BURAN: Effects of Benralizumab on Airway Dynamics in Severe Eosinophilic Asthma Using Functional Respiratory Imaging Parameters
Phase: PHASE4
Conditions: Asthma
Sponsor: AstraZeneca

Title: BURAN: Effects of Benralizumab on AiRwAy 
DyNamics in Severe Eosinophilic Asthma using 
Functional
Respiratory Imaging Parameters
Study Code: D3250R00107
NCT number: NCT05552508
Date: 08-Jan-2024

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Clinical Study Protocol 
Study Intervention
Benralizumab
Study Code
D3250R00107
Version
5.0
Date
08 January 2024
BURAN: Effects of BenralizUmab on AiRwAy DyNamics in 
Severe Eosinophilic Asthma using Functional Respiratory 
Imaging Parameters
Sponsor Name: 
Legal Registered Address: AstraZeneca AB, Södertälje, Sweden SE-15185
Manufacturer: AstraZeneca AB
Regulatory Agency Identifier Number(s): EudraCT number - 2022-000152-11
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: D3250R00107
Amendment Number: 04
Study Intervention: Benralizumab

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Study Phase: Phase 4
Short Title: BURAN: BenralizUmab on AiRwAy DyNamics in Severe Eosinophilic 
Asthma using Functional Respiratory Imaging
Acronym: BURAN 
Study Physician Name and Contact Information will be provided separately
International Co-ordinating Investigator: 
 
Phone: 
Email: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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analyses methods were updated to align with the updated primary and secondary endpoints 
of the study.
Section 1. Synopsis (Statistical Methods) and Section 9.3 Populations for Analyses (Table 
8), and Section 9.4.4 Other Analyses: Text was edited to clarify that all participants with 
baseline measurements who had taken at least 1 dose of the IP, irrespectively of whether 
they discontinued for reasons described in Section 7.1, were included in the baseline 
endpoints analysis set. This was done for clarity.
Section 2 Introduction and Section 11 References: The GINA, 2020 and GINA, 2021 
references were updated to GINA, 2023, to keep abreast with the 2023 update of the Global 
Strategy for Asthma Management and Prevention. 
Section 2.2 Background: The number of participants in the 24-week ANDHI trial was 
updated to 660, and the efficacy results from the trial were added to the protocol. This was 
done as per the IB update (Version 20.0).
Sections 2.3 Benefit/Risk Assessment and 2.3.1 Risk Assessment were edited and
restructured to improve readability, reduce repetition of potential risk information, and align 
with the Sponsor’s current position of the risk profile of benralizumab. In particular: 
1. Table 2 Risk Assessment was deleted.
2. Serious hypersensitivity reactions was noted as identified risks of biologic therapy, 
including benralizumab. 
3. Regarding the use of benralizumab in pregnant and lactating women, it was clarified 
that appropriate risk minimization measures have been implemented in the study 
protocol to address the risk of missing information. This was a minor edit for 
clarification, with no change to the risk assessment.
4. It was clarified that the clinical benefit demonstrated in clinical trials, combined 
with the overall safety profile of benralizumab, has established a positive benefit-
risk profile for the approved severe asthma indication.
Section 4.2 Scientific Rationale for Study Design: The scientific rationale for the study 
design has been updated to emphasize the relevance of CT-based mucus plug scoring in 
severe eosinophilic asthma, the way in which FRI mucus volume assessment extends mucus 
plug scoring, and the connection with other FRI assessments. Text referencing specific 
airway volume as the primary endpoint has been updated to reference mucus volume 
instead.
Section 5.2.1 Exclusion criteria: Exclusion criterion 12 was updated to specify that 
participants who received Fasenra® any time prior to Visit 0 (V0) will also be excluded. 
This was done to clarify the prohibition of prior Fasenra® usage.
Section 6.2: Preparation/Handling/Storage/Accountability: The text was regarding unique 
IDs being printed in each IP kit was deleted. This was because this will not be done in this 
open-label study. 

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Section 6.5: Concomitant Therapy (Table 4 Restricted Medications) and 6.5.1 (Rescue 
Medications), the acronym for Single Maintenance and Reliever Therapy (SMART) was 
updated to Maintenance and Reliever Therapy (MART), as per updated in the updated 
GINA report of 2023. Additionally, in Table 5 Prohibited Medications, a minor edit was 
made to clarify that the use of “Any other” Investigational product is prohibited. 
Section 8.1.1.1 FRI parameters: The list of FRI parameters was updated to include 
untrimmed total mucus volume at TLC as the primary endpoint, trimmed distal siVaw at
TLC and FRC as secondary endpoints, and to specify which FRI endpoints were trimmed or 
untrimmed. The secondary endpoints related to iRaw, iVaw, iVlobe, BVX, IAD, ventilation 
mapping and Ventilation/perfusion mapping were deleted. 
Section 8.1.1.2 Mucus plugging: Text describing the assessment of the newly added FRI 
parameter “untrimmed total mucus volume” was added. 
Section 8.2.2 Vital signs: The timepoints for vital point measurements were updated to align 
with the SoA, and to make allowance for timepoints when vital signs may be measured as 
per Standard of Care. This was a minor edit for clarity.
Section 8.4.7 Reporting of Serious Adverse Events: Templatised text about the reference 
safety documents for active comparators was deleted, as there are no active comparators 
used in this study. 
Section 8.5 Overdose: Templatised text referring the reader to the Sponsor’s SOPs was 
deleted, as the site staff would not be using the Sponsor’s internal SOPs.
Section 9.4.1 General Considerations: It was added that data may be log-transformed prior 
to analysis to reduce skewness of FRI parameters. This was done for clarity, in order to 
align with the assumptions of the planned model.
Section 9.4.2.1 Primary Objectives: The endpoint measure for the primary objective was 
updated as untrimmed total mucus volume at TLC, and the corresponding analysis method 
was updated.
Section 9.4.2.2 Secondary Objectives: The list of FRI parameters was updated to include 
untrimmed total mucus plugs score at TLC, untrimmed total air trapping at FRC, trimmed 
distal iVaww at TLC, trimmed distal siVaw at TLC and FRC, and untrimmed total iVlung at 
TLC and FRC as secondary endpoints. The secondary endpoints related to iRaw, iVlobe,
BVX, IAD, ventilation mapping and ventilation/perfusion mapping were deleted. 
Furthermore, the corresponding analyses methods were revised.
Section 9.4.3 Safety: A statement about descriptive statistics for vital sign parameters 
measured at post-baseline visits was deleted. This was done to align the text in this section 

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS .................................................................................................... 10
1
PROTOCOL SUMMARY ................................................................................ 14
1.1
Synopsis ........................................................................................................... 14
1.2
Schema............................................................................................................. 19
1.3
Schedule of Activities ....................................................................................... 20
2
INTRODUCTION............................................................................................ 25
2.1
Study Rationale ................................................................................................ 25
2.2
Background ...................................................................................................... 27
2.3
Benefit/Risk Assessment................................................................................... 28
2.3.1
Risk Assessment ............................................................................................... 29
2.3.2
Benefit Assessment........................................................................................... 31
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 31
3
OBJECTIVES AND OUTCOME MEASURES................................................ 32
4
STUDY DESIGN ............................................................................................. 35
4.1
Overall Design.................................................................................................. 35
4.2
Scientific Rationale for Study Design ............................................................... 35
4.3
Justification for Dose........................................................................................ 39
4.4
End of Study Definition.................................................................................... 39
5
STUDY POPULATION.................................................................................... 41
5.1
Inclusion Criteria .............................................................................................. 41
5.2
Exclusion Criteria ............................................................................................. 45
5.2.1
Assessments at Visit 0 (screening visit)............................................................. 45
5.2.2
Re-assessment at Visit 1.................................................................................... 48
5.3
Lifestyle Considerations ................................................................................... 49
5.3.1
Meals and Dietary Restrictions ......................................................................... 49
5.3.2
Alcohol, Tobacco, E-cigarettes and Marijuana .................................................. 49
5.3.3
Activity............................................................................................................. 49
5.4
Screen Failures ................................................................................................. 50
5.5
Visit rescheduling ............................................................................................. 51
5.5.1
Participants who do not meet criteria at Visit 1.................................................. 51
5.5.2
Participants who are unable to come for Visit 1................................................. 51
5.5.3
Visits 2, 3 and 4, and Follow-up........................................................................ 51
5.5.4
COVID-19 positive test .................................................................................... 51
6
STUDY INTERVENTION ............................................................................... 53
6.1
Study Intervention(s) Administered................................................................... 53
6.1.1
Investigational Products.................................................................................... 53
6.1.2
Medical Devices ............................................................................................... 53

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8.4.8.1
Maternal Exposure............................................................................................ 82
8.4.8.2
Paternal Exposure............................................................................................. 82
8.4.9
Medication Error, Drug Abuse, and Drug Misuse.............................................. 82
8.4.9.1
Timelines.......................................................................................................... 82
8.4.9.2
Medication Error............................................................................................... 83
8.4.9.3
Drug Abuse....................................................................................................... 83
8.4.9.4
Drug Misuse ..................................................................................................... 83
8.4.10
Medical Device Deficiencies............................................................................. 83
8.4.10.1
Time Period for Detecting Medical Device Deficiencies ................................... 84
8.4.10.2
Follow-up of Medical Device Deficiencies ....................................................... 84
8.4.10.3
Prompt Reporting of Medical Device Deficiencies to Sponsor .......................... 84
8.4.10.4
SADE Reporting............................................................................................... 84
8.4.10.5
Regulatory Reporting Requirements for Device Deficiencies............................ 85
8.5
Overdose .......................................................................................................... 85
8.6
Human Biological Samples............................................................................... 85
8.6.1
Pharmacokinetics.............................................................................................. 86
8.6.1.1
Determination of Drug Concentration ............................................................... 86
8.6.2
Immunogenicity Assessments ........................................................................... 86
8.6.3
Pharmacodynamics........................................................................................... 86
8.6.3.1
Collection of Samples....................................................................................... 86
8.7
Human Biological Sample Biomarkers ............................................................. 86
8.7.1
Collection of mandatory samples for biomarker analysis................................... 86
8.7.2
Collection of Optional Biomarker Samples ....................................................... 86
8.7.3
Other Study Related Biomarker Research ......................................................... 86
8.8
Optional Genomics Initiative Sample................................................................ 86
8.9
Health Economics OR Medical Resource Utilization and Health Economics..... 87
9
STATISTICAL CONSIDERATIONS................................................................ 88
9.1
Statistical Hypotheses....................................................................................... 88
9.2
Sample Size Determination............................................................................... 88
9.3
Populations for Analyses................................................................................... 89
9.4
Statistical Analyses ........................................................................................... 89
9.4.1
General Considerations..................................................................................... 89
9.4.2
Efficacy ............................................................................................................ 90
9.4.2.1
Primary Objectives ........................................................................................... 90
9.4.2.2
Secondary Objectives........................................................................................ 90
9.4.2.3
..................................................... 91
9.4.3
Safety ............................................................................................................... 92
9.4.4
Other Analyses.................................................................................................. 93
9.5
Interim Analyses............................................................................................... 93
9.6
Data Monitoring Committee ............................................................................. 94
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 95
11
REFERENCES............................................................................................... 129
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LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 19
Figure 2
Suggested schema of injection sites ......................................................... 56
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 20
Table 2
Objectives and Outcome Measures .......................................................... 32
Table 4
Restricted medicines................................................................................ 58
Table 5
Prohibited medicines................................................................................ 59
Table 6
Other prohibited treatments...................................................................... 60
Table 7
Laboratory Safety Variables..................................................................... 74
Table 8
Populations for Analysis .......................................................................... 89
Table S1:
Estimated radiation exposure using the low radiation scanning protocols 
recommended for this study based on a selection of CT scanner brands 
and models from four manufacturers........................................................ 96
Table S2:
Specific settings that were used in CT-expo............................................. 97
LIST OF APPENDICES
Appendix A
Radiation Exposure Calculations ............................................................. 96
Appendix B
Regulatory, Ethical, and Study Oversight Considerations......................... 99
Appendix C
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 107
Appendix D
Handling of Human Biological Samples ................................................ 113
Appendix E
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and Medical 
Device Deficiencies: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting in Medical Device Studies.......... 114
Appendix F
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 121
Appendix G
Abbreviations ........................................................................................ 124

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Overall Design
This is an interventional, single group, open-label, uncontrolled, prospective, multicenter 
clinical trial.
Disclosure Statement: This is a single group treatment study with one arm that has no 
masking.
Number of Participants:
Note: “Enrolled” means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not assigned in the study, are considered “screen failures”, unless otherwise specified 
by the protocol. 
Intervention Groups and Duration:
Each participant will be participating in the study for a minimum of 15 weeks (maximum of 
23 weeks). Informed consent will be obtained from participants between 24 hours and 30 days 
prior to screening. Participants will be given instructions on how to adequately withhold their 
maintenance and rescue asthma medications prior to their screening visit. Once participants 
are enrolled into the study after screening, there will be a run-in period of 1 to 21 days 
(3 weeks) before Visit 1 (V1) at which time participants will undergo baseline assessments 
prior to receiving the first dose of benralizumab. There will be a total of three subcutaneously 
(SC) administered doses of benralizumab 30 mg given at weeks 0 (V1), 4 (V2), and 8 (V3). 
Final measurements will be taken at V4 at a minimum of 4 weeks to a maximum of 6 weeks 
after V3, followed by a 2-week follow-up period.
During the study, dose adjustment and dose interruption of benralizumab will not be
permitted. Dosing can only be discontinued due to an AE per the Investigator’s clinical 
judgement or unforeseen circumstances. Treatment rechallenge will not be permitted in this 
study and any participants who discontinue benralizumab will be considered a study 
withdrawal (see Section 7.1 for further details on criteria for discontinuation of study 
intervention).
Enrolled
Estimated 38 participants
Assigned
N/A (single-arm study)
Evaluable participants
Estimated 34 participants
Primary analysis population
Estimated 29 participants

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Data Monitoring Committee: Not applicable
Statistical Methods: 
Statistical methods used for the primary objective and secondary objective 1 will be univariate
paired t-tests and mixed effects modelling. Scatter plots and correlation calculations will be 
used to assess the baseline association between all FRI parameters of interest and conventional 
lung function measures, FEV1 and FVC, for the secondary objective 2. For secondary 
objective 2, linear regression models will also be fitted to quantify the baseline relationship 
between each FRI endpoint of interest and the conventional lung function measures. For 
secondary objective 3, scatter plots and correlation calculations will be used to assess the 
association between change from baseline in each FRI parameter and change from baseline in 
the conventional measures. For secondary objective 3, a linear model for FRI endpoints will 
also be estimated, both adjusted for FEV1 and FVC and unadjusted for these measurements. 
These models will include an indicator variable for week 13 to quantify the change from 
baseline in FRI endpoints. Additional details and methods for other outcomes are provided in 
Section 9.4.2.
The sample size estimate required to detect a change from baseline in the primary endpoint 
(untrimmed total mucus volume at TLC) is 29 participants. This estimate is based on results 
from another study of a biologic treatment and FRI parameters, with the calculation details 
and corresponding assumptions enumerated in Section 9.2.
Safety analyses will be performed using the safety analysis set. Safety data will be presented 
using descriptive statistics unless otherwise specified. 
The populations to be analyzed consist of:

Participants who completed the study per protocol definition and had no exacerbation 
during the study period (primary analysis population)

All participants who completed the study per protocol definition

Participants who completed baseline measurements at Visit 1 and had at least one dose 
of IP, irrespectively of whether they discontinued for reasons as described in 
Section 7.1 (the baseline endpoints analysis set).

Subgroup analyses

Mucus plugging status: Participants with or without mucus plugs identified 
using CT scans (Section 8.1.1.2) taken at Visit 1 (week 0)

OCS dependency status: OCS-dependent and Non-OCS-dependent participants 
as defined by the inclusion criteria #4 (Section 5.1)
No interim analyses have been planned for this study.
See Section 9 for further details on the statistical methods and subgroup analyses.

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j All CT scans will be conducted with respiratory gating using equipment (CE-marked) provided by the central vendor.
k Maintenance and rescue asthma medications need to be adequately withheld prior to Visit 0, 1 and 4 for the spirometry testing and/or CT procedures that will be 
scheduled during these visits (see Section 8.1.1 for CT scan procedures and Section 8.1.2 for spirometry procedures).
l Reversibility testing should be conducted if participants do not have historical documentation (medical records) of reversibility post-BD. Participants will need 
either documented reversibility post-BD either historically (medical records) or at screening visit to fulfil inclusion criterion #2 (see Section 5.1).
m Spirometry test conducted during Visit 1 and 4 should always be performed after the participants undergo the CT scan procedure. If not feasible, there should 
be at least 30 min between the spirometry test and subsequent CT scan procedure.
n For WOCBP only, study intervention should only be administered after confirmation with a negative urine pregnancy test.
 AE = adverse event; 
; BD = bronchodilator; CT = computed 
tomography; CSP = Clinical Study Protocol; ECG = electrocardiogram; eCRF = electronic case report form; E/D = Early study intervention discontinuation; 
HIV = Immunodeficiency virus; ICF = informed consent form; IP = investigational product; N/A = not applicable; SAE = serious adverse event; 
; WOCBP = women of childbearing potential.
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2
INTRODUCTION
Asthma is a chronic inflammatory airway disorder caused by the interaction of genetic and 
environmental factors. It is characterized by widespread, variable, reversible airflow 
obstruction, airway inflammation, excessive mucus production, and airway 
hyper-responsiveness that led to recurrent episodes of wheezing, breathlessness, chest 
tightness, and coughing (The Collaborative Study on the Genetics of Asthma, 1997; GINA, 
2023). 
The current guidance on the management of patients with asthma is a stepwise intensification 
of a daily maintenance regimen primarily centered around the combination of inhaled 
corticosteroids (ICS) and long-acting β2 agonists (LABA) (GINA, 2023, GINA, 2021). In 
patients with moderately severe asthma, an add-on of tiotropium or leukotriene receptor 
antagonists (LTRA) is recommended, while the add-on of tiotropium or anti-immunoglobulin 
E (IgE), anti-interleukin-5/5 receptor (anti-IL5/5R), or anti-IL4R is recommended for those 
with severe asthma (GINA, 2023).
A review of the clinical responses following treatment with currently available asthma 
therapies uncovered variability that may be related, in part, to distinctive inflammatory 
phenotypes (Wenzel, 2012). Noteworthy is asthma associated with eosinophilic inflammation 
in the airway (also referred to as eosinophilic asthma) representing approximately 40% to 60% 
of patients with asthma; these patients exhibit a degree of eosinophilia associated with clinical 
severity including the risk of asthma exacerbations (Bousquet et al., 1990; Louis et al., 2000; 
Di Franco et al., 2003; Scott and Wardlaw, 2006, Simpson et al., 2006; Zhang and Wenzel,
2007). Also of interest is the observed reduction in the frequency of asthma exacerbations 
when conventional ICS-based asthma therapy was adjusted according to the degree of sputum 
eosinophils as a biomarker of disease activity in prospective trials (Green et al., 2002; 
Jayaram et al., 2006).
IL-5 is a cytokine factor essential for eosinophil trafficking and survival (Molfino et al., 2011). 
Benralizumab is an anti-IL5R monoclonal antibody developed as add-on therapy for patients 
with severe eosinophilic asthma.
2.1
Study Rationale
To date, benralizumab has proven efficacy and safety in both randomized clinical trials (Phase 
3 and 4) as well as in studies using real-world data. Functional changes on airway dynamics
and their correlation to the clinical benefits measured by conventional lung function and 
patient-reported outcomes (PROs) following treatment with benralizumab, have yet to be fully 
explored.
Studies utilizing 129Xe magnetic resonance imaging (MRI) demonstrated clinically relevant 
VDP improvements as early as at 14-days post-benralizumab in participants with minimal 

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changes in spirometry measures (McIntosh et al., 2020).
In this study, Functional Respiratory Imaging (FRI) will be used to measure changes in airway 
dynamics. FRI is a relatively novel quantitative method to measure biological responses to 
therapeutic interventions using a combination of high-resolution computed tomography (CT)
and computational fluid dynamics (CFD). FRI provides detailed visualization and evaluation 
of the lungs and airway structures, allowing for an in-depth description of baseline lung health 
and level of deterioration and a better understanding of post-treatment effects. By assessing 
changes close to the site of action of the intervention, the method is more sensitive (higher 
effect size) compared with standard lung function tests (De Backer et al., 2012a). Several 
clinical trials in patients with asthma (De Backer et al., 2008; Vos et al., 2013; De Backer et 
al., 2015) and chronic obstructive pulmonary disease (COPD) showed significant correlations 
between the change in forced expiratory volume in 1 second (FEV1), other pulmonary function 
test parameters or asthma control, and the change in both image-based volume and/or airway 
resistance following bronchodilation or resolution of exacerbation (De Backer et al., 2011; 
Vos et al., 2016; De Backer et al., 2018; Van Geffen et al., 2018). The background variance of 
well controlled imaging such as FRI is lower relative to pulmonary function testing due to the 
exclusion of confounding factors such as upper airway properties, patient effort, and coaching. 
This means that FRI has enhanced sensitivity (better signal to noise ratio) compared with 
conventional spirometry (Ides et al., 2012; De Backer et al., 2013).
In addition to bronchoconstriction and airway thickening, mucus plugging is common and 
often persistent in patients with asthma and seen on CT scans of most patients. Eosinophils are 
the major cell type found in the Charcot-Leyden crystals in mucus plugs of asthmatics. Mucus 
plugs with eosinophilic inflammation may have a profound effect on pulmonary function and 
the development of exacerbations, and imaging of bronchial segments and scoring of mucus 
plugging is a well-accepted research tool in respiratory disease (Oguma et al., 2021).
Depletion of eosinophils should lead to a reduction in mucus plugging on imaging and 
improvement of airway patency and airflow distribution. Kooner et al. demonstrated that 
patients with high baseline mucus score had significant improvements in VDP and asthma 
control post-benralizumab while participants with low mucus score did not (Kooner et al., 
2021).
Ongoing trials like the CHINOOK study will also evaluate the relationship between any 
observed effects on airway remodeling, improvements in lung physiology and airway 
dynamics in response to benralizumab; however, this study is primarily focused on the impact 
on airway remodeling by morphological and histological measures in subjects with severe 
eosinophilic asthma (NCT03953300; ClinicalTrials.Gov). 
This mechanistic study will thus investigate the short-term benefits of sustained depletion of 
airway eosinophils by benralizumab on airway dynamics and mucus plugs in participants with 

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severe eosinophilic asthma. The relationships between airway dynamic measurements and 
 
 will also be explored, 
aiming to identify a link between 
 with functional 
parameters measured at baseline and following treatment with benralizumab.
2.2
Background
Benralizumab is currently approved for clinical use by the United States Food and Drug 
Administration (US FDA) and European Medicines Agency (EMA) as add-on maintenance 
treatment of patients with severe asthma and with an eosinophilic phenotype. It is a 
humanized, afucosylated, monoclonal antibody against the IL-5R α subunit that induces 
direct, rapid, and near-complete depletion of eosinophils in blood, airway tissue, and bone 
marrow through enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) (Tan et al., 
2016). Natural killer cells are involved in this apoptotic process resulting in controlled 
eosinophilic elimination (Kolbeck et al., 2010; Pham et al., 2016). 
The efficacy and safety of benralizumab has been evaluated in four phase 3 randomized 
controlled clinical trials. Benralizumab significantly decreased the rate of annual 
exacerbations and improved FEV1, compared with placebo, in patients with severe 
uncontrolled asthma who were receiving high-dose inhaled corticosteroids and long-acting β2
agonists in the SIROCCO (Bleecker et al., 2016) and CALIMA (FitzGerald et al., 2016) trials. 
In the 24-week ANDHI trial (n = 660), benralizumab significantly reduced exacerbation risk 
compared with placebo in addition to statistically significant improvements from baseline to 
week 24 in 
 versus placebo. Benralizumab also improved pulmonary 
function as measured by change from baseline in pre-BD FEV1 (Harrison et al., 2021, 
Investigator’s Brochure). The rate of AEs was similar between the benralizumab and placebo 
groups (Harrison et al., 2021). This analysis included patients with an eosinophilic phenotype 
defined as an EOS count of ≥ 150/μl plus at least one of the following: maintenance OCS, 
nasal polyps, FVC < 65% predicted, 3 or more exacerbations in the prior year and adult onset 
of disease (Harrison et al., 2021).
In the 28-week ZONDA trial, benralizumab significantly reduced the need for oral 
corticosteroids as well as the rate of asthma exacerbations in an OCS dependent population 
when compared to placebo (Nair et al., 2017).
The efficacy and safety of benralizumab was also evaluated in open label trials, such as the 
open-label extension trials, MELTEMI (Korn et al., 2021) and PONENTE (Menzies-Gow et 
al., 2021), with both efficacy and safety results consistent with the pivotal trials.
Nevertheless, the shorter-term effects of benralizumab on airway dynamics remain to be fully 
elucidated. A deeper understanding of this could provide additional useful insights into the 
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clinically relevant improvements observed early in the course of treatment. 
A detailed description of the indication, chemistry, pharmacology, efficacy, and safety of 
benralizumab is provided in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
The clinical benefit-risk balance for benralizumab was evaluated by taking into consideration 
data from preclinical and clinical studies, as well as a review of the available information for
monoclonal antibodies that are approved for and are in development for the treatment of 
severe asthma. Benralizumab has been well tolerated, with the most frequently observed AEs 
from the Phase 3 controlled studies being generally reflective of a severe asthma patient 
population.
More detailed information about the known and expected benefits and potential risks of 
benralizumab may be found in the Investigator’s Brochure.

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2.3.1 Risk Assessment

For the following potential risks of clinical significance, summary of data related to 
these risks, and corresponding mitigation strategies for the investigational product (IP), 
benralizumab, may be found in the Investigator's Brochure.Serious hypersensitivity 
reactions (including anaphylaxis) are identified risks of biologic therapy, including 
benralizumab. Anaphylaxis may be life-threatening. Risk minimization recommends a 
minimum of a 1-hour observation period at the clinical site following IP administration 
for the appearance of any acute drug reactions.

Development of anti-drug antibodies (ADA) to benralizumab has been documented. 
Theoretical risks of developing ADA include decreased drug efficacy and 
hypersensitivity reactions. There was no apparent impact of ADA on overall 
benralizumab safety or efficacy in the phase 3 trials.

Eosinophils are a prominent feature of the inflammatory response to helminthic 
parasitic infections. Therefore, there is a theoretical risk that prolonged eosinophil 
depletion may diminish the ability to defend against helminthic parasites. There were 
no reports of helminth infection in the phase 3 asthma exacerbation studies.

Malignancies have been reported at a low incidence in the completed and ongoing 
studies of benralizumab. Eosinophils have been found in association with solid tumors, 
especially tumors of epithelial origin (breast and colon), and may play an active role in 
tumor defense by modulating host defenses, or may be a bystander effect. However, 
the cause and consequences (ie, pro-tumorigenic versus antitumorigenic) of eosinophil 
recruitment and accumulation into tumors are unclear (Jacobsen et al., 2012).

Serious infections have been reported for benralizumab. The incidence of serious 
infections was similar across groups in the phase 3 asthma exacerbation studies. A 
relationship between eosinophil depletion and serious infection has not been 
established.

Information regarding the use of benralizumab in pregnant and lactating women is 
currently missing. Appropriate risk minimization measures have been implemented in 
the study protocol (see Section 1.3, 5.2 and 7.1).
The clinical benefit demonstrated in clinical trials, combined with the overall safety profile of 
benralizumab has established a positive benefit-risk profile for the approved severe asthma 
indication. Risk minimization measures include the exclusion of participants with allergy or 
reaction to any component of the benralizumab formulation, untreated helminth parasitic 
infection and active or recent malignancy, while concurrently performing routine 
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Risks of the study design are those associated with computed tomography (CT). In clinical 
practice, patients with asthma are not subjected to many high-resolution CT scans. As such, 
undergoing the CT procedure during this study may result in a benign or incidental finding. 
The use of CT also involves ionizing radiation that increases the risk of radiogenic tumors in 
participants and may also pose a risk to embryo fetal development and infant. Steps will be 
taken to minimize these risks including the exclusion of pregnant and lactating women in the 
study. Further information on the steps taken to reduce radiation exposure are detailed below. 
The CT procedures incorporated into this study design are aligned with the directives 
presented in the European Union (EU) guidance (Directorate-General – Environment, nuclear 
safety and civil protection, 1998a). Participants will be informed of the risks associated with 
the CT procedure before entering the study.
In this study, extra attention will be paid to reduce radiation by providing low radiation 
scanning protocols tailored to the specific scanner available at participating sites. Low 
radiation scanning protocol guidance will be provided to sites before any subject scan visits. 
Participating study centers will be required to set up a study-allocated CT scanner with a low 
radiation scanning protocol and conduct a phantom scan using this protocol. The phantom 
scan will be sent to a central vendor supporting this study for FRI analysis for review and 
confirmation for the low radiation CT scanner settings. All study team personnel involved in 
the CT scanning procedure will also undergo training to ensure quality and consistency of the 
high-resolution CT scans are maintained across study centers. Study centers will only be 
certified for the CT scanning procedure after the phantom scan is approved by the central 
vendor and all relevant study team personnel have successfully completed their training.
Specifically, the amount of radiation exposure for participants in this study is dependent on 
the scanner used. The software CT-expo is used to give an estimation of the radiation dose a 
patient will get from a FRC/TLC CT scan. CT-expo’s calculations are based on computational 
methods which were used to evaluate the data collected in both German surveys on CT 
exposure practice in 1999 and 2002 (Stamm and Nagel, 2014). A comprehensive description 
of these methods can be found in the book ‘Radiation Exposure in Computed Tomography’ 
(Nagel and Walter, 2002). Based on a selection of CT scanner brands and models from four 
manufacturers, the estimated radiation exposure using the low radiation scanning protocols 
recommended for this study can be found on Table S1 (Appendix A). Specific settings that 
were used in CT-expo are described on Table S2 (Appendix A).
The average effective dose for a high-resolution CT scan that will be conducted for this study 
averaged over all scanner types mentioned in Table S1 (Appendix A) is 1.945 mSv. The 
average estimated radiation exposure received by participants in this study for four 
high-resolution CT scans will be 7.78 mSv (based on the scanner brands and models in Table 
S1 [Appendix A]; note this calculation is dependent on body size and composition). This dose 
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Directorate-General – Environment, nuclear safety and civil protection 1998a).
It is noteworthy that while a high-resolution CT scan taken with the recommended low 
radiation protocol in this study is higher than a standard chest x-ray or mammogram at 
0.02 mSv and 0.13 mSv respectively according to the US Environmental Protection Agency 
(US Environmental Protection Agency, 2021a), the average estimated radiation exposure 
received by participants in this study for four high-resolution CT scans at 7.78 mSv (based on 
the scanner brands and models in Table S1 [Appendix A]) is approximately 4 times lower than 
four standard chest CT scans which would expose a person to 32 mSv of radiation (8 mSv per 
scan [US Environmental Protection Agency, 2021b]). 
An average US citizen receives an annual natural background radiation exposure from natural 
sources of 3.1 mSv (United States Nuclear Regulatory Commission, 2017). Participants 
completing this study will therefore receive an equivalent of 2.5 years background radiation 
based on the average estimated radiation exposure in Table S1 (Appendix A). Based on the 
estimated total amount of radiation exposure for each participant, the potential benefits of the 
study are also expected to be Category IIB following the European Union (EU) guidance 
document (Directorate-General – Environment, nuclear safety and civil protection 1998b) 
targeting the diagnosis, cure, or prevention of disease.
Further calculations on the relative risk increase were conducted and demonstrated a relative 
risk increase of 0.033% for the 7.78 mSv received from all scans in the current study, based 
on the detriment adjusted nominal risk coefficient for an adult at 4.2% per Sv as published by 
the International Commission on Radiological Protection (ICRP) in 2007 (ICRP, 2007).
2.3.2 Benefit Assessment
Benefits of benralizumab include clinically and statistically significant reductions in annual 
exacerbation rate, improved lung function, and improved symptom control. These would in 
turn result in better health-related quality of life and lower systemic steroid exposure. 
Participants in this study will also contribute to furthering the understanding of the short-term 
benefits of sustained depletion of airway eosinophils by benralizumab on airway dynamics 
and mucus plugs in severe eosinophilic asthma. 
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants participating in this 
study, the potential risks identified in association with benralizumab are justified by the 
anticipated benefits that may be afforded to participants with severe asthma and with an 
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a.
FRI endpoints are untrimmed unless otherwise specified (Section 8.1.1.1).
b.
The primary FRI endpoint is total mucus volume at TLC; secondary FRI endpoints for evaluation under 
secondary objectives include total mucus plugs score at TLC, total air trapping at FRC; trimmed distal 
iVaww at TLC; trimmed distal siVaw at TLC and FRC; total iVlung at TLC and FRC; and total mucus 
plugs score at TLC.
; AE = 
adverse event; 
; FEV1 = Forced expiratory volume in 1 second; FRC = Functional 
residual capacity; FRI = Functional Respiratory Imaging; FVC = Forced vital capacity; IP = 
investigational product; iVaww = Airway wall volume, iVlung = Lung volume, 
 
; 
; 
; 
siVaw = Specific airway volume; TLC = Total Lung Capacity.
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4
STUDY DESIGN
4.1
Overall Design
This is an interventional single group, open-label, uncontrolled, prospective, multicenter
clinical trial.
The study will be conducted in male and female participants ≥18 years old with established 
severe eosinophilic asthma, as defined by ERS/ATS clinical guidelines (Chung et al., 2014), 
inadequately controlled by treatment with ICS-LABA with or without oral corticosteroids 
(OCS) or other asthma controller medications.
There will be no study intervention assignment applied as this is a single group study.
Each participant will participate in the study for a minimum of 15 weeks and up to 23 weeks 
from the time when informed consent is obtained through to end of study, inclusive of study 
follow-up. The following are the sequence and duration of study periods:

Informed consent and instructions for withholding maintenance and rescue asthma 
medications for screening (24 hours to 30 days prior to screening)

Screening visit (V0)

Visit 1 (V1; week 0; within 1 to 21 days of screening)

Visit 2 (V2; week 4 ± 5 days) 

Visit 3 (V3; week 8 ± 5 days) 

Visit 4 (V4; week 13 ± 5 days)

Follow-up (2 weeks [± 7 days] after V4) - Phone call follow-up
Refer to Table 1 for further information on the Schedule of Activities (SoA) to be performed 
throughout the study.
Patients will be discharged from the study after the phone call follow-up is completed. This 
study will not be extended and there will be no roll-over studies. Refer to Section 6.7 for 
further information on intervention after the end of the study.
4.2
Scientific Rationale for Study Design
Single-arm design
The decision to conduct a single-arm study instead of a placebo-controlled study was based on 
several factors. 
Firstly, benralizumab has been approved in all major markets, and its efficacy is established in 
the target patient population. While it is of scientific value to add a placebo arm to this study, 
this addition in the context of a phase IV study in a population prone to exacerbations, and 

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with the availability of other biologics for asthma, will complicate study enrolment and 
increase the number of patients enrolled on both arms, thus delaying the availability of 
important results from this study. Furthermore, having a placebo arm would be unnecessarily 
exposing patients to radiation through the study procedure. 
Next, as previously discussed, it is noteworthy that FRI endpoints, unlike those derived from 
spirometry are not influenced by patient effort or muscle force, and are thus less likely to 
change due to a non-disease-related placebo effect. Several studies in asthma and COPD have 
demonstrated very low variability in FRI parameters when patients are not subjected to an 
intervention or when imaged after equivalent maintenance medication withhold periods (De 
Backer et al., 2012a; De Backer et al., 2016; De Backer et al., 2018; Langton et al., 2019).
A study in an asthmatic population showed no change in airway volumes (siVaw) in repeated 
high resolution CT scans after 3 to 7 days when equivalent wash-out periods were observed 
(De Backer et al., 2016). Another study of patients with severe asthma who underwent 
bronchial thermoplasty also demonstrated that airways in the untreated lung did not change 
significantly after 4 weeks (Langton et al., 2019). Subsequent variability analysis was 
undertaken on untreated subjects from a previous double-blind placebo-controlled study on 
the longitudinal change in FRI endpoints to inform expectations for endpoint progression in 
untreated patients (data on file). FRI endpoints were measured at weeks 0 and 12 among 
22 placebo subjects selected based on similar characteristics to that in the current study 
(sputum eosinophilia and persistent, moderate-to-severe asthma). In the placebo group, siVaw 
changed (decreased) an average of -3.46% between weeks 0 and 12, with a 95% CI of 
(-7.50%, 0.584%), suggesting that subjects not receiving treatment are likely to exhibit stable 
or declining endpoint values. It should be noted that measures will also be taken during the CT 
image acquisition process to ensure variability is reduced during this procedure. This includes, 
but is not limited to, the use of phantom scans to ensure every site adheres to specific scanning 
protocols provided to them. These quality assurance measures will further improve the signal-
to-noise ratio.
Apart from the above, previous studies have reported a worsening in airway endpoints in 
patients treated with placebo. This was observed in a placebo-controlled cross-over study 
assessing the effect of budesonide/formoterol in patients with COPD (De Backer et al., 
2012a), as well as in another placebo-controlled cross-over study assessing the effect of 
glycopyrrolate/formoterol fumarate in patients with COPD (De Backer et al., 2018). 
Therefore, the proposal to study within-patient changes from baseline in a single-arm study 
may perhaps be a more conservative approach compared with a placebo-controlled study 
design. 
Taking the above rationales into consideration, the proposal of a single-arm study design may 
be the most appropriate approach to meet the study aims and intention. Placebo data in 

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patients with severe asthma will become available from other studies of biologics in severe 
asthma (NCT04400318) and could be used as a placebo group in future post-hoc analysis.
Correlation analysis conducted by De Backer and colleagues on both patients with asthma 
(n = 79) and those with COPD (n = 49) suggest that the effect size of FRI outcomes in 
response to respiratory treatment in asthma and COPD appear to be three-to-four times larger 
than those in FEV1, the current gold standard efficacy endpoint (De Backer et al., 2015). The 
investigators concluded that FRI may be a good tool for evaluating the potentially subtle 
changes in lung function caused by anti-inflammatory compounds (De Backer et al., 2015).
FRI studies in patients with severe asthma following treatment with other biologics are 
ongoing and data are not available presently.
CT-based mucus plug scoring has been shown to be positively associated with asthma linked 
eosinophilia (Dunican et al., 2018). Moreover, in patients with asthma, the presence of mucus 
plugs in four or more lung segments occurred in 67% of patients with FEV1 (percent 
predicted) of less than 60%, 19% of patients with FEV1 from 60%-80%, and 6% of patients 
with FEV1 greater than 80% (Dunican et al., 2018). These results suggest that airway 
occlusion by mucus is plausibly a mechanism underlying airflow obstruction in eosinophilic 
asthma. Therefore, it could be speculated that benralizumab-mediated eosinophil depletion in 
severe eosinophilic asthmatics may reduce mucus burden and correspondingly, the degree of 
airway obstruction.
Current methods for mucus plug scoring are discrete counts that disregard mucus plug size.
However, a novel method has been developed as part of FRI that extends mucus plug scoring 
by measuring the volume of mucus plugs in the airways visible via CT imaging, thereby 
accounting for variations in mucus plug size through this assessment. Given the established 
relationship between mucus plugs and airway obstruction, it is also plausible that reduced 
mucus volume will result in reduced air trapping and increased airway volume as assessed via 
FRI. These changes may lead to improvements in the participant’s lung function and patient-
reported outcomes (PROs), ultimately allowing the participant to breathe more easily and thus 
feel better and experience a better quality of life. A clinically meaningful change in the 
primary endpoint would be a significant change in total untrimmed mucus volume at week 13 
from baseline after treatment with benralizumab. Significant changes in FEV1, forced vital 
capacity (FVC) and scores from 
, and positive correlations between 
these changes and the changes in the primary endpoint would further reflect and support the 
clinically meaningful improvements in outcomes under benralizumab. It will also allow the 
results from the current study to be put into context with previous or future findings from 
studies on benralizumab treatment (see below for further details regarding PROs conducted in 
previous studies on benralizumab treatment).
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Study duration
The primary aim of this study is to understand the short-term impact of benralizumab on 
airway dynamics and structure that would reflect as improvements in lung function and PRO
measurements, that of which were well established in previous trials studying the effects of 
benralizumab treatment. These improvements in lung function and PRO measurements were 
also confirmed in real-world evidence studies and seen in clinical practice.
The duration of this study is based on previous severe eosinophilic asthma imaging-based 
studies that have shown a rapid response on VDP and some PROs, such as 
 
 at 28-days post-benralizumab, with changes detected as early as 14 days, and 
pronounced effects on patients with SEA and mucus plugs (McIntosh et al., 2020; McIntosh et 
al., 2021; Oguma et al., 2021) following treatment with benralizumab every 4 weeks.
Based on the observations from the imaging studies, further analyses were conducted on the 
results from the phase 3 SIROCCO and CALIMA studies on a subgroup of participants with a 
similar baseline profile for age, baseline eosinophilic levels, ICS dose and pre-BD FVC, to 
those who will be included in the current study. The results show improvements in change 
from baseline in FEV1 as early as week 8 following treatment with benralizumab 30 mg every 
4 weeks compared with the placebo arm (data on file). These observations provide support for 
assessing outcomes in patients treated with benralizumab for a shorter duration, while ongoing 
trials like the CHINOOK study with a study duration of one year, will take measurements as 
early as 8 weeks and will be repeated at week 48. 
A 13 (± 1) week study duration was selected for this study to evaluate outcomes under 
treatment based on the above. Further, it is also to ensure the evaluation occurs at the middle 
time point between the third and fourth dose of benralizumab 30 mg to increase the likelihood 
that participants have optimal serum concentrations during evaluation of the final 
measurements for the study.
Patient-reported Outcomes (PROs)
The benefits shown on other PROs at 28-days post-benralizumab (McIntosh et al., 2020; 
McIntosh et al., 2021; Oguma et al., 2021) also suggest the possible value of exploring the 
relationship with 
 - a new tool, and potentially understand how it could correlate 
with the airway dynamic measurements. The inclusion of other fit-for-purpose PROs
 
Change in 
 following benralizumab treatment was studied in phase 3 asthma 
exacerbation studies, SIROCCO (Bleecker et al., 2016) and CALIMA (FitzGerald et al., 
2016), the OCS reduction study, ZONDA (Nair et al., 2017), long-term extension trial, BORA
(Fitzgerald et al., 2019), and the phase 3b ANDHI study in patients with severe uncontrolled 
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asthma on standard of care (Harrison et al., 2021), and will also be studied in ongoing trials 
like CHINOOK (NCT03953300, ClinicalTrials.Gov). In SIROCCO and CALIMA, 
improvements in ACQ-6 score were reported following benralizumab treatment in participants 
treated every 4 weeks and every 8 weeks (Bleecker et al., 2016; FitzGerald et al., 2016; 
Fitzgerald et al., 2019). Benralizumab also improved ACQ-6 scores at week 24 versus 
placebo, with differences observed within weeks 1 to 4 of treatment in the ANDHI study –
notably, the first three doses of benralizumab were given 4 weeks apart followed by dosing 
every 8 weeks (Harrison et al., 2021). Changes in 
 score was also studied in the ANDHI 
trial where 24 weeks of benralizumab treatment provided clinically meaningful and 
statistically significant improvements in
 total score versus placebo (Harrison et al., 
2021). The inclusion of 
will also thus allow the outcomes from the 
current study to be put into context from previous PRO-related findings following 
benralizumab treatment, as well as explore content similarities and differences between
Age Selection
Only participants ≥18 years old will be eligible to participate in the study as there is currently 
no data are available for children aged 6 to 11 years old with the treatment of benralizumab, 
and while data is available in adolescents aged 12 to less than 18 years old permitting use of 
benralizumab in this patient group by the US FDA in the United States, the EMA made no 
recommendation on a posology. The current study will enroll participants from the US and 
EU. Therefore, an older age limit has been placed to allow only participants ≥18 years old.
There are no overall differences in safety or effectiveness observed between geriatric patients 
and younger patients, and other reported clinical experience has not identified differences in 
responses between the elderly and younger patients. However, participants older than 70 years 
will not be allowed to participate. 
4.3
Justification for Dose
For this drug-device study intervention, the term “dose” refers to the amount of benralizumab
administered via its device to the participant at weeks 0 (Visit 1), 4 (Visit 2), and 8 (Visit 3) 
respectively. In this study, participants will receive a total of three subcutaneously (SC) 
applied doses of 30 mg benralizumab.
The 30 mg Q4W (for the first 3 doses) then Q8W (for subsequent doses) dosing regimen is
currently approved for treatment of severe asthmatics with an eosinophilic phenotype by the 
US FDA and EMA. Therefore, based on the duration of this study ie, 13 weeks, a 30 mg dose 
of benralizumab will be administered SC Q4W for the 3 doses at weeks 0, 4 and 8.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
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the study including all procedures listed in the Schedule of Activities (SoA) at week 13 
(± 1 week).
The end of the study is defined as the date of the last expected visit/contact of the last 
participant undergoing the study.

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5
STUDY POPULATION
This mechanistic study will investigate the short-term benefits of sustained depletion of 
airway eosinophils by benralizumab on airway dynamics and mucus plugs in participants with 
severe eosinophilic asthma. The inclusion and exclusion criteria listed below were defined to 
ensure that the patient population of interest will be enrolled, reflecting similar criteria as the
SIROCCO and CALIMA studies, and consistent with the population where benralizumab is 
approved by the US FDA. 
In addition, a review of the results from previous phase 3 and 4 trials was performed to enable 
participants in the current study to reflect the more severe patient population and those who 
are more prone to mucus plugging, therefore poorer outcomes, and would benefit most from
benralizumab treatment. Specific criteria (e.g., FVC and ACQ-6) were selected through this 
review.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, are not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply at 
Visit 0 (V0; screening visit):
Age
1
Participants must be 18 to 70 years of age inclusive.
Type of Participant and Disease Characteristics
2
Participants who are diagnosed with asthma according to the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) clinical guidelines (2014) (Chung et al., 
2014), with documented reversibility post-bronchodilator (after 2 to 4 puffs of albuterol
[in the US] or salbutamol [in other countries] – see Section 8.1.2), either historical 
(medical records) or at Visit 0 (V0).

Reversibility is defined as an increment of ≥12% and ≥200 mL in FEV1 and/or FVC 
compared with baseline during a single testing session in accordance with the 2005 
ERS/ATS guidelines (Pellegrino et al., 2005).
3
Participants who have documented treatment with ICS and LABA for ≥ 3 months prior to 
Visit 0 (V0), with or without oral corticosteroids and additional asthma controllers. 

ICS and LABA can be components of a fixed dose combination product or given as 
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
ICS dose must be > 500 μg/day fluticasone propionate dry powder formulation or 
equivalent daily. 

For ICS/LABA combination preparations, the highest approved maintenance dose in 
the local country will meet this ICS criterion.
4
Participants who have documented peripheral blood eosinophil count ≥ 300 cells/μL at 
Visit 0 (V0), or if OCS-dependent, a documented peripheral blood eosinophil count 
≥150 cells/μL at Visit 0 (V0). For study sites in Belgium, all participants, irrespective of 
OCS-dependency must have a blood eosinophil count ≥ 300 cells/μL at Visit 0 (V0):

OCS-dependent asthma is defined as long-term OCS therapy (prednisone ≥5 mg/day 
for ≥3 continuous months directly preceding Visit 0 (V0) documented on medical 
records;

Are required to receive stable OCS dosage for ≥4 weeks before Visit 0 (V0).

Alternate OCS dosing (e.g., every other day), other dosing frequencies, and OCS 
therapy other than prednisone/prednisolone are allowed provided the average daily 
dose is equivalent to ≥5 mg of prednisone.

Should remain on stable OCS dosing for the duration of the study.
5
Participants who have had a minimum of 2 exacerbations in the last 12 months prior to 
Visit 0.

Last exacerbation is required to be no less than 6 weeks before Visit 0 (V0)

Asthma exacerbation is defined by a worsening of asthma requiring: 
–
Use of systemic corticosteroids (or a temporary increase in a stable oral 
corticosteroid background dose) for at least 3 days; a single depo-injectable dose 
of corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids 
–
An emergency room/urgent care visit (defined as evaluation and treatment for 
< 24 hours in emergency room [ER] or urgent care center) due to asthma that 
required systemic corticosteroids (as per above) 
–
An inpatient hospitalization due to asthma (defined as an admission to an 
inpatient facility and/or evaluation and treatment in a healthcare facility for 
≥24 hours)
6
Participants who have pre-bronchodilator FEV1/FVC ≤70% at Visit 0 (V0).
7
Participants who have pre-bronchodilator FEV1 < 80% of predicted at Visit 0 (V0).
8
Participants who have ACQ-6 score ≥1.5 at Visit 0 (V0).
9
Participants who are non-smokers or ex-smokers who have stopped smoking at least 
12 month(s) prior to Visit 0 (V0) and have a smoking history of < 10 pack years at Visit 0 
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!
Participants who use e-cigarettes or smoke marijuana will be excluded from the 
study.
10 Participants who have stable asthma regimen apart from the use of rescue medication 
including the use of any other asthma medication for at least 3 months prior to Visit 0
(V0).
11 Participants who are medically able to tolerate permitted medications without significant 
adjustment of dosage, formulation or dosing interval for the duration of the study, and is 
deemed able to withhold therapy for the specified time interval by the Investigator prior 
to Visit 0, 1 and 4. This includes the ability to withhold all inhaled 
 
for at least 6 hours, all short-acting muscarinic antagonists (SAMAs) 
and all 
/SAMA combinations for at least 12 hours prior to lung function 
assessments and/or high-resolution CT scans on Visit 0, 1 and 4.
12 Participants who can perform acceptable and repeatable spirometry according to the 
ATS/ERS 2019 criteria (Graham et al., 2019) and/or protocol-defined criteria.
!
Note: If the participant cannot meet this criterion, retest is permitted and will be 
considered a rescreen. See Section 5.4 for further details.
13 Participants who can withhold asthma maintenance medication for at least 12 hours prior 
to Visit 0, 1 and 4 where spirometry and/or CT scan procedures will be performed, except 
for once-a-day dosage where 24 hours will be required.
14 Participants who are free of any concomitant conditions or treatments (including use of 
oral or ophthalmic beta blockers and/or immune suppressive medications), in the opinion 
of the investigator, that could interfere with study conduct, influence the interpretation of 
study observations/results, or put the patient at increased risk during the study.
15 Participants must be able to understand and complete the protocol requirements, PRO
 
and protocol-stated restrictions and be able to 
adhere to regularly scheduled asthma medication as judged by the investigator.
Sex and Gender
16 Persons of any sex and gender
17 Female participants:
Female participants who cannot bear children as evidenced by:
!
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 will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous 
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hormonal treatment and follicle stimulating hormone (FSH) levels in the 
postmenopausal range. Until FSH is documented to be within menopausal 
range treat the patient as women of childbearing potential (WOCBP)
–
Women ≥50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment

If the above criteria are not met, the participant should be regarded as having 
childbearing potential.
Persons capable of becoming pregnant and both of the following conditions are met:
–
Have a negative pregnancy test (urine/serum as per current clinical study protocol 
[CSP] template) prior to administration of the investigational product (IP) and 
high-resolution CT scan and 
–
Must agree to use a highly effective method of birth control (confirmed by the 
investigator – and consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies) from randomization 
throughout the study duration and within 12 weeks after last dose of IP. Highly 
effective methods (those that can achieve a failure rate of less than 1% per year 
when used consistently and correctly) include:
–
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation- oral, intravaginal, or transdermal
–
Progestogen-only hormonal contraception associated with inhibition of 
ovulation- oral, injectable, or implantable
–
Intrauterine device (IUD)
–
Intrauterine hormone-releasing system (IUS)
–
Bilateral tubal occlusion
–
Sexual abstinence, ie, refraining from heterosexual intercourse (The 
reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the 
patient)
–
Vasectomized sexual partner provided that partner is the sole sexual partner 
of the WOCBP study patient and that the vasectomized partner has received 
medical assessment of the surgical success 

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Informed Consent
18 Provision of signed informed consent as described in Appendix B which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
5.2
Exclusion Criteria
5.2.1 Assessments at Visit 0 (screening visit)
Participants are excluded from the study if any of the following criteria apply at Visit 0 (V0; 
screening visit):
Medical Conditions
1
Participants who are unstable or who experienced an exacerbation/infection in the 
6 weeks before Visit 0 (V0).

Note: Participants may be rescreened after resolution of the exacerbation/infection 
and at least 4 weeks after the last dose of any medication to treat the 
exacerbation/infection (or return to baseline dose of OCS for those on chronic OCS).
2
Participants with acute upper or lower airway infection in the 6 weeks before Visit 0 
(V0).
3
Participants with current malignancy or history of malignancy (Except for: Participants 
who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in 
situ carcinoma of the cervix are eligible, provided that the patient is in remission and
curative therapy was completed at least 12 months prior to the date informed consent, and 
assent when applicable, was obtained.)

Participants who have had other malignancies are eligible provided that the patient is 
in remission and curative therapy was completed at least 5 years prior to Visit 0 (V0), 
and assent when applicable, was obtained.
4
Participants diagnosed with clinically important pulmonary disease other than asthma 
(including but not limited to active lung infection, COPD, presence of emphysema on 
previous CT imaging, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation 
syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, active 
tuberculosis, and primary ciliary dyskinesia) or participants who have ever been 
diagnosed with pulmonary or systemic disease, other than asthma, that are associated with 
elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary 
aspergillosis/mycosis, Churg-Strauss syndrome and hypereosinophilic syndrome).
5
As judged by the investigator, any evidence or history of other clinically significant 
disease or abnormality such as congestive heart failure, uncontrolled hypertension, 
uncontrolled coronary artery disease, myocardial infarction, stroke, glaucoma or cardiac 
dysrhythmia, untreated moderate to severe sleep apnea, malignancy (excluding basal cell 

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carcinoma), a helminth parasitic infection diagnosed within 24 weeks prior to Visit 0 (V0) 
which has not been treated with or has failed to respond to standard of care therapy. In 
addition, historical or current evidence of significant hematologic, hepatic, neurologic, 
psychiatric, renal, pulmonary, or other diseases which in the investigator's opinion would 
put the participant at risk through study participation, or would affect the study analyses if 
the disease exacerbated during the study.
6
Participants with current active liver disease:

Chronic stable hepatitis B and C (including positive testing for hepatitis B surface 
antigen [HBsAg] or hepatitis C antibody), or other stable chronic liver disease are 
acceptable if subject otherwise meets eligibility criteria. Stable chronic liver disease 
should generally be defined by the absence of ascites, encephalopathy, coagulopathy, 
hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis.

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times 
the upper limit of normal (ULN), confirmed by repeated testing during screening 
period. Transient increase of AST/ALT level that resolves by the time of study entry
is acceptable if in the investigator’s opinion the subject does not have active liver 
disease and meets other eligibility criteria.
7
Participants known to have tested positive for human immunodeficiency virus.
8
Participants with inability to discontinue prohibited medications during Visit 0 (V0) and 
treatment periods.
9
Participants with documented or suspected viral or bacterial, ongoing infections, or illness 
within 4 weeks prior to the Visit 0 (V0).
10 Current evidence or known history of alcohol or substance abuse that could be of clinical 
significance as determined by the investigator as any conditions associated with poor 
compliance.
11 Participants who are scheduled to be admitted to hospital or undergo inpatient surgery 
during the study.
Prior/Concomitant Therapy
12 Receipt of any biologic products for asthma (e.g., omalizumab, mepolizumab) within 4 
months or 5 half-lives prior to Visit 0 (V0), whichever is longer. Participants who 
received Fasenra® any time prior to Visit 0 (V0) will also be excluded.
13 Receipt of live acting live attenuated vaccines 30 days prior to Visit 0 (V0).
14 History or current use of chronic (ie, > 4 weeks) immunosuppressive medication 
(including but not limited to: methotrexate, troleandomycin, cyclosporine, azathioprine, 
intramuscular long-acting depot corticosteroid, chronic systemic corticosteroid including 
OCS [for conditions other than asthma], or any experimental anti-inflammatory therapy) 
within 3 months prior to Visit 0 (V0).

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
Receipt of immunoglobulin or blood products within 30 days prior to Visit 0 (V0).

Receipt of live attenuated vaccines 30 days prior to Visit 0 (V0). Receipt of 
inactive/killed vaccinations (e.g., inactive influenza) is allowed provided they are not 
administered within 1 week before/after any IP administration.

Change to allergen immunotherapy or new allergen immunotherapy within 30 days 
prior to Visit 0 (V0) and anticipated changes in immunotherapy during the study.
15 History of lung volume reduction surgery, lung resection, thermal bronchoplasty at any 
time before visit 0 (V0) or on active phase of pulmonary rehabilitation. 
Prior/Concurrent Clinical Study Experience
16 Participation in another clinical study with an Investigational biologic product within 
4 months or 5 half-lives prior to Visit 0 (V0), whichever is longer.
17 Participation in another clinical study with an Investigational nonbiologic administered 
within 30 days or 5 half-lives prior to Visit 0 (V0), whichever is longer.
18 Participants with a known hypersensitivity to benralizumab or any of the excipients of the 
product.
19 Participants with history of anaphylaxis to any biologic therapy or vaccine.
Diagnostic Assessments
20 Participants with any clinically significant abnormal findings in physical examination, 
vital signs, hematology or clinical chemistry during screening/run-in period, which in the 
opinion of the Investigator, may put the participant at risk because of his/her participation 
in the study, or may influence the results of the study, or the participant’s ability to 
complete entire duration of the study.
Other Exclusions
21 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site and their immediate relative(s)).
22 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
23 Previous enrolment in the present study unless participant fulfils on criteria for 
rescreening (see Section 5.4). 
24 For women only - currently pregnant, lactating or breastfeeding, or plans to become 
pregnant during the study period or for 30 days after the participant’s last study-related 
visit (for eligible participants only, if applicable). Eligible female participants unwilling to 
employ appropriate contraceptive measures to ensure that pregnancy will not occur during 

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the study will be excluded. Any participants becoming pregnant during the study will be 
withdrawn from the study.
25 Judgement by the investigator that there are physical factors (e.g., infirmity, disability, or 
geographic location) that the Investigator determines would likely limit compliance with 
the study protocol or study visits.
26 Participants who are current smokers or ex-smokers who have stopped smoking within 
12 month(s) prior to Visit 0 (V0) and/or have a smoking history of > 10 pack years, or 
who use e-cigarettes or smoke marijuana will be excluded from the study.
27 COVID-19: 
Participants with:

Positive COVID-19 test (as per prevailing local guidelines for COVID-19 testing at 
the time of the COVID-19 test) at Visit 0 (V0).
–
Participants that are asymptomatic and tested positive at Visit 0 (V0) may be 
rescreened after a minimum of 2 weeks at the investigator’s discretion.

COVID-19 disease within 6 weeks before Visit 0 (V0).
–
Participants may be rescreened after a minimum of 6 weeks at the investigator’s 
discretion only if they had mild or moderate COVID-19 disease.

History of severe COVID-19 disease at any time, defined by the need for Intensive 
Care Unit stay or Mechanical Ventilation (invasive or non-invasive) or per 
investigator’s judgement.
–
Rescreening is not permitted for participants who had severe COVID-19 
disease.
5.2.2 Re-assessment at Visit 1
Participants should have the following criteria reviewed at Visit 1 (V1), before any baseline 
assessment is performed. 
1
Stable asthma regimen apart from the use of rescue medication including the use of any 
other asthma medication for ≥ 3 months prior to Visit 1 (V1).
2
OCS-dependent participants (as defined per the inclusion criterion #4) are required to 
receive stable OCS dosage for ≥4 weeks before Visit 1 (V1).
3
Last exacerbation (as defined per the inclusion criterion #5) is required to be no less than 
6 weeks before Visit 1 (V1).
Visit 1 (V1) may be rescheduled 1 time per Section 5.5 in cases where baseline assessments 
cannot be performed because participants did not fulfil any of the above criteria at Visit (V1),
(see Section 5.5).

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5.3
Lifestyle Considerations
1)
Persons who are having sexual relationships in which they may become pregnant must 
use highly effective contraceptive methods throughout the study and at least for 12 weeks 
after last dose of study intervention, as stated in inclusion criterion #17, Section 5.1.
2)
Participants must abstain from donating blood, plasma, or platelets from the time of 
informed consent or assent (if applicable) and for 12 weeks after last dose of study 
intervention.
3)
Live attenuated vaccines
(a) Receipt of live attenuated vaccines is disallowed 30 days prior to first dose of study 
intervention, during study intervention administration, and for 12 weeks after last 
dose of study intervention.
4)
Inactive/killed vaccinations (e.g., inactive influenza)
(a) Not recommended within the 7 days before or within 7 days after any study 
intervention dosing study visit.
5)
Any investigational product
(a) Investigational biologic product not allowed within 4 months or 5 half-lives prior to 
Visit 0 (V0), whichever is longer.
(b) Investigational product administered within 30 days or 5 half-lives prior to Visit 0 
(V0) is not allowed, whichever is longer.
5.3.1 Meals and Dietary Restrictions
1)
Participants should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the center.
5.3.2 Alcohol, Tobacco, E-cigarettes and Marijuana
1)
Alcohol or drug abuse (including smoking of marijuana) is prohibited prior to screening
and throughout the conduct of the study.
2)
Use of tobacco products (including nicotine patches, marijuana and e-cigarettes) is 
prohibited within 12 months prior to screening and throughout the conduct of the study 
(see Section 5.2.1, criterion #26, for specific criteria for ex-smokers).
5.3.3 Activity
1)
Blood pressure (BP) and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (e.g., television, cell phones). 
Respiratory rate will be obtained after participant has been resting for at least 5 minutes.

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2)
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all lung function assessments at the center.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned in the study, unless otherwise specified by the protocol. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes visit date (VISIT) demography (DM), informed consent (CONSENT),
screen failure details, eligibility criteria (IE), and any serious adverse event (SAE).
For participants considered as “screen failure” due to one or more of the criteria listed below, 
there is an opportunity to be rescreened once. If a second rescreening is required, these cases 
should be discussed with the AstraZeneca Study Physician and documented in the investigator 
study file (ISF). Rescreened participants should be assigned a new participant number.

Inability to perform acceptable and repeatable spirometry according to the ATS/ERS 
2019 criteria (Graham et al., 2019) and/or protocol-defined criteria

If the participant cannot meet the criterion, the test may be rescheduled 1 week/7 
days later and participants may be rescreened at the date of the retest.

Participants who are unstable, who developed an exacerbation/infection in the 6 weeks 
before Visit 0 (V0).

Participants may be rescreened after resolution of the exacerbation/infection and at 
least 4 weeks after the last dose of any medication to treat the exacerbation/infection.

Participants with positive COVID-19 test at Visit 0 (V0) - as per prevailing local 
guidelines for COVID-19 testing

Participants that tested positive at Visit 0 (V0) may be rescreened after a minimum of 
2 weeks if they had an asymptomatic COVID-19 infection. 

Participants that tested positive at Visit 0 (V0) and presented with mild or moderate 
COVID-19 disease may be rescreened after a minimum of 6 weeks at the 
investigator’s discretion (see Section 5.2.1, criterion #27).

Reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits, etc.), 
or due to a civil crisis, natural disaster, or public health crisis. 

Note that these cases should be discussed with the AstraZeneca Study Physician and 
documented in the ISF. Re-screening of a participant for any other reason may be 
allowed only upon approval of the AstraZeneca Study Physician.

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Any rescreened participant will be re-enrolled and assigned a new enrolment number after 
signing a new ICF and after all assessments during the screening visit (V0) have been 
performed as listed in Table 1. A documented approval for re-screening for any other reasons 
not mentioned above or a for a second rescreening should be filed in the ISF.
5.5
Visit rescheduling
Visits may be rescheduled within the visit window established in the SoA (Table 1). If a visit 
needs to be rescheduled outside the pre-specified visit window and the participant did not 
meet any of the conditions specified in Sections 5.5.1, 5.5.2 and 5.5.3 below, the case should 
be discussed with the AstraZeneca Study Physician and documented in the ISF. Extension of 
the run-in period for a participant for any other reason may only be allowed upon approval of 
the AstraZeneca Study Physician.
5.5.1 Participants who do not meet criteria at Visit 1
Participants who do not meet the criteria at Visit 1 (Section 5.2.2) are not allowed to proceed 
with any study baseline assessments and Visit 1 should be rescheduled to a timepoint where
participants can fulfil these criteria. For acute asthma exacerbation or acute upper or lower 
respiratory tract infection, refer to Section 8.3.
5.5.2 Participants who are unable to come for Visit 1
Visit 1 should be rescheduled as soon as possible, or when considered safe as judged by the 
Investigator in the following transient situations/reasons:

Including, but not limited to, study-supplied equipment failure, unforeseen personal 
events that mandate missing Visit 1, etc.

Civil crisis, natural disaster, or public health crisis.
5.5.3 Visits 2, 3 and 4, and Follow-up
In general, Visits 2, 3, and 4, and the follow-up may be re-scheduled within the respective visit 
windows established in the SoA (Table 1). Rescheduling of visits beyond the visit window 
indicated in the SoA (Table 1) should be an exception and the reason should be recorded in the 
ISF.
5.5.4 COVID-19 positive test
COVID-19 testing should follow prevailing local guidelines at the time of the COVID-19 
testing procedure and participants are considered as having positive COVID-19 test when they 
fulfill the criteria defined as per aforementioned local guidelines.

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Participants who have a positive COVID-19 test and are asymptomatic (or have mild disease 
without lower respiratory tract symptoms – per investigator’s judgement) are allowed to have 
the visits rescheduled as follows:

Participants who have a positive COVID-19 test immediately before Visit 1 AND are 
asymptomatic: delay Visit 1 up to 14 days (in accordance with local guidelines for 
quarantine and re-testing procedure) from the date when the test was performed.

Participants who have a positive COVID-19 test immediately before Visit 2 or Visit 3 
AND are asymptomatic should receive the study intervention drug within the allowed 
visit window established in the SOA (Table 1).

Participants who have a positive COVID-19 test immediately before Visit 4 AND are 
asymptomatic: delay Visit 4 up to 14 days (in accordance with local guidelines for 
quarantine and re-testing procedure) from the date when the test was performed.
Participants with any moderate or severe COVID-19 disease, or COVID-19 disease with 
lower respiratory tract symptoms, irrespective of severity, at any time during the study period 
shall be discontinued (see Section 7.1).
In case the reason for postponing is an acute exacerbation or respiratory tract infection, refer 
to Section 8.3 for instructions.

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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.
6.1
Study Intervention(s) Administered
6.1.1 Investigational Products
Arm name
Benralizumab
Intervention name
Benralizumab (Fasenra)
Type 
Combination Product
Dose formulation
Single-use pre-filled syringe (injection)
One mL solution in a single-use pre-filled syringe made from type I glass with a 
staked 29-gauge ½-inch (12.7 mm) stainless steel needle, rigid needle shield, 
and Fluorotec-coated plunger stopper in a passive safety device.
Unit dose strength(s)
30 mg
Dosage level(s)
3 doses, once every 4 weeks (at baseline [V1], week 4 [V2] and week 8 [V3])
Route of 
administration
Subcutaneous
Use
Other (Phase 4) - Treatment of severe asthma per current approved USPI and 
EU SmPC/European Public Assessment Report (EPAR)
IMP and NIMP
IMP 
Sourcing
Provided centrally by the sponsor; manufactured by AstraZeneca AB 
Packaging and 
labelling
Study Intervention will be provided in pre-filled syringe. 
Each pre-filled syringe will be labelled in
accordance with Good Manufacturing Practice (GMP) Annex 13 and as 
required per country regulatory requirement. Label text will be translated into 
local languages as required
[Current/former 
name(s) or alias(es)]
MEDI-563
6.1.2 Medical Devices
6.1.2.1
Benralizumab pre-filled syringe
1)
The AstraZeneca manufactured medical devices (or medical devices manufactured for 
AstraZeneca by a third party) provided for use in this study are,

Syringe prefilled with benralizumab (Status, US FDA and EMA approved)

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2)
Instructions for medical device use are provided in Product Full Prescribing Information / 
Product Package Leaflet, Product Instructions for Use in the local language (for home 
administration) and/or patient information leaflet.
3)
All medical device deficiencies (including malfunction, use error and inadequate 
labelling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.10) and appropriately managed by the sponsor.
6.1.2.2
Respiratory Gating Device
1)
The Geratherm Respiratory manufactured medical devices (or medical devices 
manufactured for Geratherm Respiratory by a third party) provided for use in this study 
are,

Spirotik (Status, CE-marked [according to Medical Device directive])
This is a portable spirometer that comes with disposable mouth pieces and 
nose clips, and operates through a software, Blue Cherry (Geratherm 
Respiratory), using a laptop. This device will be used to monitor 
participants’ breathing during the CT scan procedure to ensure CT scans are 
taken at the correct breathing level.
2)
Instructions for medical device use are provided in a separate CT scan manual and e-
course materials provided by a central vendor.
3)
All medical device deficiencies (including malfunction, use error and inadequate 
labelling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.10) and appropriately managed by the sponsor.
6.2
Preparation/Handling/Storage/Accountability
1)
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.
2)
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff.
3)
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).
4)
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.

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The IP will be administered at the study site on Visit 1, 2 and 3. IP will be supplied to the site 
in a kit with a single-use pre-filled syringe of benralizumab. Dosing should be performed 
following the completion of all visit assessments for Visit 1, 2 and 3.
All shipments of IP include a data logger which will allow the Investigator or designee to
confirm appropriate temperature conditions have been maintained during transit for all study
treatment received and any discrepancies are reported and resolved before the use of the study
treatment. Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply the study treatment.
Only authorized site staff may administer the study treatment. 
Before investigational product administration
Prior to each IP administration:
1)
The Investigator/authorized delegate will assess the injection site as per the standards of 
medical care. 
2)
For WOCBP, a urine pregnancy test will be performed; IP will be administered only if the 
result of the test is negative.
Investigational product administration
The IP will be administered by the Investigator/authorized delegate. Investigational product at 
a dose of 30 mg should be administered SC using the pre-filled syringe into the upper arm, 
thighs, or the abdomen (see Figure 2). It is suggested that the site of injection is rotated such 
that the participant receives IP at a different anatomical site at each treatment visit. 
Investigational product should not be administered into areas where the skin is tender, bruised, 
erythematous, infected or hardened, or where there is an open graze.

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Figure 2
Suggested schema of injection sites
Further details on IP administration are described in the IP Handling Instruction provided to
study sites. Investigational product administration must be carried out in line with the
Instruction.
After investigational product administration
Participants should be observed according to clinical practice after administration of IP for the
appearance of any acute drug reactions.
Conditions requiring investigational product administration rescheduling
Administration of the IP may only be rescheduled if:
1)
Rescheduled date of IP administration falls within the visit window indicated in the SoA.

Note: Dose interruptions requiring rescheduling of IP administration outside the visit 
window indicated in the SoA are not permitted (see Section 7.1.1 for further details).
2)
Participant needs to reschedule Visit 1 per Section 5.5.1 and 5.5.2 (see Section 5.5 for 
further details).
6.3
Measures to Minimize Bias: Randomization and Blinding
The current study is an open-label study with no blinding at site level.
6.4
Study Intervention Compliance
The administration of all study treatments should be recorded in the appropriate section of the 
electronic Case Report Form (eCRF). The study treatment provided for this study will be used 
only as directed in this CSP. The study treatment will be administered at the study site on 
treatment visits (Visit 1, 2 and 3) as specified in the SoA (Table 1). Participants who cannot 

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receive the first study treatment at Visit 1 as described in Section 5.5.1 and 5.5.2 may be 
rescheduled (see Section 5.5 for further information). The second and third study treatment 
must be administered within the visit window as specified in the SoA (Table 1). Any change 
from the dosing schedule (dose interruptions or dose discontinuations) should be recorded in 
the eCRF. It should be noted that dose modifications are prohibited and will be considered as a 
discontinuation of study intervention.
The participants will receive study intervention directly from the investigator or designee, 
under medical supervision. The date, and time if applicable, of dose administered in the clinic 
will be recorded in the source documents and recorded in the eCRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
Study site personnel will examine the pre-filled syringe to ensure that the study intervention 
was administered completely.
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
6.5
Concomitant Therapy
The participants’ ICS or OCS and additional asthma maintenance medication at enrolment 
will remain unchanged during the run-in and treatment period. Maintenance and rescue 
asthma medications are not regarded as an IP and will not be provided/reimbursed by 
AstraZeneca.
To satisfy inclusion criterion #3, a history of continuous treatment with high-dose ICS and 
LABA for ≥ 3 months prior to Visit 0 (V0), with or without oral corticosteroids and additional 
asthma controllers should be documented in source and recorded in the eCRF at Visit 0 (V0).
If the participant is taking ICS plus LABA, the ICS and LABA can be parts of a combination 
product or given by separate inhalers. The ICS dose must be > 500 μg/day fluticasone 
propionate dry powder formulation or equivalent daily. For ICS/LABA combination 
preparations, the highest approved maintenance dose in the local country will meet this ICS 
criterion.
In order to satisfy inclusion criterion #4, a history of OCS therapy (prednisone ≥5 mg/day for 
≥3 continuous months directly preceding Visit 0 (V0) and stable OCS dosage for ≥4 weeks 
before Visit 0 (V0) should be documented in source and recorded in the eCRF at Visit 0 (V0).
Alternate OCS dosing (e.g., every other day), other dosing frequencies, and OCS therapy 
other than prednisone/prednisolone are allowed provided the average daily dose is equivalent 
to ≥ 5 mg of prednisone. Participants should also remain on stable OCS dosing for the 
duration of the study.
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asthma treatment regimen apart from the use of rescue medication including the use of any 
other asthma medication for at least 3 months prior to Visit 0 (V0). The Investigator will 
record information on background therapy compliance during the study in the eCRF.
All medications taken in the 3 months prior to Visit 0 (V0) and throughout the study must be 
recorded in the eCRF along with the reason for treatment by the Investigator/authorized
delegate at each visit, as specified in Table 1.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the participant is 
receiving at the time of enrolment or receives during the study must be recorded along with:
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
Table 4
Restricted medicines
Medication/class of drug
Usage (including limits for duration permitted and special 
situations
Maintenance treatment with ICS and 
LABA (including ICS/LABA 
combinations)
No changes in either dose or regimen are allowed from screening 
visit (V0) and throughout the IP treatment.
Budesonide/Formoterol “MART” reliever therapy is allowed as 
rescue medication and its use as a rescue medication will be recorded 
in the eCRF.
Twice daily BDs should be withheld for at least 12 hours prior to 
Visit 0, 1 and 4 at the site.
Once daily BDs should be withheld for at least 24 hours prior to 
Visit 0, 1 and 4 at the site.
Maintenance treatment with LAMA 
(isolated or in combinations)
No changes in either dose or regimen are allowed from screening 
visit (V0) and throughout the IP treatment.
Twice daily LAMAs should be withheld for at least 12 hours prior to 
Visit 0, 1 and 4 at the site.
Once daily LAMAs should be withheld for at least 24 hours prior to 
Visit 0, 1 and 4 at the site.
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Medication/class of drug
Usage (including limits for duration permitted and special 
situations
Short-acting muscarinic antagonist 
(SAMA)
SAMA is allowed as rescue medication.
SAMA should be withheld for at least 12 hours prior to Visit 0, 1 
and 4 at the site.
/SAMA combinations
/SAMA combination is allowed as rescue medication.
/SAMA combination should be withheld for at least 12 hours 
prior to Visit 0, 1 and 4 at the site.
Additional maintenance controllers
Leukotriene receptor antagonists (LTRA) should be restricted for at 
least 24 hours prior to the scheduled spirometry test at Visit 0 (V0), 
and prior to scheduled Visit 1 and 4, at the site.
Twice daily theophyllines should be withheld for at least 12 hours 
prior to Visit 0, 1 and 4 at the site.
Once daily theophyllines should be withheld for at least 24 hours 
prior to Visit 0, 1 and 4 at the site.
Intranasal steroid
Intranasal steroid is allowed at the discretion of the Investigator.
Chronic immunosuppressive 
medication (including corticosteroids)
or any experimental anti-inflammatory 
therapy
Not allowed within 3 months prior to Visit 0 (V0) as per exclusion 
criterion #14.
Chronic oral corticosteroids for asthma are allowed as per 
Section 5.1, inclusion criterion #3
Topical administration of immunosuppressive medication may be
administered at the Investigator’s discretion as clinically indicated.
Allergen immunotherapy
Allowed if on stable therapy for at least 30 days prior to Visit 0 
(V0), with no anticipated change during the study.
The participant should not receive an allergen immunotherapy 
injection on the same day as the IP administration.
Inactive/killed vaccinations
Receipt is allowed provided they are not administered within 7 days
before/after any IP administration.
Table 5
Prohibited medicines
Prohibited medication/class of drug:
Immunoglobulin or blood products
Use prohibited within 30 days prior to visit 0 (V0). Immunoglobulin 
is not allowed during the study except for treatment of an AE, as 
judged by the Investigator.
Marketed or investigational biologic
(monoclonal or polyclonal antibody)
Use prohibited within 4 months or 5 half-lives (whichever is longer) 
prior to Visit 0 (V0), and during the study.
Live/attenuated vaccines
Use prohibited 30 days prior to Visit 0 (V0), during the treatment 
period, and for 12 weeks after the last dose of the IP.
Previously received benralizumab
Prohibited.
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Prohibited medication/class of drug:
Any other Investigational product
Use prohibited within 30 days or 5 half-lives (whichever is longer) 
prior to Visit 0 (V0) and during the study.
Oral or ophthalmic non-selective β-
adrenergic antagonist
Use prohibited as per inclusion criterion #14 unless it does not 
interfere with study conduct, influence the interpretation of study 
observations/results, or put the participant at increased risk during 
the study.
Change to allergen immunotherapy or 
new allergen immunotherapy
Use prohibited within 30 days prior to visit 0 (V0).
Over-the-counter inhaled epinephrine
Use prohibited.
Paracetamol/Acetaminophen, at doses of # 2 grams/day, is permitted for use any time during 
the study. Other concomitant medications not excluded based on inclusion criterion #14 and
exclusion criteria #12 to #14, #16 and #17 are permitted for use any time during the study (see 
Section 5.1 and 5.2.1).
Table 6
Other prohibited treatments
Prohibited treatments
Lung volume reduction surgery
Prohibited
Lung resection
Prohibited
Thermal bronchoplasty
Prohibited
Pulmonary rehabilitation
Active phase of rehabilitation is prohibited prior to 
screening and through the study
6.5.1 Rescue Medicine
The sponsor will not supply any rescue medication.
Rescue use of medications administered via nebulization is discouraged, except as urgent 
treatment during an asthma exacerbation. Occasions where medications are administered via 
nebulization will be recorded separately from metered dose inhaler inhalations.
The following rescue medications may be used:
!
∀
!
Short-acting muscarinic antagonists (SAMAs)
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∀
Short-acting muscarinic antagonists (SAMAs) should be withheld for at least 
12 hours prior to Visit 0, 1 and 4 at the site.
!
 and SAMA combinations
∀
/SAMA combinations should be withheld for at least 12 hours prior to Visit 0, 
1 and 4 at the site.
!
Maintenance and reliever therapy (MART)
∀
MART reliever therapy and the use of Budesonide/formoterol as a rescue medication 
are allowed at the Investigator's discretion. Total ICS dose of MART maintenance 
therapy and whether it is used as rescue medication will be recorded in the eCRF.
∀
MART reliever therapy should be withheld for at least 12 hours prior to Visit 0, 1 and 
4 at the site (Table 4).
!
Oral corticosteroids (OCS)
∀
OCS use for the treatment of asthma exacerbation is allowed for the duration of 
≤4 weeks. Longer treatment with OCS should be discussed with the AZ Study 
Physician to decide on the participant’s disposition. Please refer to Section 8.3.1 for 
further instructions on study procedures in case of acute asthma exacerbation or 
respiratory tract infection.
6.6
Dose Modification
This protocol does not permit dose modification (see Section 4.3). Dosing can only be 
discontinued due to an AE per the Investigator’s clinical judgement or unforeseen 
circumstances (see Section 7.1).
Any change from the dosing schedule (dose interruptions or dose discontinuations) should be 
recorded in the eCRF.
6.7
Intervention After the End of the Study
The investigator will discuss the available treatment options with participants who complete 
the study or who withdraw early from the study. The sponsor will not provide benralizumab 
upon study completion or early study withdrawal.
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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Procedures for E/D follow-up should be followed as specified in SoA and the participant will 
be withdrawn from the study. 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
If a participant has no baseline assessments which are successfully performed (PROs, CT scan 
or Spirometry) then the participant must be withdrawn from the study. Procedures and study 
intervention should be discontinued. 
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.
7.1
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 remain in the study to be 
evaluated for safety and, if he/she had completed the study procedures at Visit 1 and have had 
at least one dose of the study intervention, baseline measurements will also be evaluated. 
If a participant discontinued study intervention, procedures for an Early Study Intervention 
Discontinuation (E/D) follow-up should be followed as described in the SoA. Refer to Table 1
for data to be collected at the time of discontinuation of study intervention and follow-up and 
for any further evaluations that need to be completed
Participants may be discontinued from IP in the following situations.

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment (see Section 7.2).

An AE that is considered to jeopardize the safety of a participant participating in the study 
as judged by the Investigator or AstraZeneca.

Positive pregnancy test at any time during the study (see Section 8.4.8 Pregnancy), or 
breastfeeding.

Severe non-compliance with the CSP.

Development of any study-specific criteria for discontinuation, including:

An anaphylactic reaction to the IP,

A helminth parasitic infestation requiring hospitalization,

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o
requiring hospitalization for more than 24h or intubation,
o
requiring OCS treatment after week 11 (see Section 8.3.1 for further details)

Any new or recurrent malignancy, except non-melanoma skin cancers,

-19

Moderate or severe disease at any time during the study period.

Mild disease with lower respiratory tract symptoms at any time during the study 
period.

Mild disease without lower respiratory tract symptoms may continue in the study at
the investigator’s discretion and visits rescheduled per Section 5.5.4.

Asymptomatic patients with COVID-19 positive test should not be discontinued and 
visits rescheduled per Section 5.5.4.
For details relating to dose modifications, see Section 6.6.
7.1.1 Temporary Discontinuation
Dose interruption requiring rescheduling of IP administration outside the visit window 
indicated in the SoA (Table 1) should be an exception and the reason should be recorded in the 
eCRF. Dose delays longer than 10 days may only happen upon approval of the AstraZeneca 
Study Physician and at the discretion of the Study Physician, and if not authorized will be 
considered a discontinuation of study intervention. Procedures for E/D follow-up should be 
followed as specified in the SoA (Table 1). Study treatment may be temporarily discontinued 
for reasons such as the following:

Adverse event

Unforeseen circumstances resulting in delayed visit (ie, illness, or personal events)
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.
A participant who considers withdrawing from the study must be informed by the investigator 
about modified follow-up options (e.g., 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. See SoA for data to be 
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need to be completed. Then the participant will discontinue the study intervention and be 
withdrawn from the study at that.
A participant who withdraws consent will always be asked about the reason(s) and the 
presence of any AE and history of asthma exacerbation. The Investigator will follow up 
participants as medically indicated. A withdrawal visit is essential to collect as much safety 
data, as possible for the participant as per E/D described in the SoA (Table 1).
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If participant chooses to withdraw from the study and as a result discontinues from the study 
intervention, if possible, an E/D follow-up should be conducted, as shown in the SoA (see 
Section 7.2 for further details). 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 Study Team.
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 
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Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants enrolled, including those 
who did not get investigational product. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be involved in 
any attempts to collect vital status information.
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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 Investigator will ensure that data are recorded in the eCRFs. An electronic system will be 
used for data collection and query handling. The Investigator will also ensure the accuracy, 
completeness, legibility, and timeliness of the data recorded and of the provision of answers to 
data queries according to the Clinical Study Agreement. The Investigator will sign the 
completed eCRFs. A copy of the completed eCRFs will be archived at the study site. In case 
of civil crisis, natural disaster, or public health crisis, additional data to assess the impact of 
such events will be collected.
Immediate safety concerns should be discussed with the sponsor 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, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
The average amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will be approximately 30 mL
(depending on the local laboratory sample processing procedure) and will not exceed 50 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Efficacy Assessments
8.1.1 Functional Respiratory Imaging (FRI)
Functional Respiratory Imaging (FRI) is a quantitative method to measure biological 
responses to therapeutic interventions through structural and functional parameters using 
high-resolution CT and computational fluid dynamics. All CT scanners used in this study must 
be at least a 64-slice scanner. For a helical scan, the scanner should be able to acquire at least 
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64 x 0.625 mm, 128 x 0.5 mm, 256 x 0.6 mm, etc.) using a tube voltage of 100kV. FRI 
analyses will be conducted by a central vendor who will provide further guidance on the CT 
scanner requirements, CT scan procedure and scanner-specific scanning protocol settings
required for the current study in a separate manual and guidance document. Study team 
training will also be provided by the central vendor to all relevant study team members prior 
to study center activation. Clinical evaluation of CT scans should be done by the study team as 
per local practice, and any abnormality identified should be recorded as an AE in the eCRF.
8.1.1.1
FRI parameters
Image acquisition
In this study, the FRI parameters will be obtained through first the acquisition of low dose, 
high-resolution computed tomography (CT) thorax scans of participants in the study using a
low radiation scanning protocol installed on a study-allocated CT scanner before study 
initiation at the study center.
All participants in the study will undergo two high-resolution scans, one each at Total Lung 
Capacity (TLC) and Functional Residual Capacity (FRC) with gating, at both Visits 1 and 4 as 
specified in the SoA (Table 1). All CT scans will be conducted with respiratory gating using 
equipment (CE-marked) provided by the central vendor. All CT scan procedures should also 
be conducted before spirometry testing (see Section 8.1.2 for further details).
Participants should withhold their usual maintenance and rescue therapies before Visit 1 and 
Visit 4 where CT procedures will be scheduled as below:
!
 
!
Short-acting muscarinic antagonists (SAMAs) or 
/SAMA combinations should 
be withheld at least 12 hours prior to Visit 1 and Visit 4 at the site.
!
Twice daily LABA-containing therapies should be withheld for at least 12 hours prior 
to Visit 1 and Visit 4 at the site.
!
Once daily LABA-containing therapies should be withheld for at least 24 hours prior 
to Visit 1 and Visit 4 at the site.
!
Once daily LAMA-containing therapies should be withheld for at least 24 hours prior 
to Visit 1 and Visit 4 at the site.
!
Twice daily LAMA-containing therapies should be withheld for at least 12 hours 
prior to Visit 1 and Visit 4 at the site.
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!
LTRA should be restricted for at least 24 hours prior to Visit 1 and Visit 4 at the site.
!
Twice daily theophyllines should be withheld for at least 12 hours prior to Visit 1 and 
Visit 4 at the site.
!
Once daily theophyllines for at least 24 hours prior to Visit 1 and Visit 4 at the site.
Image processing
All high-resolution CT images should be de-identified before upload to the central vendor
where they will be imported into Mimics, a commercial, Food and Drug Administration 
approved, medical image processing software package (Materialise, Leuven, Belgium, Food 
and Drug Administration, K073468; CE certificate, BE 05/1191 CE01). Trained FRI analysts 
will implement validated protocols and algorithms to convert the high-resolution CT images 
into patient specific, segmented, three-dimensional (3D) computer models of the lung lobes, 
the airway lumen and wall, and the vascular tree. These models will then be used for 
performing measurements of the following structural and functional FRI parameters and used 
for further evaluations of functional FRI parameters that utilize computational fluid dynamics 
(CFD).
The following are the relevant structural and functional FRI parameters:
1. Untrimmed total mucus volume at TLC (Primary)
2. Untrimmed total mucus plugs score at TLC (Secondary)
3. Untrimmed total air trapping at FRC (Secondary)
4. Trimmed distal airway wall volume (iVaww) at TLC (Secondary)
5. Trimmed distal specific airway volume (siVaw) at TLC (Secondary)
6. Trimmed distal specific airway volume (siVaw) at FRC (Secondary)
7. Untrimmed total lung volume (iVlung) at TLC (Secondary)
8. Untrimmed total lung volume (iVlung) at FRC (Secondary)
9.
The computational fluid dynamics (CFD) approach will also be used to model exposure to 
inhaled particles. Specifically, aerosol deposition using CFD simulates the particle flow and 
particle behavior of within the reconstructed lungs of participants as a function of the specific 
inhalation profile, geometry of the airways and the drug particle size. In this study, aerosol 
deposition will be simulated based on inhalation of a generic 
 
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inhaler using selected inhalation flow profiles. Specific particle mass median 
aerodynamic diameter (MMAD +/- geometric standard deviation) of the relevant drug will be 
taken from published literature or data on file and 3D computer-aided design (CAD) file of the 
 inhaler device will be obtained to conduct the aerosol deposition simulation. 
Deposition in the intrathoracic and peripheral airways will be measured using 
drug deposition ratio before and after benralizumab treatment using 
lung models from high-resolution CT scans at week 0 (baseline) and week 13 (± 5 days). 
Central airway will be defined as the trachea and all airways with diameter > 1–2 mm and 
reaching out to 7–10th generation of dichotomous branching, while the peripheral airways will 
be defined as airways with a diameter < 1–2 mm and > 10 generations of branching. As 
detailed in the above list of relevant structural and functional FRI parameters, FRI analyses on 
CT scans at baseline (Visit 1) and following benralizumab treatment (at Visit 4) will be 
conducted on untrimmed or trimmed airways. Untrimmed analyses will include all airway 
branches visible at each visit, while the trimmed analysis will only include airway branches 
visible across both visits 1 and 4. All FRI parameters will be assessed in the different zones of 
the respiratory system - right upper lobe (RUL), right middle lobe (RML), right lower lobe 
(RLL), left upper lobe (LUL) and left lower lobe (LLL), as well as into central and distal 
regions, the latter two regions only for FRI parameters related to the airways (siVaw, and 
iVaww). Specifically, all FRI parameters related to the airways (siVaw and iVaww) will be 
assessed from generations 1 to 10 and reported by different zones of the respiratory system 
and by central and distal regions. Additionally, airway wall volume (iVaww) will be at 
generations 3 and 4, based on assessments planned for similar ongoing studies.
8.1.1.2
Mucus Plugging
As detailed in the previous section, untrimmed total mucus volume at TLC and untrimmed 
mucus plugs score at TLC are FRI parameters of interest in the study. 
Mucus plugging will be assessed visually through diligent segmentation of the airways. 
Airways will be segmented from central airways to distal airways by means of a deep learning 
Convolutional Neural Network (CNN) model to the extent which the resolution of the scanner 
allows. After segmentation of the airways, a mucus plug will be identified as such if the plug 
prematurely blocks or ends the airway segmentation and presents with an open airway after 
the plug (full occlusion). The above approach to mucus plug assessment allows for multiple, 
sequential mucus plugs from central to distal areas in the airway tree to be detected and
included for analysis. Each bronchopulmonary segment will be given a score that directly 
represents the number of mucus plugs within that segment. Therefore, mucus plugs will be 
counted per segmental airway branch, and the total number of mucus plugs will be presented 
on a segmental, lobar (RUL, RML, RLL, LUL and LLL), and total level, by summing up the 
scores over the specific zones mentioned.
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The volume of the mucus plugs will also be determined on lobar (RUL, RUML, RLL, LUL 
and LLL) and presented on the total level, by summing up the mucus volumes over the 
specific zones mentioned.
Next, with the use of data presented from the mucus plugging assessment above, mucus plugs 
will also be scored with a scoring system similar to that by Dunican et al. with the Severe 
Asthma Research Program (SARP) (Dunican et al., 2018), based on bronchopulmonary 
segmental anatomy. Each bronchopulmonary segment will be given a score of 1 (mucus plug 
present) or 0 (mucus plug absent). The segment scores of each lobe will be summed to 
generate a total mucus score for both lungs, yielding a mucus score ranging from 0-20. Of 
note is the means of determining whether a particular segment contained a mucus plug will 
differ from that described in Dunican et al., 2018 in that airways will be segmented as 
described above. The presence or absence of mucus within a given CNN-segmented airway 
will be determined according to the method also described above.
8.1.2 Spirometry
Lung function measurements will be assessed as part of efficacy assessment and at screening 
(Section 5.1 and 5.2).
Participants will need to undergo pre- and/or post-bronchodilator (pre-BD and post-BD) 
spirometry tests for this study to fulfil the inclusion criteria. Pre-BD spirometry testing will be 
conducted during Visit 0, Visit 1 and Visit 4 in accordance with the SoA (Table 1). Post-BD 
spirometry with reversibility testing will be conducted during Visit 0 if participants do not 
have historical documented reversibility available in medical records. If participants are 
unable to perform acceptable and repeatable spirometry during screening, a retest is permitted 
(see Section 5.4).
Post-BD spirometry should be initiated at least 15 minutes after BD dosing and should ideally 
be completed within 1 hour after BD administration. If more than 1 hour has passed since the 
BD dosing, additional puffs can be administered at the discretion of the Investigator.
The BD will be administered as follows: after a gentle and complete exhalation, 4 inhalations 
of albuterol (US; 90 μg metered dose) or salbutamol (other countries; 100 μg metered dose) 
should be administered using a spacer device. In rare cases where a participant has an adverse 
or allergic reaction to albuterol/salbutamol, levalbuterol (45 μg metered dose, 4 inhalations) 
can be used (Sorkness et al., 2008). A nebulizer should not be used. A lower total dose (e.g.,
2 inhalations instead of 4 and if required up to a maximum of 4 puffs) can be used if there is a 
concern about any effect on the participants heart rate, tremor or safety; the reason should be 
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Lung function (FEV1 and FVC) will be measured by spirometry using equipment available at 
the study site. The highest technically acceptable pre- and/or post-BD FEV1 and FVC will be 
captured. Spirometry will be performed by the Investigator or authorized delegate according 
to the 2005 ERS/ATS guidelines (Pellegrino et al., 2005). The responsible delegate at the 
facility where spirometry is conducted by the study center will be responsible for assuring that 
the spirometer is properly calibrated, meets ATS/ERS recommendations, and that the study 
center personnel who will be performing the testing are properly certified.
Participants should note the following before spirometry testing:
1)
Avoid engaging in strenuous exertion for at least 30 minutes prior to spirometry test at the 
center.
2)
Avoid eating a large meal or drinking alcohol or caffeine containing beverages for at least 
2 hours prior to spirometry test at the center.
3)
Withhold their usual maintenance and rescue therapies before Visit 0, Visit 1 and Visit 4 
where spirometry testing will be scheduled as below:
!
) should be withheld at least 6 hours prior to Visit 0, 
Visit 1 and Visit 4 at the site.
!
Short-acting muscarinic antagonists (SAMAs) or 
/SAMA combinations should 
be withheld at least 12 hours prior to Visit 0, Visit 1 and Visit 4 at the site.
!
Twice daily LABA-containing therapies should be withheld for at least 12 hours 
prior to Visit 0, Visit 1 and Visit 4 at the site.
!
Once daily LABA-containing therapies should be withheld for at least 24 hours prior 
to Visit 0, Visit 1 and Visit 4 at the site.
!
Twice daily LAMA-containing therapies should be withheld for at least 12 hours 
prior to Visit 1 and Visit 4 at the site.
!
Once daily LAMA-containing therapies should be withheld for at least 24 hours prior 
to Visit 0, Visit 1 and Visit 4 at the site.
!
LTRA should be restricted for at least 24 hours prior to Visit 0, Visit 1 and Visit 4 at 
the site.
!
Twice daily theophyllines should be withheld for at least 12 hours prior to Visit 0, 
Visit 1 and Visit 4 at the site.
!
Once daily theophyllines for at least 24 hours prior to Visit 0, Visit 1 and Visit 4 at 
the site.
On Visit 1 and Visit 4, the spirometry test should always be performed after the participants 
undergo the CT scan procedure as the procedures conducted during spirometry may impact 
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the CT scans. If not feasible, there should be at least 30 min between the spirometry test and 
subsequent CT scan procedure.
8.1.3
 
 
 
 
 
 
 
 
 
 
 
 
. 
8.1.4
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.5
 
 
 
 
 
 
 
 
 
 
 
administration at 
Visit 1, and prior to the CT scan procedure and spirometry test at Visit 4.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1 Physical Examinations
A brief physical examination will be performed and include, at a minimum, assessments of the 
lungs, chest, head, eyes, ears, nose and throat.
Physical examination will be performed at timepoints as specified in the SoA (Table 1).
Any evidence of clinically significant abnormalities identified during the physical 
examination at screening and during the study will be recorded in the eCRF. Clinically 
significant abnormalities identified during physical examinations during the study should also 
be reported per Section 8.4.5.
8.2.2 Vital Signs
Vital signs (blood pressure and pulse) will be performed at timelines as specified in the SoA
(Table 1).
Vitals signs will be measured during screening, at unscheduled visits and during an early 
CCI
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discontinuation visit. As per standard of care, vital signs may also be taken before blood 
draws, CT scan procedures, IP administration, and, prior to usual asthma maintenance 
medication Blood pressure and pulse measurements will be assessed in a sitting position with 
a completely automated device. Manual techniques will be used only if an automated device is 
unavailable. Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, cell phones).
Any clinically significant abnormalities will be recorded in the eCRF and reported per 
Section 8.4.5.
8.2.3 Electrocardiogram
An electrocardiogram (ECG) will be performed at screening to access eligibility for the study
as specified in the SoA (Table 1).
A12-lead ECG will be taken in supine position at screening (Visit 0), prior to blood draw, 
spirometry, and BD administration if applicable, at a local facility.
The Investigator or authorized delegate will be responsible for the overall interpretation and
determination of clinical significance of any potential ECG findings. The Investigator’s
interpretation should be noted on the printout and recorded in the eCRF. A copy of the ECG 
will be produced and kept in case of further need for re-evaluation.
Any clinically significant abnormalities will be reported per Section 8.4.5.
8.2.4 Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry and hematology will be taken 
at the visits indicated in the SoA (Table 1).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges as 
specified in eCRF completion instructions) will be recorded on the appropriate eCRF.
Clinical chemistry and hematology will be performed at a local laboratory at or near to the 
investigator site. Sample tubes and sample sizes may vary depending on laboratory method 
used and routine practice at the site.
The following laboratory variables will be measured:
Table 7
Laboratory Safety Variables
Haematology (whole blood)
Clinical Chemistry (serum or plasma)

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Hemoglobin (Hb)
Alkaline phosphatase (ALP)
Leukocyte count
Alanine transaminase (ALT)
Leukocyte differential count (absolute count; 
including eosinophil absolute count)
Aspartate transaminase (AST)
Platelet count
Bilirubin, total
Creatinine
Glucose
Potassium
Sodium
NB. In case a participant shows an AST or ALT ≥3 ×ULN at screening, participant will be 
excluded from the study. 
8.2.4.1
Pregnancy test
The following tests are applicable to female participants only, and will be conducted in
accordance with the SoA (Table 1).
1)
Serum β-human chorionic gonadotropin (β-HCG) – the test will be mandatory at
screening for WOCBP. Testing will be conducted at a local laboratory at or near to the 
investigator site.
2)
FSH – the test performed at screening only, for female participants to
confirm postmenopausal status in women < 50 years who have been amenorrheic for
> 12 months. Testing will be conducted at a local laboratory at or near to the investigator 
site.
3)
Urine HCG – the test will be performed at the study site for WOCBP at Visits 1, 2, 3 and
4 using a dipstick. A negative urinary pregnancy test is required for WOCBP prior to 
study entry, CT scan procedure and administration of IP. A positive urine test result must 
be confirmed with serum β-HCG and if necessary, the visit can be rescheduled according 
to the SoA (Table 1).
Results from the tests should be recorded in the eCRF. Participants will be immediately
discontinued from all study procedures and administration of IP following a positive urine 
pregnancy test and will be withdrawn from the study following confirmation with serum
pregnancy test (see Section 7.1 and 8.4.8). Procedures for E/D follow-up should be followed 
as indicated in the SoA (Table 1).
8.2.5 COVID-19 Testing
Each investigator site shall follow prevailing local guidelines for COVID-19 testing before 
any visits or procedures.
If a participant presents with a positive COVID-19 test result, visits are permitted to be
rescheduled per guidance provided in Section 5.5.4.

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Participants with a positive COVID-19 test result and symptomatic disease should have their 
situation assessed and either discontinued per section 7.1 or have the visit rescheduled per 
Section 5.5.4.
Results from the tests should be recorded in the ISF.
8.3
Asthma Exacerbations and Respiratory Tract Infections
Acute asthma exacerbation, respiratory tract infections and their treatments may alter the 
inflammatory profile of the airways. The assessment for acute exacerbation and other acute 
respiratory tract infection should therefore occur before any other assessments are performed. 
During the study, an asthma exacerbation will be defined as a worsening of asthma that leads 
to any of the following:

Use of systemic corticosteroids (or a temporary increase in a stable oral corticosteroid 
background dose) for at least 3 days; a single depo-injectable dose of corticosteroids 
will be considered equivalent to a 3-day course of systemic corticosteroids.

An emergency room/urgent care visit (defined as evaluation and treatment for 
< 24 hours in an ER or urgent care center) due to asthma that required systemic 
corticosteroids (as per above).

An inpatient hospitalization due to asthma (defined as an admission to an inpatient 
facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours).
The start of an exacerbation is defined as the start date of systemic corticosteroids, date of ER 
or urgent care visits requiring systemic corticosteroids, or date of hospital admission due to 
asthma, whichever occurs earlier.
The end date of an exacerbation is defined as the last date of systemic corticosteroids, return
to baseline dose of OCS for those on chronic OCS, date of ER or urgent care visit, or date of 
hospital discharge, whichever occurs later.
8.3.1 Study Visit Procedures Following Determination of An Acute Asthma 
Exacerbation or Respiratory Tract Infection
All asthma exacerbations that occur during the treatment and study period must be recorded in 
the exacerbation eCRF. Asthma exacerbation should be recorded as an AE only if it fulfils any 
of the criteria for SAE (Section 8.4.7), or the AE leads to IP discontinuation.
Participants who have an asthma exacerbation (worsening of asthma) or respiratory tract 
infection requiring hospitalization (defined as an admission to an inpatient facility and/or 
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center) will be discontinued from the study (see Section 7.1) and procedures for an Early 
Study Intervention Discontinuation (E/D) follow-up should be followed as described in the 
SoA. (Refer to Table 1 for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed). 
Participants who have an asthma exacerbation (worsening of asthma) or respiratory tract 
infection that does not require hospitalization (defined above), but require use of antibiotics 
and/or systemic corticosteroids (or a temporary increase in a stable oral corticosteroid 
background dose) for at least 3 days [a single depo-injectable dose of corticosteroids will be 
considered equivalent to a 3-day course of systemic corticosteroids] should have their visit 
schedule adjusted per the following guidance, according to when it occurs:

Before Visit 1 (V1), this visit should be rescheduled to occur after resolution of the 
exacerbation/infection and at least 4 weeks after the last dose of any medication to 
treat the exacerbation/infection, provided that there are no safety concerns as judged 
by the Investigator.

Between Visit 1 (V1) and Visit 3 (V3), there will be no changes to the study activities 
and the SoA should be followed (Table 1).

Between Visit 3 (V3) and Visit 4 (V4), the participant will be permitted to undergo the 
study assessments for Visit 4, but it should be delayed to ensure an interval between 
Visit 4 and the last dose of antibiotic or OCS, whichever ends later (or return of 
OCS dose to previous maintenance dose) of at least 7 days, but no longer than 14 days, 
per investigator’s discretion.
In case of uncertainty related to procedures following an exacerbation, please consult with the 
AstraZeneca US study team.
8.4
Adverse Events and Serious Adverse Events
The Principal Investigator (PI) 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 C.
The definitions of medical device-related safety events, (Medical device (SAE), adverse 
device effects [ADEs] and SADEs), can be found in Appendix E. (Medical Device 
deficiencies are covered in Section 8.4.10).
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 

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The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. See Section 8.4.2 for information on how to 
follow-up AEs and SAEs.
8.4.1 Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from after the participant received the first dose of the study 
intervention, throughout the treatment period and including the follow-up period (Visit 5, last 
contact), or up until follow-up for early discontinuation.
SAEs will be recorded from the time of signing of the informed consent form.
If the investigator becomes aware of a serious adverse event with a suspected causal 
relationship to the investigational medicinal product 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 serious adverse event to the sponsor.
8.4.2 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

Intensity of the AE

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to Investigational Product

AE caused participant’s withdrawal from study (yes or no)

Treatment for AE

Outcome

Causality assessment in relation to study procedure (yes or no)
In addition, the following variables will be collected for SAEs:

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
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

AE description
8.4.3 Causality Collection
The investigator should assess causal relationship between IMP, Investigational Medical 
devices and/or study procedure and each AE and/or Incident, 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 investigational product?’
For SAEs and Serious Incidents, causal relationship should also be assessed for other 
medication and study procedures and/or medical devices. Note that for SAEs that could be 
associated with any study procedure the causal relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix C to the Clinical 
Study Protocol. For medical devices, a guide to the interpretation of the causality question can 
be found in Appendix E.
8.4.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.4.5 Adverse Events Based on Examinations and Tests
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summarized in the Clinical Study Report (CSR). 
Deterioration as compared to baseline in protocol-mandated vital signs, physical examination 
and spirometry (FEV1) measurements should therefore only be reported as AEs if they fulfil 
any of the SAE criteria, are the reason for discontinuation of treatment with the investigational 
product or are considered to be clinically relevant as judged by the investigator (which may 
include but not limited to consideration as to whether treatment or non-planned visits were 
required or other action was taken with the study intervention, e.g., dose adjustment or drug 
interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator
uses the clinical, rather than the laboratory term (e.g., anemia versus low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
Upper and lower respiratory tract infections will be recorded as AEs.
8.4.6 Disease Under Study
Symptoms of disease under study (DUS) are those which might be expected to occur as a 
direct result of usual, intermittent variations in disease status or response to environmental 
stimuli (e.g., allergens or weather) or routine pulmonary procedures (e.g., spirometry). Events 
which are unequivocally due to disease under study should not be reported as an AE during 
the study unless they meet SAE criteria or lead to discontinuation of the investigational 
product, or is a sign or symptom that is new to the participant or inconsistent with the 
participant’s pre-existing asthma history as judged by the Investigator.
Asthma exacerbation should be recorded as an AE only if it fulfils any of the criteria for SAE 
(see Section 8.4.7) or if the AE leads to IP discontinuation.
8.4.7 Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 

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product, 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. Any updated SAE data will be submitted by 
the Investigator to the sponsor within 24 hours of it being available.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
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 investigators or other site personnel indicate an AE is serious in the Electronic Data 
Capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative. 
If the electronic AE/SAE reporting is unavailable, AE/SAE should be reported on paper. Fax 
cover sheet and SAE Report Form (available in the Site File) are to be used.

Initial notification via EDC does not replace the need for the Investigator to complete 
and sign the SAE paper data collection tool within the designated reporting time 
frames.
For further guidance on the definition of a SAE, see Appendix C of the Clinical Study 
Protocol.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
8.4.8 Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
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8.4.8.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product 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 during the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.4.7) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.4.8.2
Paternal Exposure 
There is no restriction on fathering children or donating sperm during the study.
8.4.9 Medication Error, Drug Abuse, and Drug Misuse
8.4.9.1
Timelines
If a medication error, drug abuse, or drug misuse occurs during the study, then the investigator
or other site personnel informs the appropriate AstraZeneca representatives within 1 calendar 
day, ie, immediately but no later than 24 hours of when they become aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error, drug abuse, or misuse (see Section 8.4.7) and 
within 30 days for all other medication errors.

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8.4.9.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP that either causes harm to the participant or has the 
potential to cause harm to the participant.
The full definition and examples of Medication Error can be found in Appendix C4.
8.4.9.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP for 
a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix C4.
8.4.9.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP for 
medicinal purposes outside of the authorized product information, or for unauthorized IMP, 
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 C4.
8.4.10 Medical Device Deficiencies
Medical devices are being provided for use in this study as the study intervention is supplied 
in prefilled syringes are being utilized to deliver the IMP under study. In order to fulfil
regulatory reporting obligations worldwide, the investigator is responsible for the detection 
and documentation of events meeting the definitions of medical device deficiency that occur 
during the study with such medical devices.
The definition of a Medical Device deficiency can be found in Appendix E.
NOTE: Incidents and deficiencies fulfilling the definition of an AE/SAE will also follow the 
processes outlined in Appendix E of the protocol. 
In this study any deficiency observed with a third-party medical device will be collected and 
reported to the manufacturer.
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer.
The AstraZeneca medical device complaint report will be used to collect the deficiency.

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8.4.10.1
Time Period for Detecting Medical Device Deficiencies
Medical device incidents or malfunctions of the medical device will be detected, documented, 
and reported during all periods of the study in which the medical device is used.
If the investigator learns of any medical device deficiency at any time after a participant has 
been discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting Medical Device Deficiency is provided in Appendix E.
8.4.10.2
Follow-up of Medical Device Deficiencies
Follow-up applies to all participants, including those who discontinue study intervention.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.4.10.3
Prompt Reporting of Medical Device Deficiencies to Sponsor
Medical device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency.
In this study, deficiency observed with any of study treatment medical devices (benralizumab 
[Fasenra®]) will be collected and reported to the manufacturer using the form available on the 
Pharmacy manual (for more details please follow up Pharmacy manual).
The third-party medical device deficiency (Spirostik) will be reported by Investigator on the 
paper form as per the User Manual.
The sponsor will be the contact for the receipt of medical device deficiency reports.
8.4.10.4
SADE Reporting
NOTE: There are additional reporting obligations for device constituent deficiencies that are 
potentially related to SAEs that must fulfil the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to device 
constituents being used in clinical studies.

Any device constituent deficiency that is associated with an SAE must be reported to 
the sponsor within 24 hours after the investigator determines that the event meets the 
definition of a device constituent deficiency.

The sponsor will review all device constituent deficiencies and determine and 

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document in writing whether they could have led to an SAE. These device constituent 
deficiencies will be reported to the regulatory authorities and IRBs/IECs as required by 
national regulations.
8.4.10.5
Regulatory Reporting Requirements for Device Deficiencies
The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (e.g., the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of medical device deficiencies to the IRB/IEC.
For further guidance on the definition of an SAE, see Appendix E of the CSP.
8.5
Overdose
For this study, any single dose of benralizumab greater than > 30 mg will be considered an 
overdose.
There is currently no specific treatment in the event of overdose of IP and possible symptoms 
of an overdose are not established.

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 data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.4.7) and within 
30 days for all other overdoses.
8.6
Human Biological Samples
The collection and handling of biological samples should be conducted per site’s local 
procedures. Samples should be stored in a secure storage space with adequate measures to 
protect confidentiality. For further details on Handling of Human Biological Samples see 
Appendix D.

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8.6.1 Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.6.1.1
Determination of Drug Concentration
Pharmacokinetic parameters will not be evaluated in this study. Therefore, the determination 
of drug concentration will not be conducted.
8.6.2 Immunogenicity Assessments
Immunogenicity assessments will not be conducted in this study.
8.6.3 Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.6.3.1
Collection of Samples
Pharmacodynamic parameters will not be evaluated in this study. Therefore, no sample 
collection will be conducted for this purpose.
8.7
Human Biological Sample Biomarkers
8.7.1 Collection of mandatory samples for biomarker analysis
Biomarkers will not be evaluated in this study. Therefore, no mandatory sample collection will 
be conducted for this purpose.
8.7.2 Collection of Optional Biomarker Samples
Biomarkers will not be evaluated in this study. Therefore, no optional sample collection will 
be conducted for this purpose.
8.7.3 Other Study Related Biomarker Research
Other study related biomarker research will not be conducted in this study. 
8.8
Optional Genomics Initiative Sample
Optional Genomics Initiative research will not be a part of this study.

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8.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.

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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
For the primary and secondary objectives, measures of mean within subject difference in FRI 
parameters (enumerated in Table 3) between weeks 0 and 13 the null hypothesis is a difference 
of 0, an assumption based on existing data described in Section 4.2 suggesting untreated
participants are likely to exhibit stable or declining primary endpoint values over a similar 
(12 week) time period.
9.2
Sample Size Determination
 
 
 
 
 
 
 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not assigned in the study, are considered” screen failures”, unless otherwise specified 
by the protocol. 
CCI
CCI
CCI

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9.3
Populations for Analyses
The following populations are defined:
Table 8
Populations for Analysis
Population/Analysis set
Description
Enrolled 
All participants who sign the informed consent form
Randomly assigned to study 
intervention
NA (single-arm study)
Evaluable
All participants who have completed three doses of investigational product, 
and have baseline and post-benralizumab treatment study evaluation (PROs, 
CT scans and spirometry tests) - the evaluable population.
Primary analysis population
The portion of the evaluable population that did not have an acute asthma 
exacerbation nor lower respiratory tract infection during the study period 
will be the primary analysis population for the endpoints in this study. 
Baseline endpoints analysis set
Participants who have baseline measurements and who have had at least one 
dose of investigational product, irrespectively of whether they discontinued 
for reasons described in Section 7.1 will be included for analyses conducted 
on the study population who at least started treatment. 
Safety analysis set
The Safety analysis set consists of all participants who have received at least 
one dose of investigational product. 
9.4
Statistical Analyses
The statistical analysis plan will be finalized prior to Data Base Lock, and it will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints.
9.4.1 General Considerations
All continuous variables (including FRI parameters, pre-BD FEV1, pre-BD FVC, 
 
) will be summarized using means, standard deviations and 95% 
ranges, or medians and inter-quartile ranges, depending on the distributions of the data. Mean 
changes from baseline in continuous variables will be reported, including asymptotic 95% 
confidence intervals and standard errors. Categorical data (e.g.,
 control 
 
 asthma control category) will be summarized as the number and percentage 
among patients with non-missing data. Descriptive statistics will also be calculated for the 
data stratified by gender. Unless otherwise stated, all hypothesis tests are two-sided and all 
hypothesis tests will be performed at a 5% significance level. Analyses will be carried out for 
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overall patients and subgroups as specified in Section 9.4.4. Data may be log-transformed 
prior to analysis to reduce skewness of FRI parameters.
9.4.2 Efficacy 
9.4.2.1
Primary Objectives
For the primary objective, a paired t-test will be used to determine if there is a significant 
difference between the mean of untrimmed total mucus volume at TLC at week 0 vs week 13, 
irrespective of patient characteristics.
Secondary analysis of the primary endpoint (untrimmed total mucus volume at TLC) will be a
mixed-effects model to incorporate the repeated measurements (corresponding to the different 
lobes) for each subject. The outcome of change from baseline in the primary endpoint at 
week 0 vs week 13 per lobe will be modelled in terms of a fixed effect for lobe and a patient-
level random effect to estimate the heterogeneity across lobes. Adjustment will be made for 
baseline mucus volume per lobe. The fitted model will estimate the average  change from 
baseline in mucus volume at week 0 vs week 13 per lobe.
9.4.2.2
Secondary Objectives
For the secondary objective 1, univariate paired t-tests and mixed effects modelling will be 
used to assess whether there are statistically significant differences in the means of secondary 
FRI endpoints (untrimmed total mucus plugs score at TLC, untrimmed total air trapping at 
FRC, trimmed distal iVaww at TLC, trimmed distal siVaw at TLC and FRC, and untrimmed 
total iVlung at TLC and FRC) at week 0 vs week 13, unadjusted for patient characteristics.
Secondary analysis of each secondary endpoint will be a mixed-effects model to incorporate 
the repeated measurements (corresponding to the different lobes) for each subject. The model
will estimate the average change from baseline in secondary endpoint at week 0 vs week 13 
per lobe, after accounting for the baseline measurement of the secondary endpoint per lobe
and heterogeneity across lobes.
For secondary objective 2, a scatter plot will be used to display values of imaging endpoints 
(primary and secondary FRI parameters) and conventional lung function measures (pre-BD 
FEV1 and pre-BD FVC response) at week 0, to get a first indication of the relationship 
between endpoints at baseline. Spearman’s rank correlation coefficients will describe the 
strength of the association between two endpoints. Pearson correlation will also be 
used for linear relationships. Regression models will be used to estimate the average increase 
in imaging endpoints per unit increase in conventional lung function measures, with 95% 
confidence intervals.
For secondary objective 3, a scatter plot will be used to display changes from baseline at 

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week 13 in imagine endpoints (primary and secondary FRI parameters) against changes from 
baseline at week 13 in conventional lung function measures (pre-BD FEV1 and pre-BD FVC 
response). Both Spearman’s rank and Pearson correlation coefficients will describe the 
strength of the association. If changes from baseline in conventional lung function measures at 
week 13 are related to baseline values, as indicated by fitted regression models, correlation 
coefficients will be reported per subgroup defined by baseline value.
A linear regression model for imaging endpoints will be fitted, consisting of a binary 
explanatory variable (corresponding to week 13). The regression coefficient for time will 
estimate the change from baseline (week 13 vs week 0) in the imaging endpoint. The model 
will be fitted with and without the inclusion of the change from baseline in pre-BD FEV1 and 
pre-BD FVC as individual covariates. Estimated regression coefficients for time from the 
unadjusted and adjusted models will be compared, to indicate whether the change from 
baseline in the imaging parameter is explained by changes in pre-BD FEV1 and pre-BD FVC. 
Estimated regression coefficients for changes in pre-BD FEV1 and pre-BD FVC will be 
reported, to quantify the average change in each imaging endpoint for every one percent 
increase in pre-BD FEV1 and pre-BD FVC.
9.4.2.3
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.4.3 Safety
Safety analyses will be performed using the safety analysis set. Adverse events will be coded 
using the most recent version of the Medical Dictionary for Regulatory Activities that will 
have been released for execution by the Sponsor/designee.
Safety data will be presented using descriptive statistics unless otherwise specified. 
The AEs will be presented by system organ class and/or preferred term covering number and 
percentage of patients reporting at least 1 event and number of events where appropriate. An 
overview of AEs will present the number and percentage of patients with any AE, AEs with 
outcome of death, SAEs, and AEs leading to discontinuation of IP. Separate AE tables will be 
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provided taken into consideration relationship as assessed by the Investigator, intensity, 
seriousness, death, and events leading to discontinuation of IP. An additional table will present 
number and percentage of patients with the most common AEs. 
Vital signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, Min, Q1, median, Q3, and Max.
Details of vital sign analyses will be provided in the SAP. 
9.4.4 Other Analyses 
Further analyses will be conducted for the secondary objectives related to cross-
sectional associations between imaging (FRI) endpoints and conventional lung function 
measurements (FEV1 and FVC) at week 0. These analyses will use measurements from the
study population that includes both participants who completed the study per protocol 
definition, and those who completed baseline measurements at Visit 1 and had at least one 
dose of IP irrespectively of whether they discontinued for reasons described in Section 7.1.
 
The evaluable population (Table 4) will be analyzed for the same outcome measures 
conducted for the primary analysis population (Table 4).
Additional analyses will be conducted for all outcome measures for both the primary analysis 
population and the evaluable population for the following subgroups:
!
Mucus plugging status: Participants with or without mucus plugs identified at the CT 
scans (Section 8.1.1.2) at Visit 1 (week 0)
!
OCS dependency status: OCS-dependent and Non-OCS-dependent participants as 
defined by the inclusion criteria #4 (Section 5.1)
Results from subgroup analyses above will be compared with corresponding results from the 
evaluable population.
9.5
Interim Analyses 
No interim analyses have been planned for this study.
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9.6
Data Monitoring Committee
No Data Monitoring Committee will be used in this study.

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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Radiation Exposure Calculations
The estimate radiation exposures presented in the following table are based on a selection of 
CT scanners and is not representative of all CT scanners that can be used for the current study. 
A CT scanner may be used for the current study as long as it meets the minimum requirements 
stated in Section 8.1.1.
Table S1:
Estimated radiation exposure using the low radiation scanning protocols
recommended for this study based on a selection of CT scanner brands 
and models from four manufacturers 
Scanner Type
Estimated radiation 
per HRCT scan
(CTDIvol [mGy] 
(Effective dose [mSv]))
Estimated radiation for 
4 HRCT scans
(CTDIvol [mGy] 
(Effective dose [mSv]))
Scanner selected in CT-Expo
GE Discovery HD750 64
4.6 mGy (2.5 mSv)
18 mGy (10.0 mSv)
Not applicable
GE LightSpeed VCT 64 slices
4.5 mGy (2.2 mSv)
18 mGy (8.8 mSv)
Not applicable
GE Optima CT 660
4.9 mGy (2.5 mSv)
19.6 mGy (10.0 mSv)
Not applicable
GE Revolution 128
3.8 mGy (1.9 mSv)
15.2 mGy (7.6 mSv)
Revolution CT 
(Large body)
GE Revolution CT 256
3.8 mGy (1.9 mSv)
15.2 mGy (7.6 mSv)
Revolution CT 
(Large body)
Philips Brilliance 64
3.2 mGy (1.7 mSv)
12.8 mGy (6.8 mSv)
Not applicable
Philips (Brilliance) iCT
3.4 mGy (1.8 mSv)
13.6 mGy (7.2 mSv)
Not applicable
Philips Ingenuity 128
3.3 mGy (1.8 mSv)
13.2 mGy (7.2 mSv)
Not applicable
Siemens Somatom Perspective 128
4.5 mGy (2.4 mSv)
18.0 mGy (9.6 mSv)
Siemens Somatom 
Perspective
Siemens Somatom Perspective 32
4.5 mGy (2.4 mSv)
18.0 mGy (9.6 mSv)
Siemens Somatom 
Perspective
Siemens Somatom Perspective 64 
Slices
4.5 mGy (2.4 mSv)
18.0 mGy (9.6 mSv)
Siemens Somatom 
Perspective
Siemens Somatom Definition 64
3.6 mGy (1.6 mSv)
14.4 mGy (6.4 mSv)
AS series
Siemens Somatom Definition 128
3.6 mGy (1.6 mSv)
14.4 mGy (6.4 mSv)
AS series
Siemens Somatom Definition 256
3.6 mGy (1.6 mSv)
14.4 mGy (6.4 mSv)
AS series
Siemens Somatom Definition Edge 
128
3.4 mGy (1.4 mSv)
13.6 mGy (5.6 mSv)
Not applicable
Siemens Somatom Definition Flash 
128
3.4 Gy (1.7 mSv)
13.6 mGy (6.8 mSv)
Tube A
Siemens Somatom Sensation 40/64
3.1 mGy (1.8 mSv)
12.4 mGy (7.2 mSv)
Not applicable
Siemens Somatom Force
3.6 mGy (1.9 mSv)
14.4 mGy (7.6 mSv)
BS normal
Siemens Somatom Edge Plus
3.4 mGy (1.4 mSv)
13.6 mGy (5.6 mSv)
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Scanner Type
Estimated radiation 
per HRCT scan
(CTDIvol [mGy] 
(Effective dose [mSv]))
Estimated radiation for 
4 HRCT scans
(CTDIvol [mGy] 
(Effective dose [mSv]))
Scanner selected in CT-Expo
Toshiba Aquillion Prime 160
4.1 mGy (2.4 mSv)
16.4 mGy (9.6 mSv)
Prime (BS medium)
Toshiba Aquillion 64
6.5 mGy (4.0 mSv)
26 mGy (16.0 mSv)
Aquillion -8 to -64
CT, computed tomography; CTDIvol, volume computed dose index.
Note: The calculations for the effective dose strictly apply only for an average male patient 
with a height of 170 cm (5’ 7”), a weight of 70 kg (154 lbs) and a trunk diameter of 28.3 cm.
The CTDIvol refers to standardized cylindrical phantoms made from PMMA of diameter 32 
cm and is thus independent of patient dimensions. The effective dose is dependent on patient 
size, therefore these calculations are just an indication. Spiral scans require additional data at 
the start and the end of the spiral. Given the spiral mode is on, an overranging correction is 
introduced, which will increase the effective dose. When using CT-Expo, the typical total 
error in dose calculation is ±10 to ±15% for those quantities which can also be measured 
(CTDIvol, CTDIw [weighted computed tomography dose index], DLPw [dose length product]) 
and ±20 to ±30% for those quantities which can only be derived by using conversion 
coefficients (effective dose). A manual calculation for the radiation dose was done for a GE 
Lightspeed VCT and the result corresponds to the calculation of CT-Expo within the accuracy 
range. A dose estimation report of the Siemens scanner gave a value for the CTDIvol of 3.86 
mGy. Calculation by CT-Expo with same scanner settings gave a value of 3.2 mGy. The CT-
Expo manual states that the typical total error for CTDIvol lies within a range of 15%. Irvin 
and Ireland (2014) indicate that a scanner’s estimation for the CTDIvol also contains a certain 
error, varying from -22% to 15% depending on the scanner type. Taking this information into 
consideration, the values for CT-Expo’s calculation and the scanner’s estimation are within 
the error range, providing support that the estimations from CT-Expo gives a good indication 
for the radiation dose a patient will receive.
Table S2:
Specific settings that were used in CT-expo 
Settings
Value used
U
100
I
200
T
0.6
N*hcol
40
TF
55
hrec
0.3
Spiral mode
On
Longitudinal dose modulation
On
Gender
Male
Scan range
40-70
ICRP
60

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Hrec, reconstructed slice thickness; I, electrical tube current in mA; 
ICRP, International Commission on Radiological Protection; N*hcol, beam width;
t, acquisition time per slice or rotation time (spiral scans); TF, table feed per rotation; 
U, kilovolts. 

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Appendix B
Regulatory, Ethical, and Study Oversight Considerations
B 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 (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., 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 amendments to the 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 CRO but 
the accountability remains with AstraZeneca.
The investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 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 the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor 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. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and investigators.
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

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
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the [Investigator’s Brochure or state other documents] and will notify the 
IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the EMA CTIS. It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS.

The investigator should have a process in place to ensure that:
o
The site staff or service providers delegated by the investigator/institution are 
able to identify the occurrence of a (potential) serious breach

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
B 2
Financial Disclosure
Include text related to financial disclosure if not included in another document.
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.

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B 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 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 (HIPAA) 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.
Participants who are rescreened are required to sign a new ICF.
B 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.

The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure
and use of their data must also be explained to the participant in the 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 the 
sponsor, 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 authorised or does not have a business need to know the 
information. 

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
The participant must be informed that in some cases their data may be pseudonymised. 
The General data Protection Regulation (GDPR) defines pseudonymisation as the 
processing of personal data in such a way that the personal data can no longer be 
attributed to a specific individual without the use of additional information, provided 
that such additional information is kept separately and protected by technical and 
organisational measures to ensure that the personal data are not attributed to an 
identified or identifiable natural person.
Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised 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.

Whilst 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:

Site staff or service providers delegated by the investigator/institution are allowed 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 (e-mail 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 is 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 subjects, the notification 
will be done directly by the Study Monitor in collaboration with the site and/or 
Principal Investigator, acting on behalf of the Sponsor, so that AstraZeneca has no 

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access to the 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 coordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and participants, where applicable.
B 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com; 
http://www.clinicaltrials.gov and https://www.clinicaltrialsregister.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.
B 6
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted 
to the sponsor 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 (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.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organizations).

Study monitors will perform ongoing source data verification 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 

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approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or 
as required by local regulations, according to the AstraZeneca Global retention and 
Disposal (GRAD) Schedule. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to another 
location or party without written notification to the sponsor.
B 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 source data agreement and 
computerized data checklist for electronic source data.
B 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 first patient screened.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

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
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor 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.
Participants from terminated sites cannot be transferred to another site to continue the study.
B 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 the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments.
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix C
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
C 1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
C 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 (AEs) for malignant tumors reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement 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 fulfil 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 (e.g., hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, 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 
judgement must be used.

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:
1)
Mild (awareness of sign or symptom, but easily tolerated)
2)
Moderate (discomfort sufficient to cause interference with normal activities)
3)
Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 

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intensity whereas seriousness is defined by the criteria in Appendix C 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix C 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix C 2.
C 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.
The causality assessment is performed based on the available data including enough 

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information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
C 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 that either causes harm to the participant or has the potential 
to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were 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, for example, 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 fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of 
the above listed events that would otherwise have been a medication error 

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
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

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
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 for a perceived reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site using the Drug Abuse Report Form. This form should be used both if the 
drug abuse happened in a study participant or if the drug abuse involves a person not enrolled 
in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant 
or a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP for 
medicinal purposes outside of the authorized product information, or for unauthorized IMPs, 
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).
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

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
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 D
Handling of Human Biological Samples
D 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers

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Appendix E
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and 
Medical Device Deficiencies: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting in Medical 
Device Studies
The definitions and procedures detailed in this appendix are in accordance with International 
Organization for Standardization 14155 and European MDR 2017/745 for clinical device 
research (if applicable). 
Both the investigator and the sponsor will comply with all local reporting requirements for 
medical devices.
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study. See Section 6.1.2 for the list of sponsor medical 
devices.
E 1
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition
An AE is any untoward medical occurrence in a clinical study participant, users, or other 
persons, temporally associated with the use of study intervention, whether or not considered 
related to the investigational medical device. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of an investigational medical device. This 
definition includes events related to the investigational medical device or comparator and 
events related to the procedures involved.
An adverse device effect (ADE) is defined as an AE related to the use of an investigational 
medical device. This definition includes any AE resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction 
of the investigational medical device as well as any event resulting from use error or from 
intentional misuse of the investigational medical device.
E 2
Definition of Medical Device SAE, SADE and USADE
A Medical Device SAE is an any serious adverse event that:
a.
Led to death
b.
Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury. The term “life-threatening” in the definition of 
“serious” refers to an event in which the participant was at risk of death at the time of 
the event. It does not refer to an event, which hypothetically might have caused death 
if it were more severe.

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
A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.

Chronic disease (MDR 2017/745).
c.
Led to fetal distress, fetal death, or a congenital anomaly or birth defect
SADE definition
A SADE is defined as an adverse medical device effect that has resulted in any of the 
consequences characteristic of an SAE.
Any medical device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
Unanticipated SADE (USADE) definition
An USADE (also identified as UADE in United States Regulations 21 CFR 813.3), is defined 
as a serious adverse medical device effect that by its nature, incidence, severity, or outcome 
has not been identified in the current version of the risk analysis report (see Section 2.3).
E 3
Definition of Medical Device Deficiency
Medical Device Deficiency Definition
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer.
E 4
Recording and Follow-up of AE and/or SAE and Medical Device 
Deficiencies
AE, SAE, and Medical Device Deficiency Recording
When an AE/SAE/medical device deficiency occurs, it is the responsibility of the investigator 
to review all documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
The investigator will then record all relevant AE/SAE/medical device deficiency information 
in the participant’s medical records, in accordance with the investigator’s normal clinical 
practice and on the appropriate form.

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It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE/SAE/medical device deficiency form.
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to the Sponsor.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
For medical device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a medical 
device deficiency. This includes any amendment to the medical device design to 
prevent recurrence.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE/SAE/medical device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE/medical device deficiency.
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship, cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 

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considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) or USPI / EU SmPC in 
his/her assessment.
For each AE/SAE/medical device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/medical device deficiency and has provided an 
assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the Sponsor.
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
MDCG 2020 Guidance 
For the purpose of harmonizing reports, each SAE will be classified according to five
different levels of causality. The sponsor and the investigators will use the following
definitions to assess the relationship of the serious adverse event to the investigational2
device or procedures.

Not related: Relationship to the device or procedures can be excluded when:

the event has no temporal relationship with the use of the investigational 
device or the procedures;

the serious event does not follow a known response pattern to the
medical device (if the response pattern is previously known) and is
biologically implausible;
                                               
2 Investigational device: any device object of the clinical investigation, including the comparators

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
the discontinuation of medical device application or the reduction of the level
of activation/exposure - when clinically feasible - and reintroduction of its
use (or increase of the level of activation/exposure), do not impact on the 
serious event;

the event involves a body-site or an organ not expected to be affected by the 
device or procedure;

the serious event can be attributed to another cause (eg, an underlying or
concurrent illness/clinical condition, an effect of another device, drug, 
treatment or other risk factors);

the event does not depend on a false result given by the investigational device 
used for diagnosis, when applicable;
In order to establish the non-relatedness, not all the criteria listed above might be met at the
same time, depending on the type of device/procedures and the serious event.
Unlikely: The relationship with the use of the device seems not relevant and/or the event
can be reasonably explained by another cause, but additional information may be obtained.
Possible: The relationship with the use of the investigational device is weak but cannot be
ruled out completely. Alternative causes are also possible (eg, an underlying or concurrent
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were
relatedness cannot be assessed or no information has been obtained should also be classified 
as possible.
Probable: The relationship with the use of the investigational device seems relevant
and/or the event cannot be reasonably explained by another cause, but additional 
information may be obtained.
Causal relationship: the serious event is associated with the investigational device or 
with procedures beyond reasonable doubt when:

the event is a known side effect of the product category the device
belongs to or of similar devices and procedures;

the event has a temporal relationship with investigational device
use/application or procedures;

the event involves a body-site or organ that
o
the investigational device or procedures are applied to;
o
the investigational device or procedures have an effect on;

the serious event follows a known response pattern to the medical device
(if the response pattern is previously known);

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
the discontinuation of medical device application (or reduction of the level
of activation/exposure) and reintroduction of its use (or increase of the level
of activation/exposure), impact on the serious event (when clinically
feasible);

other possible causes (e.g. an underlying or concurrent illness/ clinical
condition or/and an effect of another device, drug or treatment) have been
adequately ruled out;

harm to the participant is due to error in use;

the event depends on a false result given by the investigational device used
for diagnosis, when applicable;
In order to establish the relatedness, not all the criteria listed above might be met at the
same time, depending on the type of device/procedures and the serious event.
Follow-up of AE/SAE/Medical Device Deficiency
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor to 
elucidate the nature and/or causality of the AE/SAE/medical device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the Sponsor with a copy of any postmortem findings including 
histopathology. 
New or updated information will be recorded in the originally completed form.
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt 
of the information.
E 5
Reporting of SAEs
SAE Reporting to the Sponsor via Paper Data Collection Tool
The SAEs, pregnancies and overdose to be reported in the EDC first. Only report on
paper if EDC is unavailable. Fax cover sheet and SAE Report Form (available in the Site File) 
are to be used.

Initial notification via EDC does not replace the need for the Investigator to complete 
and sign the SAE paper data collection tool within the designated reporting time 
frames.
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE paper data collection tool within the designated reporting time frames.

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Contacts for SAE reporting can be found in the paper SAE form available in the Site File.
E 6
Reporting of SADEs
SADE Reporting to the Sponsor
NOTE: There are additional reporting obligations for medical device deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to medical 
devices being used in clinical studies.
Any medical device deficiency that is associated with an SAE must be reported to the sponsor 
within 24 hours after the investigator determines that the event meets the definition of a 
medical device deficiency.
The sponsor will review all medical device deficiencies and determine and document in 
writing whether they could have led to an SAE. These medical device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national regulations.
Contacts for SAE reporting can be found in the Site File.

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Appendix F
Changes Related to Mitigation of Study Disruptions Due to
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
During civil crisis, natural disaster, or public health crisis, some study assessment and 
procedures may not be conducted due to international or local policies or guidelines, hospital 
or clinic restrictions, and other measures implemented to ensure patient’s safety. In case of 
doubts please contact the AZ Study Physician.
The current protocol allows for rescreening of participants for 1 time only if the reason for 
screen failure was due to a civil crisis, natural disaster, or public health crisis (see Section 5.4).
Participants may also reschedule Visit 1 due to a civil crisis, natural disaster, or public health 
crisis per Section 5.5. Any changes to the allowances for rescreening and rescheduling of 
visits due to a civil crisis, natural disaster, or public health crisis beyond the current protocol
may only be considered at the Sponsor’s discretion and Investigators will be informed 
accordingly.
Changes described in F 1 to F 5 below may only be implemented at the Sponsor’s 
discretion during study disruptions due to any of or a combination of civil crisis, natural 
disaster, or public health crisis (e.g., during quarantines and resulting site closures, regional 
travel restrictions and considerations if site personnel or study participants become 
infected/quarantined due to SARS-CoV-2 or similar pandemic infection) during 
which participants may not wish to or may be unable to visit the study site for study 
visits. These changes should only be implemented if allowable by local/regional guidelines 
and following notification from the Sponsor and instructions on how to perform these 
procedures will be provided at the time of implementation.
Refer to the Study Instructions for Mitigation Due to Civil Crisis, Natural Disaster, or Public
Health Crisis for Benralizumab and Study Instructions for At-home or Remote Location
Administration of Benralizumab by the Participant and/or His/Her Caregiver for step-by-step
guidance.
F 1
Consent/Reconsent of Study Participants During Study 
Interruptions
During study interruptions, it may not be possible for the participants to complete study visits
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, e.g., telemedicine visits. Consent/reconsent should be obtained for the 
alternative means of carrying out visits and assessments and should be obtained prior to 
performing the procedures described in Sections F 2 to F 5. Local and regional regulations 
and/or guidelines regarding consent/reconsent of study participants should be checked and 
followed. Reconsent may be verbal if allowed by local and regional guidelines (note, in the 

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case of verbal reconsent the ICF should be signed at the participant’s next contact with the 
study site). Visiting the study sites for the sole purpose of obtaining consent/reconsent should 
be avoided.
F 2
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix and the associated Study Instructions for Mitigation Due to Civil Crisis, 
Natural Disaster, or Public Health Crisis for Benralizumab, the term telemedicine visit refers 
to remote contact with the participants using telecommunications technology including virtual
or video visits.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication, any worsening of 
underlying asthma symptoms/asthma exacerbations since last contact with the participant to 
be reported and documented. If applicable, safety procedures will be performed according to 
the revised SoA in the Study Instructions for Mitigation Due to Civil Crisis, Natural Disaster, 
or Public Health Crisis for Benralizumab.
On-site visits that may be replaced by a Telemedicine Visit only apply for Visit 2 and Visit 3
of this study.
F 3
At-home or Remote Location IP Administration Instructions
During a civil crisis, natural disaster, or public health crisis, if a site visit is not possible, at-
home administration of IP may be performed by the participant or his/her caregiver. The 
option of at-home IP administration ensures participants' safety in cases of a pandemic where 
participants may be at increased risk by traveling to the site/clinic. This will also minimize 
interruption of IP administration during other study disruptions, e.g., site closures due to 
natural disaster.
At-home IP administration may be conducted for Visit 2 and Visit 3 of this study via a 
Telemedicine Visit.
At-home or Remote Location IP Administration by the Participant or His/Her Caregiver
Prior to at-home or remote location IP administration the Investigator must assess the 
participant or his/her caregiver to determine whether they are appropriate for at-home or 
remote location administration of IP. Once the participant or his/her caregiver is deemed 
appropriate for at-home or remote location administration, he/she must receive appropriate 
training. All necessary supplies and instructions for administration and documentation of IP 
administration will be provided. More information related to the visit can be obtained via a 
telemedicine visit. All process for at-home or remote location IP administration will be 
witnessed by the Investigator/authorized delegate virtually during a telemedicine visit.

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F 4
Data Capture During Telemedicine Visits
Data collected during telemedicine visits will be captured by the qualified HCP from the study 
site in the source documents during the visit.

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Appendix G
Abbreviations
Abbreviation or special 
term
Explanation
3D
3-dimensional
β-HCG
β-human chorionic gonadotropin 
ACT
Asthma Control Test
ADA
Anti-drug antibody
ADE
Adverse device effect
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/transaminase
AST
aspartate aminotransferase/transaminase
ATS
American Thoracic Society
BD
Bronchodilator
BP
Blood pressure
BVX
Blood vessel measurements
CAD
Computer-aided design
CFD
Computational fluid dynamics
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
COPD
Chronic obstructive pulmonary disease
CONSORT
The Consolidated Standards of Reporting Trials
CRO
Contract Research Organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTDIvol
Volume computed dose index
CTDIw
Weighted computed tomography dose index
CTIS
Clinical Trial Information System
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Abbreviation or special 
term
Explanation
DLPw
Dose length product
DUS
Disease Under Study
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
E/D
Early Study Intervention Discontinuation
EDC
Electronic data capture
EOT
End of treatment
EMA
European Medicines Agency
EPAR
European public assessment report
ePRO
Electronic patient-report outcome
ER
Emergency room
ERS
European Respiratory Society
EU
European Union
FDA
United States Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FRC
Functional residual capacity
FRI
Functional Respiratory Imaging
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GMP
Good Manufacturing Practice
Hb
Hemoglobin
HBsAg
Hepatitis B surface antigen 
HCG
Human chorionic gonadotropin
HCP
Healthcare professional
HIPAA
Health Insurance Portability and Accountability Act
HIV
Immunodeficiency virus
HLT
High level term
HPF
High power field
IAD
Internal airflow distribution
IB
Investigator’s Brochure
IATA
International Airline Transportation Association

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Abbreviation or special 
term
Explanation
ICF
informed consent form
ICH
International Council for Harmonisation 
ICS
inhaled corticosteroids
ID
Identifier
IEC
Independent Ethics Committee
IgE
Immunoglobulin E
IL-4R
Interlukin-4 receptor
IL-5
Interleukin-5
IL-5R
Interlukin-5 receptor
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator study file
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
iVaww
Airway wall volume
iVlung
Lung volume
IWRS
Interactive Web Response System
LABA
Long-acting β2 agonists
LAMA
Long-acting muscarinic antagonist
LLL
Left lower lobe
LRI
Lower respiratory infection
LTRA
leukotriene receptor antagonists 
LUL
Left upper lobe
MART
Maintenance and reliever therapy
MDR
Medical Device Regulation
MedDRA
Medical Dictionary for Regulatory Activities
MMAD
Mass median aerodynamic diameter
MRI
Magnetic resonance imaging
NA
Not applicable
OCS
Oral corticosteroids
PI
Principal investigator 

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Abbreviation or special 
term
Explanation
PROs
Patient-reported outcomes
PT
Preferred term
Q4W
Every 4 weeks
Q8W
Every 8 weeks
RBC
Red blood cells
RLL
Right lower lobe
RML
Right middle lobe
RTSM
Randomization and Trial Supply Management
RUL
Right upper lobe
SADE
Serious adverse device effect
SAE
Serious adverse event 
SAP
Statistical analysis plan
SARP
Severe Asthma Research Program
SC
Subcutaneously
SD
Standard deviation
siVaw
Specific airway volume
MART
Maintenance and reliever therapy
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SOC
System organ class
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
TLC
Total lung capacity
ULN
Upper limit of normal
URI
Upper respiratory infection
USADE
Unanticipated serious adverse device effect
USPI
United States Prescribing Information
V
Visit
VDP
Ventilation defect percent
WBC
White blood cells
CCI
CCI
CCI
CCI
CCI
CCI

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Abbreviation or special 
term
Explanation
WOCBP
Women of childbearing potential

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11
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