A Phase 2b Multinational, Randomised, Double-blind, Parallel- Group, 24-week Placebo-controlled Study With 28-week Extension to Investigate the Use of Benralizumab in Patients With Chronic Spontaneous Urticaria Who Are Symptomatic Despite the Use of Antihistamines (ARROYO)
Phase: PHASE2
Conditions: Chronic Spontaneous Urticaria
Sponsor: AstraZeneca

Clinical Study Protocol 
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Clinical Study Protocol 
 
Study Intervention 
Benralizumab 
 
Study Code 
D3259C00001 
 
Version 
4 
 
Date 
31 May 2021 
 
 
A Phase 2b Multinational, Randomised, Double-blind, Parallel-
group, 24-week Placebo-controlled Study with 28-week Extension 
to Investigate the Use of Benralizumab in Patients with Chronic 
Spontaneous Urticaria Who are Symptomatic Despite the Use of 
Antihistamines (ARROYO) 
 
 
 

Clinical Study Protocol 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 3 
31 May 2021 
Amendment 2 
16 October 2020 
Amendment 1 
11 June 2020 
Original Protocol 
20 January 2020 
  
Amendment 3 (31 May 2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment is to align the contents of the clinical study protocol with the 
updated project specific safety requirements for benralizumab studies. Other changes were made as 
points of clarification, alignment with the updated protocol template, and correction of minor errors or 
omissions.   
Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
Throughout 
The term ³medical monitor´ was replaced 
by ³study physician´. 
To ensure consistency 
with the latest protocol 
template. 
Non-substantial 
Throughout 
The term ³congenital abnormalities´ was 
amended to ³congenital anomalies´. 
To ensure consistency 
with the latest protocol 
template. 
Non-substantial 
Throughout 
The term ³women´ was amended to 
³females´. 
To ensure consistency 
throughout the 
protocol. 
Non-substantial 
Throughout 
Minor editorial changes. 
To ensure consistency 
with the latest protocol 
template. 
Non-substantial 
Title Page 
The local amendment number changed to 3.  
Updated to reflect the 
correct amendment 
number of this protocol 
version. 
Non-substantial 
1.3 
Schedule of 
Activities 
The immunogenicity sample collection was 
removed from the follow-up visit.  
This assessment is not 
needed for the 
follow-up visit and thus 
was removed. 
Non-substantial 

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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
5.2 
Exclusion 
Criteria 
Exclusion criterion 10 has been removed: 
³Doses administered daily or every other 
day for 5 or more consecutive days of 
systemic or topical corticosteroids, 
hydroxychloroquine, methotrexate, 
cyclosporine, cyclophosphamide, or (IV) 
immunoglobulin within 30 days before 
day -14.´ 
Text amended to 
remove duplication of 
updated exclusion 
criterion 11 (now 
numbered 10). 
Non-substantial 
 
Criterion 10 (previous criterion 11) was 
replaced with the following ³Use of 
immunosuppressive medication, including, 
but not limited to: methotrexate, 
cyclosporine, azathioprine, topical and 
systemic corticosteroids within 4 weeks or 
5 half-lives prior to the date informed 
consent is obtained, whichever is longer.´ 
Text amended to align 
with the updated 
project specific safety 
requirements for the 
benralizumab 
development program 
Non-substantial 
 
Criterion 18 was updated to clarify that 
planned elective major surgical procedures 
during the conduct of the study is reason to 
not enroll the patient. 
Updated for improved 
clarity. 
Non-substantial 
5.3 
Lifestyle 
considerations 
The inclusion criterion number referring to 
the definition of females of childbearing 
potential was updated from 10 to 9. 
Updated to reflect the 
correct number in this 
protocol version. 
Non-substantial 
6.5 
Concomitant 
Medications 
Clarified in the text that any prior biologic 
medication(s) are to be collected in the 
electronic case report form. 
Updated to clarify that 
prior biologic 
medication(s) are to be 
collected. 
Non-substantial 
6.5.4 
Restrictions 
The following bullet was added to the 
restrictions: 
 
Plasmapheresis is prohibited within 
30 days prior to screening. 
Omitted in error. 
Non-substantial 
 
The following bullet was added to the 
restrictions: 
 
Receipt of inactive/killed vaccinations 
(eg, inactive influenza) is allowed 
provided they are not administered 
within 1 week before/after any IP 
administration; additionally, it is 
recommended to rotate the next IP site 
Exclusion of inactive 
vaccines was 
inadvertently not 
included in the 
previous versions and 
has been added so as to 
align with the current 
Non-substantial  

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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
injection to a site distant from the 
vaccine site injection. 
 
benralizumab safety 
information.   
8 
Study 
assessments 
and procedures 
A note was added, stating that if not all 
laboratory kits are available at a given visit, 
the Investigator should contact the Study 
Physician to confirm whether the assessment 
is critical or may be postponed until supplies 
are available.  
 
To allow for improved 
feasibility and to 
conduct study visits, in 
case specific laboratory 
kits are not available at 
a given time point. 
Non-substantial 
8.2.1.1 
Pregnancy tests 
The inclusion criterion number referring to 
the definition of females not of childbearing 
potential was updated from 11 to 10. 
Updated to reflect the 
correct number in this 
protocol version. 
Non-substantial 
8.2.3 
Vital signs 
Wording was updated to clarify that pulse 
rate and blood pressure will be (instead of 
³should be´) measured after the participant 
has been resting for at least 5 minutes, and 
that the pulse rate should be (instead of ³will 
be´) obtained before blood pressure. 
Updated for improved 
clarity. 
Non-substantial 
8.3 
Adverse 
Events and 
Serious 
Adverse 
Events 
The following text was removed: 
³Care will be taken not to introduce bias 
when detecting AEs and/or SAEs. Open-
ended and non leading verbal questioning of 
the subject is the preferred method to inquire 
about AE occurrences.´ 
Text updated to clarify 
AE reporting 
procedures and to align 
with the current 
protocol template 
(Section 8.3.4 already 
provides the method for 
questioning for AE-
related verbal 
questioning).  
Non-substantial 
8.3.2 
Follow-up of 
AEs and SAEs 
The following text was removed: 
³After the initial AE/SAE report, the 
Investigator is required to proactively follow 
each participant at subsequent 
visits/contacts. All AEs will be followed 
until resolution, stabilisation, the event is 
otherwise explained, or the participant is lost 
to follow-up.´ 
Text updated to clarify 
AE reporting 
procedures and to align 
with the current 
protocol template  
Non-substantial 
 
³Description of AE´ was included as one of 
the variables to be collected for SAEs. 
Omitted previously 
from the protocol by 
error. 
Non-substantial 
8.3.8.1 
Maternal 
Exposure 
The following text was added: 
³The PREGREP module in the eCRF is used 
to report the pregnancy and the paper-based 
Text updated to clarify 
pregnancy reporting 
procedures and to align 
Non-substantial 

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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial/Non-
substantial 
PREGOUT module is used to report the 
outcome of the pregnancy.´ 
with the current 
protocol template  
8.3.8.2 
Paternal 
Exposure 
Section removed from the protocol. 
Text amended to align 
with the updated 
project specific safety 
requirements for the 
benralizumab 
development program. 
Non-substantial 
8.4 
Overdose 
It was reinforced that overdoses associated 
with an SAE will be reported to the 
AstraZeneca Patient Safety data entry site 
within 1 or 5 calendar days, consistent with 
the standard SAE reporting procedures. 
Text updated to clarify 
overdose reporting 
procedures and to align 
with the current 
protocol template 
Non-substantial 
Appendix A 1 
Regulatory and 
Ethical 
Considerations 
The following text has been included: 
³The Investigator will be responsible for 
providing oversight of the conduct of the 
study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the 
IRB/IEC, European Regulation 536/2014 for 
clinical studies (if applicable), European 
Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and 
all other applicable local regulations.´ 
To align with the 
updated protocol 
template. 
Non-substantial 
Appendix A 3 
Informed 
Consent 
Process 
The following text was removed:  
³If the participant¶s partner becomes 
pregnant, despite prevention, state that the 
partner will be asked to sign an ICF for 
pregnant partners.  
If a participant¶s partner becomes pregnant 
during or within 12 weeks after the last dose 
of study drug, the partner will be asked to 
sign the ³Adult Study Informed Consent 
Form for Pregnant Partners of Study 
Participants´ and provide information about 
the pregnancy accordingly.´ 
Text amended to align 
with the updated 
project specific safety 
requirements for the 
benralizumab 
development program. 
Non-substantial 
Appendix A 6 
Dissemination 
of Clinical 
Study Data 
The link http://astrazenecaclinicaltrials.com 
was replaced with 
http://astrazenecagrouptrials.pharmacm.com.  
To align with the 
updated protocol 
template. 
Non-substantial 
Appendix A 7 
Data Quality 
Assurance 
Text updated to clarify that the Investigator 
is responsible for verifying that data entries 
are accurate and correct by electronically 
signing the electronic case report form. 
To align with the 
updated protocol 
template and 
procedures. 
Non-substantial 

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AE, adverse event; CFR, Code of Federal Regulations; eCRF, electronic case report form; ICF, informed consent 
form; ICH, International Council for Harmonisation; IEC, Independent Ethics Committee; IP, investigational 
product; IRB, Institutional Review Board; IV, intravenous; SAE, serious adverse event. 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................... 8 
LIST OF TABLES .................................................................................................................. 11 
LIST OF FIGURES ................................................................................................................. 11 
LIST OF APPENDICES ......................................................................................................... 11 
1 
PROTOCOL SUMMARY ................................................................................... 12 
1.1 
Synopsis ................................................................................................................ 12 
1.2 
Schema .................................................................................................................. 18 
1.3 
Schedule of Activities ........................................................................................... 20 
2 
INTRODUCTION ................................................................................................ 25 
2.1 
Study Rationale ..................................................................................................... 25 
2.2 
Background ........................................................................................................... 25 
2.3 
Benefit/risk Assessment ....................................................................................... 27 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 28 
4 
STUDY DESIGN ................................................................................................. 30 
4.1 
Overall Design ...................................................................................................... 30 
4.1.1 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 32 
4.1.2 
Investigational Product Dosing Regimen ............................................................. 33 
4.2 
Scientific Rationale for Study Design .................................................................. 35 
4.3 
Justification for Dose ............................................................................................ 36 
4.4 
End of Study Definition ........................................................................................ 37 
5 
STUDY POPULATION ....................................................................................... 37 
5.1 
Inclusion Criteria .................................................................................................. 38 
5.2 
Exclusion Criteria ................................................................................................. 40 
5.3 
Lifestyle Considerations ....................................................................................... 42 
5.4 
Screen Failures ..................................................................................................... 42 
5.4.1 
Re-screening ......................................................................................................... 42 
6 
STUDY INTERVENTION .................................................................................. 43 
6.1 
Study Interventions Administered ........................................................................ 43 
6.1.1 
Investigational Products ....................................................................................... 43 
6.1.2 
Investigational Product Administration Re-scheduling ........................................ 45 
6.2 
Preparation/handling/storage/accountability ........................................................ 46 
6.2.1 
Preparation and Handling of Investigational Product ........................................... 47 
6.2.2 
Shipping and Storage ............................................................................................ 47 
6.2.3 
Accountability ...................................................................................................... 48 
6.3 
Measures to Minimise Bias: Randomisation and Blinding .................................. 48 
6.3.1 
Randomisation ...................................................................................................... 48 

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6.3.2 
Blinding ................................................................................................................ 48 
6.3.3 
Methods for Unblinding ....................................................................................... 50 
6.4 
Study Intervention Compliance ............................................................................ 51 
6.5 
Concomitant Therapy ........................................................................................... 51 
6.5.1 
Background Medication ....................................................................................... 52 
6.5.2 
Other Concomitant Treatment .............................................................................. 52 
6.5.3 
Rescue Medication ............................................................................................... 52 
6.5.4 
Restrictions ........................................................................................................... 52 
6.6 
Dose Modification ................................................................................................ 53 
6.7 
Intervention After the End of the Study ............................................................... 53 
7 
DISCONTINUATION OF STUDY INTERVENTION AND  
PARTICIPANT DISCONTINUATION/WITHDRAWAL ................................. 53 
7.1 
Discontinuation of Study Intervention ................................................................. 53 
7.1.1 
Procedures for Early Discontinuation of Study Intervention and at End of 
Study ..................................................................................................................... 54 
7.1.1.1 
Early Discontinuation of Study Intervention ........................................................ 55 
7.1.1.2 
Discontinuation of Study Intervention Upon Notification of  
Closure of Study ................................................................................................... 55 
7.1.2 
Procedures for Handling Incorrectly Enrolled or Randomised  
Participants ........................................................................................................... 55 
7.2 
Participant Withdrawal from the Study ................................................................ 56 
7.2.1 
Discontinuation or Suspension of the Whole Study Program .............................. 56 
7.3 
Lost to Follow-up ................................................................................................. 56 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 57 
8.1 
Efficacy Assessments ........................................................................................... 58 
8.1.1 
Urticaria Patient Daily Diary (UPDD) ................................................................. 59 
8.1.2 
Urticaria Control Test (UCT) ............................................................................... 59 
8.1.3 
Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) ............................... 60 
8.1.4 
Dermatology Life Quality Index (DLQI) ............................................................. 60 
8.1.5 
Patient Global Impression of Severity (PGI-S) .................................................... 60 
8.1.6 
European Quality of Life-5 Dimensions (EQ-5D-5L).......................................... 60 
 
 
8.1.8 
Patient-Reported Experience ................................................................................ 60 
8.2 
Safety Assessments ............................................................................................... 61 
8.2.1 
Clinical Safety Laboratory Assessments .............................................................. 61 
8.2.1.1 
Pregnancy Tests .................................................................................................... 62 
8.2.1.2 
Serology ................................................................................................................ 62 
8.2.2 
Physical Examinations .......................................................................................... 63 
8.2.3 
Vital Signs ............................................................................................................ 63 
8.2.4 
Electrocardiograms ............................................................................................... 64 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 64 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 64 
8.3.2 
Follow-up of AEs and SAEs ................................................................................ 65 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 84 
11 
REFERENCES ................................................................................................... 123 
 
LIST OF TABLES 
Table 1 
Primary and Secondary Objectives ............................................................. 13 
Table 2 
Schedule of Site Visit Activities ................................................................. 21 
Table 3 
Schedule of PRO Assessments .................................................................... 24 
Table 4 
Study Objectives ......................................................................................... 28 
Table 5 
Investigational Products .............................................................................. 43 
Table 6 
Assessment of CSU disease activity in study participants .......................... 59 
Table 7 
Laboratory Safety Variables ....................................................................... 61 
Table 8 
Populations for Analyses ............................................................................. 77 
 
LIST OF FIGURES 
Figure 1 
Investigational Product Administration ...................................................... 16 
Figure 2 
Study Design ............................................................................................... 19 
Figure 3 
Investigational Product Administration ...................................................... 34 
Figure 4 
Injection Sites and Examples of Rotation Scheme ..................................... 45 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 85 
Appendix B 
Adverse Events: Definitions and Procedures for Recording,  
Evaluating, Follow-Up, and Reporting ....................................................... 90 
Appendix C 
Handling of Human Biological Samples ..................................................... 95 
Appendix D 
Optional Genomics Initiative Sample ......................................................... 97 
Appendix E 
Anaphylaxis: Definition, Signs, Symptoms, and Management ................ 101 
Appendix F 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 104 
Appendix G 
Abbreviations ............................................................................................ 107 
Appendix H 
Protocol Amendment History ................................................................... 110 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: A Phase 2b Multinational, Randomised, Double-blind, Parallel Group, 
24-week Placebo-controlled Study with 28-week Extension to Investigate the Use of 
Benralizumab in Patients with Chronic Spontaneous Urticaria Who Are Symptomatic 
Despite the Use of Antihistamines (ARROYO) 
Short Title: A phase 2b study to investigate the use of benralizumab in patients with 
chronic spontaneous urticaria who are symptomatic despite the use of antihistamines 
(ARROYO) 
Rationale: The aim of this study is to investigate the use of benralizumab as treatment for 
patients with chronic spontaneous urticaria (CSU) who are symptomatic despite the use of 
antihistamines. It is proposed that benralizumab will deplete eosinophils and basophils from 
affected skin, improve symptoms of CSU, and improve CSU-related quality of life. This 
Phase 2b study is designed to evaluate 2 induction doses of benralizumab (60 mg and 30 mg) 
compared to placebo, and a comparison of maintenance dosing regimens (every 8 weeks 
[Q8W] versus every 4 weeks [Q4W]) in the 28-week extension period. 
Objectives and Endpoints: 
The primary and secondary objectives and associated endpoints are detailed in Table 1. For 
tertiary/exploratory objectives and endpoints, see Section 3 of this protocol. 
 

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Table 1 
Primary and Secondary Objectives 
Primary Objective: 
Estimand description / endpoints 
To determine the clinical efficacy of benralizumab 
compared to placebo in patients with CSU who are 
symptomatic despite the use of H1 antihistamine 
treatment. 
 
Population: Full Analysis Set:  
 
Endpoint: Change from baseline in ISS7 at Week 
12 
 
Intercurrent events: All data up to Week 12 will 
be included regardless of randomised treatment 
adherence or rescue medication received 
 
Summary measure: difference in least squares 
mean change from baseline in ISS7 at Week 12 
between benralizumab and placebo 
Secondary Objectives: 
Endpoint/variable: 
To evaluate the effect of benralizumab compared to 
placebo on supportive measures of clinical efficacy in 
patients with CSU who are symptomatic despite the 
use of H1 antihistamine treatment. 
 Key secondary endpoint: change from baseline in 
UAS7 at Week 12 a 
 Change from baseline in UAS7 at Week 24 
 Proportion of responders (UAS7  6) at Week 12  
 Change from baseline in HSS7 at Week 12  
 Time to  5 point decrease (clinically relevant 
decrease) in ISS7  
 Proportion of participants with complete UAS7 
response (UAS7 = 0) at Week 12  
 Measures of angioedema activity at Week 12 in 
participants with angioedema at baseline  
 Change from baseline in UCT at Week 12 
 
To evaluate the effect of benralizumab on patient-
reported health-related quality of life measures in 
patients with CSU who are symptomatic despite the 
use of H1 antihistamine treatment. 
 Change from baseline in CU-Q2oL at Weeks 12 and 
24 
 Change from baseline in DLQI at Weeks 12 and 24 
 
To assess the PK and immunogenicity of 
benralizumab 30 mg and 60 mg in patients with CSU 
who are symptomatic despite the use of H1 
antihistamine treatment. 
 Serum benralizumab concentration 
 ADA 
 
To evaluate the longer-term effect of benralizumab 
compared to placebo at Week 24 on measures of 
clinical efficacy in patients with CSU who are 
symptomatic despite the use of H1 antihistamine 
treatment. 
 Change from baseline in ISS7 at Week 24 
 Change from baseline in UAS7 at Week 24 
 Proportion of responders (UAS7  6) at Week 24  
 Change from baseline in HSS7 at Week 24 
 Proportion of participants with complete UAS7 
response (UAS7 = 0) at Week 24  
 Measures of angioedema activity at Week 24 in 
participants with angioedema at baseline 
 Change from baseline in UCT at Week 24 
 

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Table 1 
Primary and Secondary Objectives 
To evaluate the efficacy of administration of 
benralizumab Q8W versus Q4W up to Week 52 in 
patients with CSU who are symptomatic despite the 
use of H1 antihistamine treatment. 
 Change from baseline in ISS7 at Week 52 
 Other supportive efficacy assessments at Week 52 
in participants on a Q8W dosing regimen compared 
to those on a Q4W dosing regimen. 
 
Safety Objective: 
Endpoint/variable: 
To assess the safety and tolerability of benralizumab 
in patients with CSU who are symptomatic despite 
the use of H1 antihistamine treatment. 
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, and clinical laboratory values. 
Assessments related to AEs cover: 
 Occurrence/frequency 
 Relationship to IP as assessed by Investigator 
 Intensity 
 Seriousness 
 Death 
 AEs leading to discontinuation of IP 
 
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height. 
Assessments related to vital signs cover: 
 Observed value 
 Absolute and percent change from baseline values 
over time 
 
a 
The key secondary endpoint will use the same treatment policy strategy estimand as outlined for the 
primary endpoint. All other estimands will be detailed fully in the Statistical Analysis Plan (SAP). 
ADA, anti-drug antibodies; AE, adverse event; CU-Q2oL, Chronic Urticaria Quality of Life Questionnaire; CSU, 
chronic spontaneous urticaria; DLQI, Dermatology Life Quality Index; HSS7 hives severity score over 7 days; 
ISS7, itch severity score over 7 days; IP, investigational product; PK, pharmacokinetics; Q4W, every 4 weeks; 
Q8W, every 8 weeks; UAS7, urticaria activity score over 7 days; UCT, Urticaria Control Test. 
 
Overall Design 
This is a Phase 2b, multinational, randomised, double-blind, parallel-group, 24-week 
placebo-controlled study with 28-week extension to evaluate the efficacy and safety of 
benralizumab in participants  18 years of age with CSU refractory to standard of care 
treatment, which may include second generation H1 antihistamines (at approved or up to 
4 times approved doses) as monotherapy, or in combination with leukotriene receptor 
antagonists and/or H2 blockers. The study is designed to evaluate 2 induction doses of 
benralizumab (60 mg and 30 mg) compared to placebo, and a comparison of maintenance 
dosing regimens (Q8W versus Q4W) in the 28-week extension period. 
The study comprises the following consecutive periods: 

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A 10-day to 4-week run-in period 
 
A 24-week placebo-controlled, double-blind treatment period (comprising an initial 
12-week µinduction dose¶ period followed by an additional 12-week dosing period) 
 
A 28-week blinded-to-dosing regimen extension period for maintenance treatment. 
 
Disclosure Statement: 
This is a Phase 2b parallel-group, placebo-controlled study with 5 treatment groups. 
Number of Participants: 
Approximately 240 participants will be enrolled/screened in order to achieve 160 eligible 
study participants randomly assigned to study intervention. 
Note: "Enrolled" is defined as a participant's agreement to participate in a clinical study 
following completion of the informed consent process. Potential participants who are screened 
for the purpose of determining eligibility for the study but are not randomised to the study will 
be considered ³screen failures´, unless otherwise specified by the protocol. 
Intervention Groups and Duration: 
Following a 10-day  to 4-week run-in period, approximately 160 participants will be 
randomised in a ratio of 3:3:3:3:4, respectively, to one of the following 5 treatment sequences 
as illustrated in Figure 1 and Figure 2: 
 
Benralizumab 60 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q8W during the extension period until Week 52 (n = 30) 
 
Benralizumab 60 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q4W during the extension period until Week 52 (n = 30) 
 
Benralizumab 30 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q8W during the extension period until Week 52 (n = 30) 
 
Benralizumab 30 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q4W during the extension period until Week 52 (n = 30) 
 
Placebo Q4W until Week 24, benralizumab 30 mg Q4W until Week 36, and 30 mg 
Q8W until Week 52 (n = 40). 
 
Up to Week 24, ie, prior to start of the extension period evaluating Q4W and Q8W dosing 
regimens, participants in both benralizumab 60 mg initial dose treatment arms will be 
considered as a single treatment group (total n = 60), as will participants in both benralizumab 
30 mg initial dose treatment arms (total n = 60). 
Blinded investigational product (IP) (benralizumab or placebo) will be administered by 
subcutaneous (SC) injection at the investigational site Q4W for up to 48 Weeks. 

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Benralizumab is available only as a 30 mg dose in a prefilled syringe. Since the 60 mg 
treatment requires 2 SC injections, all participants will receive 2 injections during the initial 
12-week induction period to maintain the blind: 
 
Participants randomised to the benralizumab 30 mg group will receive one benralizumab 
30 mg injection and one matching placebo injection 
 
Participants randomised to the benralizumab 60 mg group will receive 2 benralizumab 
30 mg injections 
 
Participants randomised to the placebo group will receive 2 placebo injections. 
 
In the extension period, in order to maintain blinding to the benralizumab Q4W treatment 
regimen, participants that are randomised to receive benralizumab Q8W will also receive 
Q8W placebo injections at intervening visits where they are not scheduled to receive 
benralizumab (Figure 1). 
The final dose of benralizumab/placebo will be administered at Week 48. 
Figure 1 
Investigational Product Administration 
 
a 
In the extension period, participants will receive benralizumab on a Q8W or Q4W dosing regimen, as 
predetermined at randomisation (Visit 2). Participants randomised to receive benralizumab Q8W in the 
extension period will also receive placebo at intervening study visits when they are not receiving 
benralizumab. 
Q4W, every 4 weeks; Q8W, every 8 weeks. 
 
Data Monitoring Committee: No 
There is no data monitoring committee involved in the conduct of this study. 
Statistical Methods 
Approximately 160 participants will be randomised in a 3:3:3:3:4 ratio to different sequences 
of initial benralizumab dose or placebo, followed by Q4W or Q8W maintenance dosing with 

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benralizumab post Week 24 as described above. Randomisation will be stratified by region. 
Up to Week 24, ie, prior to start of the extension period evaluating Q4W and Q8W dosing 
regimens, participants in both benralizumab 60 mg initial dose treatment arms will be 
considered as a single treatment group (total n=60), as will participants in both benralizumab 
30 mg initial dose treatment arms (total n=60). 
By combining the treatment sequences with common initial benralizumab doses, the above 
randomisation will provide a 3:3:2 ratio across the benralizumab 60 mg and 30 mg initial dose 
groups and the placebo treatment arm (n=40), respectively, in order to assess the primary 
endpoint at Week 12. This provides 90% power for statistical significance at the 2-sided 2.5% 
level within each induction dose comparison versus placebo if the assumed effect is a 4.7 
point mean difference in change in itch severity score over 7 days (ISS7) between 
benralizumab and placebo, assuming a standard deviation (SD) of 6 for the change in ISS7 
and a 10% dropout rate. 
The primary efficacy analyses will be based on the double-blind, 12-week placebo-controlled 
induction period. In this part of the study and the following 12 weeks (up to Week 24) all 
efficacy analyses will use the Full Analysis Set (FAS), defined as all randomised participants 
who received at least 1 dose of IP, irrespective of their protocol adherence and continued 
participation in the study, according to the Intent-to-Treat principle. 
The primary endpoint, change from baseline in ISS7 at Week 12, will be compared between 
each benralizumab initial treatment group (60 mg and 30 mg) with placebo using a Mixed-
effect Model for Repeated Measures (MMRM). The dependent variable in this model will be 
the change from baseline in ISS7 at post-baseline protocol-specified visits (up to the Week 24 
visit). Treatment group will be included as an explanatory variable along with the baseline 
ISS7 score, region, visit and treatment-by-visit interaction as fixed effects. An unstructured 
covariance structure will be used to model the within-patient errors. If the model fails to 
converge, the following structures will be attempted in the specified order: Toeplitz, first-
order autoregressive, compound symmetric, and variance components. Least squares mean 
estimates for change from baseline at Week 12 and differences in least squares mean estimates 
between the treatment groups and placebo will be obtained from this model.  
To make a comparative assessment of the efficacy of the Q4W and Q8W dosing regimens 
between Weeks 24 and 52, the efficacy endpoints will be assessed out to Week 52 using the 
5 treatment groupings described above. If appropriate, each of the Q4W and Q8W 
maintenance treatment arms will be pooled across initial benralizumab doses to allow a single 
comparison of Q8W versus Q4W dosing.  The group of participants receiving placebo and 
then benralizumab will also be presented in these analyses but not formally compared to the 
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1.2 
Schema 
The general study design is summarised in Figure 2. 

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1.3 
Schedule of Activities 
The Schedule of Activities (SoA) at each site visit for this study is provided in Table 2. 
Details of the schedule of at home and site visit patient-reported outcome (PRO) assessments 
are provided in Table 3. 

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All within-window PRO assessments (Table 3) that have not been completed prior to a site 
visit will be completed at the site before any other study procedures are conducted. 
Table 3 
Schedule of PRO Assessments 
Instruments 
Schedule 
Daily PRO: UPDD Question 1 
Every morning a. First assessment at home the day 
after Visit 1. 
Daily PROs: UPDD Questions 2-7 
Every evening b. First assessment at home on the day 
of Visit 1. 
Weekly PRO: PGI-S 
At site at Visits 1 and 2. At home every 7 ± 3 days 
after Visit 2.  
Monthly PROs: UCT, DLQI, CU-Q2oL 
At site at Visits 1 and 2. 
At home every 28 ± 3 days after Visit 2. 
EQ-5D-5L 
At site at Visits 1, 2, 3, 4, 5, and 15. 
 
 
a 
Morning is defined as 05:00 to 12:00 on day n. 
b 
Evening is defined as 17:00 on Day n to 04:00 on Day n + 1. 
CU-Q2oL, Chronic Urticaria Quality of Life Questionnaire; DLQI, Dermatology Life Quality Index; EQ-5D-5L, 
European Quality of Life-5 Dimensions; 
 PGI-S, Patient 
Global Impression of Severity; PRO, patient-reported outcomes; UCT, Urticaria Control Test; UPDD, Urticaria 
Patient Daily Diary. 
 
 

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2 
INTRODUCTION 
2.1 
Study Rationale 
Chronic spontaneous urticaria (CSU), which affects between 0.5% and 1% of the global 
population, is difficult to treat and a substantial burden on patients (Maurer et al 2018); 
however, treatment options are limited for patients with symptoms not well controlled by 
standard of care with antihistamines (Maurer et al 2011, Zuberbier et al 2018). 
Mast cells and basophils have been traditionally regarded as the main effector cells in CSU 
(Bracken et al 2019); however, the role of eosinophils in CSU pathology is emerging. 
Eosinophils are elevated in diseased tissue but remain within the normal range in blood, and 
the presence of elevated levels of eosinophils and basophils within diseased tissue has been 
correlated with CSU disease severity (Kay et al 2014, Marques et al 2016). Basopenia has 
been linked to severe antihistamine-resistant CSU, and type IIb autoimmunity and eosinopenia 
have been associated with high disease activity, as well as autoimmunity and poor response to 
treatment in patients with CSU (Kolkhir et al 2019). The role of eosinophils and basophils in 
the pathophysiology of CSU suggests that a direct eosinophil/basophil-depleting approach, as 
provided by benralizumab, may prove beneficial in the treatment of CSU. 
Benralizumab 30 mg administered SC Q4W was shown in a Phase 2a pilot study to reduce 
signs and symptoms of CSU and improve health-related quality of life after 12 weeks of 
treatment (Bernstein and Singh 2019). Reduced disease activity and symptoms of chronic 
symptomatic dermographism (pruritus, itchy wheals upon skin exposure to friction), a form of 
chronic inducible urticaria, after 3 months of treatment with benralizumab was described in a 
recent case report of a patient who received benralizumab 30 mg Q4W for his severe allergic 
eosinophilic asthma (Bergmann et al 2019). Additionally, results from a pilot study of patients 
with hypereosinophilic syndrome showed improvements in skin-related symptoms, with 
eosinophil depletion seen in skin biopsies after 12 weeks of treatment with benralizumab 
(Kuang et al 2019). Based on these results, further investigation of the efficacy and safety of 
benralizumab in treating CSU is warranted. 
2.2 
Background 
CSU is defined as the spontaneous appearance of wheals, angioedema, or both for a duration 
of at least 6 weeks or more due to known (eg, autoimmune) or unknown causes  
(Zuberbier et al 2018). Wheals are accompanied by pruritus, which can range from mild in 
intensity to sufficiently bothersome to interfere with normal daily activity or sleep. More than 
30% of CSU patients with moderate to severe symptoms will continue to have CSU after 5 
years (Maurer et al 2018, Nettis et al 2018, O¶Donnell et al 1997). The impact of CSU on 
patients¶ quality of life is substantial; health status scores and subjective satisfaction in 
patients with CSU are lower than in healthy subjects as well as in patients with respiratory 
allergy (Maurer et al 2018, Zuberbier et al 2018). Productivity, sleep, and daily activities are 

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2.3 
Benefit/risk Assessment 
The efficacy and safety of benralizumab have been established in patients with asthma. 
Previous studies have shown that the overall safety profile of benralizumab in severe asthma 
patients is similar to placebo for exposures up to approximately one year (Bleecker et al 2016 
and FitzGerald et al 2016). The most commonly reported adverse events (AEs) included 
nasopharyngitis, asthma, and upper respiratory tract infections. Most AEs were mild to 
moderate in nature. Fewer patients in the benralizumab group reported serious adverse events 
(SAEs) compared with placebo. Longer-term safety studies have been conducted in asthma 
patients who completed one of the predecessor studies for up to an additional one year (adults) 
and 2 years (adolescents). In general, the safety results were commensurate with the 
predecessor studies (Busse et al 2013). Safety and tolerability data from the Phase 2a study of 
benralizumab in patients with CSU showed that benralizumab was well-tolerated, with no AEs 
attributable to treatment with benralizumab (Bernstein and Singh 2019). 
Serious hypersensitivity reactions (including anaphylaxis) are an identified risk of biologic 
therapy, including benralizumab. Anaphylaxis may be life-threatening. Risk minimisation 
includes observation in line with clinical practice following IP administration for the 
appearance of any acute drug reactions. 
Serious infections have been reported for benralizumab. A relationship between eosinophil 
depletion and serious infection has not been established. 
Development of anti-drug antibodies (ADA) to benralizumab has been documented. Potential 
risks of developing ADA include decreased drug efficacy and hypersensitivity reactions (eg, 
anaphylaxis or immune complex disease). To date, no confirmed cases of immune complex 
disease have been observed and no appearance of a relationship between ADA and treatment-
emergent AEs has been established. There was no impact of ADA on overall benralizumab 
safety or efficacy in the previous Phase 3 studies in asthma. 
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 tumours. Helminthic parasitic infections and 
malignancy will continue to be monitored as part of routine pharmacovigilance practices. 
Based on the results of previous studies, expected benefits of benralizumab over placebo 
include clinically significant improvements in symptoms of CSU disease activity and health-
related quality of life of patients with CSU despite treatment with H1 antihistamines.  
The benefit/risk assessment for benralizumab in patients with CSU based on results from the 
previous clinical experience in other eosinophil-driven diseases (asthma and hypereosinophilic 
syndrome) and the Phase 2a study is expected to continue to be favourable. Based on the 
extensive safety data already available, the benefit risk profile in patients with CSU is 

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expected to be commensurate with that observed in the benralizumab asthma pivotal trials. 
Risk minimisation measures include exclusion of patients with allergy or reaction to any 
component of the IP formulation, untreated parasitic infection, a history of anaphylaxis to any 
biologic therapy, active or recent malignancy, and exclusion of pregnant females. Risk 
minimisation measures will be maintained during the conduct of this study, in conjunction 
with the performance of AstraZeneca¶s routine pharmacovigilance activities. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of benralizumab may be found in the Investigator¶s Brochure. 
3 
OBJECTIVES AND ENDPOINTS 
Table 4 lists the objectives of this study and the endpoints for each objective. 
Table 4 
Study Objectives 
Primary Objective: 
Estimand description / Endpoints 
To determine the clinical efficacy of benralizumab 
compared to placebo in patients with CSU who are 
symptomatic despite the use of H1 antihistamine 
treatment. 
 
Population: Full Analysis Set:  
 
Endpoint: Change from baseline in ISS7 at Week 
12 
 
Intercurrent events: All data up to Week 12 will 
be included regardless of randomised treatment 
adherence or rescue medication received 
 
Summary measure: difference in least squares 
mean change from baseline in ISS7 at Week 12 
between benralizumab and placebo 
 
Secondary Objectives: 
Endpoint/variable: 
To evaluate the effect of benralizumab compared to 
placebo on supportive measures of clinical efficacy in 
patients with CSU who are symptomatic despite the 
use of H1 antihistamine treatment. 
 Key secondary endpoint: change from baseline in 
UAS7 at Week 12a 
 Change from baseline in UAS7 at Week 24 
 Proportion of responders (UAS7  6) at Week 12 
 Change from baseline in HSS7 at Week 12  
 Time to  5 point decrease (clinically relevant 
decrease) in ISS7  
 Proportion of participants with complete UAS7 
response (UAS7 = 0) at Week 12  
 Measures of angioedema activity at Week 12 in 
participants with angioedema at baseline  
 Change from baseline in UCT at Week 12 
To evaluate the effect of benralizumab on patient-
reported health-related quality of life measures in 
patients with CSU who are symptomatic despite the 
use of H1 antihistamine treatment. 
 Change from baseline in CU-Q2oL at Weeks 12 and 
24 
 Change from baseline in DLQI at Weeks 12 and 24 
 

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Table 4 
Study Objectives 
To assess the PK and immunogenicity of 
benralizumab 30 mg and 60 mg in patients with CSU 
who are symptomatic despite the use of H1 
antihistamine treatment. 
 Serum benralizumab concentration 
 ADA 
 
To evaluate the longer-term effect of benralizumab 
compared to placebo at Week 24 on measures of 
clinical efficacy in patients with CSU who are 
symptomatic despite the use of H1 antihistamine 
treatment. 
 Change from baseline in ISS7 at Week 24 
 Change from baseline in UAS7 at Week 24 
 Proportion of responders (UAS7  6) at Week 24  
  Change from baseline in HSS7 at Week 24 
 Proportion of participants with complete UAS7 
response (UAS7 = 0) at Week 24  
 Measures of angioedema activity at Week 24 in 
participants with angioedema at baseline 
 Change from baseline in UCT at Week 24 
To evaluate the efficacy of administration of 
benralizumab Q8W versus Q4W up to Week 52 in 
patients with CSU who are symptomatic despite the 
use of  H1 antihistamine treatment. 
Change from baseline in ISS7 at Week 52 
Other supportive efficacy assessments at Week 52 in 
participants on a Q8W dosing regimen compared to 
those on a Q4W dosing regimen. 
Safety Objective: 
Endpoint/variable: 
To assess the safety and tolerability of benralizumab 
in patients with CSU who are symptomatic despite 
the use of H1 antihistamine treatment. 
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, and clinical laboratory values. 
Assessments related to AEs cover: 
 Occurrence/frequency 
 Relationship to IP as assessed by Investigator 
 Intensity 
 Seriousness 
 Death 
 AEs leading to discontinuation of IP 
 
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height. 
Assessments related to vital signs cover: 
 Observed value 
 Absolute and percent change from baseline values 
over time 
Tertiary/exploratory 
Endpoint/variable: 
To evaluate the effect of benralizumab compared to 
placebo on healthcare resource utilisation due to CSU 
in patients with CSU who are symptomatic despite 
the use of H1 antihistamine treatment. 
Rate of CSU-related healthcare resource utilisation 
during the study 
To evaluate the effect of benralizumab compared to 
placebo on overall severity of disease patients with 
CSU who are symptomatic despite the use of H1 
antihistamine treatment. 
Change from baseline in PGI-S score at Week 12 and 
at Week 24 

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analyses may be performed to report data accumulated during the extension part of the study if 
needed to support end of Phase 2 decision making. Participants and investigators will remain 
blinded to the treatment and regimen (refer to Section 4.1.2) until the final DBL. 
For an overview of the study design, see Figure 2. For details of the treatments administered 
and dosing regimen during the study, see Section 4.1.2 and Figure 3. For details of the 
efficacy and safety endpoints, see Section 3. 
4.1.1 
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 clinical study 
protocol (CSP) and should be implemented only during cases of civil crisis, natural disaster, 
or public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study participants become infected with 
SARS-CoV-2 or similar pandemic infection) which would prevent the conduct of 
study-related activities at study sites, thereby compromising the study site staff or the 
participant¶s ability to conduct the study. The investigator or designee should contact the 
study Sponsor representative to discuss whether the mitigation plans below should be 
implemented. The study participants will be required to complete the screening and 
randomization visits on site prior to having the option to participate in the mitigation plans.   
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 participants, 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 
participant¶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). 
 
Telemedicine visit: Remote contact with the participants 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 participant or the participant¶s caregiver, if possible. 
Additional information related to the visit can be obtained via telemedicine. 
 
If patient testing is performed due to the public health crisis the results may be 
documented for this study. 

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For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix F.  
4.1.2 
Investigational Product Dosing Regimen 
Participants who meet entry criteria will be randomised 3:3:3:3:4 by the interactive voice/web 
response system (Interactive Voice Response System [IVRS]/Interactive Web Response 
System [IWRS]) to one of the 5 treatment sequences described in Section 4.1. 
Figure 3 presents an overview of the IP that will be administered for each randomised 
treatment group. 
 

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Dosing Regimen at Visits 2, 3, and 4 (Initial Double-blind 12-week Treatment Period)  
All participants will receive randomised double-blind study medication Q4W at Visits 2 ,3 
and 4 (ie, Weeks 0, 4, and 8; Figure 3). 
Dosing Regimen at Visits 5, 6, and 7 
Participants randomised to receive either 60 mg or 30 mg benralizumab during the initial 12-
week period will receive 30 mg benralizumab Q4W at Visits 5, 6 and 7 (ie, Weeks 12, 16 and 
20; Figure 3). 
Participants receiving placebo will continue to receive placebo (Figure 3). 
Dosing Regimen at Visits 8 Through 14 
At Week 24 (Visit 8), participants initially randomised to benralizumab 60 mg or 
benralizumab 30 mg will receive benralizumab 30 mg Q4W or Q8W according to their 
original randomisation at Week 2. Participants randomised to the Q8W regimen will receive 
placebo at Week 24 and benralizumab 30 mg at Week 28 (Figure 3). 
At Weeks 24, 28, and 32 (ie, Visits 8, 9 and 10), participants initially randomised to placebo 
will receive benralizumab 30 mg Q4W. At Week 36 (ie, Visit 11), participants randomised 
initially to placebo will receive benralizumab 30 mg Q8W; these participants will receive 
placebo at Week 36 and benralizumab 30 mg at Week 40 (Visit 12) (Figure 3). 
Participants transitioned to the benralizumab 30 mg Q8W dosing regimen will remain on the 
Q8W dosing regimen. Participants will continue to receive SC injections Q4W at the study 
site visits; thus, participants receiving benralizumab 30 mg Q8W will receive placebo at every 
other site visit (Figure 3). 
The final dose of benralizumab or placebo will be administered at Week 48 (Visit 14). 
4.2 
Scientific Rationale for Study Design 
This is a Phase 2b study designed to evaluate the efficacy and safety of benralizumab in the 
treatment of participants with CSU. 
This study¶s inclusion/exclusion criteria and run-in period are designed to capture a 
population appropriate for treatment with benralizumab, that is participants with chronic 
spontaneous urticaria that are symptomatic despite treatment with H1 antihistamine. Both 
patient-reported symptoms and prior diagnosis of disease will be captured to ensure the 
participant population is appropriate for the study and to establish baseline measurements for 
determining clinical effect. 
The study¶s initial randomised, double-blind, placebo-controlled, parallel-group treatment 
period is designed to demonstrate the efficacy and safety of benralizumab. This design is 

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considered the gold standard for demonstrating efficacy and safety without bias in a clinical 
trial. The duration of the placebo-controlled period is limited to 24 weeks as it is considered 
the maximum duration of treatment with placebo that is ethically appropriate in this disease. 
The primary endpoint chosen is change in (itch severity score) ISS7 score from baseline to 
Week 12. The ISS7 is the itch subscore of UAS7. UAS7 is the commonly used diary-based 
patient-reported outcome measure that assesses the severity of the key sign (wheals) and 
symptom (pruritus) of CSU. UAS7 is recommended by international guidelines to be used in 
clinical practice to determine disease activity and response to treatment. The ISS7 is 
considered to be more clinically relevant than the UAS7 because improvements in UAS7 
could potentially be driven by decreasing number of hives without corresponding 
improvement in symptoms of itch. Therefore, ISS7 is considered to directly assess a benefit to 
participants and has been used in clinical trials for the registration of other products for the 
treatment of CSU. Onset of effect is important for patients, and the assessment at 12 weeks 
has been chosen as primary analysis based on results of a Phase 2a study that showed 
improvements in skin-related symptoms and eosinophil depletion in skin biopsies after 12 
weeks of treatment with benralizumab (Kuang et al 2019). Additional secondary endpoints are 
included to provide a complete picture of the efficacy achieved with benralizumab treatment. 
Assessments of the benefits of benralizumab at 24 weeks is included to determine if efficacy 
observed in the initial 12-week period is sustained through Week 24. 
The 28-week extension period will provide an opportunity to evaluate the effect of a Q8W 
maintenance dosing regimen versus that of the Q4W dosing regimen for comparison over the 
longer-term treatment period. To provide a preliminary evaluation of the efficacy and safety 
of the approved severe asthma dosing regimen when administered to patients with CSU, 
participants in the placebo group during the previous 24-week treatment period will switch to 
benralizumab 30 mg treatment and will receive 3 doses Q4W followed by Q8W dosing for the 
duration of the extension period. 
4.3 
Justification for Dose 
The pharmacokinetics (PK) of benralizumab are well-characterised (Wang et al 2017), and 
benralizumab is expected to demonstrate consistent PK across different disease populations. 
The safety and tolerability of a range of doses of benralizumab have been demonstrated. In 
Phase 3 asthma studies, over 3500 patients have received benralizumab 30 mg. In Phase 2 and 
3 studies in participants with chronic obstructive pulmonary disease, over 1100 participants 
have received benralizumab 30 mg, and over 1100 participants have received benralizumab 
100 mg. No dose-limiting safety issues have been identified with dosing in clinical studies up 
to 100 mg Q8W for 52 weeks (refer to the Investigator Brochure for details). 
The approved dosing regimen of benralizumab in severe asthma is 30 mg Q4W for the first 3 
doses, followed by 30 mg Q8W thereafter. In adult and adolescent patients with severe asthma 

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Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be randomised to IP. Under no circumstances can there be exceptions to 
this rule. Participants who do not meet the entry requirements are screen failures (Section 5.4). 
In this protocol, ³enrolled´ is defined as a participant¶s agreement to participate in a clinical 
study following completion of the informed consent process. ³Randomised´ participants are 
defined as those who undergo randomisation and receive a randomisation number. 
For procedures for withdrawal of incorrectly enrolled participants, refer to Section 7.1.2. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent/Age/Gender 
1 
Provision of the signed and dated written informed consent of the participant prior to any 
mandatory study-specific procedures, sampling, and analyses. The informed consent 
process is described in Appendix A 3. 
2 
Adult participants  18 years of age at the time of signing the Informed Consent Form 
(ICF). 
 
Type of Participants and Disease 
3 
Physician-confirmed diagnosis of CSU (also known as chronic idiopathic urticaria) for at 
least 6 months prior to screening (Visit 1). 
4 
Presence of pruritus and wheals for at least 6 consecutive weeks prior to screening  
(Visit 1), despite receiving standard of care, which may include second generation H1 
antihistamines (at approved or up to 4-times approved doses) as monotherapy or in 
combination with LTRAs and/or H2 blockers. 
5 
Symptomatic during run-in, defined by the following: 
(a) UAS7 total score of  16 with an ISS7 of  8, during the 7 days prior to 
randomisation (Visit 2) 
(b) In-clinic UAS total score of  4 on at least one of the screening days. 
6 
Willing to use a second-generation H1 antihistamine at the approved dose and as 
monotherapy (Section 6.5.1) from the screening visit (Visit 1) until the end of the study. 
7 
Participants must complete daily PRO assessments and meet the following compliance 
criteria: 
(a) Complete at least 80% of daily PRO assessments between Visit 1 and Visit 2 and 
(b) Complete at least 6 of 7 daily PRO assessments in the 7 days prior to Visit 2. 

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8 
Compliance with the locally-approved dose of antihistamine (see Section 6.5.1), 
maintained at randomisation. 
 
Reproduction 
9 
Females of childbearing potential (FOCBP) must agree to use a highly effective method 
of birth control (confirmed by the Investigator) from randomisation, throughout the study 
duration, and within 12 weeks after last dose of IP and have a negative serum pregnancy 
test result on Visit 1. 
Highly effective methods of birth control include: 
(a) Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, or transdermal. 
(b) Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, or implantable. 
(c) Intrauterine device. 
(d) Intrauterine hormone-releasing system. 
(e) Bilateral tubal occlusion or ligation. 
(f) Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the participant). 
(g) Vasectomised sexual partner (provided that partner is the sole sexual partner of the 
FOCBP study participant and that the vasectomised partner has received medical 
assessment of the surgical success). 
10 Females not of childbearing potential are defined as females who are either permanently 
sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are 
postmenopausal. Females will be considered postmenopausal if they have been 
amenorrhoeic for  12 months prior to the planned date of randomisation without an 
alternative medical cause. The following age-specific requirements apply: 
(a) Females < 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle-stimulating hormone (FSH) levels in the postmenopausal 
range. Until FSH is documented to be within menopausal range, the participant 
should be treated as a FOCBP. 
(b) Females  50 years old will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatment. 
 

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5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
Participants with predominant inducible urticaria, ie, urticaria that is predominantly due to 
a clearly defined stimulus (eg, pressure [dermographism], delayed pressure, cold, heat, 
sunlight, vibration, water, physical exercise, or increased body temperature [cholinergic]). 
2 
Participants with diseases, other than chronic urticaria, with urticaria or angioedema 
symptoms such as urticaria vasculitis, erythema multiforme, cutaneous mastocytosis 
(urticaria pigmentosa) and hereditary or acquired angioedema (eg, due to C1-inhibitor 
deficiency). Additionally, any other skin disease associated with chronic itching and/or 
skin lesions that, in the investigators opinion, might influence the study evaluations and 
results (eg, atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, senile 
pruritus, etc.). 
3 
Current malignancy, or history of malignancy, with the exception of: 
(a) Participants who have had basal cell carcinoma, localised squamous cell carcinoma 
of the skin, or in situ carcinoma of the cervix are eligible provided that the participant 
is in remission and curative therapy was completed at least 12 months prior to the 
date informed consent, was obtained. 
(b) Participants who have had other malignancies are eligible provided that the 
participant is in remission and curative therapy was completed at least 5 years prior to 
the date informed consent, was obtained. 
4 
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: 
(a) Affect the safety of the participant throughout the study 
(b) Influence the findings of the studies or their interpretations 
(c) Impede the participant¶s ability to complete the entire duration of study. 
5 
History of anaphylaxis to any biologic therapy or vaccine. 
6 
 A helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent is obtained that has not been treated with, or has failed to respond to standard of 
care therapy. 
7 
Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening/run-in period which, in 
the opinion of the Investigator, may put the participant at risk because of his/her 
participation in the study, or may influence the results of the study, or the participant¶s 
ability to complete entire duration of the study. 

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8 
Current active liver disease: 
(a) 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 participant 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. 
(b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level  3 times 
the upper limit of normal (ULN), confirmed by repeated testing during the run-in 
period. Transient increase of AST/ALT level that resolves by the time of 
randomisation is acceptable if in the Investigator¶s opinion the participant does not 
have an active liver disease and meets other eligibility criteria. 
9 
A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test. 
 
Prior/concomitant Therapy 
10 Use of immunosuppressive medication, including, but not limited to: methotrexate, 
cyclosporine, azathioprine, topical and systemic corticosteroids within 4 weeks or 
5 half-lives prior to the date informed consent is obtained, whichever is longer. 
11 Known history of allergy or reaction to any component of the IP formulation. 
 
Other 
12 Receipt of immunoglobulin or blood products within 30 days prior to the date informed 
consent is obtained 
13 Receipt of any marketed (eg, omalizumab) or investigational biologic within 4 months or 
5 half-lives prior to the date informed consent is obtained, whichever is longer. 
14 Receipt of live attenuated vaccines 30 days prior to the date of randomisation 
15 Receipt of any investigational nonbiologic within 30 days or 5 half-lives prior to the date 
informed consent is obtained, whichever is longer 
16 Previously received benralizumab (MEDI-563, FASENRA) 
17 Change to allergen immunotherapy or new allergen immunotherapy within 30 days prior 
to the date of informed consent and anticipated changes in immunotherapy throughout the 
study 
18 Planned elective major surgical procedures during the conduct of the study 
19 Previous randomisation in the present study 
20 Concurrent enrollment in another clinical trial 
21 AstraZeneca staff involved in the planning and/or conduct of the study 

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22 For females only: Currently pregnant, breastfeeding, or lactating females 
(a) A serum pregnancy test will be done for FOCBP at Visit 1 and a urine pregnancy test 
must be performed for FOCBP at each treatment visit prior to IP administration. A 
positive urine test result must be confirmed with a serum pregnancy test. If serum test 
is positive, the participant should be excluded. 
 
5.3 
Lifestyle Considerations 
Females of childbearing potential must use highly effective contraceptive methods throughout 
the study and at least for 12 weeks after last administration of the IP, as stated in inclusion 
criterion 9, Section 5.1. 
Participants must abstain from donating blood, plasma, or platelets from the time of informed 
consent and for 12 weeks after last dose of IP. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria not fulfilled, and any SAE. A pregnancy 
test is not required for FOCBP who are screen failures. 
These participants should have the reason for study withdrawal recorded as µScreen Failure¶ 
(ie, participant does not meet the required inclusion/exclusion criteria) in the eCRF. This 
reason for study withdrawal is only valid for screen failures and not randomised participants. 
5.4.1 
Re-screening 
If the reason for screen failure can be resolved (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits, transient 
events during the screening period that contraindicate IP dosing, etc), participants may 
potentially be re-screened. These cases must be discussed with the AstraZeneca study 
physician prior to randomisation and documented in the Investigator Study File. 
Re-screening of a participant for any reason will also be allowed only upon approval of the 
AstraZeneca study physician and allowed only once per participant. A documented approval 
for re-screening should be filed in the Investigator Study File. 

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Re-screened participants should be assigned the same participant number as for the initial 
screening, meaning that the participant should keep the same E-code as was originally 
assigned. 
Re-screened participants should sign a new ICF. All procedures from the screening period 
should be repeated (eg, a serum pregnancy test must be completed for FOCBP). 
6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. Study intervention in this study refers to benralizumab and placebo, both 
provided in a prefilled syringe. 
6.1 
Study Interventions Administered 
6.1.1 
Investigational Products 
Descriptions of the IPs are provided in Table 5. 
Table 5 
Investigational Products 
 
Study Intervention 
 
Benralizumab 
Placebo 
Dosage 
formulation 
Benralizumab 30 mg/mL solution (20 mM 
L-histidine/L-histidine hydrochloride 
monohydrate, 0.25 M trehalose dihydrate 
and 0.006% [w/v] polysorbate 20, pH 6.0) 
for injection in APFS, 1 mL fill volume 
Matching placebo solution (20 mM 
L-histidine/L-histidine hydrochloride 
monohydrate, 0.25 M trehalose dihydrate 
and 0.006% (w/v) polysorbate 20, pH 6.0) 
for injection in an APFS, 1 mL fill volume 
Route of 
Administration 
Subcutaneous injection 
Subcutaneous injection 
Dosing 
Instructions 
Benralizumab active solution will be 
administered subcutaneously to participants 
by health care professionals using an APFS 
Placebo solution will be administered 
subcutaneously to participants by health 
care professionals using an APFS 
Use 
Experimental 
Placebo-comparator 
IMP and NIMP 
IMP 
IMP 
Sourcing 
AstraZeneca 
AstraZeneca 
Packaging and 
Labelling 
Study intervention will be provided in an 
APFS. 
Each syringe will be labelled in accordance 
with GMP Annex 13 and per country 
regulatory requirement. 
Study intervention will be provided in an 
APFS. 
Each syringe will be labelled in 
accordance with GMP Annex 13 and per 
country regulatory requirement. 

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APFS, accessorised pre-filled syringe; GMP, Good Manufacturing Practice; IMP Investigational Medicinal 
Product; NIMP Non-Investigational Medicinal Product; w/v, weight by volume. 
 
Before IP Administration 
All applicable visit procedures, including collection of 
, PK, and ADA samples and 
on-site PRO assessments, should be completed prior to IP administration. 
Prior to each IP administration: 
 
For FOCBP, the urine pregnancy test must be performed; IP will be administered only 
when the result of the test is negative (see Section 8.2.1.1). 
 
Investigator, or designee, will evaluate the participant's condition for potential 
contraindications for dosing (see Section 6.5.4). 
 
Investigator, or designee, will assess the injection site as per standards of medical care. 
 
IP Administration 
The IP will be administered SC as 2 single injections via the accessorised prefilled syringe 
(APFS) by the Investigator, or designee during the initial 12-week treatment period; a single 
SC injection will be administered thereafter (Section 4.1.2). 
During the initial 12-week treatment period, the 2 injections will be administered at the same 
anatomical site with a distance of at least 3 cm between the 2 injections. It is advised that the 
site of IP injection be rotated such that the participant receives IP at a different anatomical site 
at each treatment visit. Suggested injection site rotation sequence is presented below (see 
Figure 4). The injection site must be documented in the source at each treatment visit and 
recorded in the electronic case report form (eCRF). The date and time of all IP 
administrations, as well as any missed doses, should be recorded in the appropriate section of 
the eCRF. 

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The participant has an intercurrent illness that, in the opinion of the Investigator, may 
compromise the safety of the participant in the study. 
 
The participant has signs of a clinically significant infection. Benralizumab should not be 
administered to a participant with a clinically significant active infection treated with oral 
or IV antimicrobials, antivirals, or antifungals until it is confirmed by the Investigator that 
the infection has resolved. 
 
The participant is febrile (  38°C;  100.4°F) within 72 hours prior to IP administration. 
 
Any event or laboratory abnormality that, in the opinion of the Investigator or 
AstraZeneca, contraindicates dosing or could result in complications. 
 
It is recommended that the AstraZeneca study physician, or designee, be contacted in case of 
any questions. 
When IP dosing needs to be postponed, it is recommended that all scheduled treatment visit 
procedures (except for IP administration) are still performed within the visit window. 
Re-scheduled IP dose can then be administered at an unscheduled visit. The vital signs 
assessments are the minimum procedures to be performed at this visit. It may also include 
remaining visit procedures (not performed at the scheduled visit) and additional assessments 
as deemed necessary by the Investigator. 
If the visit procedures cannot be conducted within the window (eg, the participant is unable to 
attend the study site), then the entire visit will be re-scheduled along with IP dose. 
If a dose is significantly delayed, it is recommended to keep at least a 2-week interval before 
the next dose. If a postponed dose overlaps with the next treatment visit window, the 
postponed dose will be skipped, and the next dose of IP given at the regularly scheduled visit. 
The visit schedule will always be calculated from the randomisation visit date. 
If 2 or more doses (consecutive or non-consecutive) of IP are missed, a conversation between 
the Investigator and the AstraZeneca study physician should take place to review treatment 
compliance and decide on the participant's further disposition. All participants, regardless of 
whether they remain on IP or not, will be encouraged to remain in the study through the end of 
the treatment period (Visit 16). Discontinuation procedures are described in Section 7.1.1). 
6.2 
Preparation/handling/storage/accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment and only authorised site 
staff may supply or administer study treatment. All study treatments must be stored in a 

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secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the Investigator and authorised site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 
6.2.1 
Preparation and Handling of Investigational Product 
The IP will be administered at the study site, on treatment visits, and within visit windows as 
specified in the SoA (Table 2). The IP will be supplied to the site in kits with an APFS of 
either benralizumab or placebo. Each kit will have a unique identifier (ID) that is printed on 
all labels within the kit (ie, the outer carton label and the label of each container within the 
carton). 
Only participants randomised to the study may receive IP and only authorised site staff may 
dispense and administer IP. 
6.2.2 
Shipping and Storage 
All shipments of IP include a data logger which will allow the Investigator, or designee, to 
confirm that appropriate temperature conditions have been maintained during transit for all IP 
received. Any discrepancies must be reported and resolved before use of the IP. 
In the following cases, the site staff should not use affected IP and should immediately contact 
the AstraZeneca representative for further guidance: 
 
Temperature excursion upon receipt or during storage at the study site 
 
Damaged kit upon receipt 
 
Damaged syringe/cartridge 
 
Damaged or temperature excursed IP should be documented using the IVRS/IWRS (please 
refer to IVRS/IWRS manual and the Pharmacy manual for further details). 
All IP (ie, benralizumab and matching-placebo) must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, in the original outer container. The IP 
(ie, benralizumab and matching-placebo) must be kept under conditions specified on the label 
(refrigerated between 2°C to 8°C [36°F to 46°F], protected from light, and must not be 
frozen), with access limited to the Investigator and authorised site staff. The temperature 
should be monitored on a daily basis and documented in the temperature monitoring log. 

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6.2.3 
Accountability 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
A site monitor will account for all IP received at the site, for unused IP, and for appropriate 
destruction of unused study treatments. Any unused kits will be destroyed locally (for further 
details, refer to the Pharmacy Manual). Documentation of IP delivery and destruction should 
be maintained according to applicable AstraZeneca and institution procedures. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual (provided to the sites). In the case of a malfunctioning IP 
APFS device, the site should contact the study monitor to initiate a product complaint process 
according to applicable guidelines. 
6.3 
Measures to Minimise Bias: Randomisation and Blinding   
6.3.1 
Randomisation 
All participants will be centrally assigned to randomised IP using an IVRS/IWRS. 
Randomisation codes will be assigned strictly sequentially in each stratum as participants 
become eligible for randomisation. Randomisation will be stratified by region. Participants 
who fail to meet the inclusion/exclusion criteria should not, under any circumstances, be 
randomised or receive IP. There can be no exceptions to this rule. Participants may be 
rescreened under certain conditions (Section 5.4.1). 
If a participant withdraws from the study, then his/her enrollment/randomisation code cannot 
be reused unless the participant is rescreened. Withdrawn participants will not be replaced. 
6.3.2 
Blinding 
Benralizumab and placebo will not be visually distinct from each other. All packaging and 
labelling of the IP will be done in such a way as to ensure blinding for all AstraZeneca, 
AstraZeneca representative and investigational site staff. Neither the participant nor any of the 
Investigators, AstraZeneca or the AstraZeneca representative staff who are involved in the 
treatment, clinical evaluation, and monitoring of the participants will be aware of the 
treatment received. Since benralizumab and placebo are not visually distinct, IP will be 
handled by an appropriately qualified member of the study team (eg, pharmacist, Investigator, 
or designee) at the site. 
Benralizumab is available only as a 30 mg dose in a prefilled syringe. Since the 60 mg 
treatment requires 2 SC injections, all participants will receive 2 injections during the initial 
12-week treatment period (ie, at Visits 2, 3, and 4) to maintain the blind: 

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Participants randomised to the benralizumab 30 mg group will receive one benralizumab 
30 mg injection and one placebo injection 
 
Participants randomised to the benralizumab 60 mg group will receive 2 benralizumab 30 
mg injections 
 
Participants randomised to the placebo group will receive 2 placebo injections 
 
All participants will receive one SC injection at Visit 5 through Visit 16 (End of Treatment 
[EOT]). During the extension period, participants receiving benralizumab 30 mg Q8W will 
receive a placebo injection at every other site visit; thus, the investigational staff, participants, 
and AstraZeneca will remain blinded to the participant¶s dosing regimen (refer to 
Section 4.1.2 for details on dosing regimens). 
A site monitor will perform IP accountability. If the treatment allocation for a participant 
becomes known to the Investigator or other study staff involved in the management of study 
participants or needs to be known to treat an individual participant for an AE, the AstraZeneca 
representative must be notified promptly by the Investigator and before unblinding (if 
possible). 
The following personnel will have access to the randomisation list during the study, prior to 
the primary DBL: 
 
Those generating the randomisation list 
 
Personnel at the IWRS/IVRS company 
 
The AstraZeneca supply chain department 
 
Participant safety department at AstraZeneca 
 
Bioanalytical laboratory performing the PK and ADA sample analysis 
 
The information in the randomisation list will be kept from other personnel involved in the 
conduct of the study in a secure location until the after primary DBL. No other member of the 
extended study team, including AstraZeneca, or any Contract Research Organisation handling 
data, will have access to the randomisation scheme during the conduct of the study. 
Maintaining the Blind to the Participant¶s Blood Eosinophil and Basophil Counts and 
Blood eosinophil-derived neurotoxin (EDN) Level 
Participants on active benralizumab treatment are expected to have lower eosinophil and 
basophil blood counts and lower levels of blood EDN than participants on placebo based on 
its established mechanism of action. Procedures to prevent unblinding based on eosinophil and 
basophil counts  and blood EDN levels will be in place during the induction, maintenance, and 
extension treatment periods (from Week 0 through Week 52): 

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however, this may not be mandatory and should not cause any delay in unblinding in case of 
emergencies. The treatment assignment will be unblinded by the Investigator through 
IVRS/IWRS. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to IP and that potentially require expedited reporting to 
regulatory authorities. Randomisation codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented. 
6.4 
Study Intervention Compliance 
Participants are dosed at the site, receiving study intervention directly from the Investigator or 
designee, under medical supervision. The administration of all study treatments should be 
recorded in the appropriate section of the eCRF. The study treatment provided for this study 
will be used only as directed in this Clinical Study Protocol (CSP). 
The IP will be administered at the study site on treatment visits and within visit windows as 
specified in the SoA (Table 2). Any change from the dosing schedule, dose interruptions, or 
dose discontinuations must be recorded in the eCRF; dose modifications are prohibited. Sites 
should call participants 1 to 2 days before each visit to remind the participant of the visit. 
6.5 
Concomitant Therapy 
Any prior biologic medication(s) and concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the eCRF, along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency 
 
Investigator, or designee, will collect and record information about concomitant 
medications as follows: 
 
Background long-acting H1 antihistamines 
 
All other medications taken for any reason in the 3 months prior to Visit 1 (except for 
prior biologic medication[s], which will be collected regardless of the time of 
administration) 
 
Concomitant treatments given during the study (at each study visit). 
 

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6.5.1 
Background Medication 
From Visit 1 and throughout the study, participants will be required to maintain stable, locally 
approved second generation H1 antihistamine treatment for CSU. The permitted doses allowed 
during the study are: 
 
Cetirizine hydrochloride tablets, 5 or 10 mg once daily (QD) 
 
Levocetirizine dihydrochloride 2.5 or 5 mg QD  
 
Fexofenadine 60 mg twice per day or 180 mg QD, 
 
Loratadine 10 mg QD 
 
Desloratadine 5 mg QD. 
 
6.5.2 
Other Concomitant Treatment 
Medication other than that described in Section 6.5.1 (CSU therapy), which is considered 
necessary for the participant¶s safety and well-being, may be given at the discretion of the 
Investigator and must be recorded in the appropriate sections of the eCRF. 
6.5.3 
Rescue Medication 
Throughout the study (ie, from the screening visit to end of treatment visit), participants are 
permitted to take additional doses of pre-randomization background medication on days on 
which symptoms are intolerable. Increase in background antihistamine will be allowed up to 
four times the labelled dose as permitted by local regulations and as directed by the 
investigator. A switch of the rescue medication for an individual participant is not permitted. 
The participants will be instructed on the use of rescue medication for CSU symptoms that are 
severe enough to impact normal daily activities and how rescue use should be recorded in the 
ePRO device. 
The number of tablets of the rescue medication taken is recorded in the handheld ePRO device 
as part of the UPDD. 
6.5.4 
Restrictions 
Use of any of the following concomitant treatments will not be permitted throughout the study 
duration, unless otherwise specified: 
 
Immunosuppressive medication including corticosteroids (other than for treatment for 
AEs where no alternative treatment is available); see µangioedema¶ below. 
 
Topical immunosuppressive medications for non-CSU related dermatological 
conditions (eg, poison ivy) may be permitted for short term use (7 days). 
 
Topical antihistamines. 

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Intravenous and/or oral first generation antihistamines (eg, cetirizine hydrochloride IV 
injection and diphenhydramine); see µangioedema¶ below. 
 
Leukotriene inhibitors or H2 blockers as treatments for CSU are prohibited within 7 days 
prior to Day -14. 
 
Regular (daily/every other day) doxepin (oral) use is prohibited within 14 days prior to 
Day -14. 
 
Plasmapheresis is prohibited within 30 days prior to screening. 
 
Receipt of live attenuated vaccines is not allowed within 30 days prior to randomisation, 
during the treatment period, and for 12 weeks after the last dose of IP. 
 
Receipt of inactive/killed vaccinations (eg, inactive influenza) is allowed provided they 
are not administered within 1 week before/after any IP administration; additionally, it is 
recommended to rotate the next IP site injection to a site distant from the vaccine site 
injection. 
 
Any marketed or investigational biologic (monoclonal or polyclonal antibody) is not 
allowed within 4 months or 5 half-lives (whichever is longer) prior to randomisation, 
during the treatment period, and is not ideally recommended within 4 months or 5 half-
lives (whichever is longer) after the last dose of the IP. 
 
Other IPs for 30 days prior to randomisation and during the study period. 
 
Oral first-generation antihistamines may also be necessary as treatment for clinically 
significant CSU-related angioedema. Treatment for life threatening CSU-related angioedema, 
posing a risk to the airways may include systemic glucocorticoids and/or IV antihistamines. 
These participants may require discontinuation of IP and should be discussed with study 
physician/sponsor. 
Participants should not receive allergen immunotherapy on the same day as the IP 
administration. 
6.6 
Dose Modification 
Modification of the dose (benralizumab or placebo) is not permitted.  
6.7 
Intervention After the End of the Study 
After the end of the study, the participant should be given standard of care therapy according 
to local practice, at the discretion of the Investigator. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention  
Participants who prematurely discontinue from IP will be asked to come in for all visits and 
study assessments at the IP Discontinuation (IPD)/EOT visit. 

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Discontinuation from IP does NOT automatically lead to a complete withdrawal from the 
study. Participants discontinuing from IP are strongly encouraged to continue in the study up 
to the study completion (Visit 17, Week 60) as described in Section 7.1.1. 
Participants will be discontinued from IP in the following situations: 
 
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. The participant should always be asked about the reason(s) 
and presence of any AEs. 
 
AE that, in the opinion of the Investigator, contraindicates further dosing 
 
Severe non-compliance with the CSP 
 
Risk to participant as judged by the Investigator or AstraZeneca 
 
Pregnancy  
 
IP unblinding 
 
Development of any of the following study-specific criteria for discontinuation: 
 
Anaphylactic reaction to IP administration, in the opinion of the Investigator, 
requiring administration of epinephrine 
 
Development of helminth parasitic infestation requiring hospitalisation. 
 
Refer to the SoA (Table 2) and Section 7.1.1 (IPD visit) for data to be collected at the time of 
IPD and follow-up and for any further evaluations that need to be completed.  
The reason for premature discontinuation of IP should be documented in the source 
documentation and recorded in the eCRF. 
7.1.1 
Procedures for Early Discontinuation of Study Intervention and at End 
of Study 
A participant who decides to discontinue IP should always be asked about the reason(s) and 
the presence of any AEs. The reason for discontinuing treatment and the date of last IP 
administration should be recorded in the eCRF. Participants permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of 
the Investigator. Participants who discontinue IP at any time will be allowed to modify their 
antihistamine background therapy and still be followed at study visits. Discontinuation of IP 
will be captured in the eCRF. 
See the SoA (Table 2) for data to be collected at the IPD visit and for any further evaluations 
to be completed. 

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7.1.1.1 
Early Discontinuation of Study Intervention 
All participants who prematurely discontinue IP should return to the study site for IPD visit 4 
weeks ( ± 7 days) after the last dose of IP for procedures, or as soon as feasible if this interval 
is missed (eg, if decision on discontinuation was made later), as described in Table 2. 
At the IPD visit, the participant will be offered the following options for further follow-up: 
 
Participants are encouraged to return to all scheduled site visits and perform all 
procedures/blood draws, but without IP administration, until end of the treatment period 
(Visit 16). 
 
If the participant is unwilling or unable to attend the scheduled site visits until the end of 
the double-blind treatment period, he/she will be offered a follow-up option that includes 
monthly telephone contact instead. During follow-up telephone contact, the Investigator 
will collect information about concomitant medications, information on CSU symptoms, 
and AE/SAE(s) (Section 8.3). 
 
7.1.1.2 
Discontinuation of Study Intervention Upon Notification of Closure of Study 
The IPD visit (4 weeks [ ± 7 days] after the last dose of IP) should be conducted for all 
ongoing participants within 3 months of notification from AstraZeneca of closure of the study 
(Section 7.2.1). 
7.1.2 
Procedures for Handling Incorrectly Enrolled or Randomised 
Participants 
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive IP. Participants who are enrolled but subsequently found not to meet all 
the eligibility criteria must not be randomised and must be withdrawn (screen failed) from the 
study. 
Where a participant does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on IP, 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 participant from IP. 
If the agreed decision is to discontinue IP, participants should be encouraged to remain in the 
study and continue to be followed-up until the end of the treatment period. 
The decision to discontinue/continue IP must be appropriately documented, including 
rationale, particularly if the agreed decision is to continue IP treatment. 

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7.2 
Participant Withdrawal from the Study 
 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon. 
 
A participant who considers withdrawing from the study must be informed by the 
Investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records). 
 
At the time of withdrawal from the study, if possible, the IPD visit should be conducted. 
See the SoA (Table 2) for data to be collected at the time of study withdrawal and follow-
up and for any further evaluations that need to be completed. 
 
The participant will discontinue the study intervention and be withdrawn from the 
study at that time. 
 
If the participant withdraws consent for disclosure of future information, AstraZeneca 
may retain and continue to use any data collected before such a withdrawal of consent. 
 
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be carried 
out in line with what was stated in the informed consent and local regulations. The 
Investigator must document the decision on use of existing samples in the site study records 
and inform AstraZeneca or their representative. 
Participants who withdraw from the study will return the handheld ePRO device. 
7.2.1 
Discontinuation or Suspension of the Whole Study Program 
If AstraZeneca decides to prematurely terminate or suspend the study, the Investigator and 
regulatory authorities should receive written notification of the reasons for the premature 
termination or suspension. The Investigator will immediately notify the decision to the 
participants and, if relevant, give appropriate medical treatment, take necessary measures, and 
document these in the source notes. 
There are no pre-specified stopping rules or criteria for this study. 
7.3 
Lost to Follow-up 
A participant will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.  

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To prevent a participant being lost to follow-up, it is recommended that the study sites 
maintain up-to-date contact details for participants, including next of kin or other emergency 
contacts (if allowed by national regulation). 
The Investigator should educate the participant on the importance of maintaining contact with 
the Investigator/study site throughout the study. 
The following actions must be taken if a participant fails to return to the site for required study 
visits: 
 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule. 
 
Repeated attempts must be made to regain contact with the participant or next of 
kin/emergency contact by repeat telephone calls, emails, and/or certified letter. These 
contact attempts should be documented in the participant¶s medical record. 
 
Efforts to reach the participant should continue until the end of the study. 
The participant will be classified as lost to follow-up only if he/she has failed to return for the 
required study visits and his/her vital status remains unknown at the end of the study, despite 
all above listed efforts. For the primary analysis purposes, a participant will be classified as 
lost to follow-up if he/she has failed to return for the required study visits and his/her vital 
status remains unknown at the time of primary DBL. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised in the SoA (Table 2).  
The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture system will be used for data collection and query handling. 
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed eCRFs 
will be archived at the study site. 
Immediate safety concerns should be discussed with the AstraZeneca representative 
immediately upon occurrence or awareness to determine if the participant should continue or 
discontinue IP. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 

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All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant¶s routine clinical management (eg, blood test, 
echocardiography, biopsy, etc.) and obtained before signing of the ICF may be utilised for 
screening or baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA. 
Note: for laboratory assessments, if not all laboratory kits are available at a given visit, the 
Investigator should contact the Study Physician to confirm whether assessment is critical or 
may be postponed until supplies are available. 
8.1 
Efficacy Assessments 
Participants will complete all PRO assessments using a handheld device. The handheld device 
will be the only accepted source of PRO data. 
The Investigator will ensure that participants are properly trained on the use of this device and 
the importance of completing assessments as scheduled. 
The handheld ePRO device will be programmed at Visit 1 with reminder alarms for the daily 
diary. Study site staff will be able to adjust alarms for specific participant needs as needed. 
The participant will be required to complete a training module before taking the device home. 
The Investigator or designee will be responsible for ensuring that the participant is completing 
the daily diary and follow-up as necessary to minimise missing data. Participant compliance 
should be checked weekly (at a minimum) to ensure that the participant is completing the 
assessments as scheduled. Monitoring of participant compliance with completion of the diary 
is critical between Visit 1 and Visit 2 to ensure that the participant meets applicable criteria 
for randomisation. If the participant does not meet the randomisation requirements, the device 
will be deactivated and retained at the site for future use. 
Review of participant compliance with the assessment schedule, completion of any available 
assessments, and logging of the visit on the handheld device should be completed prior to 
other study procedures. 
Compliance with the assessment schedule should be completed weekly throughout the study 
and follow-up with participants via phone and at the visits. Compliance review is required to 
ensure sufficient data are available for supporting the primary endpoint of this study. 
The timing and frequency for each PRO is provided in Table 3. 

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8.1.1 
Urticaria Patient Daily Diary (UPDD) 
The Urticaria Patient Daily Diary (UPDD) will be completed twice daily (morning and 
evening; Table 3) to capture key measures of urticaria disease activity. Compliance with 
twice-daily completion of the UPDD will be reviewed at every visit (Table 2). 
Participants will be asked to document twice a day (morning and evening) the intensity of itch 
and number of hives they experienced over the previous 12 hours. The criteria used to define 
itch severity score (ISS) and hives severity score (HSS), respectively, on a 0- to 3-point scale 
are shown in Table 6. 
Table 6 
Assessment of CSU disease activity in study participants 
Score 
Itch intensity 
Intensity (number) of hives 
0 
None 
None 
1 
Mild 
Mild (1 - 6 hives/12 hour) 
2 
Moderate 
Moderate (7 - 12 hives/12 hour) 
3 
Severe 
Intense (> 12 hives/12 hour) 
Scoring criteria are as defined in omalizumab Study Q4882g (EUDRACT: 2010-022785-27). 
 
The mean of the morning and evening itch scores is taken as the ISS for the day. The mean of 
the morning and evening hive scores is taken as the HSS for the day. The sum of the HSS and 
the ISS for the day is the urticaria activity score (UAS) for the day. 
ISS7 is the sum of ISS scores for the previous 7 days. UAS7 is the sum of UAS for the 
previous 7 days, ie, the sum of HSS7 and ISS7. HSS7 is the sum of HSS scores for the 
previous 7 days. 
The minimum UAS7 is 0 and the maximum is 42. The baseline UAS7 will be the sum of the 
UAS during the 7 days prior to randomisation. The UAS7 at Week 12 will be the sum of the 
daily UAS during the previous 7 days. 
In addition to the itch and hives questions, the UPDD also includes a daily yes/no question 
asking whether the participant experienced angioedema. If yes, the participant is asked a 
follow-up question about how they treated the swelling. 
8.1.2 
Urticaria Control Test (UCT) 
Urticaria disease control will be assessed by the Urticaria Control Test (UCT). The UCT is the 
first valid and reliable tool to assess disease control in participants with chronic urticaria. It 
has a retrospective approach using a recall period of 4 weeks and responses on 4-point Likert 
scales. 

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8.1.3 
Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) 
The Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) is a 23-item assessment of 
CSU-specific health-related quality of life (Baiardini et al 2005). Participants are asked to rate 
their CSU symptoms and the impact of their symptoms on several domains: Pruritus, 
Swelling, Impact on Life Activities, Sleep Problems, Limits, and Looks. Both the overall 
score and domain scores will be calculated. 
8.1.4 
Dermatology Life Quality Index (DLQI) 
The Dermatology Life Quality Index (DLQI) is a 10-item assessment of dermatology-specific 
health-related quality of life (Finlay and Khan 1994). Participants are asked to rate their 
symptoms and the impact of their symptoms on several domains: Symptoms and Feelings, 
Daily Activities, Leisure, Work and School, Personal Relationships, and Treatment. Both the 
overall score and domain scores will be calculated. 
8.1.5 
Patient Global Impression of Severity (PGI-S) 
Patient Global Impression of Severity (PGI-S) is a single item designed to capture the 
participant¶s perception of overall symptom severity at the time of completion using a 6-point 
categorical response scale (no symptoms to very severe symptoms). 
8.1.6 
European Quality of Life-5 Dimensions (EQ-5D-5L) 
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty. 
The participant will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale (VAS), where the participant will be asked to rate current health status on a 
scale of 0 to 100, with 0 being the worst imaginable health state. 
8.1.8 
Patient-Reported Experience 
Participants will be asked to respond in writing (free text) to 3 open-ended questions about 
their experience with CSU and their study intervention. The assessment will be conducted 

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during the site visits specified in Table 2, using a provisioned tablet to access the secure web 
form. 
Data from the free text collection will be used for exploratory descriptive analysis using 
machine learning technologies. Due to the qualitative nature of the data and the analysis, the 
results will be presented in a separate report (not in the Clinical Study Report [CSR]) and the 
data will not be entered into the study database. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Table 2). 
8.2.1 
Clinical Safety Laboratory Assessments 
Table 7 lists the clinical safety laboratory tests to be performed. Refer to the SoA (Table 2) for 
the timing and frequency. All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the Laboratory Manual and the SoA (Table 2).  
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
site as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.5. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded in the participant¶s medical records. 
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory. 
Instructions for sample collection, processing, storage, and shipment are provided in the 
central laboratory manual. 
Table 7 
Laboratory Safety Variables 
Clinical chemistry 
Haematology 
Urinalysis 
Alkaline phosphatase 
Gamma-GT (gamma-
glutamyl transpeptidase) 
Haematocrit 
Appearance 
ALT (alanine 
aminotransferase) 
Glucose 
Haemoglobin 
Blood 
AST (aspartate 
aminotransferase) 
Phosphorus 
Mean corpuscular 
volume (MCV) 
Color 
BUN (blood urea 
nitrogen) 
Potassium 
Platelet count 
Ketones 

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Table 7 
Laboratory Safety Variables 
Clinical chemistry 
Haematology 
Urinalysis 
Calcium 
Sodium 
Red blood cell (RBC) 
count 
Microscopy including 
White blood cell 
(WBC)/high power field 
(HPF), RBC/HPF 
Chloride 
Total bilirubin 
WBC count (absolute 
and differential) a 
pH 
CO2 (carbon dioxide) b 
Uric acid 
 
Specific gravity 
Creatinine 
Creatine kinase 
 
 
TSH (Thyroid 
Stimulating Hormone) 
 
 
 
a 
Eosinophil, basophil, and monocyte counts will be redacted from the central laboratory reports starting from 
Visit 2 (see Section 6.3.2). 
b 
Measured as bicarbonate. 
 
8.2.1.1 
Pregnancy Tests 
The following tests are applicable to female participants only and will be conducted in 
accordance with the schedules provided in the SoA (Table 2). 
 
Serum beta-human chorionic gonadotropin (HCG): To be performed for all female 
participants at Visit 1 except for those who are NOT of childbearing potential as defined 
in inclusion criterion 10. This test is to be sent to and analysed at the central laboratory. 
 
FSH: To be performed at Visit 1 only for female participants < 50 years who have been 
amenorrhoeic for  12 months prior to the planned date of randomisation to confirm 
postmenopausal status. This test is to be sent to and analysed at the central laboratory; all 
females should be treated as pre-menopausal until results are received from the central 
laboratory. 
 
Urine HCG (dipstick): To be performed locally at the study site before each IP 
administration (starting at Visit 2 through the EOT), and at IPD visits for all female 
participants except for those who are NOT of childbearing potential as defined in 
inclusion criterion 10. A positive urine test result must be confirmed with serum 
beta-HCG. 
 
8.2.1.2 
Serology 
Hepatitis B surface antigen and hepatitis C antibody tests will be assessed in accordance with 
the SoA (Table 2); test to be performed at the central laboratory. 
In case of positive result of hepatitis B surface antigen or hepatitis C virus antibody, additional 
testing (eg, hepatitis C ribonucleic acid [RNA] polymerase chain reaction test) may be 
performed. 

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HIV-1 and HIV-2 antibodies (along with p24 Antigen): To be performed only at screening; 
test to be performed at central laboratory. 
Instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
8.2.2 
Physical Examinations 
Physical examinations (complete or brief), including height (only at baseline) and weight, will 
be conducted in accordance with the schedule provided in Table 2. Baseline data will be 
collected at the randomisation visit (Visit 2) before first dose of IP. Any new findings or 
aggravated existing abnormalities, judged as clinically significant by the Investigator , will be 
reported as an AE as described in Section 8.3.5. 
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. 
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular, and respiratory system. For the brief physical examination, only 
information on whether the assessment was performed or not is to be recorded. 
Weight measurements will be performed in light clothing and without shoes and will be 
recorded in kilograms. 
8.2.3 
Vital Signs 
Pre-dose vital signs (pulse rate, blood pressure, respiratory rate, and body temperature) will be 
assessed in accordance with the SoA (Table 2). 
It is recommended that vital signs are assessed before any interventional study procedures 
(blood test collection, IP administration). 
Body temperature will be measured in Celsius in accordance with local standards. 
Blood pressure and pulse measurements will be assessed while sitting with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. The pulse rate and blood pressure will be measured after the participant has been 
resting for at least 5 minutes in a quiet setting without distractions (eg, television, cell 
phones). The pulse rate should be obtained before blood pressure. 
The respiration rate will be obtained after the participant has been resting for at least 5 
minutes, by counting the number of breaths (how many times the chest rises) for one minute. 

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8.2.4 
Electrocardiograms 
Single 12-lead electrocardiogram (ECG) will be obtained locally during screening (Table 2) 
using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and 
QT intervals. The ECG results will be interpreted locally.  
The Investigator or authorised delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. The ECG printouts will 
be signed and dated by the Investigator and stored at the study site. Any findings will be 
recorded in the eCRF. 
ECG will be taken in the supine position, after the participant has been resting for at least 
5 minutes. The assessment should be performed before interventions with the participant 
(eg, IP administration). 
8.3 
Adverse Events and Serious Adverse Events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.2. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs will be collected starting from Visit 1, throughout the treatment period, and including 
the follow-up period last contact with participant. 
Serious AEs will be recorded from the time the participant signs the ICF, throughout the 
duration of the study. All SAEs will be recorded and reported to AstraZeneca or designee 
within 24 hours, as indicated in Appendix B. The Investigator will submit any updated SAE 
data to the AstraZeneca representative within 24 hours of it being available. 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the Investigator shall, without undue delay, report the SAE to the 
AstraZeneca representative. 

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8.3.2 
Follow-up of AEs and SAEs 
Any AEs that are unresolved at the end of the study (final DBL) will be followed-up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse Event Variables 
The following variables will be collected for each AE: 
 
AE (verbatim) 
 
The date when the AE started and stopped 
 
Maximum intensity 
 
Whether the AE is serious or not 
 
Investigator causality rating against the IP (yes or no) 
 
Action taken with regard to the IP 
 
AE caused participant¶s withdrawal from study (yes or no) 
 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
 
Description of AE 
 
Date AE met criteria for SAE 
 
Date Investigator became aware of SAE 
 
AE is serious due to (see definition of SAE in Appendix B 2)  
 
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 
 
8.3.3 
Causality Collection 
The Investigator will assess causal relationship between IP and each AE, and answer µyes¶ or 
µno¶ to the question µDo you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?¶ 

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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 µyes¶. 
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 
Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: µHave you had any health problems since the 
previous visit/you were last asked?¶, or revealed by observation will be collected and recorded 
in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
8.3.5 
Adverse Events Based on Examinations and Tests 
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values and 
vital signs should therefore only be reported as AEs if they fulfill any of the SAE criteria, are 
the reason for discontinuation of treatment with the IP, or are considered to be clinically 
relevant as judged by the Investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, drug interruption). 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia 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). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 
Disease Under Study 
Symptoms of disease under study are those which might be expected to occur as a direct result 
of CSU (eg, pruritis, wheals, and angioedema). Events which are unequivocally due to CSU 

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should not be reported as an AE during the study unless they meet SAE criteria or lead to 
discontinuation of the IP. 
CSU-related angioedema is episodic and can last for hours or days with recurrence. It is 
characterized by several features (Zuberbier et al 2018): 
 
a sudden, pronounced erythematous or skin coloured swelling of the lower dermis and 
subcutis or mucous membranes, 
 
sometimes pain, rather than itch. 
 
a resolution slower than that of wheals (can take up to 72 hours). 
 
Angioedema related to CSU may be treated with rescue antihistamines (Section 6.5.3). 
Participants with angioedema with airway compromise may be treated with IV antihistamines 
and/or systemic steroids as indicated at the discretion of the investigator. The investigator will 
also need to evaluate whether the angioedema was related to CSU or an anaphylactic reaction 
(refer to Appendix E). Actions and/or treatments related to angioedema occurrences will be 
documented. In cases of life-threatening CSU-related angioedema, participants may require 
discontinuation of IP and this should be discussed with study physician/sponsor. 
8.3.7 
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 eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.  
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one 
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of 
it). 
If the electronic data capture system is not available, then the Investigator or other study site 
staff reports an SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 

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The reference document for definition of expectedness/listedness is the Investigator's 
Brochure for benralizumab.  
For further guidance on the definition of an SAE, see Appendix B. 
8.3.8 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the AstraZeneca 
representative unless the pregnancy is discovered before the study participant has received any 
IP. 
If a pregnancy is reported, the Investigator should inform the AstraZeneca representative 
within 24 hours of learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.8.1 
Maternal Exposure 
If a participant becomes pregnant during the course of the study, IP should be discontinued 
immediately. 
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 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed-up and documented even if the 
participant was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within one day (ie, immediately but no 
later than 24 hours of when he or she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (Section 8.3.7) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy. 

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8.3.9 
Device Constituent Deficiencies 
 
In a combination drug-device IP (eg, 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. 
 
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. 
 
8.3.10 
Serious Adverse Device Effect 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.  
 
8.3.11 
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 one day (ie, 
immediately but no later than 24 hours of when he or she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 

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An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel inform appropriate AstraZeneca representatives immediately, or no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.7) and within 30 days 
for all other overdoses. 
8.5 
Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples, see Appendix C. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  
 
PK samples will be disposed of after the Bioanalytical Report finalisation or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier), unless consented 
for future analyses. 
 
PK samples may be disposed of or anonymised by pooling. Additional analyses may 
be conducted on the anonymised, pooled PK samples to further evaluate and validate 
the analytical method. Any results from such analyses may be reported separately 
from the CSR. 
 
Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterisation of any ADAs, confirmation and/or requalification of the 
assay as well as additional assay development work. The results from future analysis will 
not be reported in the CSR. 
 
8.5.1 
Pharmacokinetics 
All PK samples will be collected before administration of study medication according to the 
SoA (Table 2). 

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Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
AstraZeneca and site study files but will not constitute a protocol amendment. The 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be informed of 
any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
For the PK analysis, it is important that the date, time, and location of each SC injection is 
recorded for each participant. 
Instructions for sample collection, processing, storage, and shipment are provided in the 
Laboratory Manual. 
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report. 
8.5.1.1 
Determination of Drug Concentration 
Samples for determination of benralizumab concentration in serum will be assayed by 
bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately 
validated bioanalytical method. Full details of the analytical method used will be described in 
a separate report. Only samples from the benralizumab treatment arm will be analyzed.  
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 
8.5.2 
Immunogenicity Assessments 
Blood samples for determination of ADA in serum will be assayed at the discretion of 
AstraZeneca by bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the methods used will be 
described in a separate report. 
ADA samples may also be further tested for characterisation of the ADA response. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 

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8.5.3 
Pharmacodynamics 
Blood and tissue eosinophil and basophil levels are an important marker of the 
pharmacodynamic effect of benralizumab and blood levels will be assessed as part of the 
haematology safety testing (Section 8.2.1). Tissue eosinophil and basophil levels will be 
assessed as part of the 
 
 
8.6.1.1 
Serum and Plasma 
Serum and plasma samples will be collected according to the SoA (Table 2) to evaluate the 
pharmacodynamics of benralizumab including 
 
. Additional markers of cellular inflammation 
and/or activation may be assessed including, but not limited to, those associated with T cell 
subsets (eg, IL-13, IFN- , IL-17), eosinophil granule proteins (eg, MBP, eosinophil 
peroxidase), epithelial cell damage (eg, TSLP, IL-25, IL-33), itch (IL-31), and pain (substance 
P). The results from such studies will not be reported in the CSR but in separate reports or 
publications as appropriate. 
Instructions for sample collection, processing, storage, and shipment will be found in the 
Laboratory Manual. 

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8.6.1.4 
Transcriptomic (RNA) Assessments in Blood and Skin Biopsies  
Transcriptome studies will be conducted using microarray, RNA-sequencing, and/or 
alternative equivalent technologies which facilitate the simultaneous measurement of the 
relative abundances of thousands of RNA species resulting in a transcriptomic profile for each 
blood or tissue sample. This will enable the evaluation of baseline transcript levels and disease 
activity in CSU and/or response to benralizumab as well as changes in transcriptomic profiles 
that may correlate with mechanism and therapeutic response with benralizumab.  
 
 
 

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8.8 
Healthcare Resource Utilisation 
Broad-based CSU-related healthcare resource utilisation information will be collected by the 
Investigator, or designee, in accordance with the SoA (Table 2) and recorded in the 
appropriate eCRF module. Protocol-mandated procedures, tests, and encounters are not 
included. 
At randomisation, retrospective CSU-related healthcare resource utilisation information will 
be collected with a one-year recall period. At all subsequent visits, CSU-related healthcare 
resource utilisation information will be collected with a recall period of µsince last scheduled 
visit¶. 
The data collected may be used to conduct exploratory economic analyses and include: 
 
Number and duration of medical care encounters 
 
Duration of hospitalisation (total days or length of stay, including duration by wards 
[eg, intensive care unit]) 
 
Number and type of diagnostic and therapeutic tests and procedures 
 
Outpatient medical encounters and interventions (including physician or emergency room 
visits, tests and procedures, and medications). 

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Note: Cases of hospitalisation occurring after signing of the ICF must be reported as an SAE 
(see Section 8.3). 
9 
STATISTICAL CONSIDERATIONS 
The primary DBL is targeted to occur when all participants have completed the 24-week 
double-blind treatment period. The final DBL will occur when all participants have completed 
the 52-week treatment period and the Week 60 follow-up visit and/or the IPD/EOT visit. 
An additional analysis may be performed between the primary and final DBLs, to report data 
accumulating during the extension part of the study if needed to support end of phase 2 
decision making. 
The CSR will be based on the final DBL and will include all data for the study. 
9.1 
Statistical Hypotheses 
For the primary endpoint, change from baseline in ISS7 score to Week 12, for each dose of 
benralizumab the null hypothesis (H0) is that the change in ISS7 at Week 12 on benralizumab 
is equal to the change in ISS7 at Week 12 on placebo. The alternative hypothesis is that the 
change in ISS7 with benralizumab treatment is not equal to the change in ISS7 for placebo: 
 
H0: Change from baseline ISS7 at Week 12 (benralizumab 60 mg ± Placebo)  =  0 
 
H1: Change from baseline ISS7 at Week 12 (benralizumab 60 mg ± Placebo)    0 
 
H0: Change from baseline ISS7 at Week 12 (benralizumab 30 mg ± Placebo)  =  0 
 
H1: Change from baseline ISS7 at Week 12 (benralizumab 30 mg ± Placebo)    0 
 
Hypothesis testing for the primary analyses will be performed according to the multiple 
testing procedure described in Section 9.4.6. If the p-value is less than 0.025 (or 0.05 if alpha 
can be recycled from the other dose group), the null hypothesis (H0) will be rejected and the 
alternative hypothesis (H1) will be accepted. 
A multiple testing procedure will be applied to the primary endpoint and the key secondary 
endpoints at Week 12 and Week 24; details are provided in Section 9.4.6. 
9.2 
Sample Size Determination 
Approximately 160 participants will be randomised in a ratio of 3:3:3:3:4, respectively, to 
receive one of the 5 treatment sequences as follows:  
 
Benralizumab 60 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q8W during the extension period until Week 52 (n = 30) 

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Benralizumab 60 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q4W during the extension period until Week 52 (n = 30) 
 
Benralizumab 30 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q8W during the extension period until Week 52 (n = 30) 
 
Benralizumab 30 mg Q4W until Week 12, 30 mg Q4W until Week 24, and 30 mg 
Q4W during the extension period until Week 52 (n = 30) 
 
Placebo Q4W until Week 24, benralizumab 30 mg Q4W until Week 36, and 30 mg 
Q8W until Week 52 (n = 40). 
 
Up to Week 24, ie, prior to start of the extension period evaluating Q4W and Q8W dosing 
regimens, participants in both benralizumab 60 mg initial dose treatment arms will be 
considered as a single treatment group (total n=60), as will participants in both benralizumab 
30 mg initial dose treatment arms (total n=60). Together with the 40 participants in the 
placebo treatment arm the above randomisation will provide a 3:3:2 ratio across the treatment 
group to assess the primary endpoint at Week 12. 
This provides 90% power for statistical significance at the 2-sided 2.5% level within each 
induction dose comparison versus placebo if the assumed effect is a 4.7 point mean difference 
in change in ISS7 between benralizumab and placebo, assuming a SD of 6 for the change in 
ISS7 and a 10% dropout rate. These assumptions are in line with those for previous CSU trials 
(Saini et al 2015). The proposed sample size also provides a robust dataset to assess the key 
secondary endpoints, assess potential responders in sub-populations, and make a comparative 
assessment of the Q4W and Q8W dosing regimens in the maintenance period. 
9.3 
Populations for Analyses 
The populations for purposes of analyses are defined in Table 8: 
Table 8 
Populations for Analyses 
Population 
Description 
All participants analysis set  
All participants who sign the ICF 
Full analysis set 
The full analysis set will comprise all randomised participants who receive 
at least one dose of IP, irrespective of their protocol adherence and 
continued participation in the study. Participants will be analysed according 
to their randomised treatment irrespective of whether or not they were 
prematurely discontinued, according to the ITT principle. Data for 
participants who withdraw consent to participate in the study will be 
included up to the date of permanent discontinuation. 

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Table 8 
Populations for Analyses 
Population 
Description 
Safety analysis set 
The safety analysis set will comprise all participants who receive at least 
one dose of IP. Erroneously-treated participants (eg, those randomised to 
treatment A but actually given treatment B) will be included in the group of 
the treatment they received. A participant who receives at least one dose of 
active IP will be classified as active and included in the active IP treatment 
group. A participant who receives both active dose regimens will be 
classified as the higher active dose regimen (ie, 60 mg).  
Pharmacokinetic analysis set 
All participants who received benralizumab and from whom PK blood 
samples are assumed not to be affected by factors such as protocol 
violations (eg, received wrong dose) and who had at least one quantifiable 
serum PK observation post first dose. All PK summaries will be based on 
this analysis set. 
Placebo-to-benralizumab 
extension analysis set 
All participants who received benralizumab at the start of the extension 
period who were previously on placebo. 
ICF, Informed consent form; IP, Investigational product; ITT, Intent-to treat; PK, Pharmacokinetic. 
 
9.4 
Statistical Analyses 
A comprehensive statistical analysis plan (SAP) will be developed and finalised prior to the 
primary DBL and will include a more technical and detailed description of the statistical 
analyses described below. The SAP will describe the participant populations to be included in 
the analyses and the procedures for accounting for missing, unused, and spurious data. Any 
deviations from this plan will be reported in the CSR. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
All personnel involved in the analyses of the study will remain blinded until the primary DBL 
and protocol deviations are identified. 
Analyses will be performed by AstraZeneca or its representatives. 
Categorical variables will be summarised using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population unless otherwise stated. 
Continuous variables will be summarised with descriptive statistics of number of available 
observations, mean, SD, median, minimum and maximum, and quartiles where more 
appropriate. 
All point estimates will be presented together with 95% confidence intervals (CIs) as 
measures of precision, and nominal 2-sided p-values. 

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9.4.1 
General Considerations 
All analyses across the 24-week double-blind period will include 3 treatment groups 
comprising, respectively, all participants randomised to benraliuzmab 60 mg initial dose 
(n=60), all participants randomised to benraliuzmab 30 mg initial dose (n=60) and all 
participants randomised to placebo initial dose (n=40). 
The primary efficacy analyses will be based on the double-blind, 12 week placebo-controlled 
induction period. In this part of the study and the following 12 weeks (up to Week 24) all 
efficacy analyses will use the full analysis set as defined above.  
The primary estimand, analysed using the treatment-policy strategy, is the difference in mean 
change from baseline at Week 12 in ISS7 between each benralizumab dose and placebo, using 
the full analysis set, including all data up to week 12 regardless of discontinuation of IP or 
whether use of rescue medication has or has not occurred. As all participants who prematurely 
discontinue from IP in the study are asked to come in for all visits and study assessments up to 
Week 52, the amount of missing data expected in the analysis is assumed to be low and this 
estimand strategy is considered appropriate. However, sensitivity analyses may be performed 
to assess the robustness of the efficacy results to the missing data assumptions as described in 
individual endpoint analysis methods and Section 9.4.7. 
As described above, in general, analyses will follow an Intention-to-Treat principle, and while 
changes to background medications for CSU and related treatments are discouraged, if any do 
occur, data following any changes to background therapies, or post missed doses or 
discontinuation of IP will still be included in the analyses. However, sensitivity analyses may 
be performed to assess any impact of changes in study and background medications if deemed 
appropriate. 
Demography and baseline characteristics will be summarised by treatment group for the FAS. 
If there are major differences between the FAS and safety analysis set, the summaries will 
also be repeated and presented for the safety analysis set. 
9.4.2 
Efficacy 
9.4.2.1 
Primary Endpoint 
Change from Baseline in (ISS7)  
The primary endpoint, change from baseline in ISS7 score at Week 12, will be compared 
between each benralizumab initial treatment group (60 mg and 30 mg) with placebo using 
MMRM) analyses. The dependent variable in this model will be the change from baseline in 
ISS7 at post-baseline protocol-specified visits (up to the Week 24 visit). Treatment group will 
be included as an explanatory variable along with the baseline ISS7 score, region, visit and 
treatment-by-visit interaction as fixed effects. An unstructured covariance structure will be 
used to model the within-participant errors. If the model fails to converge, the following 

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structures will be attempted in the specified order: Toeplitz, first-order autoregressive, 
compound symmetric, and variance components. Least squares mean estimates for change 
from baseline at Week 12 and differences in least squares mean estimates between the 
treatment groups and placebo will be obtained from this model. 
The missing at random assumption for the analysis is considered appropriate and justified as 
the primary estimand includes all data collected up to Week 24 in the analysis regardless of 
discontinuation of randomised treatment, as described in Section 9.4.1, and so the amount of 
missing data is expected to be low and is considered not likely to impact the primary results. 
Sensitivity analyses to alternative missing data assumptions may be performed as described in 
Section 9.4.7. 
9.4.2.2 
Secondary Endpoints 
The key secondary endpoint of change from baseline UAS7 at Week 12 for both benralizumab 
60 mg and benralizumab 30 mg treatment groups will be analysed using MMRM models in a 
similar way to that described for the primary endpoint analyses. For these analyses, the 
dependent variable will be the change from baseline in the respective continuous endpoint at 
post-baseline protocol-specified visits up to Week 24, and each analysis will include the 
relevant baseline score as a covariate as well as the other covariates listed for the primary 
endpoint analysis. 
The secondary endpoints of proportion of responders (UAS7  6) at Weeks 12 and 24 will be 
compared between the benralizumab 60 mg and placebo treatment groups, and the 
benralizumab 30 mg and placebo treatment groups, respectively, using logistic regression. The 
model will include terms for treatment group and region. The results of the analyses will be 
presented as an odds ratio, together with its associated 95% confidence intervals (CIs) and 2-
sided p-value. Results will also be transformed into a difference in proportions for ease of 
interpretation. The number and percentage of responders will also be summarised by 
randomised treatment with CIs around the proportions. 
Continuous secondary endpoints collected by visit, including changes from baseline in ISS7 
and UAS7 at Week 24 for both benralizumab 60 mg and benralizumab 30 mg treatment 
groups, will be analysed using MMRM models in a similar way to that described for the 
primary endpoint analyses. For these analyses, the dependent variable will be the change from 
baseline in the respective continuous endpoint at post-baseline protocol-specified visits up to 
Week 24, and each analysis will include the relevant baseline score as a covariate as well as 
the other covariates listed for the primary endpoint analysis. 
Other continuous secondary endpoints collected by visit up to Week 12 and 24 including 
changes from baseline in HHS7, UCT, CU-Q2oL, and DLQI will be analysed using MMRM 
models in a similar way to that described for the primary endpoint. For these analyses the 
dependent variable will be the change from baseline in the respective continuous endpoint at 

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post-baseline protocol-specified visits up to Week 12 and 24, respectively, and each will 
include the relevant baseline score as a covariate as well as the other covariates listed for the 
primary endpoint analysis. Additional responder analyses and descriptive summaries of the 
PRO assessments may be produced to further characterise participant symptomatology and 
health status. Summaries of number of angioedema free days will be produced for participants 
with angioedema at baseline. 
The secondary endpoints of proportion of participants achieving UAS7 = 0 at Week 12 and 24 
will be analysed using logarithmic regression in a similar way to the key secondary endpoint 
of responders (UAS7  6). Results will be displayed as difference in proportions with 95% CI 
and 2-sided p-value. 
The secondary endpoints of time to  5 point decrease (clinically relevant decrease) for ISS7 
will be summarised using descriptive statistics. Details will be provided in the SAP. 
To make an assessment of the efficacy of Q8W dosing relative to Q4W as a benchmark 
between Weeks 24 and 52, the efficacy endpoints outlined above will be assessed out to week 
52 using the 5 treatment sequences described in the randomisation of the study. The focus will 
be to compare effects on the Q4W and Q8W maintenance regimens. The group of participants 
receiving placebo and then benralizumab will also be presented in these analyses but not 
formally compared to the other treatment groups. As an example, for the change from baseline 
in ISS7 score endpoint an MMRM model will be fit over the entire 52-week treatment period 
as described for the primary analysis, but with the 5 individual treatment groups to initial dose 
and maintenance regimen. If it is suitable to pool the data across the initial dose groups to 
enable one comparison of Q4W vs Q8W with 60 participants per arm, then this will be 
performed by fitting an MMRM model over the entire 52-week treatment period then 
including 3 treatment groups (those randomised to benralizumab then Q4W maintenance, 
those randomised to benralizumab then Q8W maintenance and those randomised to placebo 
followed by benralizumab treatment). Similar analyses may be performed for other efficacy 
endpoints as appropriate. 
Full details will be provided in the SAP. 
9.4.2.3 
Tertiary/exploratory Endpoints 
Analyses for exploratory objectives will be specified in the SAP or in an exploratory analysis 
plan. 
9.4.3 
Safety Analyses 
Safety analyses will be performed using the safety analysis set. 

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Analyses will be presented for the overall study period split by the 5 treatment sequences and 
presented separately for the first 24 weeks split by the 3 induction dose treatment groups as 
noted in Section 9.2. 
Participants will be analysed according to the treatment they received. 
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of IP. Details will be described in the SAP. 
Adverse Events 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities that will have been released for execution at AstraZeneca/designee. 
Safety data will be presented using descriptive statistics unless otherwise specified in the SAP. 
Adverse events will be presented for each treatment group by system organ class and 
preferred term, including the number and percentage of participants reporting at least 
one event, number of events and exposure-adjusted rates, where appropriate. 
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE, AEs with outcome of death, serious AEs, and AEs 
leading to discontinuation of IP. 
Separate AE tables will be provided taking into consideration the relationship as to IP 
assessed by the Investigator, maximum intensity, seriousness, death and events leading to 
discontinuation of IP, as well as other action taken related to IP. 
Key participant information will be presented for participants with AEs with outcome of 
death, serious AEs, and AEs leading to discontinuation of IP. 
An AE listing for the safety analysis set will cover details for each individual AE. 
Full details of AE analyses will be provided in the SAP. 
Treatment Emergent 
The following events are considered treatment emergent: 
 
Adverse events with an onset date on or after the first dose of IP 
 
Worsening of pre-existing events on or after first dose of IP 
 

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Clinical Laboratory Safety Assessments 
Laboratory data for haematology and clinical chemistry will be summarised. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given. Shifts from normal to abnormal between baseline 
and each post-baseline time point will be evaluated for urinalysis. 
Vital Signs and Physical Examination 
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, Minimum, Q1, median, Q3, and Maximum. 
Frequency tables cover number and percentage of participants in the respective category. 
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and absolute change from baseline. 
Changes in vital signs will be examined at each visit. Frequencies of clinically noteworthy 
values (defined in the SAP) occurring during the clinical study will be presented. 
Details of vital sign analyses will be provided in the SAP. 
Shifts from normal to abnormal between baseline and post-baseline visits will be evaluated for 
the physical examination. 
9.4.4 
Immunogenicity Analyses 
Anti-drug antibodies to benralizumab will be summarised using descriptive statistics at each 
visit by treatment group based on the safety analysis set. The ADA titres-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. Further details will be provided in the SAP. 
9.4.5 
Other Analyses 
Pharmacokinetic and pharmacodynamic exploratory analyses will be described in the SAP 
which will be finalised before primary DBL. 
9.4.6 
Methods for Multiplicity Control 
To control the overall type I error rate to be  0.05 for the multiple comparisons in the primary 
and the key secondary endpoints, a Multiple Testing Procedure (MTP) with Bonferroni-Holm 
over groups, and Fixed-Sequence within groups will be applied. Specifically, there will be 
2 groups defined by the doses of 30 and 60 mg, and within each group there will be a 
pre-defined fixed-sequence MTP of comparisons of the primary and key secondary endpoints 
vs placebo (ie, change from baseline in ISS7 at W12, then change from baseline in UAS7 at 

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W12) at level of /2. If the null hypotheses for 1 dose group can be rejected entirely (ie, 
significant difference between active vs placebo for both endpoints at =0.025), one will 
increase the level to  (ie, 0.05) for the other group. This amounts to using Bonferroni-Holm 
over groups, and fixed-sequence within groups. This multiplicity adjustment method follows 
the general results described by Bretz (Bretz et al 2009) and by Burman (Burman et al 2009). 
9.4.7 
Sensitivity Analyses 
Sensitivity analyses for the primary and key secondary endpoints based on different missing 
data mechanism assumptions including those expected to be more conservative, such as 
missing not at random, may be used to explore the robustness of any treatment effect 
including multiple imputation approaches. Full details of sensitivity analyses will be pre-
specified in the SAP and documented prior to primary DBL of the studies. 
Sensitivity analyses may also be considered to explore the effect of extreme outliers on 
individual endpoints, such as rank-based methods. Full details of these will be pre-specified in 
the SAP. 
9.4.8 
Subgroup Analysis 
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
variable, subgroup analyses will be provided. Details of these analyses will be provided in the 
SAP. 
9.5 
Interim Analyses 
No formal interim analysis is planned for the study.  
Analyses will begin with the primary DBL which is targeted to occur when all participants 
have completed the 24-week double-blind treatment period. The final DBL will occur when 
all participants have completed the 52-week treatment period and the Week 60 follow-up visit 
and/or the IPD/EOT visit. An additional analysis may be performed between the primary and 
final DBLs, to report data accumulating during the extension period if needed to support end 
of phase 2 decision making. 
 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS