A Multicentre, Randomised, Double-blind, Parallel Group, Placebocontrolled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) Added to Medium to High-dose Inhaled Corticosteroid Plus Long-acting β2 Agonist in Patients With Uncontrolled Asthma.
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance Benralizumab (MEDI-563)
Study Code
D3250C00036
Version
5.0
Date
18 Dec 2020
A Multicentre, Randomised, Double-blind, Parallel Group, Placebo-
controlled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) 
Added to Medium to High-dose Inhaled Corticosteroid Plus Long-acting .2
Agonist in Patients with Uncontrolled Asthma
Sponsor: PPD

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VERSION HISTORY
DOCUMENT HISTORY
Document
Date
Version 5.0
18-Dec-2020
Version 4.0
17-Dec-2019
Version 3.0
25-Apr-2018
Version 2.0
28-Nov-2016
Original Protocol (Version 1.0)
25-Nov-2014
The Protocol Amendment Summary of Changes Table before Version 5.0 is located in 
Appendix H.
Version 5.0 (18-Dec-2020)
This amendment is considered to be substantial based on the criteria set fort in Article 10(a) of 
Directive 2001/20/EC of  the European Parliament and the Council of European Union
Overall Rationale for the Amendment:
The primary rationale for this amendment is to add study mitigation language which will 
provide sites with measures that may be implemented if a participant is not able to visit a 
study site to ensure that the clinical trial can continue whilst minimizing risk to the participant, 
maintaining compliance with GCP, and minimizing risks to the study integrity.
Version 5.0, 18 December 2020
Section # and name
Description of Change
Brief rationale for Change
Protocol Synopsis
Extend the estimated date 
of last patient completed to 
Q1 2023
Extend the study timeline 
based on the current 
recruitment plan
Protocol Synopsis/Section 1.4 
Study Design/Section 3.3 
patient enrolment and 
randomisation
Change the percentage of 
China patients from 
approximately 80% to at 
least 70%
Allow patient redistribution 
and competitive
recruitment among 
countries, while keeping 

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Remove specific regions
the overall sample size the 
same.
Protocol Synopsis Strata
closure process/Section 1.4 
Study Design
Include “other asthma 
controllers” in patient 
maintenance therapy
Clarify that asthma 
controllers should be stable 
throughout the study
Protocol Synopsis 
Objectives/Section 2.2 
Secondary Objectives
Including incidence of 
nAb, ADA titer into the 
secondary objective of 
characterizing 
immunogenicity of 
benralizumab
Clarify the outcome 
measures for 
immunogenicity
Section 1.3 Benefit/risk and 
ethical assessment
Add statement of no 
apparent impact of ADA 
on overall benralizumab 
safety or efficacy in the 
previous Phase 3 studies. 
Add information about 
important risk of serious 
hypersensitivity reactions.
Keep consistent with 
updated IB
Section 3.1 Inclusion Criteria 3
Update the time period of 
female patients using an 
effective form of birth 
control from 16 weeks to 
12 weeks.
Update contraceptive 
methods wording to 
removing brand name, etc. 
Keep consistent with 
current knowledge of 
benralizumab PK 
parameters 
Follow CTFG 
recommendation for 
contraception wording 
revision.
Section 3.1 Inclusion Criteria 4
Delete the criteria of male 
contraception requirement.
Keep consistent with 
current knowledge of 
benralizumab 
Section 3.1 Inclusion Criteria 8 
(inclusion criteria 9 in CSP V4)
Change documented post-
bronchodilator (post-BD) 
reversibility in FEV1 of 
>12% and >200 ml to I 
12% and I200 ml
Keep consistent with other 
sections of the protocol or 
other sections

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Section 3.2 Exclusion Criteria
10
Remove ALT and AST 
requirement 
Only keep one exclusion 
criteria to liver function 
avoiding duplication
Section 3.2 Exclusion Criteria 
12
Change the criteria for 
current smokers or former 
smokers 
Specify the criteria for 
former smokers
Section 3.2 Exclusion Criteria 
27
Update ALT and AST 
requirement
Keep it consistent with 
requirement of liver disease 
Section 3.6 Methods for 
ensuring blinding
Add statement to specify 
unblinded treatment data 
will be available to 
bioanalytical lab personnel 
for PK sample analysis 
during the conduct of 
study. 
Facilitate the new process 
that PK sample will be 
analysed only for patients 
receiving benralizumab and 
to clarify how these data 
will remain blinded to the 
study team and site during 
the study conduct. 
Section 3.8.2 Other medication 
restrictions
Update the time period of 
vaccine receipt from 16 
weeks to 12 weeks
Keep consistent with 
current knowledge of 
benralizumab PK 
parameters
Section 3.8.3 Other restrictions
Update the time period of 
using effective 
contraceptive methods 
from 16 weeks to 12 weeks
Delete male contraception 
restriction.
Keep consistent with 
current knowledge of 
benralizumab PK 
parameters
Section 3.9 Discontinuation of 
investigational product/Section 
7.4 IP administration and 
treatment compliance
Remove the criteria of 2 
consecutive doses IP 
missed for discontinuation
Add the statement of how 
to deal with the cases of a 
patient missing more than 
2 doses within a calendar 
year
Make consistent with 
contents in recent 
benralizumab protocols

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Section 3.9.1 Procedures for 
discontinuation of a patient 
from investigational product
Re-organize the wording to 
make it easy to be 
understood.
For clarity. 
Section 3.9.1 Procedures for 
discontinuation of a patient 
from investigational 
product/Section 4.2 Treatment 
period
Update the time frame of 
IPD visit within 8 weeks 
+7 days after the last dose 
of IP for all patients
Keep the same time frame 
for all scenarios of IP 
discontinuation
Section 4.1.1 Enrolment (Visit 
1)
Add the statement of EOS 
retest
Re-screen because of 
eosinophil is replaced by 
eosinophil retest to reduce 
the burden of subjects
Section 4.1.3 Re-screening
Remove the statement of 
rescreening patients with 
EOS < 300 cell/uL at Visit 
1
Rescreening is not needed 
since EOS retest is added
Section 4.4 Study Conduct 
Mitigation During Study 
Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, 
or Public Health Crisis
New wording was added 
which would give guidance 
on how the study could 
continue in the event of a 
serious disruption with 
details of mitigation that 
could be employed to 
ensure study continuity.
The impact of COVID-19 
has highlighted the risk to 
continuity of clinical trials 
during times of study 
disruption, whether by civil 
crisis, natural disaster or 
public health crisis. This 
section details the measures 
that may be implemented if 
a patient is not able to visit 
a study site to ensure that 
the clinical trial can 
continue whilst minimizing 
risk to the patient, 
maintaining compliance 
with GCP, and minimizing 
risks to study integrity, 
These changes will only be 
initiated at a time of study 
disruption.

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Section 5.1.2 Spirometry
Change “2 best efforts that 
meet the ATS/ERS 
acceptability and 
reproducibility criteria will 
be recorded” to “the best 
effort that meets the 
ATS/ERS acceptability and 
reproducibility criteria will 
be analysed”.
Keep consistent with 
company standard process
Section 5.3.2.2 Asthma control 
questionnaire (ACQ-6)
Change ACQ-6 score range 
from “between 0.75 and 
<=1.5” to between 0.75 
and <1.5”. Change the 
score which indicates not 
well controlled asthma to 
>= 1.5
Remove ACQ-6 between 
Visit 2 and Visit 3 on a 
weekly basis
Keep consistent with 
guideline
Update due to no plan to 
analyse ACQ-6 between 
Visit 2 and Visit 3 
Section 5.3.5 Pharmacokinetics
Add statement to specify 
PK sample will be 
analysed only for patients 
receiving benralizumab.
Specify the new process for 
PK lab sample analysis. 
Section 5.3.8 Patient Testing 
Due to Public Health Crisis
Section included if patient 
testing is performed due to 
the public health crisis, the 
results may be documented 
for this study.
Section added for test 
results secondary to public 
health crisis to be collected 
allowing for an evaluation 
of the public health crisis 
on the study.
Section 6.2 Definitions of 
serious adverse event
Additional malignancy 
relevant text added to be 
consistent with latest CSP 
template
Follow updated latest CSP 
template
Section 6.5 Overdose
Update the definition of 
overdose
Follow latest IB content.

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Section 6.6.2 Paternal Exposure
Remove male 
contraception requirement 
wording
Keep consistent with 
current knowledge of 
benralizumab 
Section 6.8 Device Constituent 
Deficiencies
Add the section of Device 
Constituent Deficiencies
Benralizumab is considered 
a drug-device combination 
(biologic device 
combination) for regulatory 
reporting guidelines.  Due 
to new regulations in EU 
and US, updates to 
respective CSP section was 
done.  
Section 7.4 IP administration 
and treatment Compliance
Remove the criteria of 2 
consecutive doses IP 
missed for discontinuation
Add the statement of how 
to deal with the cases of a 
patient missing more than 
2 doses within a calendar 
year
Make consistent with 
contents in recent 
benralizumab protocols 
Section 7.4 IP administration 
and treatment 
Compliance/Section 7.7 
Management of investigational 
product-related reactions
Remove the time limitation 
of observing acute drug 
reaction
Keep consistent with 
current knowledge of 
benralizumab 
Section 8.5 Methods for 
statistical analyses
Add “additional analyses 
assessing the impact of 
Cases of Civil Crisis , 
Natural Disaster, or Public 
Health Crisis (e.g. SARS-
CoV-2) may be included in 
the SAP”.
Specify analyses will be 
added to assess the 
COVID-19 impact and 
details will be present in 
SAP.
Section 8.5.2.1 Analysis 
methods for secondary efficacy 
variables
Replace "The ACQ-6 will 
be analyzed in terms of 
change from baseline to 
end of treatment, change 
from baseline to overall 
Clarify that change from 
baseline is compared with 
each post-baseline visit not 
compared with overall 
post-baseline mean and to 

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post-baseline mean, and 
responder status at EOT 
(i.e. baseline to EOT ACQ-
6 score change of >=-0.5 
points), and asthma 
symptom control status at 
EOT." by "The ACQ-6 will 
be analyzed in terms of 
change from baseline to 
end of treatment, change 
from baseline to each of 
post-randomisation 
periods, responder status at 
EOT (i.e. change from 
baseline to EOT<=-0.5), 
and  asthma symptom 
control status at EOT (see 
Section 8.4.3.2 for 
categorization)."
correct the responder 
definition to be consistent 
with Section 8.4.3.2.
Section 8.5.3 Subgroup analysis
Add subgroup factor 
‘Nasal polyps’ and remove 
subgroup factor ‘Race’. 
The subgroup factor ‘Nasal 
polyps’ is meaningful and 
explored in other 
Benralizumab studies.
“Race” is not meaningful 
as all the countries 
participating are in Asia.
Appendix D Anaphylaxis: 
definition, signs, symptoms and 
management Introduction
Change the wording of 
Appropriate drugs in site. 
Update monitoring time 
frame.
Keep consistent with 
current knowledge 
Appendix G Changes Related 
to Mitigation of Study 
Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, 
or Public Health Crisis
New wording is added, 
which would give guidance 
on how the study could 
continue in the event of a 
serious disruption with 
details of mitigation that 
The impact of COVID-19 
has highlighted the risk to 
continuity of clinical trials 
during times of study 
disruption, whether by civil 
crisis, natural disaster or 
public health crisis. This 
section details the measures 

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could be employed to 
ensure study continuity.
that may be implemented if 
a patient is not able to visit 
a study site to ensure that 
the clinical trial can 
continue whilst minimizing 
risk to the patient, 
maintaining compliance 
with GCP, and minimizing 
risks to study integrity, 
These changes will only be 
initiated at a time of study 
disruption.
Appendix H Protocol 
Amendment History
New Appendix is added to 
put the protocol 
amendment history from 
V1 to V4
Follow the latest CSP 
template
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
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.

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2
The eosinophil <300/UL stratum will be closed to the patients from all countries when the 
total number of patients in the eosinophil <300/UL stratum reaches approximately 222.
3
The whole study will be closed for recruitment when the total number of patients in the 
eosinophil I300/UL stratum reaches approximately 444, with at least 70% Chinese 
patients in the stratum.
After initial enrolment and confirmation of entry criteria, patients will proceed to the run-in 
period of a minimum 4 weeks to allow adequate time for all the eligibility criteria to be 
evaluated. Patients, who meet eligibility criteria, will be randomised to a 48-week treatment 
period. Patients will be maintained on their currently prescribed medium to high-dose ICS-
LABA therapy and other asthma controllers, without change, from visit 1 until the end of the 
study. 
A follow-up visit will be conducted at Week 56. 

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Objectives
Primary Objective:
Outcome Measure:
To evaluate the effect of benralizumab on 
asthma exacerbations in patients on 
medium to high-dose ICS-LABA with 
uncontrolled asthma.
Annual asthma exacerbation rate, where an 
asthma exacerbation is defined by a 
worseninga 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 an Emergency department 
(ED) or urgent care centre) due to 
asthma that required systemic 
corticosteroids for at least 3 days (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)
a
For the purpose of the protocol, worsening of asthma is defined as new or increased symptoms and/or signs 
(examination or lung function) that can be either concerning to the patient (patient-driven) or related to an 
Asthma Daily Diary alert (diary-driven). The Electronic patient reported outcome (ePRO) device will be 
programmed to alert both the patient and study centre when certain pre-specified worsening thresholds are 
crossed including: decrease in morning peak flow I30% on at least 2 of 3 successive days compared with 
baseline (last 10 days of run-in), and/or a I50% increase in rescue medication or 1 new or additional nebulized T2
agonist on at least 2 of 3 successive days compared with the average use for the previous week and/or nocturnal 
awakening due to asthma requiring rescue medication use for at least 2 of 3 successive nights, and/or; an increase 
in total asthma symptom score (the sum of day time [evening assessment] and night time [morning assessment] 
of at least 2 units above the run-in average (last 10 days of run-in), or the highest possible score (daily score of 
6), on at least 2 of 3 successive   days).
If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified objective 
measurements, the Investigator will have to justify the decision for defining the event as an exacerbation.  Events 
that are not supported by any objective assessment will be deemed not to be a protocol-defined exacerbation.

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Secondary Objective:
Outcome Measure:
To assess the effect of benralizumab on 
pulmonary function
Pre-bronchodilator Forced expiratory volume in 
1 second (FEV1) b
To assess the effect of benralizumab on 
asthma symptoms and other asthma control 
metrics (as per the ePRO)
!
Asthma symptom score (totalb, day time, 
and night time)
!
Rescue medication use
!
Home lung function (morning and evening 
PEF)
!
Nights with awakening due to asthma
!
Asthma Control Questionnaire 6 (ACQ-6)
To assess the effect of benralizumab on 
other parameters associated with asthma 
exacerbations 
Time to first asthma exacerbation and 
proportion of patients with I1 asthma 
exacerbation
To assess the effect of benralizumab on 
health-related quality of life
St. George’s Respiratory Questionnaire (SGRQ)
To assess the effect of benralizumab on 
emergency room/urgent care visits and 
hospitalizations due to asthma
Annual rate of asthma exacerbations that are 
associated with an emergency room/urgent care 
visit or a hospitalization
To evaluate the effect of benralizumab on 
health care resource utilization
Asthma specific resource utilization (eg, 
unscheduled physician visits, use of other 
asthma medications)
To characterize the PK and immunogenicity 
of benralizumab
!
PK: Serum trough concentrations
!
Immunogenicity: Incidence of anti-drug 
antibodies (ADA) and neutralizing 
antibodies (nAb), ADA titer.
To assess the impact of benralizumab on 
blood eosinophil levels
!
Blood eosinophils
b       Key secondary efficacy endpoints

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Safety Objective:
Outcome Measure:
To assess the safety and tolerability of 
benralizumab
!
Adverse event (AE)/ Serious Adverse Event 
(SAE)
!
Laboratory variables
!
Electrocardiogram (ECG)
!
Vital Signs
Target patient population
Male and female patients 12-75 years of age with asthma inadequately controlled by treatment 
with medium to high-dose inhaled corticosteroid plus long-acting T2-agonist with or without 
oral corticosteroids and other asthma controller medications.
Duration of treatment
Following initial enrolment, the patient will enter a minimum 4-week run-in period, which is 
followed by a 48-week double-blind, randomised treatment period, with the last dose of 
benralizumab/placebo administrated at Week 40.  At Week 48, an End of Treatment (EOT) 
visit will be conducted.  A Follow-up visit will be conducted at Week 56.
The total planned study duration is approximately 63 weeks.
Investigational product, dosage and mode of administration
Benralizumab 30 mg/mL solution for injection in an accessorized pre-filled syringe (APFS) 
will be administered at the study centre subcutaneously every 4 weeks for the first 3 doses and 
then every 8 weeks thereafter. 
Comparator, dosage and mode of administration
For all patients, benralizumab or matching placebo solution for injection in an APFS will be 
administered at the study site SC every 4 weeks for the first 3 doses and then every 8 weeks 
thereafter. 
Statistical methods
The primary efficacy variable is the annual asthma exacerbation rate. Exacerbation rate in the 
benralizumab group will be compared to exacerbation rate in the placebo group using a 
negative binomial model including covariates of treatment group, region (China/non-China), 
number of exacerbations in the year before the study, and the use of maintenance oral 
corticosteroids (yes/no). The logarithm of the follow-up time will be used as an offset variable 
in the model. Change from baseline in pre-bronchodilator FEV1 at Week 48 will be compared 
between benralizumab and placebo group using a repeated measures analysis. Treatment 
group will be fitted as the explanatory variable, and region (China/non-China), baseline pre-
bronchodilator FEV1, visit, visitby-treatment interaction, and the use of maintenance oral 

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corticosteroids (yes/no) will be fitted as covariates. Visit will be fitted as a categorical 
variable. Change from baseline in asthma symptom total score at Week 48 will be analysed 
using a similar model as the model for change from baseline in pre-bronchodilator FEV1. The 
primary endpoint and the 2 key secondary endpoints (change from baseline in pre-
bronchodilator FEV1 and asthma symptom total score at Week 48) will be analysed primarily 
using the patients with baseline blood eosinophil counts I300/UL in the full analysis set 
according to a gate-keeping procedure. Full analysis set includes all randomised patients who 
received at least one dose of investigational product (IP). In addition, the exacerbation rate 
and the 2 key secondary endpoints will also be summarized in patients with baseline blood 
eosinophil counts < 300/UL, < 150/UL, 150-299/UL, 300-449/UL and I450/UL separately. 
The study will randomise patients with baseline blood eosinophil counts I300/ UL and <300/
UL at a ratio of about 2:1 and the study is powered for the primary efficacy analysis of the 
patients with baseline blood eosinophils I300/ UL. For the primary endpoint, annual asthma 
exacerbation rate, approximately 222 adult and adolescent patients with baseline blood 
eosinophil counts I300/UL per treatment arm (approximately 444 in total) will need to be 
randomised to achieve 90% power of 
 
 
 
 
According to the 2:1 ratio, the study will also randomise approximately 111 patients/arm 
(approximately 222 in total) with baseline blood eosinophil counts <300/UL. Approximately 
666 patients are expected to be randomised in the study with at least 70% of patients to be 
enrolled from China.
The efficacy and safety analyses will comprise both adult and adolescent patients. All safety 
parameters will be analysed. Safety analyses will be based on the safety analysis set, defined 
as all patients who received at least 1 dose of IP.
There is no interim analysis planned for this study. The study will remain blinded until 
database lock. 
CCI

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
PROTOCOL SYNOPSIS.................................................................................................... 10
TABLE OF CONTENTS.................................................................................................... 16
1.
INTRODUCTION............................................................................................ 23
1.1
Background and rationale for conducting this study.......................................... 23
1.1.1
Background ...................................................................................................... 23
1.1.2
Rationale for conducting this study................................................................... 25
1.2
Rationale for study design, doses and control groups ........................................ 25
1.3
Benefit/risk and ethical assessment ................................................................... 26
1.4
Study Design .................................................................................................... 27
2.
STUDY OBJECTIVES..................................................................................... 30
2.1
Primary Objective............................................................................................. 30
2.2
Secondary Objectives........................................................................................ 31
2.3
Safety Objective ............................................................................................... 31
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ................... 32
3.1
Inclusion criteria*.............................................................................................. 32
3.2
Exclusion criteria.............................................................................................. 34
3.3
Patient enrolment and randomisation ................................................................ 37
3.4
Procedures for handling incorrectly randomised patients................................... 38
3.5
Methods for assigning treatment groups............................................................ 38
3.6
Methods for ensuring blinding .......................................................................... 38
3.7
Methods for unblinding..................................................................................... 39
3.8
Restrictions....................................................................................................... 40
3.8.1
Asthma medication restrictions......................................................................... 40
3.8.2
Other medication restrictions ............................................................................ 42
3.8.3
Other restrictions .............................................................................................. 43
3.9
Discontinuation of investigational product........................................................ 43
3.9.1
Procedures for discontinuation of a patient from investigational product........... 43
3.10
Criteria for withdrawal...................................................................................... 44
3.10.1
Screen failures .................................................................................................. 44
3.10.2
Withdrawal due to recruitment completion in a randomisation stratum ............. 44
3.10.3
Withdrawal of the informed consent/assent....................................................... 45
3.10.4
Withdrawal of informed consent/assent for donated biological samples ............ 45
3.10.5
Withdrawal due to repeat exacerbations during screening ................................. 46
3.11
Discontinuation of the study ............................................................................. 46

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4.
STUDY PLAN AND TIMING OF PROCEDURES ......................................... 46
4.1
Screening period............................................................................................... 52
4.1.1
Enrolment (Visit 1)........................................................................................... 52
4.1.2
Run-in (Visit 2, Visit 3) .................................................................................... 53
4.1.3
Re-screening..................................................................................................... 53
4.1.3.1
Procedures for Patients Who Experience an Exacerbation during Screening...... 54
4.2
Treatment period............................................................................................... 55
4.3
Follow-up period .............................................................................................. 56
4.4
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 56
5.
STUDY ASSESSMENTS AND PROCEDURES ............................................. 57
5.1
Efficacy assessments......................................................................................... 57
5.1.1
Assessment of asthma exacerbations................................................................. 57
5.1.2
Spirometry........................................................................................................ 58
5.1.2.1
Reversibility test............................................................................................... 60
5.1.3
Home peak expiratory flow testing.................................................................... 62
5.2
Safety assessments............................................................................................ 62
5.2.1
Physical examination ........................................................................................ 62
5.2.1.1
Complete physical examination ........................................................................ 62
5.2.1.2
Brief physical examination................................................................................ 63
5.2.2
Vital signs......................................................................................................... 63
5.2.3
ECG ................................................................................................................. 63
5.2.4
Safety laboratory tests....................................................................................... 64
5.2.4.1
Pregnancy Test ................................................................................................. 64
5.3
Other assessments and procedures..................................................................... 65
5.3.1
Weight and height............................................................................................. 65
5.3.2
Patient reported outcomes................................................................................. 65
5.3.2.1
Asthma daily diary............................................................................................ 65
5.3.2.2
Asthma control questionnaire (ACQ-6)............................................................. 66
5.3.2.3
St. George’s Respiratory Questionnaire (SGRQ)............................................... 67
5.3.3
Healthcare resource utilization.......................................................................... 68
5.3.4
Other run-in assessments .................................................................................. 68
5.3.4.1
Serology ........................................................................................................... 68
5.3.5
Pharmacokinetics.............................................................................................. 68
5.3.6
Immunogenicity................................................................................................ 69
5.3.7
Handling of biological samples......................................................................... 69
5.3.7.1
Labelling and shipment of biological samples................................................... 69
5.3.7.2
Chain of custody of biological samples............................................................. 69
5.3.8
Patient Testing Due to Public Health Crisis....................................................... 70
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................ 70
6.1
Definition of adverse events.............................................................................. 70
6.2
Definitions of serious adverse event.................................................................. 70
6.3
Recording of adverse events ............................................................................. 71

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6.3.1
Time period for collection of adverse events..................................................... 71
6.3.2
Follow-up of unresolved adverse events............................................................ 71
6.3.3
Variables .......................................................................................................... 71
6.3.4
Intensity rating scale ......................................................................................... 72
6.3.5
Causality collection........................................................................................... 72
6.3.6
Adverse events based on signs and symptoms................................................... 73
6.3.7
Adverse events based on examinations and tests ............................................... 73
6.3.8
Hy’s Law.......................................................................................................... 73
6.3.9
Symptoms of the disease under study................................................................ 73
6.4
Reporting of serious adverse events .................................................................. 74
6.5
Overdose .......................................................................................................... 74
6.6
Pregnancy......................................................................................................... 75
6.6.1
Maternal exposure ............................................................................................ 75
6.6.2
Paternal exposure.............................................................................................. 76
6.7
Medication error ............................................................................................... 76
6.8
Device Constituent Deficiencies ....................................................................... 76
6.8.1
SADE Reporting............................................................................................... 77
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS.................. 77
7.1
Identity of investigational product(s)................................................................. 77
7.2
Labelling .......................................................................................................... 78
7.3
Storage ............................................................................................................. 78
7.4
IP administration and treatment Compliance..................................................... 78
7.5
Accountability .................................................................................................. 80
7.6
Concomitant and other treatments..................................................................... 80
7.6.1
Concomitant medication ................................................................................... 80
7.6.1.1
Background medication .................................................................................... 80
7.6.1.2
Rescue medication............................................................................................ 81
7.6.2
Other concomitant treatment............................................................................. 81
7.7
Management of investigational product-related reactions.................................. 81
8.
STATISTICAL ANALYSES BY ASTRAZENECA......................................... 82
8.1
Statistical considerations................................................................................... 82
8.2
Sample size estimate......................................................................................... 82
8.3
Definitions of analysis sets................................................................................ 82
8.3.1
All patients analysis set..................................................................................... 83
8.3.2
Full analysis set ................................................................................................ 83
8.3.3
Safety analysis set............................................................................................. 83
8.3.4
Pharmacokinetic (PK) analysis set .................................................................... 83
8.4
Variables for analyses....................................................................................... 83
8.4.1
Calculation or derivation of efficacy variables .................................................. 83
8.4.1.1
Exacerbation rate.............................................................................................. 83
8.4.1.2
Proportion of patients with I1 asthma exacerbation during 48 weeks of 
treatment........................................................................................................... 84

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8.4.1.3
Time to first exacerbation ................................................................................. 84
8.4.1.4
Forced expiratory volume in 1 second............................................................... 85
8.4.1.5
Annual rate of asthma exacerbations that are associated with an emergency 
room/urgent care visit or a hospitalization......................................................... 85
8.4.2
Calculation or derivation of safety variable(s)................................................... 85
8.4.2.1
Safety variables ................................................................................................ 85
8.4.3
Calculation or derivation of patient reported outcome variables ........................ 86
8.4.3.1
Asthma Symptom Score.................................................................................... 86
8.4.3.2
Asthma Control Questionnaire (ACQ-6) ........................................................... 86
8.4.3.3
St. George’s Respiratory Questionnaire (SGRQ)............................................... 86
8.4.3.4
Electronic diary variables.................................................................................. 86
8.4.4
Calculation or derivation of pharmacokinetic variables..................................... 87
8.4.5
Calculation or derivation of immunogenicity variables ..................................... 87
8.5
Methods for statistical analyses......................................................................... 87
8.5.1
Analysis of the primary variable (s) .................................................................. 88
8.5.2
Analysis of the secondary variable(s)................................................................ 88
8.5.2.1
Analysis methods for secondary efficacy variables............................................ 88
8.5.2.2
Analysis methods for safety variables ............................................................... 90
8.5.2.3
Analysis methods for pharmacokinetic variables............................................... 91
8.5.2.4
Analysis method for immunogenicity variables................................................. 91
8.5.3
Subgroup analysis............................................................................................. 91
8.5.4
Sensitivity analysis ........................................................................................... 92
8.5.5
Interim analysis ................................................................................................ 92
8.6
Independent adjudication committee for major adverse cardiac events and 
malignancies..................................................................................................... 92
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA........................ 92
9.1
Training of study site personnel ........................................................................ 92
9.2
Monitoring of the study..................................................................................... 93
9.2.1
Source data....................................................................................................... 93
9.2.2
Recording of data.............................................................................................. 93
9.2.3
Study agreements.............................................................................................. 94
9.2.4
Archiving of study documents .......................................................................... 94
9.3
Study timetable and end of study ...................................................................... 94
9.4
Data management by AstraZeneca .................................................................... 95
10.
ETHICAL AND REGULATORY REQUIREMENTS...................................... 96
10.1
Ethical conduct of the study.............................................................................. 96
10.2
Patient data protection....................................................................................... 96
10.3
Ethics and regulatory review............................................................................. 96
10.4
Informed consent/assent.................................................................................... 98
10.5
Changes to the protocol and informed consent form/assent form....................... 98
10.6
Audits and inspections ...................................................................................... 99
11.
LIST OF REFERENCES.................................................................................. 99

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12.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................... 104
LIST OF TABLES
Table 1
Study Plan – Screening period ................................................................. 47
Table 2
Study Plan – Randomisation, treatment period, and follow-up ................. 49
Table 3
List of safety laboratory tests ................................................................... 64
Table 4
Identity of investigational product............................................................ 77
Table 5
Asthma medication restrictions.............................................................. 118
Table 6
Other medication restrictions ................................................................. 119
LIST OF FIGURES
Figure 1
Study flow chart ...................................................................................... 29
Figure 2
Reversibility testing algorithm................................................................. 61
Figure 3
Injection sites and rotation scheme........................................................... 79
LIST OF APPENDICES
Appendix A
Additional Safety Information................................................................ 105
Appendix B
International Airline Transportation Association (IATA) 6.2 Guidance 
Document .............................................................................................. 108
Appendix C
Actions Required in Cases of Combined Increase of Aminotransferase 
and Total Bilirubin - Hy’s Law .............................................................. 109
Appendix D
Anaphylaxis: definition, signs, symptoms and management................... 114
Appendix E
Background Therapy Equivalence Table................................................ 117
Appendix F
Restricted and prohibited medications.................................................... 118
Appendix G
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 121
Appendix H
Protocol Amendment History................................................................. 124
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.

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Abbreviation or 
special term
Explanation
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
Beta-hCG
Beta- human chorionic gonadotropin
BP
Blood pressure
BT
Bronchial thermoplasty 
BUN
Blood urea nitrogen
CFC
Chlorofluorocarbon
CO2
Carbon dioxide
COPD
Chronic obstructive pulmonary disease
CRO
Contract research organization
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTFG
Clinical Trials Facilitation and Coordination Group
DPI
Dry Powder Inhaler
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EC90
Benralizumab serum concentration corresponding to 90% of maximum 
efficacy
ED
Emergency department
ED90
Benralizumab dose corresponding to 90% of maximum efficacy
EOS
Eosinophil
EOT
End of Treatment
ePRO
Electronic patient reported outcome
EXACA
Exacerbation eCRF
FEV1
Forced expiratory volume in 1 second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
Gamma-GT
Gamma-glutamyl transpeptidase
GCP
Good Clinical Practice

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Abbreviation or 
special term
Explanation
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
GLI 
The Global Lung Function Initiative
HCP
Health care provider
HFA
Hydrofluoroalkane
HRU
Healthcare Resource Utilization
HRQoL 
Health-related quality of life
IATA
International Air Transport Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
IgE
Immunoglobulin E
IL
Interleukin
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IL-5R\
Interleukin-5 receptor alpha subunit
IM
Intramuscular
IMP
Investigational Medicinal Product
ICI
International Coordinating Investigator
IP
Investigational Product
IPD
Premature IP Discontinuation
IRB
Institutional Review Board
ISF
Investigator Study File
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-acting T2 agonists
LAMA
Long-acting anti-muscarinic
LDH
Lactate dehydrogenase
LDL cholesterol
Low density lipoprotein cholesterol
LTRA
Leukotriene receptor antagonists
MED
Medication
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities

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Abbreviation or 
special term
Explanation
nAb
Neutralizing antibodies
NYHA
New York Heart Association
OCS
Oral corticosteroids
pECG
Paper print-out ECG
PEF
Peak expiratory flow
PK
Pharmacokinetic(s)
PN
Predicted normal
Post-BD
Post-bronchodilator
Pre-BD
Pre-bronchodilator
PRO
Patient reported outcome
RBC
Red blood cell
SABA
Short-acting T2 agonists
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SGRQ
St. George’s Respiratory Questionnaire
TEAEs
Treatment Emergent Adverse Event
TLC
Total lung capacity
ULN
Upper limit of normal
UNS
Unscheduled
WBC
White blood cell
WBDC
Web-based Data Capture
WOCBP
Women of childbearing potential
1.
INTRODUCTION
1.1
Background and rationale for conducting this study
1.1.1
Background
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction 
and airway hyperresponsiveness.  Patients present clinically with recurrent wheezing, 
shortness of breath, cough and chest tightness.  Asthma is a leading cause of morbidity with a 
global prevalence of approximately 300 million; it is estimated that the number of people with 
asthma may increase to 400 - 450 million people worldwide by 2025 (Masoli et al 2004).
The current approach to anti-inflammatory controller therapy in asthma is based on a 
step-wise intensification of a daily maintenance regimen primarily centred around inhaled 

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corticosteroids (ICS) and leukotriene receptor antagonists (LTRA), with the addition of 
long-acting T2 agonists (LABA) in patients with more severe asthma (Global Initiative for 
Asthma (GINA 2014, NAEPP 2007).  Despite treatment per management guidelines, up to 
50% of patients have asthma that is not well-controlled (
Bateman et al 2010).  This results in considerable impact on quality of life, disproportionate 
use of healthcare resources, and adverse reactions from regular systemic steroid use. Symptom 
control in children and adolescents with asthma can be similarly challenging, due in part to the 
limitations of current therapeutic modalities. Longer treatment courses, over a period of 
months or years, and higher medication doses may be required to achieve the maximum 
possible improvement in lung function in children older than 5 years (GINA 2014). Therefore, 
there remains an unmet medical need for patients whose asthma is not controlled by existing 
therapies.
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Wenzel 2012).  In particular, 
asthma associated with eosinophilic inflammation in the airway (often referred to as 
eosinophilic asthma) is common (approximately 40% to 60% of asthmatics) with the degree of 
eosinophilia associated with clinical severity including the risk of asthma exacerbations (
Bateman et al 2010, 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). Adjusting conventional ICS-
based asthma therapy according to the degree of elevated sputum eosinophils as a marker of 
disease activity resulted in a reduction in the frequency of asthma exacerbations in prospective 
trials (Green et al 2002, Jayaram et al 2006). Interleukin-5 (IL-5) is a cytokine factor essential 
for eosinophil trafficking and survival (Molfino et al 2011). Clinical trials of neutralizing anti-
IL-5 antibodies (mepolizumab and reslizumab) in patients with uncontrolled eosinophilic 
asthma resulted in an improvement in key asthma control metrics, including asthma 
exacerbations (Castro et al 2011, Pavord et al 2012). These promising results support 
continued development of therapies targeting the IL-5 pathway in eosinophilic asthmatics 
unresponsive to standard therapies.
In contrast to anti-IL-5 therapies, benralizumab (MEDI-563) is a humanized, afucosylated, 
monoclonal antibody that binds specifically to the human IL-5 receptor alpha subunit (IL-
5R\) on the target cell. The IL-5 receptor (IL-5R) is expressed almost exclusively on the 
surface of eosinophils and basophils (Takatsu et al 1994, Toba et al 1999). Afucosylation 
confers enhanced antibody-dependent cellular cytotoxicity (ADCC) which results in highly 
efficient eosinophil depletion by apoptosis (Kolbeck et al 2012). Single and repeated doses of 
benralizumab in mild to severe asthma patients during early development or Phase 1/2 
development resulted in depletion of blood and airway eosinophils, and improvement in 
multiple metrics of asthma control including asthma exacerbations, lung function, and Asthma 
Control Questionnaire (ACQ-6) scores (Busse et al 2010, Gossage et al 2012, Molfino et al 

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2012, and Phase 2b MI-CP220 study). For further details please refer to the Investigator’s 
Brochure (IB).
1.1.2
Rationale for conducting this study
The treatment options for patients who remain uncontrolled by ICS-LABA are extremely 
limited.  In previous clinical studies, benralizumab administration resulted in rapid and 
prolonged depletion of eosinophils in the peripheral blood and in the asthmatic airway with 
associated improvements in multiple metrics of asthma control.  The magnitude of clinical 
improvement was positively correlated with baseline blood eosinophil counts and was most 
consistently observed in patients with absolute blood eosinophil counts I300/UL. In the 
pivotal studies (Bleecker et al 2016, FitzGerald et al), compared with placebo, benralizumab 
30 mg administered subcutaneously (benralizumab 30 mg every 4 weeks for the first 3 doses 
and then every 8 weeks thereafter) significantly reduced the annual asthma exacerbation rate, 
improved asthma symptom and lung function (pre-bronchodilator FEV1). The purpose of this 
trial is to confirm the efficacy and safety of benralizumab administration in asthma patients 
who are otherwise uncontrolled on current standard of care therapy.  The question of the 
baseline blood eosinophil level that predictably ensures the clinical benefit in patients will also 
be addressed in the study by inclusion of patients with blood eosinophil counts I300/UL and 
<300/UL.
1.2
Rationale for study design, doses and control groups
This is a regional study designed to investigate the safety and efficacy of the fixed dose 
benralizumab (30 mg) administered subcutaneously (SC) every 4 weeks for the first 3 doses 
and then every 8 weeks thereafter in exacerbation-prone asthma patients who remain 
uncontrolled on medium to high-doses ICS-LABA with or without oral corticosteroids and 
other asthma controller(s).
Primary efficacy will be determined based on reduction in the rate of asthma exacerbations 
over 48 weeks for benralizumab versus placebo.  In order to avoid biasing the results, the 
study will be randomised and double-blinded with stratification by age group (adult or 
adolescent), country/region and eosinophil category (>300/UL/<300/UL).
The study will randomise patients with screening blood eosinophils I300/UL and <300/UL at a 
ratio of about 2:1. The 2:1 stratification of patients with eosinophil counts I300/UL and 
<300/UL is intended as a means of enriching the population for patients most likely to respond 
to benralizumab (ie, I300/UL), while still accommodating patients below this threshold in 
order to help understand where additional benefit drops off.
The benralizumab dose (30 mg SC, fixed) and the maintenance regimens are based on all 
available safety, efficacy and immunogenicity data, as well as population exposure-response 
modeling, and stochastic trial simulations from earlier phase benralizumab trials.  In 
particular, Phase 2b MI-CP220 study (Castro et al 2014) showed that fixed doses of 

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benralizumab I20 mg administered every 8 weeks were clinically effective.  The potential 
impact on efficacy of anti-drug antibodies and body weight on pharmacokinetics (PK) were 
incorporated in a population PK model.  Analyses of efficacy endpoints (asthma 
exacerbations, forced expiratory volume in 1 second [FEV1] and ACQ) suggest 30 mg every 8 
weeks (with the first 3 doses administered every 4 weeks) is an effective and tolerable dose 
for further testing in patients with severe asthma.  This dose corresponds to the ED90
(benralizumab dose corresponding to 90% of maximum efficacy) for asthma exacerbation 
reduction and ACQ, and maintains a steady-state PK exposure close to EC90 (benralizumab 
serum concentration corresponding to 90% of maximum efficacy) levels for FEV1 and ACQ.  
Asthma manifestations and responses to existing treatments in adolescents and adults are 
similar.  With a 40 kg lower body weight limit, the projected PK exposure in adolescents 
mostly overlaps with that in adults.  The PK difference between adolescents and adults is 
expected to be small and within the normal range of between-patient variability among adults.  
Further, the 100 mg Q8W top dose investigated in Phase 2b study provided adequate exposure 
coverage.  To date, there are no data suggesting a dose- or exposure-related increase in 
treatment-emergent adverse events (TEAEs) with benralizumab in adult patients.  As such, 
adolescent patients (I40kg) will receive the 30 mg adult dose in Phase 3 studies.
Other stable asthma therapies on top of ICS-LABA that are within expert guidance and that 
are not restricted per protocol (see Section 3.8) are allowed in order to accommodate local 
standards of care.
1.3
Benefit/risk and ethical assessment
There are few treatment options for patients whose asthma remains uncontrolled on medium 
to high-dose ICS-LABA (GINA 2014).  The evidence base for oral add-on therapies (ie, oral 
corticosteroids, leukotriene inhibitors, and xanthenes) is extremely limited.  Anti-IgE therapy 
(ie, omalizumab) may improve control in patients with severe asthma and IgE-mediated 
allergy to a perennial allergen.  Tiotropium is a long-acting bronchodilator that has recently 
been shown to produce improvement in lung function and exacerbation risk (pooled data) in 
patients with severe asthma, with inconsistent effects on other measures of asthma control 
(Kerstjens et al 2012). As such, new therapies are needed for asthma management in patients 
who remain uncontrolled on standard of care.
In adult patients whose asthma was poorly controlled on medium-to-high dose ICS-LABA 
benralizumab, at fixed doses of I20 mg, produced improvements in multiple metrics of 
asthma control including the annual rate of asthma exacerbations, lung function, ACQ-6 
scores, and symptoms (Castro et al 2014).  These findings have subsequently been confirmed 
in two large Phase 3 studies (Bleecker et al 2016, FitzGerald et al) where a fixed dose of 30 
mg was given either every 4 weeks or every 8 weeks. Clinical benefit appeared to be greatest 
in patients with blood eosinophil counts I300/UL.  The blood eosinophil count below which 

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benralizumab is generally not effective remains unclear at this point in time, and will be 
explored in this study.
Development of anti-drug antibodies (ADA) to benralizumab has been documented. 
Theoretical risks of developing ADA include decreased drug efficacy and hypersensitivity 
reactions (e.g., anaphylaxis or immune complex disease). There was no apparent impact of 
ADA on overall benralizumab safety or efficacy in the previous Phase 3 studies in asthma.
Serious hypersensitivity reactions (including anaphylaxis) are an identified risk of biologic 
therapy, including benralizumab. Anaphylaxis may be life-threatening. Risk minimization 
includes observation in line with clinical practice at the clinical site following IP
administration for the appearance of any acute drug reactions.
Eosinophils are a prominent feature of the inflammatory response to helminthic parasitic 
infections, and the presence of infiltrating eosinophils has been circumstantially associated 
with a positive prognosis in certain solid tumors.  Therefore, there is a theoretical risk that
prolonged eosinophil depletion may diminish the ability to defend against helminthic 
parasites, or negatively impact the natural history of certain malignant tumors.  Risk 
minimization measures include exclusion of patients with untreated parasitic infection and 
active or recent malignancy, in conjunction with the performance of routine 
pharmacovigilance activities.
The efficacy and safety data obtained to date support the continued clinical development of 
benralizumab in asthma.
A detailed assessment of the overall risk/benefit of benralizumab in patients with asthma is 
given in the Investigator’s Brochure (IB).
1.4
Study Design 
This is a randomised, double-blind, parallel group, placebo-controlled study designed to 
evaluate the efficacy and safety of a fixed 30 mg dose of benralizumab administered 
subcutaneously for patients with a history of asthma exacerbations and uncontrolled asthma 
receiving medium to high-dose inhaled corticosteroid plus long-acting T2-agonist (ICS-
LABA) with or without oral corticosteroids and additional asthma controllers. Approximately 
666 patients are expected to be randomised in the study with at least 70% patients to be 
randomised from China. Patients will be stratified by country/region, age group (adult or 
adolescent), and peripheral blood eosinophil count at time of Visit 1 (<300 or I300 cells/UL).
All the patients will be randomised to either placebo or benralizumab, every 4 weeks for the 
first 3 doses and then every 8 weeks thereafter.
Strata closure process:

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1
The eosinophil <300/UL stratum will be closed to the patients from the China when the 
total number of Chinese patients in the stratum reaches approximately 166.
2
The eosinophil <300/UL stratum will be closed to the patients from all countries when the 
total number of patients in the eosinophil <300/UL stratum reaches approximately 222.
3
The whole study will be closed for recruitment when the total number of patients in the 
eosinophil I300/UL stratum reaches approximately 444, with at least 70% Chinese 
patients in the stratum.
After initial enrolment and confirmation of entry criteria, patients will proceed to the run-in 
period of a minimum 4 weeks to allow adequate time for all of the eligibility criteria to be 
evaluated (Figure 1). Patients who meet eligibility criteria will be randomised to a 48-week 
treatment period. Patients will be maintained on their currently prescribed medium to high-
dose ICS- LABA therapy and other asthma controllers, without change, from visit 1 until the 
end of the study.
A follow-up visit will be conducted at Week 56.

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2.
STUDY OBJECTIVES
2.1
Primary Objective
Primary Objective:
Outcome Measure:
To evaluate the effect of benralizumab on 
asthma exacerbations in patients on 
medium to high-dose ICS-LABA with 
uncontrolled asthma.
Annual asthma exacerbation rate, where an 
asthma exacerbation is defined in Section 5.1.1
by a worseninga 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 an Emergency department (ED) 
or urgent care centre) due to asthma that 
required systemic corticosteroids for at least 
3 days (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 forI 24 hours)
a
For the purpose of the protocol, worsening of asthma is defined as new or increased symptoms and/or signs 
(examination or lung function) that can be either concerning to the patient (patient-driven) or related to an 
Asthma Daily Diary alert (diary-driven). The ePRO device will be programmed to alert both the patient and 
study centre when certain pre-specified worsening thresholds are crossed including: decrease in morning peak 
flow I30% on at least 2 of 3 successive days compared with baseline (last 10 days of run-in), and/or a I50% 
increase in rescue medication or 1 new or additional nebulized T2 agonist on at least 2 of 3 successive days 
compared with the average use for the previous week and/or nocturnal awakening due to asthma requiring rescue 
medication use for at least 2 of 3 successive nights, and/or; an increase in total asthma symptom score (the sum 
of day time [evening assessment] and night time [morning assessment] of at least 2 units above the run-in 
average (last 10 days of run-in), or the highest possible score (daily score of 6), on at least 2 of 3 successive   
days.
If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified objective 
measurements, the Investigator will have to justify the decision for defining the event as an exacerbation.  Events 
that are not supported by any objective assessment will be deemed not to be a protocol-defined exacerbation.

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2.2
Secondary Objectives
Secondary Objectives:
Outcome Measure:
To assess the effect of benralizumab on
pulmonary function
Pre-bronchodilator FEV1b
To assess the effect of benralizumab on 
asthma symptoms and other asthma control 
metrics (as per the ePRO)
!
Asthma symptom score (totalb, daytime, 
and night time)
!
Rescue medication use
!
Home lung function (morning and evening 
Peak expiratory flow (PEF))
!
Nights with awakening due to asthma
!
Asthma Control Questionnaire 6 (ACQ-6)
To assess the effect of benralizumab on 
other parameters associated with asthma 
exacerbations 
Time to first asthma exacerbation and 
proportion of patients with I1 asthma 
exacerbation
To assess the effect of benralizumab on 
health-related quality of life
St. George’s Respiratory Questionnaire (SGRQ)
To assess the effect of benralizumab on 
emergency room/urgent care visits and 
hospitalizations due to asthma
Annual rate of asthma exacerbations that are 
associated with an emergency room/urgent care 
visit or a hospitalization
To evaluate the effect of benralizumab on 
health care resource utilization 
!
Asthma specific resource utilization (eg, 
unscheduled physician visits, use of other 
asthma medications)
To characterize the pharmacokinetics and 
immunogenicity of benralizumab
!
Serum trough concentrations
!
Incidence of anti-drug antibodies (ADA) 
and neutralizing antibodies (nAb), ADA 
titer
To assess the impact of benralizumab on 
blood eosinophil levels
!
Blood eosinophils
b      Key secondary efficacy endpoints
2.3
Safety Objective 
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of 
benralizumab
!
AE/SAE
!
Laboratory variables
!
Electrocardiogram ECG
!
Vital Signs

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3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria*
For inclusion in the study patients should fulfil all of the following criteria:
1
Written informed consent, and assent when applicable for study participation must be 
obtained prior to any study related procedures being performed (local regulations are to 
be followed in determining the assent/consent requirements for children and 
parent[s]/guardian[s]) and according to international guidelines and/or applicable local 
guidelines.
2
Female and male aged 12 to 75 years, inclusively, at the time of Visit 1 

For those patients, who are 17 on the day of Visit 1 but will turn 18 after this day, 
will be considered an adolescent for the purposes of this trial
3
Women of childbearing potential (WOCBP) must agree to use a highly effective method 
of birth control (confirmed by the Investigator) from enrolment, throughout the study 
duration and within 12 weeks after last dose of IP and have negative serum pregnancy test 
result on Visit 1. 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, 
i.e. 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.
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 
amenorrheic for 12 months prior to the planned date of randomisation without an 
alternative medical cause. The following age-specific requirements apply:

Women <50 years old will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 

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treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range. 
Until FSH is documented to be within menopausal range treat the patient as WOCBP.

Women I50 years old will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatment.
4
Weight of I40 kg.
5
History of physician-diagnosed asthma requiring treatment with medium-to-high dose 
ICS (>250Ug fluticasone propionate dry powder formulation equivalents total daily dose) 
and a LABA, for at least 6 months prior to Visit 1. Equivalents for fluticasone propionate 
dry powder can be found in Appendix E.
Documented treatment with medium to high dose ICS and a LABA for at least 3 
months prior to Visit 1 with or without oral corticosteroids and additional asthma 
controllers. The ICS and LABA can be part of a combination product or given by 
separate inhalers. Equivalents for fluticasone propionate dry powder can be found in  
Appendix E.
The ICS dose must be >500 mcg/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.
If patients use more than one type of ICS-containing therapy, each should be 
converted to fluticasone propionate equivalents and summed to derive the patient’s 
total daily dose.
6
Additional maintenance asthma controller medications that are locally approved in a 
country for the treatment of asthma (e.g., LTRAs, tiotropium, cromone, theophylline, oral 
corticosteroid), and have been used for at least 30 days prior to Visit 1 are allowed.  
7
At least 2 documented asthma exacerbations in the 12 months prior to the date informed 
consent, and assent when applicable, during the treatment of medium-to-high dose ICS-
LABA, that required use of a systemic corticosteroid or a temporary increase from the 
patient’s usual maintenance dose of oral corticosteroid (please refer to Section 4.1.1 ). For 
patients who are re-screened within 30 days of their screen failure date, the calculation of 
the 12 month period should be done from the original informed consent, and assent when 
applicable date.
8
Documented post-bronchodilator (post-BD) reversibility in FEV1 of I12% and I200 mL 
in FEV1 within 12 months prior to Visit 1. If historical documentation is not available, 
reversibility must be demonstrated and documented at Visit 2.
9
For WOCBP only: have a negative urine pregnancy test prior to administration of the IP 
at Visit 4.
10 Fulfilment of at least 1 of the following conditions over the 7 days prior to randomisation:

>2 days with a daytime or night time symptoms score >1

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
Rescue SABA use on >2 days 

I1 nocturnal awakening due to asthma
11 Patients demonstrate acceptable inhaler, peak flow meter, and spirometry techniques 
during run-in (from Visit 2 to Visit 4).
12 At least 70% compliance with usual asthma controller ICS-LABA during over the 14 
days prior to randomisation based on Asthma Daily Diary. Patients who experience an 
asthma exacerbation during run-in may temporarily be unable to complete their diary due 
to illness or hospitalization.  In these cases, ICS-LABA compliance will be calculated for 
the period after systemic corticosteroid therapy is complete.
13 At least 70% compliance with ePRO completion

At least 70% compliance defined as completing Asthma Daily Diary for any 10 
complete days (i.e., consecutive evening and morning, for example, Day -14 
evening + Day -13 morning) of the last 14 days of the run-in period.
14 Pre-bronchodilator (Pre-BD) FEV1 of <80% predicted (<90% predicted for patients aged 
12 to 17 years) at Visit 2.
15 ACQ-6 score > 1.5 at Visit 2. 
*: No.1 to No. 8, No.14 and No.15 are the inclusion criteria at screening; No. 9 to No.13 are the inclusion criteria 
at randomisation. 
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1
Known history of clinically important pulmonary disease other than asthma (e.g., active 
lung infection, Chronic obstructive pulmonary disease (COPD), bronchiectasis, 
pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, 
lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or 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, hypereosinophilic syndrome).
2
Known history of any disorder, including, but not limited to, cardiovascular, 
gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, 
metabolic, haematological, psychiatric, or major physical impairment that is not stable in 
the opinion of the Investigator and could:
Affect the safety of the patient throughout the study
Influence the findings of the studies or their interpretations
Impede the patient’s ability to complete the entire duration of study.
3
Known history of allergy or reaction to the investigational product (IP) formulation.

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4
Known history of anaphylaxis to any biologic therapy.
5
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent, and assent when applicable, is obtained that has not been treated with, or has 
failed to respond to standard of care therapy.
6
Acute upper or lower respiratory infections requiring antibiotics or antiviral medication 
within 30 days prior to the date informed consent, and assent when applicable, is obtained 
or during the screening period.
7
Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening period, which in the 
opinion of the Investigator, may put the patient at risk because of his/her participation in 
the study, or may influence the results of the study, or the patient’s ability to complete 
entire duration of the study.
8
Known history of any clinically significant cardiac disease (such as but not limited to 
unstable ischemic heart disease, NYHA Class III/IV left ventricular failure, myocardial 
infarction) or any ECG abnormality obtained during the screening period, which in the 
opinion of the investigator may put the patient at risk or interfere with study assessments.
9
History of alcohol or drug abuse within 12 months prior to the date informed consent, and 
assent when applicable is obtained.
10 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, hypoalbuminaemia, 
oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
11 Known history of immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test.
12 Current smokers at Visit 1 are not allowed. Former smokers with smoking history I 10 
pack-years at Visit 1 are not allowed; Former smokers with a smoking history of <10 
pack years must have stopped for at least 6 months to be eligible. 
13 Known history of cancer:

Patients 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.

Patients who have had other malignancies are eligible provided that the 
patient is in remission and curative therapy was completed at least 5 years 

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prior to the date informed consent, and assent when applicable, was 
obtained.
14 Use of immunosuppressive medication (including but not limited to: methotrexate, 
troleandomycin, cyclosporine, azathioprine, intramuscular (IM) long-acting depot 
corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to 
the date informed consent, and assent when applicable, is obtained. Chronic maintenance 
prednisone for the treatment of asthma is allowed. 
15 Receipt of immunoglobulin or blood products within 30 days prior to the date informed 
consent, and assent when applicable, is obtained.
16 Receipt of any marketed (e.g., omalizumab) or investigational biologic within 4 months 
or 5 half-lives prior to the date informed consent, and assent when applicable, is obtained, 
whichever is longer.
17 Receipt of live attenuated vaccines 30 days prior to the date of randomisation. 
       -   Receipt of inactive/killed vaccinations (e.g., inactive influenza) are allowed 
            provided they are not administered within 1 week before/after any IP 
            administration.
18 Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to 
randomisation, whichever is longer. Use of any off-label medications, for example 
medications locally approved for Chronic Obstructive Pulmonary Disease but not for 
asthma, are also not allowed from 30 days prior to visit 1 and throughout the study. 
19 Previously randomised in any benralizumab (MEDI-563) study, including the present 
study.
20 Initiation of new allergen immunotherapy is not allowed within 30 days prior to the date 
of informed consent, and assent when applicable. Immunotherapy initiated prior to this 
period or as a routine part of the patient’s seasonal treatment is allowed.  If the 
immunotherapy is delivered as an injection, there should be a gap of 7 days between the 
immunotherapy and IP administration.
21 Current use of any oral or ophthalmic non-selective T-adrenergic antagonist (e.g., 
propranolol).
22 Planned surgical procedures during the conduct of the study.
23 Currently breastfeeding or lactating women.
24 Current participation in another clinical investigational study. 
25 AstraZeneca staff involved in the planning and/or conduct of the study.
26 Employees of the study centre or any other individuals involved with the conduct of the 
study, or immediate family members of such individuals.
27 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level >3 times the 
upper limit of normal (ULN), confirmed by repeated testing during screening period. 

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Transient increase of AST/ALT level that resolves by the time of randomisation is 
acceptable if in the Investigator’s opinion the subject does not have an active liver disease 
and meets other eligibility criteria.
Note: The patients previously screen failed in this study due to this criterion are allowed to be 
rescreened if they meet this updated criterion.
28 Five-lipoxygenase inhibitors (e.g., Zileuton) and roflumilast are prohibited.
29 Received bronchial thermoplasty (BT) as treatment of asthma within 12 months prior to 
Visit 1.
For procedures for withdrawal of incorrectly randomised patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record of patients considered for and included in the study. This 
pre-screening/screening log will be evaluated periodically by AstraZeneca or its delegates 
during routine monitoring visits.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
The Investigator or designee will:
1
Obtain signed informed consent, and assent when applicable, from the potential patient 
before any study specific procedures are performed.
2
Assign each potential patient a unique enrolment number, beginning with ‘E#’ via 
interactive web/voice response system (IWRS/IVRS).
3
Determine patient’s eligibility.
4
Assign eligible patient unique randomisation code via IWRS/IVRS.
Patients will be allocated to receive benralizumab or placebo in a 1:1 ratio. The randomisation 
will be stratified by country/region, age group (adult or adolescent), and blood eosinophil 
count at Visit 1 (>300/UL or <300/UL) and the randomisation numbers will be grouped in 
blocks. The <300/UL stratum will be closed when the total number of patients in the stratum 
hits approximately 222. When a stratum is full, patients who fall within that stratum will not 
be randomised and will be withdrawn from the study (see Section 3.10.2).
Randomised patients, who discontinue from IP or withdraw from study, will not be replaced. 
If a patient withdraws from the study, then his/her enrolment number/randomisation code 
cannot be reused. 
Specific information concerning the use of the IWRS/IVRS will be provided in the separate 
manual. 

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3.4
Procedures for handling incorrectly randomised patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive study medication. There can be no exceptions to this rule. Patients, who 
are enrolled but subsequently found not to meet all the eligibility criteria, must not be 
randomised or initiated on treatment, and must be screen failed.
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment.  Study treatment must be discontinued in cases where continued treatment is 
deemed to pose a safety risk to the patient. In those cases where continuation of the study 
treatment is judged not to present a concern related to safety and disease management, the 
rationale for continuing study treatment must be clearly documented. Regardless of what is 
decided about continuation of IP or not, all randomised subjects should be encouraged to 
remain in the study and continue to be followed up in accordance with defined study 
procedures. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups 
Randomisation codes will be assigned strictly sequentially in each stratum as patients become 
eligible for randomisation. The randomisation code will be assigned from a randomisation list 
prepared by a computerized system provided by Parexel Informatics on behalf of AZ 
(AZRand).
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be randomised or receive study medication.  There can be no exceptions to this 
rule.
3.6
Methods for ensuring blinding
The study is a double-blind study. AstraZeneca staff involved in the study, the patients, and 
the investigators/site staff involved in the treatment of the patients or in their clinical 
evaluation will not be aware of the treatment allocation.
Placebo solution will be visually matched with benralizumab solution. Both benralizumab and 
placebo will be provided in an accessorized pre-filled syringe.
As PK sample will be analysed only for patients receiving benralizumab, treatment data 
(randomization list and kit list) will be available to bioanalytical lab personnel for PK sample 
analysis during the conduct of study. The bioanalytical lab personnel, are independent of the 
study team and sites, will not engage in study activities other than PK/immunogenicity sample 

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analysis. The treatment data will only be sent to the lab scientist and will be restricted within 
the lab scientist and analysts. The information in the randomization and kit list will be kept 
from other personnel involved in the conduct of the study and any CRO handling data until 
study unblinding.
Maintaining the blinding to the patient’s blood eosinophil counts
While not entirely specific, patients on active benralizumab treatment are expected to have 
lower blood eosinophil counts than patients on placebo.  Procedures to mitigate unblinding on 
this basis include:
!
From Visit 4 on, eosinophil, basophil or monocyte count will be redacted from central 
laboratory reports to prevent the Principal Investigator/designee from possibly deducing 
the ‘eosinophil + basophil’ contribution to the complete blood count. In cases where the 
Investigator requires an eosinophil, basophil or monocyte count for managing safety 
issues, AstraZeneca physician should be notified of all such cases, without being revealed 
the eosinophil, basophil or monocyte count.
!
Regarding lab results obtained during the treatment period but ordered outside of the 
clinical trial, centre staff who are directly involved in the patient’s treatment and 
evaluation should remain blinded to any eosinophil, basophil and monocyte results 
included as part of outside lab reports.  
!
If the Investigator have to order any local safety laboratory assessments to follow up 
patient’s safety, the requested tests should be restricted to the question at hand. For 
example, if a haemoglobin is desired the Investigator should avoid ordering a complete 
blood cell count with differential.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or delegate at the study centre from the 
IWRS/IVRS.  Further detail on how to unblind a patient’s treatment allocation will be 
described in the IWRS/IVRS user manual provided to each study centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation. The 
Investigator should document and report the action to AstraZeneca, without revealing the 
treatment given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to an IP and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.

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3.8
Restrictions
3.8.1
Asthma medication restrictions
(a)
Use of short-acting .2 agonists (SABA)
Regularly scheduled SABA use in the absence of any asthma symptoms and/or planned 
exercise is discouraged from enrolment and throughout the study duration.
Prophylactic use of SABA in the absence of symptoms (e.g., prior to planned exercise) is 
discouraged.  However, if deemed necessary by the patient and Investigator, it can be used, 
but prophylactic inhalations should not be recorded in the Asthma Daily Diary, such use 
should be documented in medical notes and recorded in the Electronic Case Report Form 
(eCRF).
SABA via a metered dose device is permitted as needed for worsening asthma symptoms (ie, 
rescue use) and will be recorded in the Asthma Daily Diary as number of inhalations.
Rescue use of SABA administered via jet or ultrasonic nebulisation is allowed.  Occasions 
where SABA was administered via nebulisation will be recorded separately from metered 
dose inhaler (MDI) inhalations in the Asthma Daily Diary.
(b)
Use of short acting anticholinergics (e.g., ipratropium) as a rescue treatment for 
worsening asthma symptoms outside of managing an asthma exacerbation event is 
not allowed from enrolment and throughout the study duration
(c)
Use of long-acting beta-agonists as a reliever (e.g., Symbicort Maintenance and 
Reliever Treatment) is not allowed from enrolment and throughout the study 
duration
(d)
Maintenance of asthma controller medications
The patient’s usual pre-study ICS-LABA formulation, dose and regimen, and any other 
additional allowed asthma controllers that they may have been taking prior to enrolment, 
should be continued unchanged from visit 1until the end of study. 
Additional maintenance asthma controller medications (e.g., tiotropium, LTRAs, cromone, 
theophylline, and oral corticosteroid), that are locally approved in a country for the treatment 
of asthma and that have been used for at least 30 days prior to Visit 1 are allowed. 
Changes to the patient’s background controller regimen are discouraged during the 
treatment period, unless judged medically necessary by the Investigator.  All changes in the 
patient’s background medication should be discussed beforehand with the AstraZeneca study 
physician and documented in source along with rationale for change and recorded in eCRF.  

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Asthma exacerbations should be treated with oral or other systemic corticosteroids according 
to standard practice.
(e)
Asthma medication restrictions on the days of scheduled spirometry visit
Pre- and/or post-dose spirometry assessments will be performed at the study centre at 
scheduled visits (see Table 1 and Table 2).  Restrictions to patient’s background medication 
are required prior to the spirometry as described below (also see Section 5.1.2): 
Screening Visit 2: Patients should withhold their usual ICS, LABA, Long-acting anti-
muscarinic (LAMA), LTRA or theophylline medications on the morning of the FEV1
measurement and reversibility test.  Twice daily ICS- LABA therapies should be withheld for 
12- 24 hours; once daily therapies containing ICS, LABA, LAMA, LTRA, theophylline 
therapies should be withheld for >24 hours for eligibility assessment (see Section 3.1, 
inclusion criterion 7).  
In case the patient does not meet the reversibility eligibility criteria, and a second re-test is 
done (not earlier than next calendar day and not later than 7 calendar days after the failed 
attempt), asthma medication restrictions described above should be applied. In addition, 
SABA should not be used within 6 hours of these spirometry assessments.  The patient’s usual 
asthma medications may be administered following completion of the screening lung function 
procedures.
Treatment Visits 4-17: Patients should withhold their usual ICS, LABA, LAMA, LTRA or 
theophylline medications on the morning of the scheduled spirometry.  Twice daily ICS-
LABA therapies should be withheld for 12- 24 hours; once daily therapies containing ICS, 
LABA, LAMA, LTRA or theophylline therapies should be withheld for >24 hours prior to the 
spirometry assessment.  This is especially important prior to scheduled spirometry 
assessments (see Table 2) in order to maintain the integrity of planned efficacy analyses 
around lung function improvement.  In addition, SABA should not be used within 6 hours 
prior to the spirometry assessments.  The patient’s usual asthma controller medications may
be administered following completion of the pre-BD spirograms. The suggested order of 
administration of the patient’s usual asthma controller and IP administration relative to 
scheduled pre -BD spirometry is given in Section 5.1.2.
If the patient has taken their usual ICS, LABA, LAMA, LTRA or theophylline asthma 
controller medication on the morning of the scheduled spirometry visit, the 
Investigator/authorized delegate should remind the patient of the importance of withholding 
their usual morning asthma medication, and reschedule the visit for another day, within the 
allowed window.

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If the patient has taken rescue SABA within 6 hours of the planned centre visit spirometry 
they should:
1
Remain at the centre until such time that the 6 hour withholding time has been reached if 
it does not exceed the 1.5 hour spirometry window, or
2
Return on another day, within the visit window.
(f)
Asthma medication restrictions prior to home peak expiratory flow testing
Patients should avoid taking their morning asthma controllers prior to the morning home Peak 
Expiratory Flow (PEF) testing, and should conduct the evening home PEF testing before 
taking evening asthma controllers.  When possible, home PEF testing, should be taken at least 
6 hours after the last dose of SABA rescue medication.
(g)
Asthma medication restrictions on unscheduled visits
Asthma medication restrictions on unscheduled visits may not be feasible, and may be applied 
at the discretion of the Investigator.  Timing of recent controller and rescue SABA use relative 
to the unscheduled spirometry should be noted in the record
(h)
Asthma medication restrictions at centre visits with scheduled ECG assessment
The patients should be instructed not to take their usual asthma controller medication (ie, 
LABA) prior to scheduled ECG assessment.  Use of SABA should be avoided within 6 hours 
before ECG assessments.  The medication restriction is waived for the screening ECG and 
Visit 1.
3.8.2
Other medication restrictions 
(a)
Use of immunosuppressive medication (other than prior, stable oral corticosteroid 
for the maintenance treatment of asthma) is not allowed. Topical administration of 
immunosuppressive medication may be allowed at the discretion of the Investigator 
after discussion with the AstraZeneca study physician. Please see Section 3.2
exclusion criterion 14 for examples and further details.
(b)
Receipt of live attenuated vaccines within 30 days prior to randomisation, during 
the treatment period, and for 12 weeks after the last dose of the IP is not allowed.
(c)
Patient should not receive allergen immunotherapy injection on the same day as the 
IP administration.
(d)
Patients should not take any other excluded medications:
Five-lipoxygenase inhibitors (e.g., Zileuton)
Roflumilast

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Oral or ophthalmic non-selective T-adrenergic antagonist (eg, propranolol).
A table with medication-related restrictions is presented in the Appendix F.
3.8.3
Other restrictions 
(a)
Fertile and sexually active female patients should use effective contraceptive 
methods throughout the study and at least for 12 weeks after last administration of 
the IP. (see Section 3.1, inclusion criterion 3 and Section 6.6).
(b)
Patients must abstain from donating blood, plasma from the time of informed 
consent, and assent when applicable, and for 12 weeks after last dose of IP.
3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IP) in the following situations:
1
Patient decision. Patients are free to discontinue treatment at any time, without prejudice 
to further treatment (see Section 3.10).
2
Adverse event (AE) that, in the opinion of the Investigator or AstraZeneca, 
contraindicates further dosing.
3
Risk to patient as judged by the Investigator or AstraZeneca.
4
Severe non-compliance to study protocol. 
5
Eligibility requirement found not to be fulfilled (see section 3.4).
6
Pregnancy. 
7
Lost to follow-up1.
8
Development of any study specific criteria for discontinuation:

Anaphylactic reaction to the IP requiring administration of epinephrine.

Development of helminth parasitic infestations requiring hospitalization.

An asthma-related event requiring mechanical ventilation.
If a patient misses more than 2 doses  of IP at any time within a calendar year, it is strongly 
recommended that a conversation between the investigator and AZ study physician takes 
place to review the patient's adherence to treatment and decide on further patient's disposition.
3.9.1
Procedures for discontinuation of a patient from investigational 
product 
At any time, patients are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments – see Section 3.10), without prejudice to 
                                               
1 Patient is considered lost to follow up when any of the following attempts of contact are failed: -3 attempts of 
either phone calls, faxes or emails; - having sent 1 registered letter/certified mail; 1 unsuccessful effort to check 
the vital status of the patient using publicly available sources, if allowed by local regulations.

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further treatment. A patient that decides to discontinue investigational drug will always be 
asked about the reason(s) and the presence of any adverse events. If possible, they will be seen 
and assessed by an Investigator(s). Reasons for premature discontinuation of IP should be 
recorded in the eCRF.
All patients who prematurely discontinue IP should return to the study centre and complete 
the procedures described for the Premature IP Discontinuation visit (IPD) within 8 weeks +7 
days after the last dose of IP. At that visit, patients should be encouraged to remain in the 
study to complete all subsequent study visits, procedures and assessments or alternatively 
agree to be contacted by phone calls at monthly intervals in order to collect AEs/SAEs, 
changes in concomitant medication, health care utilisation, and asthma exacerbation 
information. 
If a patient is withdrawn from study, see Section 3.10. Patients not willing to continue to 
participate in the study should return to the study centre 1 last time within16 weeks ±7 days 
after the last dose of IP for final study related assessments, ePRO devices if applicable (e.g., 
for patient reported outcomes) and all study drugs should be returned by the patient. Any AEs 
that are unresolved at the end of study will be followed up by the Investigator for as long as 
medically indicated, but without further recording in the CRF (See Section 6).
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded in eCRF as ‘Screen failure’ (the potential patient who does not meet one or more 
criteria required for participation in a trial, this reason for study withdrawal is only valid for 
not randomised patients). No further study related follow-up of these patients is required.
‘Failure to meet randomisation criteria’ should be selected for an indication that the patient 
has been unable to fulfil/satisfy the criteria required for assignment into a randomised group 
(it is only applicable for patient found not meeting criteria after randomisation). 
3.10.2
Withdrawal due to recruitment completion in a randomisation stratum
When a specific stratum is full, patients in completed stratum will not be randomised and will 
be withdrawn from the study. The reason of the withdrawal should be documented in the 
source and eCRF as ‘development of study-specific withdrawal criteria’. As with screen 
failures, no further study related follow-up of these patients is required.
Strata closure process:

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1
The eosinophil <300/UL stratum will be closed to all the patients from China when the 
total number of Chinese patients in the stratum reaches approximately 166.
2
The eosinophil <300/UL stratum will be closed to the patients from all countries when the 
total number of patients in the stratum reaches approximately 222. 
3
The whole study will be closed for recruitment when the total number of patients in the 
eosinophil I300/UL stratum reaches approximately 444, with at least 70% Chinese 
patients in the stratum.
3.10.3
Withdrawal of the informed consent/assent
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.
A patient who withdraws consent, and assent when applicable, will always be asked about the 
reason(s) and the presence of any adverse events (AE).  The Investigator will follow up AEs 
outside of the clinical study.  The patient will return electronic PRO (ePRO) devices if 
applicable.  The enrolment/randomisation code of the withdrawn patient cannot be reused.
If patient agrees, he/she will be asked to return to the study centre and complete procedures 
described for the IPD (Premature IP Discontinuation) visit. For patients who are not willing to 
continue to participate in the study, he/she will complete IPD within 8 weeks +7 days after the 
last dose of IP and Follow-up visit within 16 weeks ±7 days after the last dose of IP. 
3.10.4
Withdrawal of informed consent/assent for donated biological samples 
If a patient withdraws consent, and assent when applicable, to the use of donated biological 
samples, the samples will be disposed of/destroyed, and the action documented.  If samples 
are already analysed, AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Principal Investigator or designee:
!
Ensures patients’ withdrawal of informed consent, and assent when applicable, for the use 
of donated samples is notified immediately to AstraZeneca.
!
Ensures that biological samples from that patient, if stored at the study centre, are 
immediately identified, disposed of /destroyed, and the action documented.
!
Ensures the central laboratory (ies) holding the samples is/are informed about the 
withdrawn consent, and assent when applicable immediately and that samples are 
disposed/destroyed.
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.

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AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent, and assent when applicable immediately and that samples are disposed 
of/destroyed and the action documented and returned to the study centre.
3.10.5
Withdrawal due to repeat exacerbations during screening 
Patients who experience more than 1 asthma exacerbation between Visit 1 and Visit 4 will not 
be randomised and will be withdrawn from the study (see Section 4.1.3.1). 
The start of an exacerbation is defined as the start date of systemic corticosteroids, or the start 
date of a temporary increase in a stable oral corticosteroid background dose, or that start date 
of hospital admission, whichever occurs earlier. The end date is defined as the last day of 
systemic corticosteroids or the last day of a temporary increase in a stable oral corticosteroid 
background dose, or the date of discharge from a hospital, whichever occurs later (see Section 
8.4.1.1).
Patients who are diagnosed with an asthma exacerbation at Visit 4 will not be randomised and 
will be withdrawn from the study (see Section 4.1.3.1).
The reason of the withdrawal should be documented in the source and eCRF as ’Development 
of study-specific withdrawal criteria’.
Patients who are withdrawn due to exacerbation at Visit 4 or due to exacerbations between 
Visit 1 and Visit 4 may be re-screened twice (see Section 4.1.3.1).
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
4.
STUDY PLAN AND TIMING OF PROCEDURES 

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g.
Unscheduled visits may be initiated as needed. Adverse event, concomitant medication and assessment of asthma exacerbation are mandatory, and additional 
assessments may be performed at these visits, at the discretion of the Investigator.
h.
Pre-dose sample
D  Days; EOT  End-of-treatment; FU  Follow-up; R  Randomisation; V  Visit; UNS  Unscheduled; W  Week; IPD Premature IP Discontinuation

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4.1
Screening period
4.1.1
Enrolment (Visit 1)
Each potential patient will provide written informed consent, and assent when applicable, 
prior to any study specific procedures and undergo assessments applicable for the visit (see 
Table 1).
Patient must sign the Informed Consent Form (ICF) prior to any other Visit 1 procedures. 
Visit 1 assessments are primarily concerned with confirmation of the asthma disease state, the 
requisite level of severity based on background medications and exacerbation history.
Source documentation is required for physician-diagnosed asthma, ICS-LABA use 
(Section 3.1, criterion 5) and asthma exacerbations over the prior year (Section 3.1,
criterion 7) .  A patient verbal history suggestive of asthma symptoms and/or prior 
asthma exacerbations, but without supporting documentation, is not sufficient to satisfy 
these inclusion criteria.
Examples of acceptable documentation of the asthma disease state and prior asthma 
exacerbations include clinic visit (primary or specialist Health care provider (HCP)), 
emergency room/urgent care, or hospital records listing asthma as a current problem, 
plus documentation of at least 2 asthma exacerbations during the 12 months prior to 
ICF:
A qualifying historical asthma exacerbation is a symptomatic worsening requiring systemic 
corticosteroid (i.e., oral, intravenous (IV) or intramuscular; any healthcare setting or 
temporary increase from a stable maintenance dose of oral corticosteroid,) or that resulted in 
hospitalization.
Patients will continue on their current asthma treatment with no changes.
Central laboratory tests for absolute blood eosinophil count will be performed at Visit 1 . 
Patients who have a blood eosinophil count of <300 but I150/UL at Visit 1 can be re-tested 
once. It is recommended that any re-test for blood eosinophils is performed not earlier than 4 
weeks from the previous testing; in case of recent treatment with systemic corticosteroids, an 
interval of I6 weeks from the last dose is recommended. 

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4.1.2
Run-in (Visit 2, Visit 3)
The run-in period should be a minimum of 4 weeks in duration (from Visit 2 to Visit 4). The 
patient should remain on their current asthma treatment with no changes throughout run-in 
period.  Assessments applicable for the period are listed in Table 1.
Visit 2 is primarily concerned with evaluating whether lung function meets study eligibility 
criteria.
Visit 2 may be performed as a telephone visit if the patient is confirmed as ineligible for the 
study (e.g., based on laboratory results from Visit 1 or medical history).
Visit 2 may take place as soon as medication restrictions prior to spirometry/reversibility tests 
are met (see Section 3.8) and should occur no later than 1 week after Visit 1. Visit 2 
procedures may be performed on the same day as Visit 1 if the medication restriction is met.  
If Visit 2 procedures are actually planned at Visit 1 as a convenience, then the ICF must be 
signed prior to instructing the patient to withhold any medication.
If a patient fails the protocol-specified reversibility criterion (I12% FEV1 and I200 ml), a 
second attempt is allowed. Re-testing can only occur once during the run-in period, not earlier 
than next calendar day and not later than 7 calendar days after the failed attempt.
Note: In cases when historical proof of post-BD reversibility in FEV1 (see inclusion criterion 
8) is documented within 12 months prior to Visit 1, the screening reversibility does not need 
to be performed (see Section 5.1.2.1)
Once the reversibility criterion has been met, the patient will be supplied with an electronic 
hand-held spirometer (peak flow meter) to monitor home peak expiratory flow, and an ePRO 
device to record asthma symptoms and complete relevant questionnaires (see Section 5.3.2 for 
further details).
Visit 3 can be performed within 1 week before Visit 4. Visit 3 and Visit 4 may take place on 
the same day only for well characterized patients (those who did not have lab results outside 
the normal range at Visit 1 for parameters associated with eligibility criteria (e.g. Liver 
Function Tests)) as any such results should be retested, with results available before 
randomisation, in order to ensure patient eligibility is not affected. On Visit 4 ACQ-6 will be 
recorded (for baseline purposes only). Patient’s eligibility should be evaluated at each visit 
during the run-in period with the relevant documentation entered in the source and eCRF.
4.1.3
Re-screening
Re-screening may be allowed twice for the patient screen-failed due to asthma exacerbation, 
otherwise re-screening is only allowed once.  

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Patients who experience an asthma exacerbation during the screening period may remain in 
screening and may proceed with study visits after they completed their course of oral steroids 
or returned to their maintenance dose of oral steroids.
Patients with respiratory infections requiring antibiotics or antiviral medication within 
30 days prior to the date informed consent, and assent when applicable is obtained or 
during the screening period may also be re-screened. 
Re-screening and/or up to 14-day extension of screening period is allowed for transient 
reasons (including but not limited to study-supplied equipment failure, unforeseen personal 
events that mandate missed screening visits). These cases should be discussed with the 
AstraZeneca study physician and documented in the Investigator Study File (ISF).
For those patients who were screen failed at Visit 3 or thereafter the re-screening period can 
be reduced. Visit 1 and Visit 2 can be done at the same day; Visit 3 can be done 1 week after 
Visit 2, and Visit 4 can be done 1 week after Visit 3.
Re-screened patient should re-sign the informed consent, and assent when applicable on the 
re-screening Visit 1. All procedures from screening period should be repeated.
A second re-screening may be allowed only when the screen failure reason was asthma
exacerbation. All the cases should be discussed with the AstraZeneca study physician and 
documented in the Investigator Study File (ISF).
4.1.3.1
Procedures for Patients Who Experience an Exacerbation during Screening
Patients who experience an asthma exacerbation between Visits 1 and Visit 4 should be 
treated according to local medical practice and may continue screening at the discretion of the 
Investigator. More than 1 exacerbation during screening will result in screen-failure.
!
Exacerbations Between Visit 1 and Visit 3: 

The next regular study visit (Visit 2 or Visit 3) will be delayed and may proceed no 
sooner than 14 days after the last dose of systemic steroids. 

For patients on chronic oral steroid therapy, Visit 2 or Visit 3 can commence minimal 
14 days after the daily dose has returned to the pre-exacerbation baseline level.
!
Exacerbations Between Visit 3 and Visit 4: 

Visit 4 will be delayed. Patients will return to the centre for an unscheduled visit at 
the time their systemic steroid regimen is complete or the dose has returned to 
baseline. 

Central laboratory safety assessments will be collected (see Table 3) at the 
unscheduled visit and checked by the Investigator prior to randomisation. 

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
Randomisation at Visit 4 can commence minimal 14 days after the systemic steroid 
regimen is complete or the dose has returned to baseline.
!
Exacerbations at Visit 4: 

Patients who are diagnosed with an asthma exacerbation at Visit 4 should be screen-
failed. 
Electronic diary assessments should be completed during the delay between study visits. 
Patients who are screen-failed with an exacerbation at Visit 4 or due to exacerbation between 
Visit 1 and Visit 4 may be re-screened 2 times.
4.2
Treatment period
Inclusion criteria at randomisation will be confirmed at Visit 4. Before randomisation the 
patient’s compliance with usual asthma controller ICS-LABA and ePRO completion must be 
confirmed (see Section 3.1, inclusion criterion 12 and 13).
Patients confirmed to be eligible will be randomised at Visit 4 (Week 0). 
Adult or adolescent patients will be randomised to either placebo or benralizumab.
The first dose of the IP will be administered at Visit 4 after the patient’s randomisation via 
IWRS/IVRS. During Visit 4, but before the first dose of IP, the patient should complete the 
following PRO assessments on the ePRO device: SGRQ and ACQ-6.
For Visits 6 -16 spirometry and blood sampling (for hematology, serum chemistry, PK, 
ADA/nAb) may be performed 1 day prior to the scheduled date of IP injection, at the 
discretion of the Investigator. All other study procedures (except ACQ-6) must be done on the 
scheduled day of IP injection.  Urine pregnancy tests must be done on injection days, prior to 
IP administration.
Following randomisation the patient will receive 48-week double-blind treatment, with the 
last dose of benralizumab/placebo administered at Visit 15 (Week 40). Patients will have 
scheduled visits or phone call at 4-week interval to complete protocol-specific assessments 
and IP administration, as listed in Table 2. Restrictions as set out in Section 3.8 will continue 
to apply throughout the treatment period.  In case of asthma worsening/exacerbation (see 
Section 5.1.1), patients should be evaluated at the study centre, when feasible, at an 
unscheduled visit, or ordinary visit if the worsening happens to fall within a scheduled visit 
window.
Patients will continue to monitor lung function at home, as well as record asthma symptoms 
and responses to questionnaires using ePRO device throughout the 48-week treatment period 
(see Section 5.3.2 for details).

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At Week 48 patients will come to the centre for the End of Treatment (EOT) visit.
Patients who prematurely discontinued IP (see Section 3.9) and are not willing to continue to 
participation in the study should return to the study centre and complete procedures described 
for the IPD visit (Premature IP Discontinuation) within 8 weeks +7 days  after the last dose of 
IP and Follow-up visit within 16 weeks ±7 days after the last dose of IP, respectively.
Patients will return the ePRO device on EOT or IPD visit (for patients who are not willing to 
continue to participation in the study).
Completion or early termination of the treatment will be registered via IWRS/IVRS for each 
patient.
4.3
Follow-up period
All the patients will return at Week 56 for a final Follow-Up visit.
4.4
Study Conduct Mitigation During Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study patients become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the patient’s ability to conduct the study. The investigator 
or designee should contact the study Sponsor to discuss whether the mitigation plans below 
should be implemented.  
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 
!
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the Informed Consent Form (ICF) should be signed at the patient’s 
next contact with the study site).
!
Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician. 
!
Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV).

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!
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
!
At-home Investigational Product (IP) administration: Performed by a site qualified HCP, 
HCP provided by a TPV, or by the patients or the patient’s caregiver, if possible. 
Additional information related to the visit can be obtained via telemedicine.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix G.
5.
STUDY ASSESSMENTS AND PROCEDURES
5.1
Efficacy assessments
5.1.1
Assessment of asthma exacerbations
For the purpose of the protocol, 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 emergency department or urgent care centre) due to asthma that required systemic 
corticosteroids for at least 3 days (as per above)
!
An inpatient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for I24 hours) due to asthma
Worsening of asthma is defined as new or increased symptoms and/or signs (examination or 
lung function) that can be either concerning to the patient (patient-driven) or related to an 
Asthma Daily Diary alert (diary-driven).  The ePRO device will be programmed to alert both 
the patient and study centre when certain pre-specified worsening thresholds are crossed 
including:
!
Decrease in morning peak flow I30% on at least 2 of 3 successive days compared with 
baseline (last 10 days of run-in), and/or
!
A >50% increase in rescue medication on at least 2 of 3 successive days compared with 
the average use for the previous week, and/or use of 1 new or additional nebulized T2 
agonist on at least 2 of 3 successive days compared with the average use for the previous 
week, and/or
!
Nocturnal awakening due to asthma requiring rescue medication use for at least 2 of 3 
successive nights, and/or
!
An increase in total asthma symptom score (the sum of day time [evening assessment] 
and night time [morning assessment] of at least 2 units above the run-in average (last 10 
days of run-in), or the highest possible score (daily score of 6), on at least 2 of 3 
successive days

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If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified 
objective measurements, the Investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF.  Events that are not supported by any 
objective assessment will be deemed not to be a protocol-defined exacerbation.
An asthma exacerbation that occurs _7 days of the last dose of systemic steroids (oral, IM, 
IV), prescribed for a prior exacerbation, will be counted as the same exacerbation event.
The patient may remain in the study after an exacerbation and continue to receive IP if the 
Investigator judges that it is medically appropriate for the patient to do so.
Reasonable attempts should be made by the Investigator to bring the patient into the study 
centre for evaluation of a diary alert or patient initiated asthma worsening, particularly when it 
results in additional treatment being prescribed. Study centre evaluations for asthma 
worsening may occur as an unscheduled visit or as part of an ordinary centre visit if the 
worsening happens to be coincident with a scheduled visit window. A copy of the medical 
record should be obtained for exacerbations evaluated and treated at non-study centres (eg, by 
the primary care HCP or at an emergency department/hospital) and details entered into the 
exacerbation eCRF in a timely fashion. Changes in concomitant medication due to 
exacerbation must be recorded in the appropriate module of the eCRF.
5.1.2
Spirometry
General requirements
Lung function (FEV1 and Forced vital capacity (FVC)) at the study centre will be measured by 
spirometry using equipment provided by central vendor. Spirometry will be performed by the 
Investigator or authorized delegate according to American Thoracic Society/European 
Respiratory Society (ATS/ERS) guidelines (Miller et al 2005).
The central spirometry vendor is responsible for assuring that the spirometer meets ATS/ERS 
recommendations and that the study centre personnel who will be performing the testing are 
properly certified.  Spirometry calibration will be detailed in a separate spirometry procedures 
manual.
Important!  Patients should withhold their usual ICS-LABA, LAMA, LTRA or theophylline 
medications on the morning of the screening FEV1 measurement, reversibility test (see 
Section 3.1, inclusion criterion 8 and 11), and all scheduled spirometry visits. Twice daily 
ICS- LABA therapies should be withheld for 12- 24 hours; once daily therapies containing 
ICS, LABA, LAMA, LTRA or theophylline therapies should be withheld for I24 hours before 
scheduled centre visit spirometry as this will affect the pre-BD FEV1 value; they may be taken 
subsequently, at the centre. For the same reason patients should not use their rescue SABA 
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spirometry. This restriction is particularly critical for efficacy measures taken during the 
treatment period, but should also facilitate meeting the screening FEV1 and reversibility 
eligibility criteria. 
Options for handling patients who have inadvertently taken their asthma medication within the 
restricted window are described in Section 3.8.
Time of day for scheduled centre visit spirometry
Spirometry testing should be done according to the schedule provided in Table 1 and Table 2.  
All post-randomisation spirometry assessments should be performed within ± 1.5 hours of the 
time that the randomisation spirometry was performed.  For example, if the randomisation 
spirometry was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated 
between 6:30 AM and 9:30 AM.
Spirometry technique
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Patients should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the centre. Forced expiratory manoeuvres should be performed 
with the patient seated in an upright position.  If this is not comfortable for the patient, 
standing is permitted. The same position should be used by the patient for each forced 
expiratory manoeuvre from enrolment throughout the study. The head must not be tilted 
during manoeuvres and the thorax should be able to move freely; hence tight clothing should 
be loosened. A nose-clip should be used for the manoeuvre. Mouthpieces of the same 
dimension and shape should be used by the patient from enrolment throughout the study.
The forced expiratory manoeuvre (FEV1 and FVC) should start with a maximal inspiration 
and then followed by a fast and forceful expiration that should last for at least 6 seconds. It is 
important to encourage the patient to continue the expiration to be fast and forceful throughout 
the manoeuvre. Ensure that none of the following has occurred: coughing during the first 
second, glottis closure, leak or obstruction of the mouthpiece (by the tongue).
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
centre spirometry session and the best effort that meets the ATS/ERS acceptability and 
reproducibility criteria will be analyzed. The best efforts will be based on the highest FEV1.  
The absolute measurement (for FEV1 and FVC), and the percentage of predicted normal value 
(Quanjer et al 2012) will be recorded. The highest FVC will also be reported regardless of the 
effort in which it occurred (even if the effort did not result in the highest FEV1).
Post-bronchodilator spirometry
Post-BD spirometry will be performed to satisfy reversibility inclusion criterion 8 (for patients 
without prior documentation of reversibility) as listed in Table 2. The post BD spirometry 

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procedures should commence according to the regimen for reversibility testing outlined in 
Section 5.1.2.1. 
Order of administration of usual asthma controller medication and IP relative to 
scheduled pre-bronchodilator spirograms
The patient’s usual morning asthma controller therapy must not be given until after the initial 
pre-medication, pre-bronchodilator spirograms are complete for the reasons discussed above; 
usual asthma controller and IP may be given after final pre-bronchodilator spirograms. 
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at study centre for 
source data verification.  The printout must be marked with the study code, enrolment code, 
date and time of measurement, visit number.
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the patients 
predicted normal (PN) values and are pre-programmed into your spirometer (Quanjer et al 
2012).
FEV1 expressed as percent of the PN value will be calculated as follows:
FEV1% of PN=FEV1 measured/FEV1PN x 100
5.1.2.1
Reversibility test 
The procedure described in this section refers to the reversibility testing at Visit 2 (to evaluate 
inclusion criterion 8, if applicable).  Maximal bronchodilatation should be induced using 
albuterol (90 Ug metered dose), salbutamol (100 Ug metered dose) or levalbuterol (45 Ug 
metered dose) up to a maximum of 8 inhalations (Sorkness et al 2008).  It is highly 
recommended to use a spacer device for this procedure.  The algorithm for reversibility testing 
is outlined in Figure 2.

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Figure 2
Reversibility testing algorithm
1
Verify with the patient that the medication 
restrictions to allow the reversibility assessment have 
been met (Section 3.8)
2
After a gentle and complete expiration, albuterol, 
salbutamol or levalbuterol is inhaled in 1 breath to 
Total lung capacity (TLC) from a spacer device.  The 
breath is then held for 5–10 seconds before the patient 
exhales. Four separate inhalations are delivered at 
approximately 30- second intervals. Post-BD 
spirometry should be performed 15-20 minutes later.
3
Following this, an additional 2 inhalations of 
albuterol, salbutamol or levalbuterol should be 
administered as single inhalations, 30 seconds apart 
(for a total of 6 inhalations).  Second post-BD 
spirometry should be performed 15-20 minutes later.
4
If the incremental change in FEV1 after 6 
inhalations of albuterol, salbutamol or levelbuterol is 
_5% of the FEV1 value after 4 inhalations, the 
procedure is complete. If the change is >5% an 
additional 2 inhalations of albuterol, salbutamol or 
levalbuterol should be administered in single inhalation 
30 seconds apart and a third and final post-BD 
spirometry should be performed 15-20 minutes later.
A lower total dose, eg, 2 inhalations instead of 4 in the first round of puffs, and/or a total of 
less than 8 puffs, can be used if there is a concern about any effect on the patient’s heart rate, 
tremor or safety. For the visit 2 reversibility testing, it is acceptable to stop the procedure 
when the eligibility criterion is met. If a reversibility maneuver that meets inclusion criteria 
(I12% and I200 mL) is rejected as the best maneuver after central revision, it may still be 
used to satisfy Inclusion Criterion 8. 
The % difference comparing FEV1 after 6 puffs to the FEV1 after 4 puffs will be calculated as 
follows:
% Difference=FEV1 (6 puffs)-FEV1(4 puffs)/FEV1(4 puffs) ×100
The highest pre- and post-BD FEV1 will be used to determine reversibility. 
Reversibility is calculated as follows:
% Reversibility =
(post-BD FEV1- pre-BD FEV1) 
× 100
pre-BD FEV1

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Note: In cases when historical proof of post-BD (post-BD) reversibility in FEV1 (see inclusion 
criterion 7) is documented within 12 months prior to Visit 1 the screening reversibility test 
does not need to be performed.
5.1.3
Home peak expiratory flow testing
An electronic, hand-held spirometer (peak flow meter) will be dispensed to the patient on 
Visit 2 (after respiratory inclusion criteria have been confirmed, see Section 3.1, criterion 8
and 11).
Home peak expiratory flow (PEF) testing will be performed by the patient in the morning 
upon awakening (and prior to taking their AM asthma controller) and in the evening at 
bedtime (and prior to taking their PM asthma controller).  Recording of home peak expiratory 
flow should start from the evening of Visit 2 until the morning of Visit 17 using an ePRO 
device.  When possible, ambulatory lung function measurements should be taken at least 6 
hours after the last dose of SABA rescue medication. 
Patients should perform 3 successive peak flow manoeuvres while sitting or standing, but in 
the same position at every testing; the highest of the 3 values will be captured for the morning 
and for the evening manoeuvres.
Investigator/authorized delegate will check patient’s adherence to correct use of the peak flow 
meter at each clinic visit as shown in Table 2 (or on IPD Visit if prematurely discontinued 
from the study).
5.2
Safety assessments
5.2.1
Physical examination 
Physical examination will be done in accordance with schedule provided in Table 1 and Table 
2.
Any new finding(s) or aggravated existing finding(s), judged as clinically significant by the 
Investigator, as compared to the data collected at Visit 1, will be reported as an AE as 
described in Section 6.1.
5.2.1.1
Complete physical examination 
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems. 

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5.2.1.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system.  
5.2.2
Vital signs 
Pre-dose vital signs (pulse, blood pressure, respiration rate and body temperature) will be 
obtained in accordance with schedule provided in Table 1 and Table 2.
The vital signs will be taken prior to IP administration, and, if possible, blood drawing and 
usual asthma controller medication. If it is not logistically possible, 10 minutes should be 
allotted between phlebotomy and vital signs assessment. Vital signs should also be taken prior 
to per protocol bronchodilator administration if applicable for that visit.
Pulse rate and blood pressure should be measured after the patient has been resting for at least 
5 minutes. The measurement will be taken in sitting position. Pulse rate will be obtained 
before blood pressure. 
Respiration rate will be obtained after patient has been resting for at least 5 minutes, by 
counting number of breaths (how many times the chest rises) for 1 minute.
Body temperature will be measured in Celsius before IP administration in accordance with 
local standards.
5.2.3
ECG
ECG will be performed in accordance with schedule provided in Table 1 and Table 2.
In all patients, the printouts of the ECG will be collected and signed, dated and stored at the 
study centre along with a signed and dated copy (if the printouts are not on archive-quality 
paper).
A 12-lead ECG will be taken in supine position, after the patient has been resting for at least 5 
minutes.
The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. In case of discrepancy 
between the investigators interpretation and that provided by the ECG machine (if applicable), 
the investigators interpretation takes precedence and should be noted on the printout and 
recorded in the eCRF. ECG will be produced and quality checked and kept in case of further 
need for re-evaluation. It is highly recommended that the same machine is used for assessment 
throughout the patient’s participation in the study.
ECG evaluation will be recorded in the eCRF.

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5.2.4
Safety laboratory tests
Safety laboratory tests (list provided in Table 3) will be performed in a central laboratory. For 
information on methods of collection, assessment, labelling, storage and shipment of samples 
please refer to the separate Laboratory Manual.  Safety samples will be collected in 
accordance with the schedules provided in Table 1 and Table 2.
Haematology and urinalysis will be assessed in line with the schedules provided in the Table 1
and Table 2.
Laboratory results should be reviewed by the Investigator/authorized delegate and evaluated 
for abnormalities. Any laboratory abnormalities considered to be significant in the 
investigators’/authorized delegate’s judgement should be reported as described in Section 6.3.
The copy of laboratory result report should be signed and dated by Investigator and retained at 
the study centre.
Table 3
List of safety laboratory tests
Serum chemistry
Haematology
Urinalysis
Alkaline phosphatase
Gamma-GT (gamma-
glutamyl 
transpeptidase)
Hematocrit
Appearance
ALT (alanine 
aminotransferase)
Glucose
Hemoglobin
Blood
AST (aspartate 
aminotransferase)
Phosphorus
Mean corpuscular 
volume (MCV)
Colour
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Glucose
C-reactive protein
Sodium
Red blood cell (RBC) 
count
Ketones
Calcium
Total bilirubin
White blood cell 
(WBC) count with 
differential a
Microscopy including 
WBC/high power field 
(HPF), RBC/HPF
Chloride
CO2 (carbon dioxide)
Total cholesterol
pH
Creatinine
Uric acid
Specific gravity
a
eosinophil, basophil and monocyte counts will be redacted from the central laboratory reports, except Visit 
1 laboratory report (see Section 3.6).
5.2.4.1
Pregnancy Test 
The following tests are applicable to female patients only and will be conducted in accordance 
with the schedules provided in Table 1 and Table 2.

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!
Serum beta-HCG: To be done in all females at screening Visit 1 except for those who are 
NOT of child bearing potential as defined in inclusion criterion 3. This test is to be sent to 
and analysed at the central laboratory.
!
FSH: To be done at screening Visit 1 only, for female patients to confirm postmenopausal 
status in women <50 years who have been amenorrheic for >12 month. 
!
Urine HCG: To be performed at the study centre for all females at each clinical visit 
before IP administration except for those females who are NOT of child bearing potential 
as defined in inclusion criterion 3. A positive urine test result must be confirmed with 
serum beta HCG.
5.3
Other assessments and procedures
5.3.1
Weight and height
Weight and height will be measured in accordance with the schedules provided in Table 1 and 
Table 2.
The patient’s weight will be recorded in kilograms; height will be recorded in centimetres.
Weight and height measurements will be performed in light clothing and with shoes off.
5.3.2
Patient reported outcomes
Patients will be supplied with an ePRO device and hand-held spirometer at Visit 2 after 
respiratory criteria have been confirmed (see Section 3.1, criterion 8 and 11).  The study 
centre staff will be trained on how to use both devices and will be responsible for instructing 
patients on how to use both devices. Patients will have an opportunity to practice using the 
devices through a pre-programmed training module.  Patients should be informed that the 
recordings made electronically cannot be retrospectively or prospectively entered and must be 
completed within a defined time window. Patients will also be provided with information 
about when and where to request help if problems occur.
5.3.2.1
Asthma daily diary
The Asthma Daily Diary will be completed each day from the evening of Visit 2 to the 
morning of Visit 17.  The Asthma Daily Diary will include the following daily recordings: 
morning and evening home peak expiratory flow data (obtained from the home peak flow 
meter), asthma symptoms, inhalations of rescue medication, nights with awakenings due to 
asthma symptoms, background medication compliance. There will be triggers in the ePRO 
device to alert the patients to signs of worsening of asthma and to contact their physician in 
the setting of a diary alert, please refer to Section 5.1.1.
The Investigator/authorized delegate will check patient’s adherence to the Asthma Daily Diary 
at each visit as shown in Table 1 and Table 2.

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Home peak expiratory flow measurement
For details regarding peak expiratory flow measurement please refer to Section 5.1.3.
Asthma symptoms
Asthma symptoms during night time and daytime will be recorded by the patient each 
morning and evening in the Asthma Daily Diary, from Visit 2 to Visit 17.
Daytime is defined as the time period between the morning lung function assessment (upon 
rising in the morning) and the evening lung function assessment.  Night time is defined as the 
time period between the evening lung function assessment (at bedtime) and the morning lung 
function assessment.
Rescue medication
The number of rescue medication inhalations and nebulizer treatments taken will be recorded 
by the patient in the Asthma Daily Diary twice daily.  The number taken between the morning 
and evening lung function assessments will be recorded in the evening.  The number of 
inhalations taken between the evening and morning lung function assessments will be 
recorded in the morning.  Rescue medication usage is captured in the daily diary as the 
number of inhaler puffs and the number of times a nebulizer is used. Rescue medication usage 
will be summarized as the number of puffs with 1 instance of nebulizer use converted to 2 
puffs.
Nocturnal awakenings 
Nocturnal awakenings due to asthma symptoms will be recorded by the patient in the Asthma 
Daily Diary each morning by answering the question whether he/she woke up during the night 
due to asthma symptoms by a “yes” or “no” response.
Background medication
Background medication administration use will be recorded in the Asthma Daily Diary in the 
morning and evening as “yes” or “no” response.
5.3.2.2
Asthma control questionnaire (ACQ-6)
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time 
waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and short-
acting T2 agonist use) omitting the FEV1 measurement from the original ACQ score.
Patients are asked to recall how their asthma has been during the previous week by responding 
to 1 bronchodilator use question and 5 symptom questions.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled).  The mean ACQ-6 score is the mean of the responses.  Mean scores of _0.75 

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indicate well-controlled asthma, scores between 0.75 and <1.5 indicate partly controlled 
asthma, and a score I1.5 indicates not well controlled asthma (Juniper et al 2006).  Individual 
changes of at least 0.5 are considered to be clinically meaningful.
The questionnaire will be completed using the ePRO device. An initial screening ACQ-6 will 
be taken at Visit 2 at the study centre. The patient will bring the device to the randomisation 
visit and complete the ACQ-6 on site during the randomisation visit (Week 0). Once 
randomised, patients will be asked to complete the ACQ-6 once every 4 weeks (±3day) until 
Week 8 and then once every 8 weeks (±3day) throughout the treatment period until Week 40.  
Patients will be asked to complete the ACQ-6 at EOT, Week 48 (+7day), or IPD visit.
Visit 2 ACQ-6 scores will determine eligibility for randomisation (see Section 3.1, inclusion 
criterion 15).
The Investigator/authorized delegate will check patient’s adherence to the ACQ-6 at each visit 
as shown in Table 1 and Table 2.
5.3.2.3
St. George’s Respiratory Questionnaire (SGRQ)
The SGRQ is a 50-item PRO instrument developed to measure the health-related quality of 
life (HRQoL) of patients with airway diseases (Jones et al 1991). The questionnaire is divided 
into two parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in 
the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and 
psychosocial impacts of the individual’s respiratory condition. The SGRQ yields a total score 
and three domain scores (symptoms, activity, and impacts). The total score indicates the 
impact of disease on overall HRQoL. This total score is expressed as a percentage of overall 
impairment, in which 100 represents the worst possible HRQoL and 0 indicates the best 
possible HRQoL. Likewise, the domain scores range from 0 to 100, with higher scores 
indicative of greater impairment. Specific details on the scoring algorithms are provided by 
the developer in a user manual (Jones et al 2009).
The questionnaire will be completed using the ePRO device. The patient will bring the device 
to the study site. The patient should complete the questionnaire in a quiet area and be given as 
much time as needed to complete the assessment. Investigators should not clarify content and 
take care not to influence the patient’s responses. The questionnaire will be checked by 
Investigator or designee for completeness, and be collected before the patient leaves the study 
site. At later visits, patients are not allowed to review their previous assessments.
The SGRQ will be completed by the patients prior to study drug administration at Visit 4 
(Week 0, Day1), Visit 7 (Week 8), Visit 9 (Week 16), Visit 11 (Week 24), Visit 13 (Week 
32), Visit 15 (Week 40) and Visit 17 (Week 48, or EOT) or IPD Visit.

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5.3.3
Healthcare resource utilization
Broad-based health care utilization asthma related event information will be collected by the 
Investigator/authorized delegate at each visit (as shown in Table 2) and recorded in the 
appropriate eCRF module.
At Visit 1 Healthcare Resource Utilization (HRU) information will be collected with a 1 year 
recall period. In treatment period, HRU information will be collected with a recall period of 
‘since last visit’.
Note: Cases of hospitalization after Visit 1 also must be reported as an SAE (see Section 6.2
and 6.4).
5.3.4
Other run-in assessments
5.3.4.1
Serology
Hepatitis B surface antigen, hepatitis C antibody: To be done only at screening; test to be 
performed at central laboratory.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the centres.
5.3.5
Pharmacokinetics
For the PK analysis it is important that the date and time of each SC injection is recorded for 
each patient.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the centres.
Serum will be collected according to the schedule of study procedures (see Table 2). On the 
dosing visits (Visit 4 and Visit 11), the serum will be collected as pre-dose.
Samples for determination of benralizumab concentration in serum will be analysed by a 
central laboratory on behalf of AstraZeneca, using a validated bioanalytical method. 
Following AZ standard process, bioanalytical lab will analyse PK samples only for patients 
receiving benralizumab based on the randomization/kit list. 
After primary bioanalysis, residual PK sample aliquots may be retained for the purposes of re-
analysis at AstraZeneca or designee for a maximum of 5 years after publication of the Clinical 
Study Report or as per local regulation, after which they will be destroyed. This is intended to 
allow AstraZeneca to investigate any anomalous results, or respond to regulatory authority 
questions. Samples will only be re-analysed according to the original purpose for which they 
were collected (eg PK analysis).

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A summary of PK analysis results will be reported in the Clinical Study Report (CSR).
5.3.6
Immunogenicity 
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment can be found in the separate laboratory manual provided to the centres.
After primary bioanalysis, residual immunogenicity (ADA and nAb) sample aliquots may be 
retained for the purposes of re-analysis at AstraZeneca or designee for a maximum of 5 years 
after publication of the Clinical Study Report or as per local regulations, after which they will 
be destroyed. This is intended to allow AstraZeneca to investigate any anomalous results, or 
respond to regulatory authority questions. Samples will only be re-analysed according to the 
original purpose for which they were collected (eg ADA/nAb analysis).
Anti-benralizumab antibodies 
Serum samples to measure presence of ADA will be collected according to the schedule of 
study procedures (see Table 2). On the dosing visits (Visit 4 and Visit 11), the serum will be 
collected as pre-dose.
The assessment of ADA will be determined in the serum samples using validated bioanalytical 
methods. 
Neutralizing antibodies
All ADA positive samples will be tested for neutralizing antibodies (nAb). The presence or 
absence of neutralizing ADA will be determined using a validated bioanalytical method.
5.3.7
Handling of biological samples
5.3.7.1
Labelling and shipment of biological samples
The Principal Investigator is to ensure that samples are labelled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B.
Any samples identified as Infectious Category A materials are not to be shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.3.7.2
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their lifecycle.
The Principal Investigator at each study centre is to keep full traceability of collected 
biological samples from the patients while in storage at the study centre until shipment or 
disposal (where appropriate) and is to keep documentation of receipt of arrival.

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The sample receiver is to keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and is to keep documentation of receipt of 
arrival.
AstraZeneca will maintain oversight of the entire life cycle through internal procedures, 
monitoring of study centres and auditing of external laboratory providers.
5.3.8
Patient Testing Due to Public Health Crisis
If patient testing is performed due to the public health crisis, the results may be documented 
for this study.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils 1 or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing hospitalisation
!
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent 1 of the outcomes listed above.

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Adverse Events (AEs) for malignant tumours 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 tumour event should be assessed 
and reported as a non-serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require 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.
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol (CSP).
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
All AEs, including SAEs, will be collected from the time the patient signs the informed 
consent, and assent when applicable, throughout the treatment period and including the 
follow-up period (Visit 18, Week 56).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at follow-up in the study will be followed up by the Investigator 
for as long as medically indicated, but without further recording in the CRF. AstraZeneca 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) 
at the end of the study, if judged necessary.
The requirement to follow-up AEs is not intended to delay database lock or production of the 
Clinical Study Report (CSR). These activities should proceed as planned with ongoing AEs if 
necessary.
6.3.3
Variables 
The following variables will be collected for each AE;
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity of the AE
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)

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!
Action taken with regard to IP
!
AE caused patient’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication
!
Description of AE
6.3.4
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 
intensity whereas seriousness is defined by the criteria in Section 6.2. 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 Section 6.2. 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 Section 6.2.
6.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.

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A guide to the interpretation of the causality question is found in Appendix A to the CSP.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the 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 CRF. 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.
6.3.7
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared with baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the IP.
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 
will use the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin 
value).  In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
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. 
6.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT I 3xULN AND total bilirubin I 2xULN may need to be 
reported as SAEs. Please refer to Appendix C for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
6.3.9
Symptoms of the disease under study
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. Asthma symptoms or signs, such as wheeze, cough, chest 
tightness, dyspnoea, breathlessness and phlegm, will be recorded as AEs only when:
!
The sign or symptom is serious according to definitions, see Section 6.2
!
The patient discontinues the IP due to the sign or symptom 

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!
The sign or symptom is new to the patient or not consistent with the patient’s pre-existing 
asthma history (defined as within 1 year of Visit 1) as judged by the Investigator.
After randomisation, asthma exacerbations should be recorded in the exacerbation eCRF 
(EXACA; see Section 5.1.1).  If the exacerbation fulfils any of the above criteria, the sign or 
symptom should also be recorded as an AE.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then investigators or other centre personnel will 
inform appropriate AstraZeneca representatives within 1 day, ie, immediately but no later 
than 24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other centre personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, i.e., immediately but no later than 24 h from when he or she becomes 
aware of it.
Once the investigators or other centre personnel indicate an AE is serious in the Web-based 
Data Capture (WBDC) system, an automated email alert will be sent to the designated 
AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study centre personnel is 
to report the SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study centre personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
6.5
Overdose
!
For this study, any dose of benralizumab greater than 200 mg will be considered an 
overdose.

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!
There is no specific treatment for an overdose with benralizumab.  If overdose occurs, the 
patient should be treated supportively with appropriate monitoring as necessary.
!
An overdose with associated AEs will be recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.
!
An overdose without associated symptoms will be reported on the Overdose CRF module 
only.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other centre personnel will inform appropriate AstraZeneca representatives 
within 1 day ie., immediately but no later than 24 hours from when he or she becomes aware 
of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with the SAE, standard reporting timelines apply, see Section 6.4. 
For other overdoses, reporting should be done within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately. For pregnant patients, at IPD visit, pre-BD spirometry may be skipped, at the 
discretion of the Investigator. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/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 abnormality) should be followed up and documented even if the patient 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then investigators or other centre personnel 
will inform appropriate AstraZeneca representatives within 1 day ie, immediately but no later 
than 24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
days for SAEs, (see Section 6.4) and within 30 days for all other pregnancies.

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The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the paper-based 
pregnancy outcome report is used to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Pregnancy of the patient’s partners will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should be followed up and documented for conceptions occurring 
from the date of the first administration of IP until 12 weeks after the last administration of IP. 
The investigators must obtain the consent of the subject’s partner prior to obtaining 
information on the pregnancy.
6.7
Medication error
If a medication error occurs in 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 completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 6.4) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix A. 
6.8
Device Constituent Deficiencies
In a combination drug-device IMP (e.g. APFS), the Device Constituent deficiency is an 
inadequacy of a device constituent with respect to its identity, quality, durability, reliability, 
safety, or performance. These deficiencies include malfunctions, use errors, and information 
supplied by the manufacturer. Serious Adverse Device Effect (SADE) is defined as any 
Device Constituent 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.
- For device constituent 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 device 
constituent where such action is necessary to prevent recurrence of a device constituent 
deficiency. This includes any amendment to the device constituent design to prevent
recurrence.

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- The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the device constituent deficiency as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals.
6.8.1
SADE Reporting 
NOTE: There are additional reporting obligations for device constituent 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 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 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
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
All investigational products will be manufactured in accordance with Good Manufacturing 
Practice (GMP).
Benralizumab and placebo administered in the study will be a clear to opalescent, colourless 
to yellow solution.
Table 4
Identity of investigational product
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
30mg/mL solution for 
injection in accessorized pre-
filled syringe, 1mL fill volume
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1mL fill volume
MedImmune

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7.2
Labelling
Labelling of the IP will be carried out by AstraZeneca or designee in accordance with current 
Good Manufacturing Practice (GMP) and regulatory requirements of each country 
participating in the study. The labels will be translated into local languages where applicable.
7.3
Storage
Benralizumab/placebo is to be stored at the study centre in a secured facility with limited 
access and controlled temperature. The temperature should be monitored on a daily basis and 
documented in the temperature monitoring log.
The IP must be kept in the original outer container and under conditions specified on the label 
(between 2–8°C (36–46°F), protected from the light).
In the following cases:
!
Temperature excursion upon receipt or during storage at the site
!
Damaged kit upon receipt
!
Damaged syringe/cartridge
The centre staff should not use affected IP and should immediately contact an AstraZeneca 
representative for further guidance.  Damaged IP should be documented via IWRS/IVRS 
(please refer to IWRS/IVRS manual for further details).
7.4
IP administration and treatment Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the CRF.
The IP will be administered at the study centre on treatment visits and within visit windows as 
specified in Table 2. In cases when a treatment visit cannot be scheduled within the specified 
window, the investigator should discuss with AZ Study Physician to decide whether the IP 
administration should be skipped. 
If a patient misses more than 2 consecutive or non-consecutive doses of IP at any time within
a calendar year, we strongly recommend a conversation between the investigator and the AZ
study physician to review the patient's adherence to treatment and decide on the patient's
disposition.
If an Investigator decides to skip the IP administration due to exacerbations, the above rule 
does not apply.
Before IP administration
Prior to each IP administration:

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!
Investigator/authorized delegate will assess injection site as per standards of medical care
!
For WOCBP urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 5.2.4.1)
IP administration
The IP will be administered by the Investigator/authorized delegate.  It is advised that the site 
of injection of the IP be rotated such that the patient receives IP at a different anatomical site 
at each treatment visit.  Suggested injection site rotation sequence is presented below (see 
Figure 3).  The injection site must be recorded in the source documents and the eCRF at each 
treatment visit.
Figure 3
Injection sites and rotation scheme
In the case when rotation of the injection site is not favourable for the patient and/or 
Investigator, the reason should be recorded in the source documents. The injection site of the 
IP should be recorded in the source documents and eCRF at each treatment visit.
Further details on IP administration are provided in the IP Handling Instruction. IP 
administration must be carried out in line with the Instruction.
After investigational product administration
After IP administration at the study site, the patient should be observed in case of any 
acute drug reactions in line with clinical practice .Conditions requiring investigational 
product administration rescheduling 
If any of the following should occur, the Investigator should reschedule the visit and the IP 
should not be administered until the rescheduled visit:
!
The patient has an intercurrent illness, that in the opinion of the Investigator may 
compromise the safety of the patient in the study (e.g., viral illnesses)
!
The patient is febrile (I38°C; I100.4°F) within 72 hours prior to IP administration

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7.5
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to the patient.
The monitor will account for all study drugs received at the centre, unused study drugs, and 
for appropriate destruction.  Certificates of delivery, destruction, and/or return should be 
signed.
In the case of a malfunctioning accessorized prefilled syringe (APFS), the centre should 
contact the study monitor to initiate a product complaint process according to applicable 
guidelines.
7.6
Concomitant and other treatments 
7.6.1
Concomitant medication
Information about any treatment in the 6 months prior to the date of the informed consent, and 
assent when applicable, and all the concomitant treatments given during the study, with reason 
for the treatment, will be collected by the Investigator/authorized delegate at each visit (as 
shown in Table 1 and Table 2) and recorded in the eCRF.
7.6.1.1
Background medication 
All patients are required to be treated with medium to high dose ICS-LABA for at least 6 
months prior to Visit 1, documented medium to high dose ICS-LABA (>500 mcg/day
fluticasone propionate dry powder formulation or equivalent daily) for at least 3 months prior 
to Visit 1 and during the course of the study.
The aim of this study is to establish the treatment effect of benralizumab as add-on therapy.  
Therefore the background asthma controller medications should be maintained at a stable dose 
from Visit 1 until the end of the study. If changing the ICS-LABA dose is judged as medically 
necessary by the Investigator, the justification should be discussed beforehand with the 
AstraZeneca Study Physician, documented in the source and the change in the doses should be 
reflected in the eCRF.
Background medication is not regarded as an IP, but will be provided by or reimbursed to 
AstraZeneca according to local regulations, in order to maintain appropriate oversight and 
access to this concomitant therapy.
Additional controllers that are labeled for asthma and allowed per protocol (see Section 3.1, 
criterion 6) will be provided by or reimbursed to AstraZeneca according to local regulations.

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7.6.1.2
Rescue medication 
Salbutamol, or albuterol, or levalbuterol may be used as rescue medication during the study in 
the event of a worsening of asthma symptoms. Patients, who are already on nebulized SABA 
as rescue medication, can continue their use throughout the study.
As with background ICS-LABA medication, rescue medication is not regarded as an IP, but 
will be provided by or reimbursed to AstraZeneca according to local regulations, in order to 
ensure access to essential rescue therapy.
7.6.2
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form.
7.7
Management of investigational product-related reactions
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions must be immediately 
available. Study personnel must be trained to recognize and treat anaphylaxis (Lieberman et al 
2010). Details on anaphylaxis management are provided in Appendix D.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Simpson et al 2006).  Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both, and at least 1 of the following: a) respiratory compromise; or b) reduced 
blood pressure or symptoms of end-organ dysfunction
2
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms, and/or persistent gastrointestinal symptoms
3
Reduced blood pressure after exposure
Patients will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration and should be observed after IP administration at the study site for the 
appearance of any acute drug reactions. 
In order to help understand the potential drug-relatedness of any acute reaction, a blood 
sample should be drawn as close as possible to the event for additional ADA testing (if not 
already scheduled for this visit).  Serum tryptase or other blood testing relevant to the 
diagnosis of anaphylaxis may be obtained at a local lab at the discretion of the Investigator.

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8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
!
All personnel involved with the analysis of the study will remain blinded until database 
lock 
!
Analyses will be performed by AstraZeneca or its representatives 
!
The statistical analysis plan (SAP) will be prepared prior to first patient randomised and 
any subsequent amendments will be documented, with final amendments completed prior 
to unblinding of the data 
8.2
Sample size estimate
The study will randomise patients with baseline blood eosinophil counts I 300/UL and < 
300/UL at a ratio of about 2:1. The 2:1 stratification ratio is intended as a means of enriching 
the population for patients most likely to respond to benralizumab (i.e., I300/UL), while still 
including patients below this threshold in order to help understand efficacy and safety in this 
group. The study is powered for the primary efficacy analysis of the patients with baseline 
blood eosinophils I300/UL.
The efficacy analyses will comprise both adults and adolescent patients.
For the primary endpoint annual asthma exacerbation rate, approximately 222 adults and 
adolescent patients with baseline blood eosinophil counts I300/UL per treatment arm 
(approximately 444 in total) will need to be randomised to achieve approximately 90% power 
 
 
 As stated 
previously an about 2:1 ratio will be used for patients with baseline blood eosinophil counts 
>300/UL and <300/UL. Therefore the study will also randomise approximately 111 
patients/arm (approximately 222 in total) with baseline blood eosinophil counts <300/UL. The 
<300/UL stratum will be closed for all patients, when a total of 222 adults and adolescent 
patients have been randomised in the stratum. So a total of approximately 666 adult and 
adolescent patients are expected to be randomised in the study. Among these 666 patients, at 
least 70% patients will be randomised from China. 
8.3
Definitions of analysis sets
All efficacy analyses will be performed using an Intent-to-Treat (ITT) approach based on the 
full analysis set. For consistency, demographic and baseline characteristics will be presented 
using the full analysis set. Safety objectives will be analysed based on the safety analysis set.
CCI

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8.3.1
All patients analysis set
This analysis set will comprise all patients who signed the ICF for the study and will be used 
for reporting of disposition and screening failures.
8.3.2
Full analysis set
All patients who were randomised and received any IP will be included in the full analysis set, 
irrespective of their protocol adherence and continued participation in the study. Patients will 
be analysed according to their randomised treatment, irrespective of whether or not they have 
prematurely discontinued, according to the ITT principle. Patients who withdraw consent, and 
assent when applicable, to participate in the study will be included up to the date of their study 
termination.
8.3.3
Safety analysis set
All patients who received at least 1 dose of IP will be included in the safety analysis set.  
Patients will be classified according to the treatment they actually received. A patient who has 
on 1 or several occasions received active treatment will be classified as active. All safety 
summaries and ADA data will be based on this analysis set.
8.3.4
Pharmacokinetic (PK) analysis set
All patients who received benralizumab and from whom PK blood samples are assumed not to 
be affected by factors such as protocol deviations and who had at least 1 measurable serum 
PK observation post first dose will be included in the PK analysis set. All PK summaries will 
be based on this analysis set.
8.4
Variables for analyses
8.4.1
Calculation or derivation of efficacy variables
All efficacy objectives will be evaluated for the double-blind treatment period, defined as the 
period after administration of randomised IP at Visit 4 and the conclusion of End of Treatment 
visit.
8.4.1.1
Exacerbation rate
The annual asthma exacerbation rate will be used as the primary efficacy variable.
An asthma exacerbation is defined in Section 5.1.1.
In order to calculate the number of exacerbations experienced by a patient during the 48-week 
double-blind treatment period, the following rule will be applied.
The start of an exacerbation is defined as the start date of systemic corticosteroids, or the start 
date of a temporary increase in a stable oral corticosteroid background dose, or that start date 
of hospital admission, whichever occurs earlier. The end date is defined as the last day of 
systemic corticosteroids or the last day of a temporary increase in a stable oral corticosteroid 
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primary analysis, the number of exacerbations observed for a patient during the 48-week 
double-blind treatment period will be used as response variable.
Additional systemic corticosteroid treatments, emergency room/urgent care visits requiring 
use of systemic corticosteroids, or inpatient hospitalization due to asthma occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted for as a 
new exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled.
The primary analysis will include all available data including data collected after treatment 
discontinuation. Subjects will be encouraged to continue to undergo applicable study related 
visits/procedures for the full 48-week treatment period even after premature discontinuation of 
IP. Consequently, subjects lost to follow-up and subjects who withdraw their consent/assent 
will be the only source of missing information for the primary analysis. Maximum follow-up 
time for a patient during the treatment period is approximately 48 weeks; defined as the time 
from randomisation to the date of Visit 17. For a patient lost to follow-up or withdraw 
consent/assent, follow-up time will be defined as the time from randomisation to the time 
point after which an exacerbation could not be assessed.
In the statistical analysis, the number of asthma exacerbations experienced by a patient during 
the 48-week double-blind treatment period will be used as response variable, and the 
logarithm of the patient’s corresponding follow-up time will be used as an offset in the 
analysis to adjust for patients having different exposure times during which the events occur.
For the production of summary statistics, the annual exacerbation rate per patient is calculated 
and standardized using data from the 48-week double blind treatment period according to the 
formula described below. 
Annual Exacerbation Rate=Number of Exacerbations*365.25/(Follow-up date–Visit 4 
date+1).
8.4.1.2
Proportion of patients with ?1 asthma exacerbation during 48 weeks of 
treatment
The proportion of patients with I1 asthma exacerbation during the 48 weeks of treatment will 
be a supportive variable to the primary objective.
8.4.1.3
Time to first exacerbation 
Time from randomisation to the first asthma exacerbation will also be used as a supportive 
variable to the primary objective, and is calculated as follows:
Start Date of first asthma exacerbationcDate of Randomisation+1.
The time to first asthma exacerbation for patients who do not experience an asthma 
exacerbation during the treatment period will be censored at the date of their last visit for the 
48-week double-blind treatment period, or at the time point after which an exacerbation could 
not be assessed (for lost-to-follow-up patients or withdrawn patients).

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8.4.1.4
Forced expiratory volume in 1 second 
Pre-bronchodilator FEV1 is a key secondary efficacy endpoint of this study, and the change 
from baseline to Week 48 is included in the testing strategy.
The change from baseline to each of the post-randomisation visits (post Visit 4) up to and 
including the end of 48-week double-blind treatment visit (Visit 17) will be used as secondary 
efficacy variables. The pre-bronchodilator measurement recorded at Visit 4 will be used as 
baseline FEV1. If the Visit 4 pre-bronchodilator measurement is missing, the last non-missing 
pre-bronchodilator value before Visit 4 will be used as baseline instead.
8.4.1.5
Annual rate of asthma exacerbations that are associated with an emergency 
room/urgent care visit or a hospitalization
The annual rate of asthma exacerbations that are associated with an emergency room/urgent 
care visit or a hospitalization, as determined by the investigators will be a secondary efficacy 
variable.
The number of asthma exacerbations that are associated with an emergency room/urgent care 
visit or a hospitalization experienced by a patient during the 48-week treatment period will be 
derived according to the following rule:
The number of asthma exacerbations experienced by a patient during the 48-week treatment 
period will be derived according to rule for the primary outcome variable in Section 8.4.1.1
In the statistical analysis, the number of asthma exacerbations that are associated with an 
emergency room/urgent care visit or a hospitalization experienced by a patient during the 48-
week double-blind treatment period will be used as response variable, and the logarithm of the 
patient’s corresponding follow-up time will be used as an offset in the analysis to adjust for 
patients having different exposure times during which the events occur.
Maximum follow-up time for a patient during the 48-week double-blind treatment period is 
approximately 48 weeks, and the follow-up time is derived as described in Section 8.4.1.1.
Additionally, for the production of descriptive statistics, the annualized rate of asthma-related 
emergency room/urgent care visits and hospitalizations will be calculated using the same 
methodology as the annualized rate of exacerbations described in Section 8.4.1.1.
8.4.2
Calculation or derivation of safety variable(s)
8.4.2.1
Safety variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements. The last non-missing measurement prior 
to the first dose of study treatment will serve as the baseline measurement for safety variables. 
AEs will be summarized by means of descriptive statistics and qualitative summaries.

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8.4.3
Calculation or derivation of patient reported outcome variables
8.4.3.1
Asthma Symptom Score
The outcome variable for asthma symptom score will be the change in mean asthma symptom 
score from baseline to each of the post-randomisation periods. Asthma symptom day time 
score, night time score, and total score will be calculated separately.
Total asthma symptom score is a key secondary efficacy endpoint of this study, and the 
change from baseline to Week 48 is included in the multiple testing strategy.
8.4.3.2
Asthma Control Questionnaire (ACQ-6)
The outcome variable for ACQ-6 will be the change in mean score from baseline to each of 
the post-randomisation periods.
Patients will also be categorized according to the following limits (Juniper et al 2005):
!
ACQ-6 (End of treatment – baseline) _ - 0.5 d Improvement
!
- 0.5 < ACQ-6 (End of treatment – baseline) < 0.5 d No change
!
ACQ-6 (End of treatment – baseline) I 0.5 d Deterioration.
An ACQ-6 responder will be defined as a patient who had improvement on ACQ-6, i.e., an 
ACQ-6 responder variable takes value 1 if change from baseline to end of treatment in ACQ-6 
_ - 0.5 and 0 otherwise.
Furthermore, patients will be categorized according to their ACQ-6 end of treatment score as 
follows (Juniper et al 2006):
!
ACQ-6 (End of treatment) _ 0.75 d Well controlled
!
0.75 < ACQ-6 (End of treatment) < 1.5 d Partly controlled
!
ACQ-6 (End of treatment) I 1.5 d not well controlled
8.4.3.3
St. George’s Respiratory Questionnaire (SGRQ)
The outcome variable for SGRQ will be change in total score from baseline to each of post-
randomisation periods. Change in three domain scores from baseline to each of post-
randomisation periods will be calculated separately. 
A decrease of 4 units in the SGRQ total score compared to baseline has been established as 
the criterion for minimal meaningful improvement (Jones et al 2005). SGRQ responders will 
be those with a SGRQ total score #4 unit decrease.
8.4.3.4
Electronic diary variables
Asthma PROs (ACQ-6, SGRQ), and daily metrics (rescue medication, awakenings and peak 
flow and asthma symptom scores) derived from the Asthma Daily Diary will be summarized 
as the mean for baseline and each of the post-randomisation periods.

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Biweekly (14 days) means will be calculated for daily assessments of asthma symptoms, night 
time awakenings, rescue medication usage and peak flow. Baseline will be the 14 days prior to 
randomisation and will be summarized as a mean. Post-randomisation biweekly (14 day) 
means will be calculated for each daily assessment and then summarized as group means for 
each 14-day period post-randomisation. ACQ-6 and SGRQ baseline will be the last 
observation prior to study drug administration and summarized as mean scores for each group. 
The change from baseline to each post-randomisation period will be used as secondary 
efficacy variable.
Rescue medication usage is captured in the daily diary as the number of inhaler puffs and the 
number of times a nebulizer is used. Rescue medication usage will be summarized as the 
number of puffs with 1 instance of nebulizer use converted to 2 puffs.
8.4.4
Calculation or derivation of pharmacokinetic variables
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (pre-dose) concentrations, Ctrough. 
8.4.5
Calculation or derivation of immunogenicity variables
ADA result from each sample will be reported as either positive or negative. If the sample is 
positive, the ADA titer will be reported as well. In addition, the presence of neutralizing 
antibodies (nAb) will be tested in all ADA positive samples and the nAb results will be 
reported as positive or negative.
8.5
Methods for statistical analyses
The analysis of the primary and secondary endpoints will include all data captured during the 
48-week treatment period regardless of whether study treatment was prematurely 
discontinued, or delayed, and/or irrespective of protocol adherence.  
To control the type I error rate, a testing strategy will be applied to the primary (annual asthma 
exacerbation rate) and 2 key secondary endpoints (the change in FEV1 and asthma symptom 
score from baseline to Week 48, respectively) for patients with baseline blood eosinophil 
counts I300/UL for benralizumab. The testing strategy will be according to the following gate 
keeping procedure:
Step 1: Perform the test of annual asthma exacerbation rate (benralizumab vs. placebo) at the 
family wise error rate (FWER) of 0.05.  If the p-value is less than 0.05, then proceed to Step 2; 
otherwise no null hypothesis is rejected.
Step 2: Test the 2 key secondary endpoints at the FWER of 0.05 using a Holm Procedure 
(Holm 1979).
Demography and baseline characteristics will be summarized by treatment group for the full 
analysis set. In the event that there are major differences between the full analysis set and 
safety analysis set, these summaries will also be repeated for the safety analysis set.

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Additional analyses assessing the impact of Cases of Civil Crisis, Natural Disaster, or Public 
Health Crisis (e.g. SARS-CoV-2) may be included in the SAP.
8.5.1
Analysis of the primary variable (s)
The primary efficacy variable is the annual asthma exacerbation rate and the primary analysis 
is to compare the annual asthma exacerbation rate of benralizumab group with placebo group 
in patients with baseline blood eosinophil counts I300/UL.
The null hypothesis is that the exacerbation rate on benralizumab is equal to the exacerbation 
rate on placebo.  The alternative hypothesis is that the exacerbation rate on benralizumab is 
not equal to the exacerbation rate on placebo, ie,
H0: Rate ratio (benralizumab vs. Placebo) =1
Ha: Rate ratio (benralizumab vs. Placebo) :1
Exacerbation rate in the benralizumab group will be compared to exacerbation rate in the 
placebo group using a negative binomial model. The response variable in the model will be 
the number of asthma exacerbations over the 48-week treatment period. The model will 
include covariates of treatment group, region (China/non-China), number of exacerbations in 
the year before the study, and the use of maintenance oral corticosteroids (yes/no). The 
logarithm of the follow-up time will be used as an offset variable in the model.
The estimated treatment effect (i.e., the rate ratio of benralizumab versus placebo), 
corresponding 95% confidence interval (CI), and two-sided p-value for the rate ratio will be 
presented. In addition, the exacerbation rate and the corresponding 95% CI within each 
treatment group will be presented.
In addition, the exacerbation rate will also be summarized in patients with baseline blood 
eosinophil counts <300/UL, <150/UL, 150-299/UL, 300-449/UL and >450/UL separately. 
The individual exacerbation criteria (ER visit due to asthma that required systemic 
corticosteroids, hospitalization due to asthma, or use of systemic corticosteroids) will also be 
summarized.
8.5.2
Analysis of the secondary variable(s)
8.5.2.1
Analysis methods for secondary efficacy variables
Key secondary efficacy endpoints in this study are:
!
Change from baseline in pre-bronchodilator FEV1 at Week 48
!
Change from baseline in asthma symptom total score at Week 48
Other secondary efficacy endpoints include 
!
Proportion of patients with I1 asthma exacerbation
!
Time to the first asthma exacerbation 

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!
Annual rate of asthma exacerbations that are associated with an emergency room/urgent 
care visit or a hospitalization
!
Change from baseline in total rescue medication use (average puffs/day)
!
Change from baseline in morning and evening PEF at Week 48
!
Change from baseline in asthma symptom day time/night time scores at Week 48
!
Change from baseline in number of nights with awakening due to asthma and requiring 
rescue medication
!
ACQ-6
!
SGRQ
All the secondary efficacy endpoints will be analysed in patients with baseline blood 
eosinophil counts I 300/UL.  In addition, the 2 key secondary efficacy endpoints will be 
analysed in patients with baseline blood eosinophil counts < 150/UL, < 300/UL, 150-299/UL, 
300-449/UL and > 450/UL separately.
Change from baseline in pre-bronchodilator FEV1 at Week 48 will be compared between the 
benralizumab group and placebo using a repeated measures analysis on patients with a 
baseline pre-bronchodilator FEV1 and at least 1 post-randomisation pre-bronchodilator FEV1
in the full analysis set. The dependent variable will be the change from baseline in pre-
bronchodilator FEV1 at post-baseline protocol-specified visits (up to the EOT Visit). 
Treatment group will be fitted as the explanatory variable, and region (China/non-China), 
baseline pre-bronchodilator FEV1, visit, the interaction term of visit and treatment, and the 
use of maintenance oral corticosteroids (yes/no) will be fitted as covariates.  Visit will be 
fitted as a categorical variable, and the variance-covariance matrix will be assumed to be 
unstructured. If the procedure does not converge then a compound symmetric variance-
covariance matrix will be used instead. The model is:
Change in FEV1=Treatment group+baseline FEV1+region+maintenance oral 
corticosteroids+visit+treatment*visit
Change from baseline in asthma symptom total score; day time score, and night time score at 
Week 48 will be analysed separately using a similar model as the above model for change 
from baseline in pre-bronchodilator FEV1.
The proportion of patients with I 1 asthma exacerbation during the 48 weeks of treatment will 
be addressed as a supportive variable to the primary objective. The proportion in the 
benralizumab group will be compared with the proportion in the placebo group using a 
Cochran–Mantel–Haenszel test controlling for region (China/non-China), number of 
exacerbations in the year before the study, and the use of maintenance oral corticosteroids 
(yes/no).

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Time to first asthma exacerbation will be analysed as another supportive efficacy variable to 
the primary objective to explore the extent to which treatment with benralizumab delays the 
time to first exacerbation compared with placebo. A Cox proportional hazard model will be 
fitted to data with the covariates of treatment, region (China/non-China), number of 
exacerbations in the year before the study, and the use of maintenance oral corticosteroids 
(yes/no).
Annual rate of asthma exacerbations that are associated with an emergency room/urgent care 
visit or a hospitalization will be analysed using a similar negative binomial model as outlined 
for the primary efficacy variable in Section 8.5.1.
Change from baseline in total rescue medication use (average puffs/days) and number of 
nights with awakening due to asthma and requiring rescue medication will be analysed using a 
similar model as for change from baseline in pre-BD FEV1.
Change from baseline in morning and evening PEF at Week 48 will be analysed separately 
using similar models as the model for change from baseline in pre-BD FEV1. 
The ACQ-6 will be analysed in terms of change from baseline to end of treatment, change 
from baseline to each of post-randomisation periods, responder status at EOT (i.e. change 
from baseline to EOT _ -0.5), and asthma symptom control status at EOT (see Section 8.4.3.2
for categorization). 
The SGRQ will be analysed in terms of change from baseline to end of treatment, change 
from baseline to each of post-randomisation periods in total score and three domain scores, 
and responders as defined by those with a SGRQ total score #4 unit decrease from baseline at 
EOT.
Change in mean score from baseline for ACQ-6 and change in total score from baseline for 
SGRQ (including the domain scores) will be analysed using a similar model as for change 
from baseline in pre-BD FEV1.
Responder variables for ACQ-6 (yes/no) and SGRQ (yes/no) will be analysed using a logistic 
regression model with covariates of treatment, region (China/non-China), baseline value, and 
the use of maintenance oral corticosteroids (yes/no).
8.5.2.2
Analysis methods for safety variables
AEs will be summarized by means of counts summaries by study period (treatment period and 
follow-up period). AEs will be listed for each patient and summarized by System Organ Class 
(SOC) and Preferred Term (PT) assigned to the event by Medical Dictionary for Regulatory 
Activities (MedDRA). Laboratory safety variables will be summarized using standard 

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summary statistics and plots as appropriate. Other safety variables will be summarized as 
appropriate. Further details will be provided in the SAP.
Laboratory data for haematology and clinical chemistry will be summarized. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Central laboratory reference ranges will be used for the identification of 
abnormalities, and a shift table will be produced for each laboratory parameter to display low, 
normal, high, and missing values. Shifts from normal to abnormal between baseline and post-
baseline will be evaluated for urinalysis. Changes in vital signs will be examined at each visit 
and at endpoint. Baseline to maximum post-baseline and baseline to minimum post-baseline 
value shift tables will be generated, as applicable for each vital signs parameter. A shift table 
for ECG will be produced to display the Investigator assessment of normal, abnormal – not 
clinically significant, abnormal – clinically significant and not done between baseline and end 
of study. No separate summaries of physical examination findings will be produced since 
physical examination results will be presented in Medical History and AE summaries.
8.5.2.3
Analysis methods for pharmacokinetic variables
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development.
Benralizumab serum concentrations will be summarized using descriptive statistics by visit. 
Impact of ADA on PK will also be assessed. 
The population PK analysis will be presented separately from the main clinical study report 
(CSR).
8.5.2.4
Analysis method for immunogenicity variables
Anti-drug antibodies (ADA) to benralizumab will be summarized using descriptive statistics 
by visit. ADA titers-time profiles of benralizumab by treatment group will be generated. The 
impact of ADA on PK and eosinophil level will be assessed. The potential association of 
ADA with safety and efficacy will be evaluated. 
8.5.3
Subgroup analysis 
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
variable, subgroup analyses and statistical modeling including testing for interaction between 
treatment and covariates will be performed in patients with baseline blood eosinophil counts 
I300/UL for the following factors: Oral corticosteroids (OCS) use at baseline (yes, no), 
gender, age (<18, 18 - <65, and I65 years), region (China/non-China), country, BMI (<35, 
>35 kg/m2), the number of exacerbations during the previous year (2, >3 exacerbations), the 
number of exacerbations during medium-high ICS/LABA treatment prior to study enrolment 
(2, >3  exacerbations), ICS dose at study enrolment (medium, high) and nasal polyps (yes, 
no). Data will be analysed by negative binomial regression similar to the primary analysis and 
the same output will be presented for each subgroup as for the primary analysis. For the 

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statistical modeling including interaction effects, the estimate of the interaction effects will be 
presented together with the corresponding p-value. These analyses are to be considered as 
exploratory and will be performed on the full analysis set.
8.5.4
Sensitivity analysis 
Sensitivity analyses for the primary endpoint and the key secondary endpoints based on 
different missing data mechanism assumptions including those expected to be more 
conservative such as missing not at random will be used to explore the robustness of any 
treatment effect, including multiple imputation approaches. Full details of the sensitivity 
analyses will be pre-specified in SAP and documented prior to database lock of the study.
8.5.5
Interim analysis
There is no interim analysis planned for this study. The study will remain blinded until 
database lock.  
8.6
Independent adjudication committee for major adverse cardiac 
events and malignancies
An independent adjudication committee will be constituted to provide an independent, 
external, systematic, and unbiased assessment of blinded data to confirm the diagnosis of: 1) 
Investigator-reported non-fatal myocardial infarction, unstable angina, non-fatal stroke 
(hemorrhagic, ischemic, embolic), as well as all deaths and 2) Investigator-reported 
malignancies during the study. The committee will operate in accordance with an 
Adjudication Committee Charter/Manual of Operations, which will also provide detail on 
specific information to enable a more robust review through adjudication process. 
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and WBDC, 
IWRS/IVRS, ePROs, and other systems to be utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).

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9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study 
centre, including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
!
Perform source data verification (a comparison of the data in the CRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent, and assent when applicable of participating 
patients. This will require direct access to all original records for each patient (eg, clinic 
charts)
!
Ensure withdrawal of informed consent, and assent when applicable to the use of the 
patient’s biological samples is reported and biological samples are identified and disposed 
of/destroyed accordingly, and the action is documented, and reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Please refer to the Clinical Study Agreement (CSA) for location of source data.
9.2.2
Recording of data 
A Web-based Data Capture (WBDC) system will be used for data collection and query 
handling.  Trained study centre personnel will be responsible for entering data on the 
observations, tests, and assessments specified in the CSP into the WBDC system and 
according to eCRF instructions.  The eCRF instructions will also guide the study centre in 
performing data entry.
Data entered in the WBDC system will be immediately saved to a central database and 
changes tracked to provide an audit trail.  The data will then be source data verified, 
reviewed/queried and updated as needed.  The data will be validated as defined in the Data 
Management Documentation.  The Investigator will ensure that data are recorded on the 
eCRFs as specified in the CSP and in accordance with the instructions provided. 

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The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the CSA.  The Investigator will sign 
the completed eCRFs.  A copy of the completed eCRFs will be archived at the study centre.
9.2.3
Study agreements
The Principal Investigator at each study centre should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of 
any inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.4
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study‘.
AstraZeneca 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. The study may be stopped if, in the judgment 
of AstraZeneca, trial subjects are placed at undue risk because of clinically significant 
findings that:
meet individual stopping criteria or are otherwise considered significant 
are assessed as causally related to study drug,
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the subjects’ interests
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.

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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by 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 Good Clinical Practice (GCP) guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study intervention development
9.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Centre staff or other 
party, according to the Data Management Plan.
The data collected through third party sources will be obtained and reconciled against study 
data.
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications will be 
classified according to the WHO Drug Dictionary.  All coding will be performed by the 
Medical Coding Team at the AstraZeneca Data Management Centre or other party.
The Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  Data queries will be raised for inconsistent, impossible or missing data.  All entries 
to the study database will be available in an audit trail. The Investigator will ensure that data 
are recorded on the electronic Case Report Forms as specified in the study protocol and in 
accordance with the instructions provided.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
The Investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study Agreement.  
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked. A copy 
of the completed electronic Case Report Forms will be archived at the study centre.

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Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory (ies) internal or 
external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent/Assent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the Informed Consent/Assent Form and any other written information and/or materials to be 
provided to the patients.  The Investigator will ensure the distribution of these documents to 
the applicable Ethics Committee, and to the study centre staff.
The opinion of the Ethics Committee should be given in writing.  The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. 

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The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent/Assent Form that are 
needed to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent/Assent Form, is approved by the national regulatory 
authority or a notification to the national regulatory authority is done, according to local 
regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the IP.  AstraZeneca will provide this information to the principal Investigator so that 
he/she can meet these reporting requirements.
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.
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.

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10.4
Informed consent/assent
The Principal Investigator(s) at each study centre will:
!
Ensure each patient, parent or legal guardian is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study (before any 
study procedures are performed) as per local requirements.  The Informed Consent/Assent 
Form needs to be adjusted as per local requirements.
!
Ensure each patient, parent or legal guardian is notified that they are free to discontinue 
from the study at any time.
!
Ensure that each patient, parent or legal guardian is given the opportunity to ask questions 
and allowed time to consider the information provided.
!
Ensure each patient, parent or legal guardian provides signed and dated Informed 
Consent/Assent Form before conducting any procedure specifically for the study. Local 
regulations are to be followed in determining the assent/consent requirements for children 
of different age groups.
!
Ensure the original, signed Informed Consent/Assent Form(s) is/are stored in the 
Investigator’s Study File and kept for a period that is complaint with GCP/local 
regulatory requirements, whichever is longer.
!
Ensure a copy of the signed Informed Consent/Assent Form is given to the patient.
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the Informed Consent/Assent Form that is approved by an Ethics Committee EC/IRB.
10.5
Changes to the protocol and informed consent form/assent form
Study procedures will not be changed without the mutual agreement of the international co-
ordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol is to be approved by the relevant Ethics 
Committee and if applicable, also the national regulatory authority approval, before 
implementation.  Local requirements are to be followed for revised protocols.
AstraZeneca will distribute any new versions of the protocol to each Principal Investigator(s).  
For distribution to Ethics Committee see Section 10.3.
If a change to a Clinical Study Protocol requires a change to a study centre’s Informed 
Consent Form, AstraZeneca and the study centre’s Ethics Committee are to approve the 
revised Informed Consent Form before the revised form is used. 

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If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the study centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency or other body about an inspection or an audit at the study 
centre.
11.
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the World Allergy Organization. Allergy. 2008;63(8):1061-70.
Kerstjens et al 2012
Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in 
asthma poorly controlled with standard combination therapy. N Engl J Med. 2012 Sep 
27;367(13):1198-207.
Kolbeck et al 2012
Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM. et al. MEDI-
563, a humanized anti–IL-5 receptor a mAb with enhanced antibody-dependent cell-mediated 
cytotoxicity function. J Allergy Clin Immuno. 2010, Jun;125(6):1344-53.
Lieberman et al 2010
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM,Bernstein DI, et al. The 
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Masoli M, Holt S, Weatherall M, Beasley R. The dose-response relationship of inhaled 
corticosteroids in asthma. Curr Allergy Asthma Rep. 2004 Mar;4(2):144-8.
Miller et al 2005
Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. General 
considerations for lung function Testing. Eur Respir J 2005;26(1):153-61.
Molfino et al 2011
Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale 
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Molfino NA, Nowak R, Silverman RA, Rowe BH, Smithline H, Khan F. et al Reduction in the 
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A2753.
NAEPP 2007
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3:Guidelines for the Diagnosis and Management of Asthma;Available: 
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12.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Additional Safety Information
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE EVENT 
(SAE)
Life threatening
‘Life-threatening’ means that the patient 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 patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient or may require 
medical intervention to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:
!
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 (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse.

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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 patient 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 aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship?
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that 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.

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Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 
occurred
was identified and intercepted before the participant received the drug
did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
Drug name confusion
Dispensing error e.g., 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 e.g., tablet dissolved in water when it should be taken as a solid 
tablet 
Drug not stored as instructed e.g., kept in the fridge when it should be at room temperature 
Wrong participant received the medication (excluding IVRS/IWRS errors)
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
Participant accidentally missed drug dose(s) e.g., 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.

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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are e.g., Ebola, Lassa fever 
virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

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Appendix C
Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin - Hy’s Law
Introduction
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study (FDA 2009).
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) I3x Upper Limit of 
Normal (ULN) and Total Bilirubin (TBL) I2xULN at any point during the study irrespective 
of an increase in Alkaline Phosphatase (ALP).  The elevations do not have to occur at the 
same time or within a specified time frame.
Hy’s Law (HL)
AST or ALT I3x ULN and TBL I2xULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases, e.g., elevated ALP indicating cholestasis, viral 
hepatitis, another drug.  The elevations do not have to occur at the same time or within a 
specified time frame.
Identification of potential hy’s law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT I3xULN
!
AST I3xULN
!
TBL I2xULN

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When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Definitions of this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including 
both central and local laboratory results)
Follow-up
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
Potential Hy’s Law criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician
!
Complete the three Liver CRF Modules as information becomes available 

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!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
Review and Assessment of potential hy’s law cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other patient matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
-  Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
-  The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
-  As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above

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!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review
Actions required when potential Hy’s law criteria are met before and after starting 
study treatment 
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment. 
At the first on study treatment occurrence of PHL criteria being, even if there has been no 
significant change the patient’s condition2 compared with pre-study treatment visits, the 
Investigator will:
!
Notify the AstraZeneca representative who will inform the central Study Team. 
!
Follow the subsequent process described is Potential Hy’s Law criteria met of this 
Appendix.
Actions required for repeat episodes of potential hy’s law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease or did the patient meet PHL criteria prior 
to starting study treatment and at their first on study treatment visit as described in 
Actions required when potential Hy’s law criteria are met before and after starting 
study treatment?
If No: follow the process described in Potential Hy’s Law criteria met of this Appendix
                                               
2 A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms.  The determination of whether there has been a significant change will 
be at the discretion of the Investigator; this may be in consultation with the Study Physician if there is any 
uncertainty.

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If Yes:
Determine if there has been a significant change in the patient’s condition#3 compared with 
when PHL criteria were previously met
!
If there is no significant change no action is required
!
If there is a significant change follow the process described in Potential Hy’s Law 
criteria met of this Appendix
                                               
3 A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or a clinically 
relevant change in associated symptoms.  The determination of whether there has been a significant change will 
be at the discretion of the Investigator; this may be in consultation with the Study Physician if there is any 
uncertainty.

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Appendix D
Anaphylaxis: definition, signs, symptoms and management
Introduction
As with any antibody, allergic reactions to dose administration are possible.  The World 
Health Organization (WHO) has categorized anaphylaxis into 2 subgroups, which are 
clinically indistinguishable: immunologic [IgE-mediated and non-IgE-mediated (e.g., IgG and 
immune complex mediated) and nonimmunologic (Kemp et al 2008).  The clinical criteria for 
defining anaphylaxis for this study are listed in Clinical Criteria for Defining Anaphylaxis and 
Immune Complex Disease.  A guide to the signs and symptoms and management of acute 
anaphylaxis is provided in Signs and Symptoms and Management of Acute Anaphylaxis.  
Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical 
equipment to treat anaphylactic reactions should be available at study sites, and study 
personnel should be trained to recognise and treat anaphylaxis according to local guidelines.
If an anaphylactic reaction occurs, a blood sample should be drawn from the patient as soon as 
possible after the event, at 90 minutes±30 minutes after the event, and at discharge for 
analysis of serum tryptase at a local laboratory. Other blood testing relevant to the diagnosis 
of anaphylaxis may be obtained at a local lab at the discretion of the Investigator.
Clinical Criteria for Defining Anaphylaxis and Immune Complex Disease
Anaphylaxis
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
(a)
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(b)
Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence).
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
(a)
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b)
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).

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(c)
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence).
(d)
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting).
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease 
from that patient’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of antigen-
antibody or antigen-antibody-complement complexes on cell surfaces, with subsequent 
involvement of breakdown products of complement, platelets, and polymorphonuclear 
leukocytes, and development of vasculitis; serum sickness and nephritis is common.
Signs and Symptoms and Management of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur: 
!
Diffuse erythema
!
Pruritus
!
Urticaria and/or angioedema
!
Bronchospasm
!
Laryngeal edema
!
Hypotension
!
Cardiac arrhythmias
!
Feeling of impending doom
!
Unconsciousness
!
Shock
Other earlier or concomitant signs and symptoms can include:
!
Itchy nose, eyes, pharynx, genitalia, palms, and soles
!
Rhinorrhea
!
Change in voice
!
Metallic taste
!
Nausea, vomiting, diarrhea, abdominal cramps and bloating
!
Lightheadedness
!
Headache
!
Uterine cramps
!
Generalized warmth

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Management of Acute Anaphylaxis
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, 
as necessary, depending on the presenting signs and symptoms of anaphylaxis, to 
control signs and symptoms and prevent progression to more severe symptoms such 
as respiratory distress, hypotension, shock and unconsciousness.
Possibly appropriate, subsequent measures depending on response to epinephrine
1.
Place patient in recumbent position and elevate lower extremities.
2.
Establish and maintain airway.
3.
Administer oxygen.
4.
Establish venous access.
5.
Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
1.
Consider epinephrine infusion.
2.
Consider H1 and H2 antihistamines.
3.
Consider nebulized T2 agonist [e.g., albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
4.
Consider systemic corticosteroids.
5.
Consider vasopressor (e.g. dopamine).
6.
Consider glucagon for patient taking b-blocker.
7.
Consider atropine for symptomatic bradycardia.
8.
Consider transportation to an emergency department or an intensive care facility.
9.
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary.

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Appendix E
Background Therapy Equivalence Table
Estimated daily dosage for inhaled corticosteroids 
Asthma Therapy 
Total Daily Dose (Sg/day)
Inhaled Corticosteroid
Medium
High
Beclomethasone dipropionate (CFC)
>500 - 1000
>1000 - 2000
Beclomethasone dipropionate (HFA)
>240 - 480
>480
Beclomethasone dipropionate (Fostair)
>200 - 400
>400 - 800
Budesonide 
>400 to 800
>800 - 1600
Budesonide, if as delivered dose (e.g. 
Symbicort)
>320 to <640
>640 - 1280
Ciclesonide 
>160 - 320
>320 - 1280
Flunisolide 
>1000 - 2000
>2000
Fluticasone propionate (DPI)
>250 - 500
>500 - 1000
Fluticasone propionate (HFA)
>250 - 500 
>500
Fluticasone furoate (DPI)
NA
200
Mometasone furoate 
>220-440
>440
Triamcinolone acetonide 
>1000 - 2000
>2000
Note: Categories of “medium” and “high” doses are based on published information and available studies (at the 
time of GINA 2018 publication), including direct comparisons where available. Doses may be country-specific 
depending on labelling requirements. For new preparations, manufacturer’s information should be reviewed 
carefully; products containing the same molecule may not be clinical equivalent (GINA 2018).

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Appendix F
Restricted and prohibited medications
Asthma medication restrictions
Table 5
Asthma medication restrictions
Medication
Prohibited/
restricted
Details
Maintenance of asthma 
controller medications (ICS-
LABA)
Restricted
Changes in dose and regimen should not be 
done from visit 1 and throughout the study 
(unless there is a medical need as judged by 
the Investigator and discussed beforehand with 
AstraZeneca Study Physician)
Usual ICS-LABA should not be taken prior to 
scheduled spirometry, ECG and home PEF 
assessments (to be administered once 
assessments are completed)
Short acting beta2-agonists
(SABA)
Restricted
Regular scheduled use in the absence of any 
asthma symptoms and/or planned exercise is 
discouraged from Visit 1 throughout the study.
Rescue use of SABA administered via 
nebulisation is allowed.
SABA should not be used within 6 hours prior 
to scheduled spirometry, ECG and home lung 
function assessments.
Additional Maintenance 
Controllers (e.g. LTRAs, 
tiotropium, cromone, 
theophylline and oral 
corticosteroids)
Restricted
Have been used for at least 1 month prior to 
Visit 1; stable dose during the treatment 
period.
Usual controller should not be taken prior to 
scheduled spirometry, ECG and home PEF 
assessments (to be administered once 
assessments are completed).
Short acting anticholinergics 
(e.g. ipratropium)
Restricted
Not allowed from Visit 1 and throughout the 
study as a rescue treatment for worsening 
asthma symptoms outside of managing an 
asthma exacerbation event. 
May be used for managing an asthma 
exacerbation event.
Long-acting beta-agonists as 
a reliever (e.g. Symbicort 
Prohibited
Not allowed from Visit 1 and throughout the 
study duration

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Maintenance and Reliever 
Treatment)
Five- lipoxygenase inhibitors 
(e.g. Zileuton)
Prohibited
Not allowed 30 days prior to Visit 1; during 
treatment period
Other medication restrictions. Usage of the following restricted medications might be 
acceptable for AE treatment after discussion with AstraZeneca Study Physician.
Table 6
Other medication restrictions
Medication
Prohibited/restricted
Details
Live Attenuated Vaccines
Prohibited
Not allowed 30 days prior to
randomisation; during treatment
period, and 12 weeks after the Last 
Dose of the investigational product
Inactive/killed vaccinations
(e.g. inactive influenza)
Restricted
Allowed provided they are not
administered within 1 week
before/after any IP administration.
Any immunomodulators or
Immunosuppressives 
Prohibited
Not allowed within 3 months or 5
Half Lives (whichever is longer)
prior to
the date informed consent is 
obtained; during treatment period; 
3 Months after
Last Dose
Any immunomodulators or
immunosuppressives –
topical
Restricted
Topical administration of
immunosuppressive medication 
may
be allowed at the discretion of the
Investigator after discussion with 
the
AstraZeneca Study Physician
Blood products or
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to date 
of ICF; during treatment period.
Any marketed (e.g.
omalizumab) or
investigational biologic
treatment
Prohibited
Not allowed 4 months or 5 half-
lives
(whichever is longer) prior to Visit 
1;
during treatment period; 12 weeks 
after
the last dose of the investigational
product

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Other investigational
Products (including
investigational use of an
approved drug)
Prohibited
Not allowed 30 Days or 5 half -
lives
(whichever is longer) prior to 
randomisation;
during treatment period; and 12 
weeks after the last dose of the 
investigational product 
Allergen Immunotherapy
Restricted
Allowed if on stable therapy, or 
stable seasonal therapy, for at
least 30 days prior to date of ICF; 
Immunotherapy injections must be 
separated from IP injections by at 
least 7 calendar days
Herbal remedies with 
bronchiectasic effect
Prohibited
Not allowed 30 days prior to Visit
1; and through out study period
Roflumilast
Prohibited
Not allowed 30 days prior to Visit
1; during treatment period
Non-selective oral or 
ophthalmic T-
adrenergic antagonist (e.g.
propranolol)
Prohibited
Patients currently using any non-
selective oral or
ophthalmic T-adrenergic antagonist 
at
the time of Visit 1 are not eligible 
for the study.
Not allowed during treatment 
period.
Medications not currently 
licensed for use in the 
treatment of asthma and not 
part of current standard of 
care
Prohibited
Not allowed within 30 days prior to 
randomisation; throughout the 
duration of the study

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Appendix G
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of 
or a combination of civil crisis, natural disaster, or public health crisis (eg, during 
quarantines and resulting site closures, regional travel restrictions and considerations if site 
personnel or study patients become infected with SARS-CoV-2 or similar pandemic 
infection) during which patients 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 . 
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
patient’s safety. If in doubt, please contact the AZ Study Physician.
G 1 Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments 
may be necessary, eg, remote visits. 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 G 2 to G 6. Local and regional regulations and/or 
guidelines regarding reconsent of study patients should be checked and followed. 
Reconsent may be verbal if allowed by local and regional guidelines (note, in the case of 
verbal reconsent the ICF should be signed at the patient’s next contact with the study site). 
Visiting the study sites for the sole purpose of obtaining reconsent should be avoided. 
G 2 Rescreening of Patients To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of 
a patient and either enrolment into the study or commencing of dosing with IP. If this 
delay is outside the screening window specified in Section 4 Table 1, the patient will need 
to be rescreened to reconfirm eligibility before commencing study procedures. This will 
provide another opportunity to re-screen a patient in addition to that detailed in Section 
4.1.3. The procedures detailed in Section 3.1 and 3.2 must be undertaken to confirm 

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eligibility using the same randomization number as for the patient.
G 3 Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service may visit the patients home / or other 
remote location as per local Standard Operating Procedure (SOPs), as applicable. Supplies 
will be provided for a safe and efficient visit. The qualified HCP will be expected to 
collect information per the clinical study protocol (CSP). 
G 4 Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
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 patients will allow adverse events, concomitant medication, and other 
information including efficacy data where relevant to be collected according to study 
requirements to be reported and documented. 
G 5 At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local 
regulation/guidance, or by the patient or his/her caregiver. The option of at-home or 
remote location IP administration ensures patients safety in cases of a pandemic where 
patients may be at increased risk by traveling to the site/clinic. This will also minimize 
interruption of IP administration during other study disruptions, eg, site closures due to 
natural disaster. 
G 5.1 At-home or Remote Location IP Administration by a Qualified HCP or TPV Service
A qualified HCP from the study site or TPV service may administer the IP at the patient’s 
home or other remote location according to the CSP. All necessary supplies and 
instructions for administration and documentation of IP administration will be provided. 
Additional information related to the visit can be obtained via a telemedicine or home visit.
G 5.2 At-home or Remote Location IP Administration by the Patient or His/Her Caregiver
Prior to at-home or remote location IP administration the investigator must assess the 
patient or his/her caregiver to determine whether they are appropriate for at-home or 

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remote location administration of IP. Once the patient 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 or home / remote visit.
G 6 Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the 
qualified HCP from the study site or TPV service in the source documents, or by the 
patient themselves.

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! In Protocol Synopsis, Section 2.3, removing the “Physical Examination” as one of 
the safety objectives, because no Physical Examination results will be collected in 
eCRF. Clinically significant changes of physician examination would be reported as 
adverse event. 
! In Section 1.1.2, Added results from global pivotal studies (Bleecker et al 2016, 
FitzGerald et al). “……In the pivotal studies, compared with placebo, benralizumab 
30 mg administered subcutaneously (benralizumab 30 mg every 4 weeks for the first 
3 doses and then every 8 weeks thereafter) significantly reduced the annual asthma 
exacerbation rate, improved asthma symptom and lung function (prebronchodilator 
FEV1). The purpose of this trial is to confirm the efficacy and safety of benralizumab 
administration in asthma patients who are otherwise uncontrolled on current standard 
of care therapy.  The question of the baseline blood eosinophil level that predictably 
ensures the clinical benefit in patients will also be addressed in the study by inclusion 
of patients with blood eosinophil counts I300/UL and <300/UL.”.
! In Section 3.1, Inclusion criteria 8, to add restriction on the asthma exacerbation 
documentation, adding sentence of “at least 1 of the 2 exacerbations should occur 
during the treatment of medium-to-high dose ICS-LABA”.
! In Section 3.1, Inclusion criteria 13, for sentence “At least 70% compliance with 
usual asthma controller ICS-LABA during over the 14 days prior to randomisation 
based on Asthma Daily Diary.”, using “during over the 14 days prior to 
randomisation” replace the original ‘during run-in period (from Visit 2 to Visit 4)’ 
because the run-in period is now minimal 4 weeks instead of original 2 weeks.
! In Section 3.1, Inclusion criteria 14, removing “Minimum 80% compliance with 
ePRO completion - 80% compliance defined as completing Asthma Daily Diary for 
any 8 mornings and any 8 evenings of the last 10 days of the run-in period”, and
replace with “At least 70% compliance with ePRO completion - At least 70% 
compliance defined as completing Asthma Daily Diary for any 10 complete days (i.e.,  
consecutive evening and morning, for example, Day -14 evening + Day -13 morning) 
of the last 14 days of the run-in period.” The updated approach will be consistent with 
the post-baseline evaluation.
! In Section 3.2, combine exclusion criteria #19 and #24 for simplicity. Revised as 
“Previously randomised in any benralizumab (MEDI-563) study, including the 
present study.”.
! In Section 3.2, add the exclusion criterion #30, “Received bronchial thermoplasty 
(BT) as treatment of asthma within 12 months prior to Visit 1”, because BT is 
common in several sites in China and would impact the efficacy assessment.
! In Section 3.2, for exclusion criteria #18, add “Use of any off-label medications, for 
example medications locally approved for Chronic Obstructive Pulmonary Disease 
but not for asthma, are also not allowed from 30 days prior to randomisation and 
throughout the study.” following changes from global pivotal study SIROCCO, to 
further clarify this criterion. 

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! In Section 3.6, removing below paragraph due to operational complexity.  “Handling
of labs obtained during the treatment period but ordered outside of the clinical trial.
Centre staff who are directly involved in the patient’s management should remain 
blinded to any eosinophil, basophil and monocyte results included as part of outside 
lab reports.  To help ensure this, each investigational centre will designate an 
individual (eg, administrator or another ancillary person) not directly involved in 
patient management, to receive and blind any eosinophil, basophil, and monocyte 
results prior to the report being handed over to the centre staff involved in the 
patient’s management and prior to filing as a source document.  Similarly, eosinophil 
and basophil results must be redacted from all communications with the Sponsor.”. 
! In Section 3.6, removing below paragraph to the 1st bullet in the section: "In cases 
where the Investigator requires an eosinophil, basophil or monocyte count for 
managing safety issues he/she may order these tests.  AstraZeneca should be notified 
of all such cases.”.
! In Section 3.8.1, delete the paragraph of “Patients on theophylline should have blood 
concentration levels checked, assessed and documented prior to randomisation.  The 
theophylline level must not exceed the upper limit of the therapeutic range.”, in 
Section 3.8.2, delete the paragraph of bullet (d), “When enrolling a patient who is on 
theophylline, digoxin or other drugs with a narrow therapeutic range, the Investigator 
should ensure the levels of each of these medications must not exceed the upper limit 
of therapeutic range. The Investigator will also be responsible for ensuring that these 
levels are regularly checked, assessed and documented as per local practice (see Table 
1)”, and in Section 4, Table 1, removing “blood concentration” in Enrolment visit, 
and in Section 5.2.4, Table 3, removing “serum concentration”. The above changes 
are to improve the feasibility and simplify the procedure. Instead, the Investigator will 
regularly monitor vital signs, ECG, and AE to assess subjects’ safety.
! In Section 4, Table 1, to keep consistence with section 4.1.2, “a All visits are to be 
scheduled from the date of randomisation but not from the date of previous visit.”, are 
replaced with “a Visit 2 may take place as soon as medication restrictions prior to 
spirometry/reversibility tests are met (see Section 3.8), and should occur no later than 
1 week after Visit 1. Visit 2 procedures may be performed on the same day as Visit 1 
if the medication restriction is met.”. 
! In Section 4, Table 2, Change clinic visit to phone visit at W12, 20, 28, 36 and 44 
(the visits between contiguous IP dosing), to simplify the protocol, meanwhile still 
can assess efficacy (exacerbation) and safety (AE, concomitant medication). 
Removing the tests for “Brief physical examination”, “Vital Signs”, “Urine pregnancy 
test”, ACQ-6 adherence at W12, 20, 28, 36 and 44 to keep consistence. 
! In Section 4, Table 2, removing the PK sampling at W8, W56 and ADA/nAb 
sampling at W56. Benralizumab PK has been extensively evaluated in global phase 3 
programs. The steady-state PK will be sufficient for comparison with global outcome 
for bridging. ADA sample collection will be reduced to keep consistence with PK 
time points.

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! In Section 4, Table 2, Section 5.3.5, removing “Immunoglobulins (IgE)” related 
wording and paragraph which is not necessary for this study. 
! In Section 4, Table 2, Section 5.4.2.1, for “Urine pregnancy test”, removing 
“dipstick” to use site local lab providing sourcing data for possible regulatory 
inspection in China.
! In Section 4, Table 2, Section 5.3.6 “Neutralizing antibodies”, Section 8.4.5, 
replacing the sentence “Neutralized antibodies (nAb) is to be tested at all ADA 
collection time points of Week 16 and later in samples that are ADA positive. 
Samples that are ADA negative will not be tested for nAb.” with “All ADA positive 
samples will be tested for neutralizing antibodies (nAb).” to follow changes from 
global pivotal study SIROCCO amendment 2 and clarify the time points of the 
samples that will be tested for nAb.
! In Section 5.1.2, removing “IP dosing should also be withheld until pre-
bronchodilator spirometry is complete” to follow changes from global pivotal study 
SIROCCO amendment 1. The amendment allowing sites the option of performing 
spirometry after the IP injection will shorten the duration of injection day visits to 
accommodate patient schedules, meanwhile will not impact the assessment of lung 
function.
! In Section 5.2.4, Table 4, removing the whole Table 4 as it is necessary to have full 
panel lab tests taken at all the visits to track the patient safety.
! In Section 5.3.2.2, Asthma control questionnaire (ACQ-6), removing ACQ-6 
assessments at phone visits (i.e., remove ACQ-6 assessments at W12, W20, W28, 
W36, and W44).
! In Section 7.4, removing “The patient, in the opinion of the Investigator, is 
experiencing an acute or emerging asthma exacerbation”, following changes from 
global pivotal study SIROCCO amendment 2. The Investigator will determine if the 
visit should be rescheduled and IP administration withheld in the event the patient is 
experiencing an acute or emerging asthma exacerbation. Worsening asthma, in and of 
itself, is not a reason to not administer IP.
! In Section 7.6.1.1, Background medication, to add “medium to high dose” for ICS 
covering both adult and adolescent patients, and revise the duration for ICS, LABA 
treatment to at least 6 months prior to Visit 1 and during the study.  
! In Section 7.7, revision following changes from global pivotal study SIROCCO 
amendment 2, to allow more flexibility with the timing of the blood draw for 
additional ADA testing.
! In Section 8.4.2.2, removing this whole section related to OAE (other significant 
AEs), to keep consistence with global pivotal studies. 
! In Section 8.4.3.4, removing “Baseline is defined as the last non-missing value 
before randomisation for the asthma PROs and as the last 10 days before 
randomisation for the daily metrics. Each post-randomisation period is defined as the 
period between 2 consecutive scheduled visits (till Week 48 Visit). The change from 

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baseline to each post-randomisation period will be used as secondary efficacy 
variables.” and replacing with “Biweekly (14 days) means will be calculated for 
daily assessments of asthma symptoms, night time awakenings, rescue medication 
usage and peak flow. Baseline will be the 14 days prior to randomisation and will be 
summarized as a mean. Post-randomisation biweekly (14 day) means will be 
calculated for each daily assessment and then summarized as group means for each 
14-day period post-randomisation. ACQ-6 and SGRQ baseline will be the last 
observation prior to study drug administration and summarized as mean scores for
each group. The change from baseline to each post-randomisation period will be used 
as secondary efficacy variable.” The updated approach will be consistent with the 
post-baseline evaluation.
! In Section 8.5.2.1, add “Change from baseline in” before “Total rescue medication 
use (average puffs/day)” and “Number of nights with awakening due to asthma and 
requiring rescue medication”, following changes from global pivotal study SIROCCO 
amendment 2, to clarify a change in analysis of these secondary objectives.
! In Section 8.5.2.1, removing “The number of nights with awakening due to asthma 
and requiring rescue medication will be analysed as the response variable by fitting an 
ANCOVA model to data. Treatment group will be fitted as the explanatory variable, 
and country, baseline value, the use of maintenance oral corticosteroids (yes/no) will 
be fitted as covariates. Total rescue medication use (average puffs/day) will be 
analysed using a similar model.” , and replacing with “Change from baseline in total 
rescue medication use (average puffs/days) and number of nights with awakening due 
to asthma and requiring rescue medication will be analysed using a similar model as 
for change from baseline in pre-BD FEV1.” following changes from global pivotal 
study SIROCCO amendment 2, due to multiple post-baseline measurements, these 
endpoints will now be analysed using a repeated measures model.
! In Section 8.5.2.1, replacing “by fitting an ANCOVA model with treatment, country, 
number of exacerbations in the year before the study, and the use of maintenance oral 
corticosteroids (yes/no) as covariates” with “using a similar model as for change from 
baseline in pre-BD FEV1”, following changes from global pivotal study SIROCCO 
amendment 2, due to multiple post-baseline measurements, these endpoints will now 
be analysed using a repeated measures model.
! In Section 8.5.2.1, removing “number of exacerbations in the year before the study”, 
following changes from global pivotal study SIROCCO amendment 2, the number of 
exacerbations in the year before the study was included in model in error.
! In Section 8.6, removing the whole paragraph of “Independent adjudication 
committee” for asthma-related exacerbation, because there is no mismatch between 
reported exacerbations and adjudicated exacerbations in global pivotal studies, and 
that there is already clear definition of exacerbation in the protocol. Investigators 
should be able to make the judgement.
! In Section 8.6, replacing the whole paragraph of “Independent adjudication 
committee” with paragraph of “Independent adjudication committee for major 
adverse cardiac events and malignancies An independent adjudication committee 

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will be constituted to provide an independent, external, systematic, and unbiased 
assessment of blinded data to confirm the diagnosis of: 1) Investigator-reported non-
fatal myocardial infarction, non-fatal stroke (hemorrhagic, ischemic, embolic), as well 
as cardiovascular deaths and 2) Investigator-reported malignancies during the Phase 3 
trials. The committee will operate in accordance with an Adjudication Committee 
Charter/Manual of Operations, which will also provide detail on specific information 
to enable a more robust review through adjudication process.”.
! In Section 9.4, replacing “AstraZeneca Drug Dictionary” with “WHO Drug 
Dictionary” per new process, and made some revision per new template wording.
! Appendix F (Restricted and prohibited medications, Appendix G in Version 1 
protocol), updated following global pivotal study SIROCCO.
! Correct a few typos throughout the CSP.
! Changes made across the CSP due to the template revamp (refer to below table for the 
comparison of old and new Version 17 CSP template).
Section Number/Name in Version 2.0 
CSP 
Section Number/Name in Version1.0 CSP
Version History
PROTOCOL SYNOPSIS
PROTOCOL SYNOPSIS
TABLE OF CONTENTS
TABLE OF CONTENTS
List of abbreviations and 
definition of terms
List of abbreviations and 
definition of terms
1
Introduction 
1
Introduction
1.1
Background and rationale 
for conducting this study
1.1
Background
1.1.1
Background
1.1.2
Rationale for conducting 
this study
1.2
Rationale for conducting 
this study
1.2
Rationale for study design, 
doses and control groups
1.3
Rationale for study design, 
doses and control groups
1.3
Benefit/risk and ethical 
assessment
1.4
Benefit/risk and ethical 
assessment
1.4
Study Design
1.5
Overall study design
2
Study objectives
2
Study Objectives
2.1
Primary Objective
2.2
Secondary Objectives
2.3
Safety Objective

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3
Patient selection, 
enrolment, randomisation, 
restrictions, 
discontinuation and 
withdrawal 
3
Patient selection criteria and 
withdrawal criteria 
3.1
Inclusion criteria
3.1
Inclusion criteria
3.2
Exclusion criteria
3.2
Exclusion criteria
3.3
Patient enrolment and 
randomisation
3.3
Patient enrolment and 
randomisation
3.4
Procedures for handling 
incorrectly enrolled or 
randomised patients
3.4
Procedures for handling 
incorrectly enrolled or 
randomised patients
3.5
Methods for assigning 
treatment groups
6.5
Methods for assigning 
treatment groups
3.6
Methods for ensuring 
blinding
6.6
Methods for ensuring 
blinding
3.7
Methods for unblinding
6.7
Methods for unblinding
3.8
Restrictions
3.5.2
Restrictions
3.8.1
Asthma medication 
restrictions
3.5.2.1
Asthma medication 
restrictions
3.8.2
Other medication 
restrictions
3.5.2.2
Other medication 
restrictions
3.8.3
Other restrictions
3.5.2.3
Other restrictions
3.9
Discontinuation of 
investigational product
3.6
Discontinuation from 
investigational product
3.9.1
Procedures for 
discontinuation of a patient 
from investigational 
product
3.10
Criteria for withdrawal
3.7
Withdrawal from the study
3.10.1
Screen failures
3.7.1
Screen failures
3.10.2
Withdrawal due to 
recruitment completion in 
a randomisation stratum
3.7.2
Withdrawal due to 
recruitment completion in a 
randomisation stratum
3.10.3
Withdrawal of the 
informed consent/assent
3.7.3
Withdrawal of the informed 
consent/assent
3.10.4
Withdrawal of informed 
consent/assent for donated 
biological samples
3.8
Withdrawal of informed 
consent/assent for donated 
biological samples
3.11
Discontinuation of the 
study
4
Study plan and timing of 
procedures
4
Study plan and procedures 

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4.1
Enrolment and run-in 
period
4.1
Enrolment and 
screening/run-in period
4.1.1
Enrolment (Visit 1)
4.1.1
Enrolment (Visit 1)
4.1.2
Run-in (Visit 2, Visit 3)
4.1.2
Screening/run-in (Visit 2, 
Visit 3)
4.1.3
Re-screening
4.1.3
Re-screening
4.1.3.1
Procedures for Patients 
Who Experience an 
Exacerbation during 
Screening
4.1.3.1
Procedures for Patients Who 
Experience an Exacerbation 
during Screening
4.2
Treatment period
4.2
Randomised treatment 
period
4.3
Follow-up period
4.3
Follow-up period
5
Study assessments and 
procedures
5
Study assessments and 
procedures
5.1
Efficacy assessments
5.1
Efficacy assessments
5.1.1
Assessment of asthma 
exacerbations
5.1.1
Assessment of asthma 
exacerbations
5.1.2
Spirometry
5.1.2
Spirometry
5.1.2.1
Reversibility test
5.1.2.1
Reversibility test
5.1.3
Home peak expiratory 
flow testing
5.1.3
Home peak expiratory flow 
testing
5.2
Safety assessments
5.2
Safety assessments
5.2.1
Physical examination
5.2.1
Physical examination
5.2.1.1
Complete physical 
examination
5.2.1.1
Complete physical 
examination
5.2.1.2
Brief physical examination
5.2.1.2
Brief physical examination
5.2.2
Vital signs
5.2.2
Vital signs
5.2.3
ECG
5.2.3
ECG
5.2.4
Safety laboratory tests
5.2.4
Safety laboratory tests
5.2.4.1
Pregnancy Test
5.2.4.1
Pregnancy Test
5.3
Other assessments and 
procedures
5.3
Other assessments and 
procedures
5.3.1
Weight and height
5.3.1
Weight and height
5.3.2
Patient reported outcomes
5.3.2
Patient reported outcomes

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5.3.2.1
Asthma daily diary
5.3.2.1
Asthma daily diary
5.3.2.2
Asthma control 
questionnaire (ACQ-6)
5.3.2.2
Asthma control 
questionnaire (ACQ-6)
5.3.2.3
St. George’s Respiratory 
Questionnaire (SGRQ)
5.3.2.3
Standardised asthma quality 
of life questionnaire for 12 
years and older 
(AQLQ(S)+12)
5.3.3
Healthcare resource 
utilization
5.3.3
Healthcare resource 
utilization
5.3.4
Other run-in assessments
5.3.4
Other screening/run-in 
assessments
5.3.4.1
Serology
5.3.4.1
Serology
5.3.5
Immunoglobulins
5.3.5
Pharmacokinetics
5.3.6
Pharmacokinetics
5.3.6
Immunogenicity
5.3.7
Immunogenicity
5.3.7
Handling of biological 
samples
5.3.8
Handling of biological 
samples
5.3.7.1
Labelling and shipment of 
biological samples
5.3.8.1
Labelling and shipment of 
biological samples
5.3.7.2
Chain of custody of 
biological samples
5.3.8.2
Chain of custody of 
biological samples
6
Safety reporting and 
medical management
7
Safety Reporting
7.1
Adverse Event
6.1
Definition of adverse 
events
7.1.1
Definition of adverse events
6.2
Definitions of serious 
adverse event
7.1.2
Definitions of serious 
adverse event
6.3
Recording of adverse 
events
7.1.3
Recording of adverse events
6.3.1
Time period for collection 
of adverse events
7.1.3.1
Time period for collection 
of adverse events
6.3.2
Follow-up of unresolved 
adverse events
7.1.3.2
Follow-up of unresolved 
adverse events
6.3.3
Variables
7.1.3.3
Variables
6.3.4
Causality collection
7.1.3.4
Causality collection
6.3.5
Adverse events based on 
signs and symptoms
7.1.3.5
Adverse events based on 
signs and symptoms
6.3.6
Adverse events based on 
examinations and tests
7.1.3.6
Adverse events based on 
examinations and tests

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6.3.8
Symptoms of the disease 
under study
7.1.3.7
Symptoms of the disease 
under study
6.3.7
Hy’s Law
6.4
Reporting of serious 
adverse events
7.1.4
Reporting of serious adverse 
events
6.5
Overdose
7.2
Overdose
6.6
Pregnancy
7.3
Pregnancy
6.6.1
Maternal exposure
7.3.1
Maternal exposure
6.6.2
Paternal exposure
7.3.2
Paternal exposure
7
Investigational product 
and other Treatments
6
Management of 
investigational products
7.1
Identity of investigational 
product(s)
6.1
Identity of investigational 
product(s)
7.2
Labelling
6.2
Labelling
7.3
Storage
6.3
Storage
7.4
IP administration and 
treatment Compliance
6.8
IP administration and 
treatment compliance
7.5
Accountability
6.4
Accountability
7.6
Concomitant and other 
treatments
3.5
Concomitant medications, 
restrictions during and after 
the study
7.6.1
Concomitant medication
3.5.1
Concomitant medication
7.6.1.1
Background medication
3.5.1.1
Background medication
7.6.1.2
Rescue medication
3.5.1.2
Rescue medication
7.6.2
Other concomitant 
treatment
7.7
Management of 
investigational product-
related reactions
6.9
Management of 
investigational product-
related reactions
8
Statistical analyses by 
AstraZeneca
8
Evaluation and Calculation 
of Variables
8.1
Statistical considerations
8.1
Statistical considerations
8.2
Sample size estimate
8.2
Sample size estimate
8.3
Definitions of analysis sets
8.3
Definitions of analysis sets
8.3.1
All patient’s analysis set
8.3.1
All patient’s analysis set
8.3.2
Full analysis set
8.3.2
Full analysis set

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8.3.3
Safety analysis set
8.3.3
Safety analysis set
8.3.4
Pharmacokinetic analysis 
set
8.3.4
Pharmacokinetic analysis 
set
8.4
Variables for analyses
8.4
Variables for analyses
8.4.1
Calculation or derivation 
of efficacy variables
8.4.1
Calculation or derivation of 
efficacy variables
8.4.1.1
Exacerbation rate
8.4.1.1
Exacerbation rate
8.4.1.2
Proportion of patients with 
I1 asthma exacerbation 
during 48 weeks of 
treatment
8.4.1.2
Proportion of patients with 
I1 asthma exacerbation 
during 48 weeks of 
treatment
8.4.1.3
Time to first exacerbation
8.4.1.3
Time to first exacerbation
8.4.1.4
Forced expiratory volume 
in 1 second
8.4.1.4
Forced expiratory volume in 
1 second
8.4.1.5
Annual rate of asthma 
exacerbations that are 
associated with an 
emergency room/urgent 
care visit or a 
hospitalization
8.4.1.5
Annual rate of asthma 
exacerbations that are 
associated with an 
emergency room/urgent care 
visit or a hospitalization
8.4.2
Calculation or derivation 
of safety variable(s)
8.4.2
Calculation or derivation of 
safety variable(s)
8.4.2.1
Safety variables
8.4.2.1
Safety variables
8.4.2.2
Other significant adverse 
events
8.4.2.2
Other significant adverse 
events
8.4.3
Calculation or derivation 
of patient reported 
outcome variables
8.4.3
Calculation or derivation of 
patient reported outcome 
variables
8.4.3.1
Asthma Symptom Score
8.4.3.1
Asthma Symptom Score
8.4.3.2
Asthma Control 
Questionnaire (ACQ-6)
8.4.3.2
Asthma Control 
Questionnaire (ACQ-6)
8.4.3.3
St. George’s Respiratory 
Questionnaire (SGRQ)
8.4.3.3
Asthma Quality of Life 
Questionnaire for 12 years 
and older (AQLQ(S)+12)
8.4.3.4
Electronic diary variables
8.4.3.4
Electronic diary variables
8.4.4
Calculation or derivation 
of pharmacokinetic 
variables
8.4.4
Calculation or derivation of 
pharmacokinetic variables
8.4.5
Calculation or derivation 
of immunogenicity 
variables
8.4.5
Calculation or derivation of 
immunogenicity variables
8.5
Methods for statistical 
analyses
8.5
Methods for statistical 
analyses

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8.5.1
Analysis of the primary 
variable (s)
8.5.1
Primary analysis method(s)
8.5.2
Analysis of the secondary 
variable(s)
8.5.2
Secondary analysis methods
8.5.2.1
Analysis methods for 
secondary efficacy 
variables
8.5.2.1
Analysis methods for 
secondary efficacy variables
8.5.2.2
Analysis methods for 
safety variables
8.5.2.2
Analysis methods for safety 
variables
8.5.2.3
Analysis methods for 
pharmacokinetic variables
8.5.2.3
Analysis methods for 
pharmacokinetic variables
8.5.2.4
Analysis method for 
immunogenicity variables
8.5.2.4
Analysis method for 
immunogenicity variables
8.5.3
Subgroup analysis
8.5.3
Subgroup analysis
8.5.4
Sensitivity analysis
8.5.4
Sensitivity analysis
8.5.5
Interim analysis
8.5.5
Interim analysis
8.6
Independent adjudication 
committee
8.6
Independent adjudication 
committee
9
Study and data 
management by 
AstraZeneca
9
Study and data management 
by AstraZeneca
9.1
Training of study site 
personnel
9.1
Training of study centre 
personnel
9.2
Monitoring of the study
9.2
Monitoring of the study
9.2.1
Source data
9.2.1
Source data
9.2.2
Recording of data
9.2.2
Recording of data
9.2.3
Study agreements
9.2.3
Study agreements
9.2.4
Archiving of study 
documents
9.2.4
Archiving of study 
documents
9.3
Study timetable and end of 
study
9.3
Study timetable and end of 
study
9.4
Data management by 
AstraZeneca
9.4
Data management by 
AstraZeneca
10
Ethical and regulatory 
requirements
10
Ethical and regulatory 
requirements
10.1
Ethical conduct of the 
study
10.1
Ethical conduct of the study
10.2
Patient data protection
10.2
Patient data protection
10.3
Ethics and regulatory 
review
10.3
Ethics and regulatory 
review
10.4
Informed consent/assent
10.4
Informed consent/assent

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10.5
Changes to the protocol 
and informed consent 
form/assent form
10.5
Changes to the protocol and 
informed consent/assent 
form
10.6
Audits and inspections
10.6
Audits and inspections
11
List of References
11
List of References
Table 1
Study Plan – Enrolment, 
run-in period
Table 1
Study Plan – Enrolment, 
screening/run-in period
Table 2
Study Plan –
Randomisation, treatment 
period, and follow-up
Table 2
Study Plan –
Randomisation, treatment 
period, and follow-up
Table 3
List of safety laboratory 
tests
Table 3
List of safety laboratory 
tests
Table 4
Schedule of serum 
chemistry tests
Table 4
Identity of investigational 
product
Table 5
Identity of investigational 
product
Table 5
Asthma medication 
restrictions
Table 1 in 
Appendix 
G
Asthma medication 
restrictions
Table 6
Other medication 
restrictions
Table 2 in 
Appendix 
G
Other medication 
restrictions
Figure 1
Study flow chart
Figure 1
Study flow chart
Figure 2
Reversibility testing 
algorithm
Figure 2
Reversibility testing 
algorithm
Figure 3
Injection sites and rotation 
scheme
Figure 3
Injection sites and rotation 
scheme
Appendix 
A 
Signatures
Appendix 
A
Additional Safety 
Information
Appendix 
B
Additional Safety 
Information 
Appendix 
B
International Airline 
Transportation Association 
(IATA) 6.2 Guidance 
Document
Appendix 
C
IATA 6.2 Guidance 
document
Appendix 
C
Actions Required in Cases 
of Combined Increase of 
Aminotransferase and 
Total Bilirubin - Hy’s Law
Appendix 
D
Actions required in cases of 
combined increase of 
Aminotransferase and Total 
Bilirubin – Hy’s Law
Appendix 
D
Anaphylaxis: definition, 
signs, symptoms and 
management
Appendix F
Anaphylaxis: definition, 
signs and symptoms, 
management
Appendix 
E
Background Therapy 
Equivalence Table
Appendix 
E
Background Therapy 
Equivalence Table
Appendix 
F
Restricted and prohibited 
medications
Appendix 
G
Restricted and prohibited 
medications

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3250c00036-csp-v5
Document Title:
D3250C00036 Clinical Study Protocol version 5
Document ID:
Doc ID-003376007
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
22-Dec-2020 19:03 UTC
Management Approval
23-Dec-2020 02:36 UTC
Content Approval
24-Dec-2020 01:10 UTC
Content Approval
23-Dec-2020 12:33 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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