose PEF. 

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Percentage or Responders in ACQ-6 (≥ 0.5 Decrease Equals Response) 
Responder analyses will be performed for ACQ-6 at Week 24, over 24 Weeks or over 12 to 24 
Weeks. Responders are defined as participants with an improvement (decrease of ≥ 0.5 points) 
over baseline. The strategies for handling ICEs and missing data are similar to the ones used 
for percentage of responders in ACQ-5. Logistic regression will be used to compare the 
treatment groups, similar to the one used for percentage of responders in ACQ-5. P-values and 
Odds Ratios with 95% CIs will be produced for each treatment comparison. 
Change from Baseline in ACQ-5, ACQ-6, ACQ-7, and AQLQ(s)+12 
Change from baseline in ACQ-5, ACQ-6, ACQ-7 and AQLQ(s)+12 will each be analyzed 
using a repeated measures ANCOVA model. The model will include treatment, visit, prior 
maintenance medication (ICS versus ICS/LABA), and treatment-by-visit interaction as 
categorical covariates and baseline trough FEV1, percent reversibility, and baseline score for 
the patient-reported outcome instrument as continuous covariates. Contrasts will be used to 
obtain estimates of the treatment differences by visit for measures assessed at clinic visits, 
over 24 Weeks, and 12 to 24 Weeks. Two-sided p-values and point estimates with two-sided 
95% CIs will be produced for each treatment difference. The strategies for handling ICEs and 
missing data are similar to those ones used for percentage of responders in ACQ-5. 
Asthma Exacerbations 
Moderate/severe asthma exacerbation and severe asthma exacerbation will each be analyzed 
in a similar manner as described for the secondary endpoint of rate of severe asthma 
exacerbations utilizing the While on Treatment strategy for handling ICEs based on data from 
Study D5982C00006 only. 
Time to first severe asthma exacerbation will be analyzed with a Cox regression model in 
Studies D5982C00005 and D5982C00006 separately and with the pooled individual 
participant data from both studied (D5982C00006: BFF 320/9.6 μg, BFF 160/9.6 μg, BD 
320 μg and D5982C00005: BFF 160/9.6 μg, BD 160 μg treatment arms. The Symbicort 
treatment arm in Study D5982C00006 will not be included in the pooled analysis.), utilizing 
the While on Treatment strategy for ICEs. The Cox regression model for each study will be 
adjusted for asthma exacerbation history (0, ≥ 1), prior maintenance medication (ICS versus 
ICS/LABA), region, baseline trough FEV1, and percent reversibility. For the pooled analysis, 
a Cox regression additive model will be used which will also include study, and budesonide 
(1 if the budesonide dose is 320 μg, and 0 if the budesonide dose is 160 μg) and formoterol 
(1 if the formoterol dose is 9.6 μg, and 0 if no formoterol dose) instead of treatment as 
covariates. The comparison of interest is the formoterol effect. Time to first severe asthma 
exacerbation is the time from the first dose of study intervention to the time of onset of the 
first severe asthma exacerbation. 

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questionnaires. Descriptive statistics (number, mean, mean changes from baseline, SD, 
minimum, maximum) for the index score and VAS will be presented by treatment group and 
type of questionnaire. The index and VAS scores at each post-randomization visit and end of 
study visit will be analyzed using repeated measures ANCOVA model with age and baseline 
score as continuous covariates and region, gender, treatment, prior maintenance treatment 
(ICS vs ICS/LABA), visit, and treatment-by-visit as categorical covariates. 
AIRQ 
The AIRQ is a 10-item questionnaire with equally weighted yes/no responses. Greater values 
indicate a participant has less control. Percentage of control Well (0 to 1), Not Well (2 to 4) 
and Very Poorly (5 to 10) will be presented by treatment group. 
Furthermore, dose response will be evaluated by comparing BFF MDI 320/9.6 μg to BFF 
MDI 160/9.6 μg on lung function, symptoms, exacerbations, and PROs using the same 
estimands as for the comparison of BFF MDI 320/9.6 μg vs BD MDI. 
9.5.2.4 
Healthcare Resource Utilization  
All HCRU endpoints will be summarized for mean annualized rate or percentage by treatment 
group. Both overall and asthma specific HCRU will be reported. 
9.5.3 
Safety  
All safety summaries will be performed on the Safety set. Participants will be analyzed 
according to the actual treatment received. 
9.5.3.1 
Adverse Events  
Adverse events during the Treatment Period will be summarized by the number of participants 
experiencing an event. Adverse events will be tabulated at the level of the MedDRA system 
organ class and preferred term. The version of MedDRA current at the time of database lock 
will be used in the tabulations and listings. Tabulations will be broken down by intensity, 
seriousness, AEs leading to discontinuation, and by relationship to study intervention. No 
hypothesis testing will be performed. However, treatment groups will be compared as detailed 
in the SAP. Adverse events associated with use of ICS and LABAs will be presented in 
summary tabulations in the CSR. The selection of MedDRA terms proposed to be used in the 
assessment of these AEs will be described in the SAP. 
9.5.3.2 
Vital Signs  
Summary statistics (mean, median, SD, and range) of change from baseline will be tabulated 
by vital sign parameter and treatment for each scheduled assessment time. For vital signs, 
baseline will be defined as the last non-missing value prior to the first dose of randomized IP. 
In addition, potentially clinically significant values will be identified and summarized. 

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9.5.3.3 
Clinical Laboratory Values  
Summary statistics (mean, median, SD, and range) of change from baseline values will be 
tabulated for each treatment and each assessment time. For clinical laboratory measurements, 
baseline will be defined as the last available value prior to randomization. Potentially 
clinically significant values will be identified and summarized. 
9.5.4 
Subgroup Analyses  
Analyses of the primary, secondary, and tertiary endpoints may be performed by various 
subgroups. Any potential subgroup analyses will be described fully in the SAP. 
9.6 
Interim Analyses  
Not applicable 
9.7 
Data Monitoring Committee  
A Data Monitoring Committee will not be used in this study. 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  

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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 and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− 
Applicable ICH GCP Guidelines 
− 
Applicable laws and regulations 
• 
The protocol, revised protocol, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• 
Any revised protocol will require IRB/IEC 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 authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organization, 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 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
 
Regulatory Reporting Requirements for SAEs 
• 
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/IEC, and Investigators. 
• 
For all studies except those utilizing 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. 
• 
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 

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review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements. 
 
Regulatory Reporting Requirements for Serious Breaches of Protocol or GCP 
• 
Prompt notification by the Investigator to AstraZeneca of any (potential) serious breach 
of the protocol or regulations is essential so that legal obligations 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 
trial. 
 
AstraZeneca will comply with country-specific regulatory requirements relating to serious 
breach reporting to the regulatory authority, IRB/IEC, and Investigators. 
• 
Where the EU Clinical Trials Regulation 536/2014 applies, AstraZeneca has in place 
processes to enter details of serious breaches into the European Medicines Agency CTIS. 
It is important to note that redacted versions of serious breach reports will be available to 
the public via CTIS. 
• 
If any (potential) serious breach occurs in the course of the study, Investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately. 
 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
The Investigator should have a process in place to ensure that: 
• 
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 course 
of the study and for one year after completion of the study. 

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A 3 
Informed Consent Process  
• 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• 
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 authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
• 
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 authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented 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 
authorized representative. 
 
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 his/her 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 his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
AstraZeneca, by appropriate IRB/IEC 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 authorized or does not have a business need to know the information. 
• 
The participant must be informed that in some cases their data may be pseudonymized. 
The General Data Protection Regulation defines pseudonymization as the processing of 
personal data in such a way that the personal data can no longer be attributed to a specific 

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individual without the use of additional information, provided that such additional 
information is kept separately and protected by technical and organizational measures to 
ensure that the personal data are not attributed to an identified or identifiable natural 
person. 
 
Personal Data Breaches 
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorized disclosure of, or access to, personal data transmitted, 
stored or otherwise processed. 
• 
In compliance with applicable laws, the Data Controller1 for the processing activity where 
the personal data breach occurred (AstraZeneca or respectively the site), will notify the 
data protection authorities without undue delay within the legal terms provided for such 
notification and within the prescribed form and content. 
• 
While AstraZeneca has processes in place to deal with personal data breaches it is 
important that Investigators that work with AstraZeneca have controls in place to protect 
patient data privacy. 
 
The Investigator should have a process in place to ensure that: 
• 
allow site staff or service providers delegated by the Investigator/institution to identify the 
occurrence of a (potential) personal data breaches. 
• 
Any (potential) personal data breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (email address or telephone number) provided by 
AstraZeneca. 
 
AstraZeneca and the site must demonstrate that they: 
• 
have taken all necessary steps to avoid personal data breaches and 
 
 
 
 
 
1 The data controller determines the purposes for which and the means by which personal 
data are processed, as defined by the European Commission 

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• 
have undertaken measures to prevent such breaches from occurring in the first place and 
to mitigate the impact of occurred data breaches (eg, applying encryption, maintaining 
and keeping systems and IT security measures up-to-date, regular reviews and testing, 
regular training of employees, and developed security policies and standards). 
• 
where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and diligently to 
the occurrence of a personal data breach. 
• 
where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions. 
 
Notification of personal data breach to participants: 
• 
notification to participants is done by the site for the data breaches that occurred within 
the processing activities for which the site is the Data Controller and for data breaches 
occurred within the processing activities of AstraZeneca as the Data Controller, the 
notification is done in collaboration with the site and is performed by the site and/or 
Principal Investigator, acting on behalf of AstraZeneca, so that AstraZeneca has no access 
to the identifying personal information of the participants. The site and/or Principal 
Investigator shall conduct the notification by contacting the participants using the 
information that they gave for communication purposes in clinical research. 
• 
If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course 
after discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the 
processing activity where the breach occurred, it will be responsible for the notification to 
data protection authorities and, if applicable, to participants. If the personal data breach 
needs to be notified to the participants, the notification to participants is done in 
collaboration with the site and is performed by the site and/or Principal Investigator, 
acting on behalf of the Sponsor, so that AstraZeneca has no access to the identifying 
personal information of the participants. 
• 
If a personal data breach involving an AstraZeneca's representative device (ie, Study 
Monitor laptop), AstraZeneca representative will provide AstraZeneca with all of the 
information needed for notification of the breach, without disclosing data that allows 
AstraZeneca directly or indirectly to identify the participants. The notification will be 
done by AstraZeneca solely with the information provided by the Study Monitor and in 
no event with access to information that could entail a risk of re-identification of the 
participants. If the data breach must be notified to the data participants, the notification 
will be done directly by the Study Monitor in collaboration with the site and/or Principal 
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identifying personal information of the participants. The contract between AstraZeneca 
and the Study Monitor shall expressly specify these conditions. 
• 
The contract between the site and AstraZeneca for performing the clinical research 
includes the provisions and rules regarding who is responsible for co-ordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and participants, where applicable. 
 
A 5 
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 other statistical analysis is not relevant. 
A description of this clinical study will be available on www.astrazenecaclinicaltrials.com, 
http://www.clinicaltrials.gov, and https://euclinicaltrials.eu/ as will the summary of the study 
results when they are available. The clinical study and/or summary of study results may also 
be available on other websites according to the regulations of the countries in which the study 
is conducted. 
A 6 
Data Quality Assurance  
• 
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/IEC 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 provided 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, 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification as per the Monitoring Plan 
to confirm that data entered into the eCRF by authorized 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 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 7 
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 can be found in the Monitoring Plan. 
 
A 8 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
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. 

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The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by AstraZeneca or Investigator may include but 
are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
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 IECs/IRBs, the regulatory authorities, and any Contract Research 
Organization(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 9 
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 multicenter studies only in their entirety and not as individual site 
data. In this case, a co-ordinating 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 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
B 1 
Definition of Adverse Events  
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 unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
B 2 
Definition of Serious Adverse Events  
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
Adverse events for malignant tumors reported during a study should generally be assessed as 
Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion 
should be used. In certain situations, however, medical judgment on an individual event basis 
should be applied to clarify that the malignant tumor event should be assessed and reported as 
a non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 

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Life-threatening 
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an ER is not in itself a serious AE, although the reasons for it may be 
(eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations planned 
before or during a study are not considered AEs if the illness or disease existed before the 
participant was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
Important Medical Event or Medical Treatment 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
Examples include: 
• 
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
 
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) 
 

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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not 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 making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another etiology 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 recognized feature of overdose of the drug? 
• 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 

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The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the 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 the participant received the drug 
• 
Did not occur, but circumstances were recognized that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion 
• 
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the 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 refrigerator 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) 
 

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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 lead 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 
• 
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 forward to 
the DES using the Drug Abuse Report Form. This form should be used both in 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 authorized product information, or 
for unauthorized 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 DES 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). 

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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 
• 
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 Optional Genomics Initiative Research  
C 1 
Use/Analysis of DNA and Blood Derivatives  
• 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments, or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants. 
• 
This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 
• 
The results of genetic analyses may be reported in a separate study summary. 
• 
AstraZeneca will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
 
C 2 
Multi-omics Research Plan and Procedures  
Selection of Multi-omics Research Population 
• 
All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study. 
 
Inclusion Criteria 
For inclusion in this genetic research, participants must fulfill all of the inclusion criteria 
described in the main body of the CSP and provide informed consent for the Genomics 
Initiative sampling and analyses. 
Exclusion Criteria 
• 
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following: 
− 
Previous allogeneic bone marrow transplant 
− 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection 
− 
Adolescent participant (12 to < 18 years of age) samples will not be collected for 
Genomics Initiative. 
 

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Withdrawal of Consent for Multi-omics Research 
• 
Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2. 
 
Collection of Samples for Multi-omics Research 
• 
The blood sample for this genetic research will be obtained from the participants at 
Visit 4 after randomization. Although DNA is stable, early sample collection is preferred 
to avoid introducing bias through excluding participants who may withdraw due to an 
AE. If for any reason the sample is not drawn at Visit 4, it may be taken at any visit until 
the last study visit. Only one sample should be collected per participant for genetics 
during the study. 
 
Coding and Storage of DNA and Multi-omics Samples 
• 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached. 
• 
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca analysis laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA). 
• 
The link between the participant enrollment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent. 
 
Ethical and Regulatory Requirements 
• 
The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A. 
 

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Informed Consent 
• 
The genomic and multi-omics component of this study is optional, and the participant 
may participate in other components of the main study without participating in this multi-
omics component. To participate in the genetic component of the study the participant 
must sign and date both the consent form for the main study and the Optional Genomics 
Initiative Research Information consent form. Copies of both signed and dated consent 
forms must be given to the participant and the original filed at the study center. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely, and that 
the participant understands that they may freely withdrawal from the genetic aspect of the 
study at any time. 
 
Participant Data Protection 
• 
AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law. 
• 
Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
Investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate. 
 
Data management 
• 
Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples. 
• 
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genomics research with 
other researchers, such as hospitals, academic organizations, or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers. 
• 
Some or all of the clinical datasets from the main study may be merged with the multi-
omics data in a suitable secure environment separate from the clinical database. 
 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
122 of 130 
Section # and Name 
Description of Change 
Brief Rationale 
estimand within the Objectives and 
Endpoints Table. 
1.1 Synopsis, 3 Objectives 
and Endpoints, 9.2 Analysis 
Methods for Estimands, 
9.5.2.1 Primary Endpoints, 
9.5.2.2 Secondary 
Endpoint(s) 
Hybrid estimand strategy for ICEs 
was added as a supplemental 
estimand for primary and secondary 
endpoints for all regions, and the 
Attributable estimand approach was 
removed. 
The Hybrid estimand approach is 
deemed to answer an important 
clinical question of interest, where 
outcomes following a non-attributable 
ICE will use a Treatment Policy 
strategy and outcomes following an 
attributable ICE will be considered an 
unfavorable outcome. Attributable 
estimand removed to simplify the 
number of estimands used as 
supportive that would be reported in 
the CSR. 
1.1 Synopsis, 
9.4 Populations for 
Analysis 
Intent-to-Treat Population was 
replaced with Efficacy set; 
modified Intent-to-Treat Population 
was removed 
The terms “Intent-to-Treat analysis 
set” and modified Intent-to-Treat 
analysis set” were replaced with 
“Efficacy set”. 
1.1 Synopsis, 9.5.2 Efficacy 
Clarified that the model for analysis 
of repeatedly measured continuous 
variables is “repeated measures 
ANCOVA”. 
Model includes both continuous and 
categorical predictor variables. 
1.1 Synopsis, 
9.5.2. Efficacy 
Details of covariates updated. 
Consistency of covariates across 
analyses. Covariates deemed clinically 
relevant to the respective endpoints of 
interest and have been updated 
accordingly. 
1.3 Schedule of Activities 
Footnote “d” added stating ICF could 
be signed at or before Visit 1. 
To provide clarity. 
1.3 Schedule of Activities 
Tick mark added to Visit 1 for 
administration of Run-in BD MDI in 
clinic. 
To provide clarity that this activity 
should occur. 
1.3 Schedule of Activities 
Note added to footnote “e” allowing 
for rescheduling of Visit 1 if there are 
concerns that ICS/LABA was not 
withheld. 
To provide clarity. 
1.3 Schedule of Activities 
Note added to footnote “j” that 
spirometry should be postponed if 
participant has not washed-out 
asthma medications. 
To provide clarity. 
3 Objectives and Endpoints 
It was clarified that the safety 
objective is for comparing BFF MDI 
320/9.6 μg relative to BD MDI and 
Symbicort TBH. A comparison of 
To provide clarity on safety 
comparisons. 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
124 of 130 
Section # and Name 
Description of Change 
Brief Rationale 
Initiative Sample, 
A1 Regulatory and Ethical 
Considerations, A4 Data 
Protection, 
A5 Dissemination of 
Clinical Study Data, 
A6 Data Quality Assurance, 
B4 Medication Error, Drug 
Abuse, and Drug Misuse, 
Appendix C Optional 
Genomics Initiative 
Research 
5.2 Exclusion Criteria 
Wording added to Exclusion 
Criterion #8 to identify exact studies 
where previous or current inclusion is 
prohibited. 
To provide clarity. 
6.5.2 Prior Medications, 
Table 5 
For mometasone furoate, the specific 
dose was removed, and a statement 
added to discuss with study 
physician. 
Footnote added to clarify doses of 
Symbicort pMDI. 
To align with GINA 2022 and 
complexities around different doses 
across formulations. 
6.5.4 Prohibited 
Medication, Table 7 
Removed reference to intraocular 
corticosteroids and decreased 
cessation period for LAMAs to 
12 weeks and injectable systemic 
corticosteroids to 3 months. 
Amended to alleviate constraints on 
study recruitment. 
8.2.8.1 Paradoxical 
Bronchospasm 
Removal of Visit 6 as this is a 
telemedicine visit where this activity 
cannot occur. 
Correction of error. 
9.4 Populations for 
Analysis 
Randomized set was added. 
Randomized set defined for clarity. 
9.5.1.2 Visit Windows 
Visit windows for analysis have been 
defined. 
To map data to closest scheduled visit. 
9.5.1.3 Baseline 
Severe asthma exacerbation baseline 
definition added. 
To provide clarity. 
9.5.2.1 Primary Endpoint, 
9.5.2.2 Secondary 
Endpoint(s) 
It was clarified that data will not be 
imputed for the analyses of the 
primary endpoint and that sensitivity 
analyses exploring the robustness of 
results due to missing data will be 
conducted. 
To provide clarity. Additional details 
will be provided in the SAP. 
9.5.2.2 Secondary 
Endpoint(s), 
It was clarified that the endpoints of 
onset of action and percentage of 
To provide clarity. 

Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
125 of 130 
Section # and Name 
Description of Change 
Brief Rationale 
9.5.2.3 Tertiary/Exploratory 
Endpoints 
peak FEV1 improvement achieved are 
based on data 5 minutes post-dose on 
Day 1. 
9.5.2.3 Tertiary/Exploratory 
Endpoints 
Change from baseline in evening pre-
dose peak expiratory flow will not be 
analyzed by visit. 
Evening peak expiratory flow is not 
assessed at clinic visits. 
9.5.2.3 Tertiary/Exploratory 
Endpoints 
EQ-5D presentation will be split by 
questionnaire populations  
(12-15 years, ≥ 16 years). 
It was clarified that the EQ-5D index 
score will be analyzed using repeated 
measures ANCOVA model similarly 
to the VAS score. 
EQ-D5 presentation will be split by 
questionnaire population due to 
practical considerations in mapping 
questions from the 2 questionnaires 
(adults and adolescents). 
The analysis on index score was 
included for clarity. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized. 
 
D 2 
Amendment 1 (12 Oct 2021)  
CSP Version 2.0: 12-Oct-2021 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/ED of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific values of the study. 
Overall Rationale for the Amendment: 
Clarity added for telemedicine visit conduct, order of assessments, and birth control methods. 
Additional details added for Treatment Policy estimand and sample size calculations. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
1.2. Schema; 1.3. 
Schedule of 
Activities; 4.1. 
Overall Design 
Telemedicine visits can be 
conducted either by 
telephone or video. 
To add clarity that telemedicine 
visits can be conducted by either 
telephone or video. 
Non-substantial 
1.3. Schedule of 
Activities 
Review of inhalation 
technique and administration 
of study intervention 
requirements removed from 
Visits 6 and 8. 
Visits 6 and 8 have been modified 
to be performed as telemedicine 
(telephone or video) visits, 
therefore observing inhalation 
technique and administration of 
study intervention are no longer 
Non-substantial 

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Clinical Study Protocol - 4.0 
AstraZeneca 
Budesonide and Formoterol Fumarate - D5982C00006 
CONFIDENTIAL AND PROPRIETARY 
127 of 130 
Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
9.5.2.2. Secondary 
Endpoints 
9.3. Sample Size 
Determination 
Details of power calculation 
for FEV1 AUC0-3, at Week 
24, and using the Treatment 
Policy estimand have been 
added. 
To add clarity to power 
calculations for the primary and 
key secondary endpoints. 
Non-substantial 
9.5. Statistical 
Analyses 
Details added for when SAP 
will be finalized. 
To add clarity to timelines for 
finalization of SAP in line with 
company operating procedures 
Non-substantial 
9.5.2.3. 
Tertiary/Exploratory 
Endpoints  
Details of supportive 
analyses provided. Time to 
Peak FEV1 on Day 1 and 
Percentage of Peak FEV1 
Improvement Achieved at 
5 Minutes on Day of 
Randomization. 
To add clarity of supportive 
analyses that may be conducted 
and that details will be included in 
SAP. 
Non-substantial 
Throughout 
Minor editorial and 
document formatting 
revisions 
Minor, therefore have not been 
summarized 
Non-substantial 
 

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