A Multicenter, Open-label, Safety Extension Study With Benralizumab (MEDI-563) for Asthmatic Adults on Inhaled Corticosteroid Plus Long-acting β2 Agonist (MELTEMI)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca



Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 2.0
Date 14 October 2019
3(47)
Objectives
(a)
Primary Objective
Objective
Endpoint
!
To assess the safety and tolerability of 2 
dosing regimens of benralizumab for adult 
patients 
!
AEs/SAEs
!
Laboratory assessments
(b)
Secondary Objectives
Objective
Endpoint
!
To evaluate the effect of 2 dosing regimens 
of benralizumab on asthma exacerbations, 
and asthma-related hospitalizations and 
emergency room visits  
!
Asthma exacerbations 
!
Asthma-related hospitalizations and/or 
emergency room visits.
!
To evaluate the pharmacodynamics and 
immunogenicity of 2 dosing regimens of 
benralizumab for adult patients 
!
Eosinophil levels
!
Anti-drug antibodies (ADA)
Study design
This is an open-label study designed to evaluate the safety and tolerability of benralizumab 
30 mg administered subcutaneously (SC) for patients who complete at least 16 and not more than 
40 weeks in Study D3250C00021.  Patients who have completed 40 weeks or more in BORA 
will finish BORA to enable the objectives of that study to be met.
The 16-week treatment period in Study D3250C00021 (BORA) allows patients on placebo in 
the predecessor studies to receive at least the 3 monthly doses (“loading doses”) of benralizumab 
within BORA before transition into this study and continuing with either the every 4 week 
(Q4W) or every 8 week (Q8W) dosing regimen.
Patients transitioning to Study D3250C00037 will need to complete Study D3250C00021 end of 
treatment (EOT) assessments and sign an informed consent for Study D3250C00037, after which 
their treatment allocation will be unblinded.  Patients will then receive their first dose of 
benralizumab for Study D3250C00037and their subsequent visits will be scheduled accordingly.  
Patients on the Q4W regimen will attend study visits every 4 weeks; patients assigned to the 
Q8W regimen will attend study visits every 8 weeks.
Target patient population
Adult patients who complete at least 16 and not more than 40 weeks in Study D3250C00021.  
Patients can remain in Study D3250C00021 if they choose not to enter Study D3250C00037.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 2.0
Date 14 October 2019
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Investigational product and mode of administration
Benralizumab 30 mg/mL solution for injection in an accessorized pre-filled syringe (APFS) will 
be administered SC at the study site according to the dosing regimens described below.
Dosage 
Patients will remain on the same dosing regimen as they had received during the preceding 
D3250C00021 (BORA) study:
Patients previously randomized to the 4 week (Q4W) regimen of benralizumab in BORA will 
continue injections of active drug every 4 weeks in this open label study.  
Patients previously randomized to the 8 week (Q8W) regimen in BORA will continue to receive 
active drug every 8 weeks in this open label study.
Duration of treatment
Patients may stay on IP until it is commercially available in their local market or the candidate 
drug is withdrawn from the approval process in their local market. If transitioned to 
commercialized product at that time, no follow up visit is needed.  If the patient will not be 
transitioned to commercialized product, the patient should come in for the FU visit and complete 
the study.   For countries in which a marketing application is not submitted, patients will receive 
their last dose of benralizumab in December 2018, with EOT and FU visits in 1Q 2019.
Statistical methods 
A descriptive analysis based on the full analysis set will be performed for all endpoints.  The full 
analysis set includes all enrolled patients who received any dose of IP.
  

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
PROTOCOL SYNOPSIS.....................................................................................................2
TABLE OF CONTENTS.....................................................................................................5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................................9
1.
INTRODUCTION ............................................................................................. 11
1.1
Background........................................................................................................ 11
1.2
Rationale for conducting this study .................................................................... 12
1.3
Rationale for study design, doses, and control groups......................................... 12
1.4
Benefit/risk and ethical assessment .................................................................... 12
1.5
Overall study design........................................................................................... 13
2.
STUDY OBJECTIVES...................................................................................... 14
3.
PATIENT SELECTION CRITERIA AND WITHDRAWAL CRITERIA.......... 14
3.1
Inclusion criteria ................................................................................................ 14
3.2
Exclusion criteria ............................................................................................... 15
3.3
Patient enrolment ............................................................................................... 16
3.4
Procedures for handling incorrectly enrolled patients ......................................... 17
3.5
Concomitant medications, restrictions during and after the study ....................... 18
3.5.1
Concomitant medication .................................................................................... 18
3.5.1.1
Background medication...................................................................................... 18
3.5.2
Restrictions........................................................................................................ 18
3.5.2.1
Medication-related restrictions ........................................................................... 18
3.5.2.2
Other restrictions................................................................................................18
3.6
Discontinuation from investigational product..................................................... 18
3.7
Withdrawal from the study................................................................................. 19
3.7.1
Withdrawal of Informed Consent ....................................................................... 19
3.8
Withdrawal of informed consent for donated biological samples........................ 20
4.
STUDY PLAN AND PROCEDURES ............................................................... 21
4.1
Enrolment period ............................................................................................... 25
4.1.1
Enrolment (Visit 1) ............................................................................................25
4.2
Treatment period................................................................................................ 25
4.2.1
Dosing regimens ................................................................................................ 25
4.2.2
Treatment period assessments ............................................................................ 25

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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4.3
Follow-up period................................................................................................ 26
5.
STUDY ASSESSMENTS AND PROCEDURES............................................... 26
5.1
Efficacy assessments.......................................................................................... 26
5.2
Safety assessments............................................................................................. 26
5.2.1
Safety laboratory tests........................................................................................26
5.2.1.1
Pregnancy test....................................................................................................27
5.2.2
Vital signs.......................................................................................................... 27
5.3
Other assessments and procedures...................................................................... 28
5.3.1
Asthma exacerbations ........................................................................................ 28
5.3.2
Asthma-related hospitalizations and emergency department visits...................... 28
5.3.3
Pharmacodynamics ............................................................................................ 28
5.3.4
Immunogenicity................................................................................................. 28
5.3.5
Handling of biological samples .......................................................................... 28
5.3.5.1
Labelling and shipment of biological samples .................................................... 28
5.3.5.2
Chain of custody of biological samples .............................................................. 29
6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS................................ 29
6.1
Identity of investigational product(s)..................................................................29
6.2
Labelling............................................................................................................ 30
6.3
Storage............................................................................................................... 30
6.4
Accountability.................................................................................................... 30
6.5
Methods for assigning treatment groups............................................................. 30
6.6
Investigational Product administration and treatment compliance....................... 30
6.7
Management of Investigational Product-related reactions................................... 32
7.
SAFETY REPORTING ..................................................................................... 32
7.1
Adverse events...................................................................................................32
7.1.1
Definition of adverse events...............................................................................33
7.1.2
Definitions of serious adverse event ...................................................................33
7.1.3
Recording of adverse events...............................................................................33
7.1.3.1
Time period for collection of adverse events ...................................................... 33
7.1.3.2
Follow-up of unresolved adverse events.............................................................33
7.1.3.3
Variables............................................................................................................ 34
7.1.3.4
Causality collection............................................................................................ 34
7.1.3.5
Adverse events based on signs and symptoms....................................................34
7.1.3.6
Adverse events based on laboratory tests............................................................ 35
7.1.3.7
Symptoms of the disease under study................................................................. 35
7.1.4
Reporting of serious adverse events ................................................................... 35
7.2
Overdose............................................................................................................ 36
7.3
Pregnancy .......................................................................................................... 36
7.3.1
Maternal exposure.............................................................................................. 36

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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7.3.2
Paternal exposure............................................................................................... 37
8.
EVALUATION AND CALCULATION OF VARIABLES ............................... 37
8.1
Statistical considerations.................................................................................... 37
8.2
Sample size estimate .......................................................................................... 37
8.3
Definitions of analysis sets................................................................................. 38
8.3.1
Full analysis set..................................................................................................38
8.4
Variables for analyses ........................................................................................ 38
8.4.1
Safety variables..................................................................................................38
8.4.1.1
Calculation or derivation of safety variable(s) ....................................................38
8.4.1.2
Analysis methods for safety variables................................................................. 38
8.4.2
Other assessments.............................................................................................. 38
8.4.2.1
Asthma exacerbations ........................................................................................ 38
8.4.2.2
Asthma-related Health Care Utilization.............................................................. 38
8.4.3
Immunogenicity variables .................................................................................. 39
8.4.3.1
Calculation or derivation of immunogenicity variables....................................... 39
8.4.3.2
Analysis method for immunogenicity variables.................................................. 39
8.5
Independent adjudication committee .................................................................. 39
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 39
9.1
Training of study center personnel ..................................................................... 39
9.2
Monitoring of the study...................................................................................... 39
9.2.1
Source data ........................................................................................................ 40
9.2.2
Recording of data...............................................................................................40
9.2.3
Study agreements............................................................................................... 40
9.2.4
Archiving of study documents............................................................................ 41
9.3
Study timetable and end of study........................................................................ 41
9.4
Data management by AstraZeneca ..................................................................... 41
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 41
10.1
Ethical conduct of the study ............................................................................... 41
10.2
Patient data protection........................................................................................ 42
10.3
Ethics and regulatory review ..............................................................................42
10.4
Informed consent ...............................................................................................42
10.5
Changes to the protocol and informed consent form........................................... 43
10.6
Audits and inspections .......................................................................................43
11.
LIST OF REFERENCES ...................................................................................44

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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LIST OF TABLES
Table 1
Study Assessments Schedule – Q4W regimen – Year 1a........................21
Table 2
Study Assessments Schedule – Q8W regimen – YEAR 1a.....................23
Table 3
Identity of investigational product.........................................................29
LIST OF FIGURES
Figure 1
Injection sites and rotation scheme ........................................................31
LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 
Appendix C
IATA 6.2 Guidance document
Appendix D
Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law
Appendix E
Anaphylaxis: Definition, signs and symptoms, management
Appendix F
Restricted and prohibited medications
Appendix G
Study Plan and Procedures – Years 2, 3, and 4

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event
ALT
Alanine aminotransferase
APFS
Accessorized pre-filled syringe
AST
Aspartate aminotransferase
Beta-hCG
Beta- human chorionic gonadotropin
BUN
Blood urea nitrogen
CO2
Carbon dioxide
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency department
EOT
End of treatment
EU
European Union
FSH
Follicle-stimulating hormone
Gamma-GT
Gamma-glutamyl transpeptidase
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
IATA
International Air Transport Association
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
Ig
Immunoglobulin
IL
Interleukin

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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Abbreviation or 
special term
Explanation
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IL-5Rα
Interleukin-5 receptor alpha subunit
ICI
International Coordinating Investigator
IP
Investigational product
IPD
Premature Investigational Product Discontinuation
IRB
Institutional Review Board
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-acting β2 agonists
LTRA
Leukotriene receptor antagonists
MedDRA
Medical Dictionary for Regulatory Activities
NAEPP
National Asthma Education Prevention Program
OCS
Oral corticosteroids
PFS
Pre-filled syringe
RBC
Red blood cell
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
ULN
Upper limit of normal
UNS
Unscheduled
WBC
White blood cell
WBDC
Web-based Data Capture
WOCBP
Women of childbearing potential

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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1.
INTRODUCTION
1.1
Background
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction, 
and airway hyperresponsiveness.  Patients present clinically with recurrent wheezing, 
shortness of breath, cough and chest tightness.  Asthma is a leading cause of morbidity with a 
global prevalence of approximately 300 million; it is estimated that the number of people with 
asthma may increase to 400-450 million people worldwide by 2025 (Masoli et al 2004).
The current approach to anti-inflammatory controller therapy in asthma is based on a stepwise 
intensification of a daily maintenance regimen primarily centered around inhaled 
corticosteroids (ICS) and leukotriene receptor antagonists (LTRA), with the addition of 
long-acting β2 agonists (LABA) in patients with more severe asthma (GINA 2015, NAEPP 
2007).  Despite treatment per management guidelines, up to 50% of patients have asthma that 
is not well-controlled (Bateman et al 2010).  This results in considerable impact on quality of 
life, disproportionate use of healthcare resources, and adverse reactions from regular systemic 
steroid use.    Therefore, there remains an unmet medical need for patients whose asthma is 
not controlled by existing therapies.
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Wenzel 2012).  In particular, 
asthma associated with eosinophilic inflammation in the airway (often referred to as 
eosinophilic asthma) is common (approximately 40% to 60% of asthmatics) with the degree of 
eosinophilia associated with clinical severity including the risk of asthma exacerbations 
(Bousquet et al 1990; Louis et al 2000; DiFranco et al 2003; Scott and Wardlaw 2006, 
Simpson et al 2006; Zhang and Wenzel 2007).  Adjusting conventional ICS-based asthma 
therapy according to the degree of elevated sputum eosinophils as a marker of disease activity 
resulted in a reduction in the frequency of asthma exacerbations in prospective trials (Green et 
al 2002; Jayaram et al 2006).
Interleukin-5 (IL-5) is a cytokine factor essential for eosinophil trafficking and survival 
(Molfino et al 2011).  Clinical trials of neutralizing anti-IL-5 antibodies (mepolizumab and 
reslizumab) in patients with uncontrolled eosinophilic asthma resulted in an improvement in 
key asthma control metrics, including asthma exacerbations (Castro et al 2011and Pavord et al 
2012).  These promising results support continued development of therapies targeting the IL-5 
pathway in eosinophilic asthmatics unresponsive to standard therapies.
In contrast to anti-IL-5 therapies, benralizumab (MEDI-563) is a humanized, afucosylated, 
monoclonal antibody that binds specifically to the human IL-5 receptor alpha subunit 
(IL-5Rα) on the target cell.  The IL-5 receptor (IL-5R) is expressed almost exclusively on the 
surface of eosinophils and basophils (Takatsu et al 1994; Toba et al 1999).  Afucosylation 
confers enhanced antibody-dependent cellular cytotoxicity (ADCC) which results in highly 
efficient eosinophil depletion by apoptosis (Kolbeck et al 2012).  Single and repeated doses of 
benralizumab in mild to severe asthma patients during Phase 2 development resulted in 
depletion of blood and airway eosinophils, and improvement in multiple metrics of asthma 

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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control including asthma exacerbations, lung function, and Asthma Control Questionnaire 
(ACQ-6) scores (Busse et al 2010, Gossage et al 2012, Molfino et al 2012, and Phase 2b MI-
CP220 study).  For further details please refer to the Investigator’s Brochure.
1.2
Rationale for conducting this study
The treatment options for patients who remain uncontrolled by ICS-LABA are limited.  As 
such, patients with severe refractory asthma and an eosinophilic phenotype will be allowed to 
remain in this study and on investigational product (IP) until benralizumab is commercially 
available in their local market or the candidate drug is withdrawn from the approval process in 
that market. 
In previous clinical studies, benralizumab administration resulted in rapid and prolonged 
depletion of eosinophils in the peripheral blood in the asthmatic airway with associated 
improvements in multiple metrics of asthma control.  The purpose of this study is to continue 
to characterize the safety profile of benralizumab administration and monitor the 
pharmacodynamic activity of the drug in those asthma patients who remain on treatment for at 
least 16 weeks in the predecessor study D3250C00021 (BORA).  
1.3
Rationale for study design, doses, and control groups
This is an open-label safety extension study designed to evaluate the safety and tolerability of 
a fixed 30 mg dose of benralizumab administered subcutaneously (SC) in severe asthma 
patients on ICS-LABA therapy with or without chronic oral corticosteroids (OCS) and/or 
other asthma controllers.  All patients will receive active drug on the same dosing regimen 
they received in BORA.  In order to protect the blind of BORA, patients will remain blinded 
to treatment regimen allocation until they have completed all EOT assessments in BORA and 
signed informed consent for participation in this study, after which treatment allocation will 
be unblinded to both the investigator and the patient. 
1.4
Benefit/risk and ethical assessment
There are few treatment options for patients whose asthma remains uncontrolled on high-dose 
ICS-LABA (GINA 2015).  The evidence base for oral add-on therapies (ie, oral 
corticosteroids, leukotriene inhibitors, and xanthenes) is extremely limited.  Anti-IgE therapy 
(ie, omalizumab) may improve control in patients with severe asthma and IgE-mediated 
allergy to a perennial allergen.  Tiotropium is a long-acting bronchodilator that has recently 
been shown to produce improvement in lung function and exacerbation risk (pooled data) in 
patients with severe asthma, with inconsistent effects on other measures of asthma control 
(Kerstjens et al 2012).  As such, new therapies are needed for asthma management in patients 
who remain uncontrolled on standard of care.
In adult patients whose asthma was poorly controlled on medium-to-high dose ICS-LABA 
benralizumab, at fixed doses of ≥20 mg, produced improvements in multiple metrics of 
asthma control including the annual rate of asthma exacerbations, lung function, ACQ-6
scores, and symptoms (Phase 2b MI-CP220 study, based on the interim analysis).  Clinical 
benefit appeared to be greatest in patients with blood eosinophil counts >300/μL.  The blood 

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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eosinophil count below which benralizumab is generally not effective remains unclear at this 
point in time.
An assessment of the risk/benefit of benralizumab in patients with asthma is provided in the 
Investigator’s Brochure.
The efficacy and safety of benralizumab in asthmatic patients is being evaluated in studies 
D3250C00017 (SIROCCO), D3250C00018 (CALIMA), and D3250C00020 (ZONDA).  
Eligible patients who have completed the entire treatment period on investigational product in 
1 of these studies may be allowed to enrol in Study D3250C00021 (BORA), a safety 
extension study.  
Approximately 2200 patients are anticipated to enrol in BORA.  The Sponsor believes that 
approximately 1200 patients completing BORA are sufficient to address the primary 
objectives of that study.  As such, the remaining eligible BORA patients will be allowed to 
transition to Study D3250C00037 (MELTEMI) and have open-label access to study drug until 
benralizumab is commercially available in their local market or the candidate drug is 
withdrawn from the approval process in their local market.  For countries in which a 
marketing application is not submitted, patients will receive their last dose of benralizumab in 
December 2018, with EOT and FU visits in Q1 2019.
1.5
Overall study design
This is an open-label safety extension study designed to provide continued treatment to 
patients who have completed preceding studies in this program.  The study will evaluate the 
safety and tolerability of a fixed 30 mg dose of benralizumab administered subcutaneously 
(SC).  Patients who complete at least 16 and not more than 40 weeks in the predecessor study 
may be eligible to enrol into this study.  Patients will remain blinded to treatment regimen 
allocation until they have signed informed consent for participation in this study, after which 
treatment allocation will be unblinded to both the investigator and the patient.
Patients previously randomized to the every 4 weeks (Q4W) regimen of benralizumab in 
BORA will continue injections of active drug every 4 weeks in this open label study.  
Patients previously randomized to the every 8 week (Q8W) regimen in BORA will continue to 
receive active drug every 8 weeks in this open label study.  
Patients must remain on a medium- to high-dose ICS-LABA therapy, throughout the treatment 
period.  Any changes in ICS-LABA therapies or other background therapies must be 
documented in the appropriate eCRF.  
Patients will be allowed to remain in this study until benralizumab is commercially available 
in their local market or the candidate drug is withdrawn from the approval process in the local 
market.  For countries in which a marketing application is not submitted, patients will receive 
their last dose of benralizumab in December 2018, with EOT and FU visits in Q1 2019..

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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The total patient population for this study will be approximately 1000 patients, comprising 
patients from Study D3250C00021.  
2.
STUDY OBJECTIVES
(a)
Primary Objective
Objective
Endpoint
!
To assess the safety and tolerability of 2 
dosing regimens of benralizumab for adult 
patients 
!
AEs/SAEs
!
Laboratory assessments
(b)
Secondary Objectives
Objective
Endpoint
!
To evaluate the effect of 2 dosing regimens 
of benralizumab on asthma exacerbations, 
and asthma-related hospitalizations and 
emergency room visits  
!
Asthma exacerbations 
!
Asthma-related hospitalizations and/or 
emergency room visits.
!
To evaluate the pharmacodynamics and 
immunogenicity of 2 dosing regimens of 
benralizumab for adult patients 
!
Eosinophil levels
!
Anti-drug antibodies (ADA)
3.
PATIENT SELECTION CRITERIA AND WITHDRAWAL 
CRITERIA
3.1
Inclusion criteria
For inclusion in the study patients must fulfil all of the following criteria:
1.
Informed consent for study participation must be obtained prior to any study related 
procedures being performed and according to international guidelines and/or 
applicable European Union guidelines.
2.
Female and male patients who have completed at least 16 and not more than 40 
weeks in Study D3250C00021.
3.
Women of childbearing potential (WOCBP) must agree to use an effective form of 
birth control throughout the study duration and for 16 weeks after the last dose of 
IP.  Effective forms of birth control include: true sexual abstinence, a vasectomized 
sexual partner, Implanon, female sterilization by tubal occlusion, any effective IUD 

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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Intrauterine device/IUS Ievonorgestrel Intrauterine system, Depo-Provera™ 
injections, oral contraceptive, and Nuvaring™.  Women of childbearing potential 
(WOCBP) are defined as all females regardless of the onset of menarche who do 
not meet the definition below of women not of childbearing potential.
Women who are not of childbearing potential are defined as those who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or postmenopausal.  Women will be considered postmenopausal if 
they have been amenorrheic for 12 months prior to the planned date of enrolment 
without an alternative medical cause.  The following age-specific requirements apply:
∀
Women <50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and have follicle stimulating hormone (FSH) levels in the 
postmenopausal range
∀
Women ≥50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatment
4.
For WOCBP only: Have a negative urine pregnancy test prior to administration of 
IP at Visit 1.  
5.
All male patients who are sexually active must agree to use a double barrier method 
of contraception (condom with spermicide) from the first dose of IP until 16 weeks 
after their last dose.
3.2
Exclusion criteria
Patients must not enter the study if any of the following exclusion criteria are fulfilled:
1.
Any disorder including but not limited to cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
hematological, psychiatric or major physical impairment that is not stable in the 
opinion of the Investigator and could:
-
Affect the safety of the patient throughout the study
-
Influence the findings of the study or their interpretations
-
Impede the patient’s ability to complete the entire duration of study
2.
A helminth parasitic infection diagnosed during a predecessor study that has either 
required hospitalization, has not been treated, has been incompletely treated or has 
failed to respond to standard of care therapy
3.
Any clinically significant change in physical examination, vital signs, ECG, 
hematology, clinical chemistry, or urinalysis during the predecessor study which in 

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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the opinion of the investigator may put the patient at risk because of his/her 
participation in the study, or may influence the results of the study, or interfere with 
the patient’s ability to complete the entire duration of the study
4.
Current malignancy or malignancy that developed during the predecessor study 
(subjects that had basal cell carcinoma, localized squamous cell carcinoma of the 
skin which was resected for cure, or in situ carcinoma of the cervix that has been 
treated/cured will not be excluded).
5.
Receipt of live attenuated vaccines within 30 days prior to initiation of treatment in 
this study, during the treatment period, and for 16 weeks (5 half-lives) after the last 
dose of the IP 
6.
Receipt of immunoglobulin or blood products within 30 days prior to Visit 1
7.
Planned major surgical procedures during the conduct of the study
8.
Previous participation in the present study
9.
Concurrent enrolment in another drug-related interventional clinical trial
10.
AstraZeneca staff involved in the planning and/or conduct of the study
11.
Employees of the study center or any other individuals involved with the conduct of 
the study or immediate family members of such individuals
12.
Patients with important protocol deviations in the predecessor study at the 
discretion of the Sponsor
13.
Patients with ongoing serious adverse events (SAEs) from the prior study should 
not be enrolled into the this extension study until the SAE has resolved (see Section 
7.1.3.1)
For procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Patients who are asked to transition into this study by the Investigator must do so at the 
next odd-numbered visit in BORA (ie, Visit 5, 7, 9, or 11) once this study has started at their 
site. 
1.
Patients must have completed at least 16 and not more than 40 weeks in BORA 
before transitioning into this study 
2.
Patients can transition to this study only on the following BORA visits: 5, 7, 9, or 
11.  Patients who do not transition into this study by Visit 11 of BORA will remain 
in BORA through EOT and FU.

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3.
Provide the patient with the ICF for this study 
4.
On the day of transition, the Investigator should:
!
Confirm patient eligibility based on Sections 3.1 and 3.2.  
NOTE: Patients with an ongoing SAE will not be allowed to transfer 
into this study until the SAE is resolved.
!
Perform all EOT assessments for BORA study
!
Obtain informed consent for this study before any study-related 
procedures are performed
!
Call IVRS to register completion of BORA, obtain unblinded treatment 
regimen allocation and IP kit number to dose the patient for this study at 
this visit (Patients will retain the same eCode as in BORA.)
!
Provide the patient with information on treatment regimen and schedule 
subsequent visits accordingly
!
Dose patient with IP from this study’s supply, NOT from BORA supplies
!
Observe patient for a minimum of 2 hours for the appearance of any acute 
drug reaction
!
Record appropriate assessments in eCRF for both BORA (EOT) and this 
study (Visit 1)
5.
Patients on the Q4W regimen will attend study visits every 4 weeks, patients 
assigned to the Q8W regimen will attend study visits every 8 weeks.
Specific information concerning the use of the IWRS/IVRS will be provided in the separate 
manual. 
3.4
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not under any circumstance be enrolled 
or receive study medication.  There can be no exceptions to this rule.  Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be initiated on 
study treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is enrolled and treated in error, the 
Investigator should inform the AstraZeneca study physician immediately, and a discussion 
should occur between the AstraZeneca study physician and the investigator regarding whether 
to continue or discontinue the patient from treatment on a case by case basis.  The 
AstraZeneca study physician must ensure all decisions are appropriately documented.

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3.5
Concomitant medications, restrictions during and after the study
3.5.1
Concomitant medication
All concomitant treatments given during the study, including those which were started during 
BORA and are ongoing when the patients enters this study, will be collected by the 
Investigator/authorized delegate, with reason for treatment, at each visit (as shown in Table 1
and Table 2) and recorded in the eCRF.
3.5.1.1
Background medication 
Patients must remain on a medium- to high-dose ICS-LABA therapy, throughout the treatment 
period.  Any changes in ICS-LABA therapies or other background therapies must be 
documented in the appropriate eCRF.
Other asthma controller (eg, oral corticosteroids, long acting anti-muscarinics) and rescue use 
therapies are also allowed at the discretion of the Investigator.  If changing asthma 
medication(s) is judged necessary during the course of the study, the justification should be 
documented in the source and the change of drugs and/or doses reflected in the eCRF.  
3.5.2
Restrictions
3.5.2.1
Medication-related restrictions
A table with medication-related restrictions is presented in Appendix F.
3.5.2.2
Other restrictions
(a)
Fertile and sexually active patients or their partners should use effective 
contraceptive methods throughout the study and for at least for 16 weeks (5 half-
lives) after last administration of the IP.  Male patients should refrain from fathering 
a child or donating sperm from the time of informed consent and for 16 weeks (5 
half-lives) after last dose of IP (see Section 3.1, inclusion criteria 3, 4 and 5; 
Section 7.3.
(b)
Patients must abstain from donating blood and/or plasma from the time of informed 
consent and for 16 weeks (5 half-lives) after last dose of IP.
3.6
Discontinuation from investigational product 
Patients will be discontinued from IP in the following situations:
1.
Patient decision.  The patient is at any time free to discontinue treatment without 
prejudice to further treatment (see Section 3.7)
2.
Adverse event (AE) that in the opinion of the Investigator or Sponsor 
contraindicates further dosing
3.
Risk to patient as judged by the Investigator or AstraZeneca
4.
Severe non-compliance to study protocol
5.
Eligibility requirement found not to be fulfilled (see Section 3.4)

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6.
Worsening in asthma control as determined by the Investigator.
7.
Pregnancy
8.
Prior to conduct of any major surgical procedures.  All surgical procedures should 
be discussed with the AZ physician before continuing IP in this study.
9.
Lost to follow-up1
10.
Development of any study specific criteria for discontinuation:
(a) Anaphylactic reaction to the IP requiring administration of epinephrine
(b) Development of helminth parasitic infestation requiring hospitalization
(c) If 2 consecutive doses of IP missed. NOTE: For 8W regimen, in case one dose 
is skipped the next dose must be given within the visit window. If this is not 
possible the patient shall be discontinued.
(d) An asthma-related event requiring mechanical ventilation
Reasons for premature discontinuation of IP should be recorded in the eCRF. Premature 
discontinuation of IP is defined for the purposes of this study as discontinuation of IP before it 
is commercially available in the local market, before the candidate drug is withdrawn from the 
approval process in the local market, or before the termination of this study.  
3.7
Withdrawal from the study
3.7.1
Withdrawal of Informed Consent
Patients are free to withdraw from the study at any time (IP and assessments) without 
prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow up any ongoing AEs present at the time 
of withdrawal outside of the clinical study. The enrolment code of the withdrawn patient 
cannot be reused.
If the patient chooses to discontinue taking investigational product (no matter what is the 
cause of this decision) but agrees to return for the IPD and FU visits, then this is not 
considered a main consent withdrawal and data will continue to be collected.
The patient should then return to the study center and complete procedures described for the 
IPD and follow-up (FU) visits within 4 weeks (+7 days) and 12 weeks (±7 days) after the last 
dose of IP, respectively.
If the main informed consent is withdrawn, no further study data and samples may be 
collected.
                                               
1 Patient is considered lost to follow up when any of the following attempts of contact are failed: -3 attempts of 
either phone calls, faxes, or emails; - having sent 1 registered letter/certified mail; 1 unsuccessful effort to check 
the vital status of the patient using publicly available sources, if allowed by local regulations.

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3.8
Withdrawal of informed consent for donated biological samples 
Samples taken for the evaluation of ADA will be retained for repeat analysis of ADA at 
AstraZeneca or designee for a maximum of 1 year following completion of the clinical study 
report (CSR).  If a patient/parent or legal guardian withdraws consent to the use of blood 
samples, the samples will be disposed of/destroyed and the action documented.  If samples are 
already analyzed, AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator or designee:
!
Ensures the local laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed/destroyed.
!
Ensures that the patient and AstraZeneca or designated CRO are informed about the 
sample disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study center.
As use of the biological samples is an integral part of the study, withdrawal of informed 
consent for the use of donated samples by the patient will result in the patient being 
withdrawn from further study participation.

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4.
STUDY PLAN AND PROCEDURES
Table 1
Study Assessments Schedule – Q4W regimen – Year 1a
Assessment/ 
activity
Refer to
Treatment
EOTh
IPDi
FUh,i
UNSj
V1
V2 
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
w0
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
4 wks 
after 
last 
dose
4 
wks 
after 
last 
dose
12 
wks 
after 
last 
dose
Visit window (days) c
+0
+3
+3
+3
+3
   +3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Informed consent
10.4
X
Inclusion/exclusio
n criteria
3.1/3.2
X
Medical, surgical, 
and asthma history 
4.1.1
Xb
Hematology
5.2.1
X
X
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
X
Urine pregnancy 
test (dipstick) d
5.2.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FSH e
5.2.1.1
X
Vital signs
5.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA f,g
5.3.4
X
X
X
X
X
X
X

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Table 2
Study Assessments Schedule – Q8W regimen – YEAR 1a
Assessment/ activity
Refer to
Treatment
EOTh
IPDi
FUh,i
UNSj
V1
V2
V3
V4
V5
V6
V7
4 wks 
after 
last 
dose
4 
wks 
after 
last 
dose
12 
wks 
after 
last 
dose
w0
W8
W16
W24
W32
W40
W48
Visit window (days) c
+0
+3
+3
     +3
+3
  +3
+3
+7
+7
+7
N/A
Informed consent
10.4
X
Inclusion/exclusion criteria
3.1/3.2
X
Medical, surgical, and asthma history 
4.1.1
Xb
Hematology
5.2.1
X
X
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
X
Urine pregnancy test (dipstick) d
5.2.1.1
X
X
X
X
X
X
X
X
X
X
FSHe
5.2.1.1
X
Vital signs
5.2.2
X
X
X
X
X
X
X
X
X
X
X
ADAf,g
5.3.4
X
X
X
X
X
X
X
Assessment of asthma exacerbations and 
asthma-related HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X a
X
X
X
X
X
X
X
X
X
X
Concomitant medication
3.5
X a
X
X
X
X
X
X
X
X
X
X
Administration of IP i
6.6
X
X
X
X
X
X
X
a
Visits and treatment to continue every 8 weeks until EOT.  For Years 2, 3, and 4 (Week 56 [Visit 8] to Week 208 [Visit 27]), see Appendix G.  
b
Medical, surgical and asthma history, concomitant medications, and ongoing AEs must be entered manually.  Data will not be integrated from BORA.
c
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
d
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.

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e
FSH test done only for female patients to confirm postmenopausal status in women <50 years who have been amenorrheic for >12 months to confirm 
postmenopausal status..
f
ADA samples to be collected before IP administration.
g
In case of anaphylaxis additional samples to be taken (see Section 6.7)
h
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval 
process in the local market.  For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in 
December 2018, with EOT and FU visits in 1Q 2019.
i
IPD visit to be conducted on early discontinuation of IP (see Section 3.6).  Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 
weeks after the last dose of IP, for a final follow-up visit.
j
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week

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4.1
Enrolment period
4.1.1
Enrolment (Visit 1)
Each potential patient will provide written informed consent prior to any study specific 
procedures and undergo assessments applicable for the visit (see see Section 3.3, Table 1 or 
Table 2).  
Visit 1 of this study will be scheduled to ensure uninterrupted dosing as patients transition from 
the predecessor study (BORA) into this safety extension study, regardless of their dosing 
regimen.  In order to achieve this, patients must transition at the earliest possible odd-numbered 
BORA visit following all necessary approvals being in place at the study site, AND after 
database lock of the trial in which the patient entered this program (the latter will be confirmed 
to sites once this milestone reached).  Patients may transition into this study only at Visits 5, 7, 9, 
or 11 of BORA.  
Complete medical, surgical, and asthma history must be re-recorded in the eCRF for this study as 
data will not be integrated from BORA for the CSR.  Ongoing AEs at the end of the predecessor 
study will be considered concurrent medical history and are to be re-entered manually into the 
eCRF for this study if considered clinically relevant by the Investigator.  All concurrent 
medications taken by the patient at the time of entry into this study and the relevant condition for 
which treatment is being given are also to be re-entered manually into the eCRF for this study.
4.2
Treatment period
4.2.1
Dosing regimens
Patients previously randomized to the Q4W regimen of benralizumab in BORA will continue 
injections of active drug every 4 weeks in this open label study.  
Patients previously randomized to the Q8W regimen in BORA will continue to receive active 
drug every 8 weeks in this open label study. 
4.2.2
Treatment period assessments
Patients on the Q4W regimen will return to the study center every 4 weeks for treatment and any 
applicable study assessments.  Patients on the Q8W regimen will return to the study center every 
8 weeks for treatment and any applicable study assessments (see Table 1 and Table 2).  
After IP administration the patient should be assessed for a minimum of 2 hrs for the appearance 
of any acute drug reactions.
Patients will have scheduled visits at 4-week or 8-week intervals, depending on their assigned 
dosing regimen, to complete protocol-specific assessments and IP administration, as listed in 
Table 1 and Table 2.  Restrictions as set out in Section 3.5.2 will continue to apply throughout 
the treatment period.  In case of asthma worsening/exacerbation (see Section 5.3.1), patients 

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should be evaluated at the study center, when feasible and unscheduled (UNS) visit assessments 
(see Table 1 and Table 2) performed.
When benralizumab is approved and commercially available in the patient’s local market or 
when the drug is removed from the approval process in the patient’s local market, the patient will 
come to the center for the End of Treatment (EOT) visit.  If transitioned to commercialized 
product at that time, no follow up visit is needed.  If the patient will not be transitioned to 
commercialized product, the patient should come in for the FU visit and complete the study.  For 
countries in which a marketing application is not submitted, patients will receive their last dose 
of benralizumab in December 2018, with EOT and FU visits in 1Q 2019.
Patients who prematurely discontinue IP (see Section 3.6) should return to the study center and 
complete procedures described for the IPD and Follow-up visits within 4 weeks (+7 days) and 12 
weeks (±7 days) after the last dose of IP, respectively.
Completion or early termination of the treatment will be registered via IWRS/IVRS for each 
patient.
4.3
Follow-up period
Patients who complete an IPD visit and patients in countries in which a marketing application 
will not be submitted will return 8 weeks (±7 days) later, ie, 12 weeks after the last dose of IP, 
for a final follow-up visit.  
5.
STUDY ASSESSMENTS AND PROCEDURES
5.1
Efficacy assessments
There are no efficacy assessments in this study.
5.2
Safety assessments
All health-related assessments should be conducted as part of routine clinical care of the patient 
whether or not part of the protocol-specified assessments and must be documented in the 
patient’s source documents.  Only protocol-specified assessments will be captured in the eCRF.
5.2.1
Safety laboratory tests
Safety laboratory tests (list provided in 5.2.1) will be performed in a central laboratory.  For 
information on methods of collection, assessment, labelling, storage and shipment of samples, 
please refer to the separate Laboratory Manual.  Safety samples (as detailed in Table 3) will be 
collected in accordance with the schedules provided in Table 1 or Table 2.
Laboratory results should be reviewed by the Investigator/authorized delegate and evaluated for 
abnormalities.  Any laboratory abnormalities considered significant in the 
Investigators’/authorized delegate’s judgement should be reported as described to in 
Section 7.1.3.6.

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A copy of the laboratory results report should be signed and dated by Investigator and retained at 
the study center.  In contrast to the predecessor study, eosinophil, basophil, and monocyte results 
do not need to be redacted from the laboratory reports as this is an open-label study.
Serum chemistry
Hematology
Alkaline phosphatase
Gamma-GT (gamma-
glutamyl 
transpeptidase)
Hematocrit
ALT (alanine 
aminotransferase)
Glucose
Hemoglobin
AST (aspartate 
aminotransferase)
Phosphorus
Mean corpuscular 
volume (MCV)
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Calcium
Sodium
Red blood cell (RBC) 
count
Chloride
Total bilirubin
WBC count with 
differential
CO2 (carbon dioxide)
Total cholesterol
Creatinine
Uric acid
5.2.1.1
Pregnancy test 
The following tests are applicable to female patients only and will be conducted in accordance 
with the schedules provided in Table 1 or Table 2.
!
FSH: To be done at Visit 1 in women <50 years who have been amenorrheic for >12 
months to confirm postmenopausal status.
!
Urine HCG: To be performed at the study center for all WOCBP (see Inclusion 
criterion 4, Section 3.1) at each treatment visit before IP administration using a 
dipstick.  Positive urine test result must be confirmed with serum beta HCG.  In the 
case of a positive serum beta HCG test result, the patient must be withdrawn from IP 
immediately.  
5.2.2
Vital signs 
Pre-dose vital signs (pulse, blood pressure, respiration rate, and body temperature) will be 
obtained in accordance with schedule provided in Table 1 or Table 2.
The vital signs will be taken prior to IP administration and other study procedures at each study 
visit.  

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Body temperature will be measured in Celsius before IP administration in accordance with local 
standards.
5.3
Other assessments and procedures
5.3.1
Asthma exacerbations
In this study, an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic 
corticosteroids (or an increase in oral steroid dose for those already on systemic corticosteroids) and/or an 
in-patient hospitalization, and/or an emergency department visit.
An asthma exacerbation that occurs ≤7 days following the last dose of systemic steroids (oral, 
IM, IV), prescribed for a prior exacerbation, will be recorded as the same exacerbation event.
Asthma exacerbation information will be collected with a recall period of ‘since the last 
scheduled visit’.
5.3.2
Asthma-related hospitalizations and emergency department visits
Information on in-patient hospitalizations, number of days in the hospital, and emergency 
department (ED) visits will be collected by the Investigator/authorized delegate at each visit (as 
shown in Table 1 or Table 2) and recorded in the appropriate eCRF module.
Asthma-related hospitalization and ED visit information will be collected with a recall period of 
‘since the last scheduled visit’. 
5.3.3
Pharmacodynamics
Blood eosinophil levels will be determined by CBC with differential at a central lab according to 
the schedule of  assessments (see Table 1 and Table 2).  
5.3.4
Immunogenicity 
Instructions for immunogenicity (ADA) sample collection, processing, storage, and shipment can 
be found in the separate laboratory manual provided to the centers.
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods.  Details of the analytical methods used will be described in a 
bioanalytical report.
The immunogenicity samples will be retained for re-analysis of ADA at AstraZeneca or a 
designee for a maximum of 1 year following completion of the CSR.
5.3.5
Handling of biological samples
5.3.5.1
Labelling and shipment of biological samples
The Principal Investigator is to ensure that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 

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containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not to be shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate labelling, 
shipment, and containment provisions are approved.
5.3.5.2
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their lifecycle.
The Principal Investigator at each study center is to keep full traceability of collected biological 
samples from the patients while in storage at the study center until shipment or disposal (where 
appropriate) and is to keep documentation of receipt of arrival.
The sample receiver is to keep full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and is to keep documentation of receipt of 
arrival.
AstraZeneca will maintain oversight of the entire life cycle through internal procedures, 
monitoring of study centers, and auditing of external laboratory providers.
Samples retained will be registered in the AstraZeneca biobank system during the entire life 
cycle.
6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS
6.1
Identity of investigational product(s)
All IP will be manufactured in accordance with Good Manufacturing Practice (GMP).
Benralizumab administered in the study will be a clear to opalescent, colourless to yellow 
solution (Table 3).
Table 3
Identity of investigational product
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
30mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1mL fill volume
MedImmune

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6.2
Labelling
Labelling of the IP will be carried out by AstraZeneca or designee in accordance with current 
Good Manufacturing Practice (GMP) and regulatory requirements of each country participating 
in the study.  The labels will be translated into local languages where applicable.
6.3
Storage
Benralizumab is to be stored at the study center in a secured facility with limited access and 
controlled temperature.  The temperature should be monitored on a daily basis and documented 
in the temperature monitoring log.
The IP must be kept in the original outer container and under conditions specified on the label 
(between 2-8°C (36- 46°F), protected from the light).
In the following cases:
!
Temperature excursion upon receipt or during storage at the study site
!
Damaged kit upon receipt
!
Damaged syringe/cartridge
the center staff should not use affected IP and should immediately contact an AstraZeneca 
representative for further guidance.  Damaged IP should be documented via IWRS/IVRS (please 
refer to IWRS/IVRS manual for further details).
6.4
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to the patient.
The monitor will account for all study drugs received at the center, unused study drugs and for 
appropriate destruction.  Certificates of delivery, destruction, and/or return should be signed.
In the case of a malfunctioning accessorized pre-filled syringe (APFS), the center should contact 
the study monitor to initiate a product complaint process according to applicable guidelines. 
6.5
Methods for assigning treatment groups
All patients will be assigned to the same dosing regimen in this safety extension study as they 
received in the predecessor study.  
6.6
Investigational Product administration and treatment compliance
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the CRF.

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The IP will be administered at the study center on treatment visits and within visit windows as 
specified in Table 1 and Table 2.  In cases when a treatment visit cannot be scheduled within the 
specified window, the IP administration should be skipped.  If 2 consecutive doses of the IP are 
missed during course of the study the patient should be discontinued; please refer to Section 3.6.
Before investigational product administration
Prior to each IP administration:
!
Investigator/authorized delegate will assess injection site as per standards of medical 
care
!
For all WOCBP a urine pregnancy test will be done.  IP must only be administered 
when the result of the test is negative (see Section 5.2.1.1)
IP administration
The IP will be administered by the Investigator/authorized delegate.  It is advised that the site of 
injection of the IP be rotated such that the patient receives IP at a different anatomical site at 
each treatment visit.  Suggested injection site rotation sequence is presented below (see Figure 
1).  The injection site must be recorded in the source documents and the eCRF at each treatment 
visit.
Figure 1
Injection sites and rotation scheme
Further details on IP administration are provided in the IP Handling Instruction.  IP 
administration must be carried out in line with the Instruction.
After investigational product administration
After IP administration, the patient should be observed for a minimum of 2 hours for the 
appearance of any acute drug reactions.
Conditions requiring investigational product administration rescheduling 
If any of the following should occur, the Investigator should reschedule the visit and the IP 
should not be administered until the rescheduled visit:

Revised Clinical Study Protocol
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!
The patient has an intercurrent illness, that in the opinion of the Investigator may 
compromise the safety of the patient in the study (eg, viral illnesses)
!
The patient, in the opinion of the Investigator, is experiencing an acute or emerging 
asthma exacerbation
!
The patient is febrile (≥38°C; ≥100.4°F) within 72 hours prior to the IP administration
6.7
Management of Investigational Product-related reactions
Appropriate drugs such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as well as 
medical equipment to treat acute anaphylactic reactions must be immediately available.  Study 
personnel must be trained to recognize and treat anaphylaxis (Lieberman et al 2010).  Details on 
anaphylaxis management are provided in Appendix E.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Simpson et al 2006).  Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
!
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both, and at least 1 of the following: a) respiratory compromise or b) reduced 
blood pressure or symptoms of end-organ dysfunction
!
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms, and/or persistent gastrointestinal symptoms
!
Reduced blood pressure after exposure
Patients should have pre-assessments (ie, vital signs) as part of routine clinical care prior to IP 
administration) and must be observed after IP administration for a minimum of 2 hours for the 
appearance of any acute drug reactions. 
In order to help understand the potential drug-relatedness of any acute reaction, a blood sample 
should be drawn during any such event for additional ADA testing (if not already scheduled for 
this visit).  Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis 
may be obtained at a local lab at the discretion of the Investigator.
7.
SAFETY REPORTING
7.1
Adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.

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7.1.1
Definition of adverse events
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, 
enlarged liver), or the abnormal results of an investigation (eg, laboratory findings, 
electrocardiogram).  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has been 
administered.
The term AE is used to include both serious and non-serious AEs.
7.1.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study Protocol 
(CSP).
7.1.3
Recording of adverse events
7.1.3.1
Time period for collection of adverse events
All AEs, including SAEs, will be collected from the time the patient signs the informed consent 
at Visit 1 throughout the treatment period.  Adverse events that are ongoing at the start of this 
study and are considered clinically relevant by the Investigator must be re-entered into the eCRF 
for this study as concurrent medical history.  
7.1.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the last schedule visit in the study will be followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF.  

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AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
The requirement to follow-up AEs is not intended to delay database lock or production of the 
Clinical Study Report (CSR).  These activities should proceed as planned with ongoing AEs if 
necessary.
Any follow-up information of ongoing SAEs after database lock will be reported to AstraZeneca.  
7.1.3.3
Variables 
The following variables will be collected for each AE;
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity of the AE
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP
!
AE caused patient’s withdrawal from study (yes or no)
!
Outcome
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 7.1.2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not an SAE.  On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be an SAE.
7.1.3.4
Causality collection
The Investigator will assess causal relationship between the IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
7.1.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: ‘Have you had any health problems since the previous visit/you were last 
asked?’, or revealed by observation will be collected and recorded in the CRF.  When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 

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symptoms.  However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
7.1.3.6
Adverse events based on laboratory tests
The results from protocol-mandated laboratory tests will be summarized in the clinical study 
report.  Deterioration as compared with baseline in protocol-mandated laboratory values should 
therefore only be reported as AEs if they fulfil any of the SAE criteria or are the reason for 
discontinuation of treatment with the IP.
If deterioration in a laboratory value is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated laboratory result will be considered as 
additional information.  Wherever possible, the reporting Investigator will use the clinical, rather 
than the laboratory term (eg, anemia versus low hemoglobin value).  In the absence of clinical 
signs or symptoms, clinically relevant deteriorations in non-mandated parameters should be 
reported as AE(s).
NB. Cases in which a patient shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN 
may need to be reported as SAEs (please refer to Appendix D ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions).
7.1.3.7
Symptoms of the disease under study
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list 
of signs and symptoms. Asthma symptoms or signs, such as wheeze, cough, chest tightness, 
dyspnoea, breathlessness and phlegm, will be recorded as AEs only when:
!
The sign or symptom is serious according to definitions, see Section 7.1.2
!
The patient discontinues the study due to the sign or symptom 
!
The sign or symptom is new to the patient or not consistent with the patient’s pre-
existing asthma history (defined as within 1 year of Visit 1) as judged by the 
investigator.
7.1.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other center personnel will 
inform appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1

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calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other center personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 1 
calendar day, ie, immediately but no later than 24 hours from when he or she becomes aware of 
it.
Once the Investigators or other center personnel indicate an AE is serious in the WBDC system, 
an automated email alert will be sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study center personnel is to 
report a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study center personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
7.2
Overdose
!
An overdose with associated AEs will be recorded as the AE diagnosis/symptoms on 
the relevant AE modules in the CRF and on the Overdose CRF module
!
An overdose without associated symptoms will be reported on the Overdose CRF 
module only
If an overdose on an AstraZeneca study drug occurs in the course of the study, then Investigators 
or other center personnel will inform appropriate AstraZeneca representatives within 1 day ie, 
immediately but no later than 24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, standard reporting timelines apply, see Section 7.1.4. For 
other overdoses, reporting should be done within 30 days.
7.3
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
7.3.1
Maternal exposure
Fertile and sexually active patients or their partners should use effective contraceptive methods 
throughout the study and for at least 16 weeks (5 half-lives) after last administration of the IP.

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If a patient 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 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should be followed up and documented even if the patient was 
discontinued from the study.
If any pregnancy occurs in the course of the study, then Investigators or other center personnel 
inform appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
days for SAEs (see Section 7.1.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy (PREGREP) module in the CRF will be used to report the pregnancy and the 
pregnancy outcome (PREGOUT) module will be used to report the outcome of the pregnancy.
7.3.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 16 
weeks (5 half-lives) following the last dose.
Pregnancy of the patient’s partners will not be considered an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) should be followed up and documented for conceptions occurring from 
the date of the first administration of IP until 16 weeks (5 half-lives) after the last administration 
of IP.
8.
EVALUATION AND CALCULATION OF VARIABLES
8.1
Statistical considerations
!
Analyses will be performed by AstraZeneca or its representatives
!
The statistical analysis plan (SAP) will be prepared prior to first patient enrolled and 
any subsequent amendments will be documented, 
8.2
Sample size estimate
Patients who have completed at least 16 weeks in Study D3250C00021 (BORA) after the 
requirement for approximately 1200 patients who will go on to complete BORA has been met 

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may be eligible to transition in to this study. This safety extension study will enroll 
approximately 700-1000 patients worldwide. 
All analyses will be descriptive only.  The study is not designed to power the statistical testing of 
any null hypothesis.
8.3
Definitions of analysis sets
8.3.1
Full analysis set
All patients who received at least 1 dose of IP will be included in the full analysis set.  Patients 
will be classified according to the treatment to which they were assigned.  
8.4
Variables for analyses
8.4.1
Safety variables
8.4.1.1
Calculation or derivation of safety variable(s)
The following safety data will be collected: hematology, clinical chemistry, and reported AEs.  
Change from study baseline (Visit 1) to each post-treatment time point will be calculated for 
relevant measurements.  
Adverse events and SAEs will be reported and summarized by treatment group.
8.4.1.2
Analysis methods for safety variables
Adverse events will be summarized by treatment group.  Adverse events will be listed for each 
patient and summarized by System Organ Class (SOC) and Preferred Term (PT) assigned to the 
event by MedDRA, using n (%) and event rate per 100 patient years exposure.  Laboratory safety 
variables will be summarized using standard summary statistics and plots as appropriate.  Further 
details will be provided in the SAP.
8.4.2
Other assessments
8.4.2.1
Asthma exacerbations
In this study, an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic 
corticosteroids (or an increase in oral steroid dose for those already on systemic corticosteroids) and/or an 
in-patient hospitalization, and/or an emergency department visit.
An asthma exacerbation that occurs ≤7 days following the last dose of systemic steroids (oral, 
IM, IV), prescribed for a prior exacerbation, will be recorded as the same exacerbation event.
Asthma exacerbations will be summarized descriptively. 
8.4.2.2
Asthma-related Health Care Utilization
Asthma-related health care utilization by type of health care encounter will be summarized 
descriptively.  

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8.4.3
Immunogenicity variables
8.4.3.1
Calculation or derivation of immunogenicity variables
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer).  
8.4.3.2
Analysis method for immunogenicity variables
Anti-drug antibodies (ADA) to benralizumab will be summarized using descriptive statistics at 
each visit by treatment group.  ADA titers-time profiles of benralizumab by treatment group will 
be generated. 
8.5
Independent adjudication committee
An independent adjudication committee will be constituted to provide an independent, external, 
systematic and unbiased assessment of blinded data to confirm diagnosis of: 1) Investigator –
reported non – fatal myocardial infarction, non – fatal stroke (hemorrhagic, ischemic, embolic), 
as well as cardiovascular deaths and 2) Investigator – reported malignancies during the Phase 3 
trials. The committee will operate in accordance with an Adjudication Committee 
Charter/Manual of Operations, which will also provide detail on specific information the 
committee requires to enable a thorough adjudication.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study center personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol (CSP) and related documents with the 
investigational staff and also train them in any study specific procedures and WBDC, 
IWRS/IVRS, and other systems to be utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study center, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the case report forms (CRFs), that biological 

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samples are handled in accordance with the Laboratory Manual and that study drug 
accountability checks are being performed
!
Perform source data verification (a comparison of the data in the CRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study), including verification of informed consent of participating patients.  This will 
require direct access to all original records for each patient (eg, clinic charts)
!
Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented and reported to the patient
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the center needs information and advice about the study conduct.
9.2.1
Source data
Please refer to the Clinical Study Agreement (CSA) for location of source data.
9.2.2
Recording of data 
A Web-based Data Capture (WBDC) system will be used for data collection and query handling.  
Trained study center personnel will be responsible for entering data on the observations, tests, 
and assessments specified in the CSP into the WBDC system and according to the electronic 
CRF (eCRF) instructions.  The eCRF instructions will also guide the study center in performing 
data entry.
Data entered in the WBDC system will be immediately saved to a central database and changes 
tracked to provide an audit trail.  The data will then be source data verified, reviewed/queried 
and updated as needed.  The data will be validated as defined in the Data Management Plan.  The 
Investigator will ensure that data are recorded on the eCRFs as specified in the CSP and in 
accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the CSA.  The Investigator will sign the 
completed eCRFs.  A copy of the completed eCRFs will be archived at the study center.
9.2.3
Study agreements
The Principal Investigator at each/the study center should comply with all the terms, conditions, 
and obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this CSP and the CSA, the terms of CSP shall prevail with respect to the conduct of the 
study and the treatment of patients and in all other respects, not relating to study conduct or 
treatment of patients, the terms of the CSP shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.

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9.2.4
Archiving of study documents
The Investigator is to follow the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Q2/Q3 2016.  
Patients can remain in this study until benralizumab is available commercially in their local 
market or the candidate drug is withdrawn from the approval process.  For countries in which a 
no application for commercialization of benralizumab is submitted, patients will receive their last 
dose of benralizumab in December 2018, with EOT and FU visits in 1Q 2019.
The study may be terminated at individual study centers if the study procedures are not being 
performed according to GCP.  AstraZeneca may also terminate the entire study prematurely at its 
discretion, or if concerns for safety arise within this study, or in any other study with 
benralizumab.  
9.4
Data management by AstraZeneca
Data management will be performed by AstraZeneca Data Management Center staff according to 
the Data Management Plan
AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA). Medications will be 
classified according to the terminology of the latest version of WHODrug Global B3 Format.
All coding will be performed by the Medical Coding Team at the AstraZeneca Data Management 
Center.
The Rave Web Based Data Capture (WBDC) system will be used for data collection and query 
handling.  The Investigator will ensure that data are recorded on the electronic Case Report 
Forms as specified in the study protocol and in accordance with the instructions provided.
The Investigator will ensure the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the CSA.  The Investigator will sign the 
completed electronic CRFs.  A copy of the completed electronic CRFs will be archived at the 
study center.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 

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regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Forms will incorporate wording that complies with relevant data 
protection and privacy legislation (or, in some cases, these forms may be accompanied by a 
separate document incorporating this language, as applicable locally).
10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of the 
Informed Consent Forms and any other written information and/or materials to be provided to 
the patients.  The Investigator will ensure the distribution of these documents to the applicable 
Ethics Committee and to the study center staff.
The opinion of the Ethics Committee should be given in writing.  The Investigator should submit 
the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Forms that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Forms are approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal Investigators 
with safety updates/reports according to local requirements, including SUSARs (Suspected 
Unexpected Serious Adverse Reactions), where relevant.
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with reports 
of any serious and unexpected adverse drug reactions from any other study conducted with the 
IP.  AstraZeneca will provide this information to the Principal Investigator so that he/she can 
meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each study center will:

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!
Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study (before any study procedures are 
performed) as per local requirements.  The Informed Consent Form needs to be 
adjusted as per local requirements.
!
Ensure each patient is notified that they are free to discontinue from the study at any 
time
!
Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided 
!
Ensure each patient provides signed and dated Informed Consent before conducting 
any procedure specifically for the study.
!
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File and kept for a period that is complaint with GCP/local 
regulatory requirements, whichever is longer
!
Ensure a copy of the signed Informed Consent Form is given to the patient
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the Informed Consent Form that is approved by an Ethics Committee
10.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be documented 
in a study protocol amendment and, where required, in a new version of the study protocol 
(Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s).  For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a study center’s Informed Consent Form, 
AstraZeneca and the study center’s Ethics Committee are to approve the revised Informed 
Consent Form before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved by 
each Ethics Committee.
10.6
Audits and inspections
Authorized representatives of AstraZeneca, a regulatory authority, or an Ethics Committee may 
perform audits or inspections at the study center, including source data verification.  The purpose 

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of an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
(GCP), guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements.  The Investigator will contact AstraZeneca immediately if contacted by 
a regulatory agency or other body about an inspection or an audit at the study center.
11.
LIST OF REFERENCES
Bateman et al 2010
Bateman ED, Reddel HK, Eriksson G, Peterson S, Ostlund O, Sears MR, et al. Overall asthma 
control: The relationship between current control and future risk. American Academy of Allergy, 
Asthma & Immunology. 2010;125(3):600-08.
Bousquet et al 1990
Bousquet J, Chanez P, Lacoste JY, Barnéon G, Ghavanian N, Enander I, et al. Eosinophilic 
inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033-9.
Busse et al 2010
BusseWW,  Katial R, Gossage D, Sari S, Wang B, Kolbeck B, et al. Safety profile, 
pharmacokinetics, and biologic activity of MEDI-563, an anti–IL-5 receptor a antibody, in a 
phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010 Jun;125(6):1237-44.
Castro et al 2011
Castro M, Mathur S, Hargreave F, Boulet L-P, Xie F, Young J, et al. poorly controlled, 
eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 
2011;184:1125-32.
DiFranco et al 2003
DiFranco A, Bartoli ML, Carnevali S, Cianchetti S, Bacci E, Dente FL, et al. Analysis of sputum 
cell counts during spontaneous moderate exacerbations of asthma in comparison to the stable 
phase. J Asthma. 2003 Apr;40(2):155-62.
Friede and Schmidli 2010
Friede, T., Schmidli, H.. Blinded sample size reestimation with negative binomial counts in 
superiority and non-inferiority trials. Methods of Information in Medicine. 2010 Jan, 49, 6, 618-
24
GINA 2015
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 
April 2015. Available from: URL: http://www.ginasthma.org/guidelines-ginareport-global-
strategy-for-asthma.html.

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Study Code D3250C00037
Edition 2.0
Date 14 October 2019
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Green et al 2002
Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, et al. Asthma 
exacerbations and sputum eosinophil counts: a randomized controlled trial. Lancet. 2002 Nov 
30;360(9347):1715–21.
Gossage et al 2012
Gossage DL, Laviolette M, Gauvreau GM, Leigh R, Kolbeck R, Wu1 Yet al. Depletion Of 
Airway Eosinophils By Benralizumab An Anti-Il5 Receptor Alpha Monoclonal Antibody. Am J 
Respir Crit Care Med. 185;2012:A3961.
Hochberg 1988
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
1988;75:800-2.
Holm 1979
Holm S. A simple sequentially rejective multiple test procedure. Scand.J. Statist.1979;6:65-70.
Jayaram et al 2006
Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemière C, Pizzichini E, et al. Determining 
asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006 
Mar;27(3):483-94.
Juniper et al 1994
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a 
disease-specific quality of life instrument. J Clin Epidemiol. 1994; 47: 81-87.
Juniper et al 2005
Juniper EF, Svensson K, Mörk AK, Ståhl E. Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553-58.
Juniper et al 2006
Juniper EF, Bousquet J, Abetz L, Bateman ED,The GOAL Committee. Identifying ‘well-
controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. Respir 
Med. 2006;100:616-21.
Kerstjens et al 2012
Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al. Tiotropium in 
asthma poorly controlled with standard combination therapy. N Engl J Med. 2012 Sep 
27;367(13):1198-207.
Kolbeck et al 2012
Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, et al. MEDI-563, a 
humanized anti–IL-5 receptor a mAb with enhanced antibody-dependent cell-mediated 
cytotoxicity function. J Allergy Clin Immuno. 2010, Jun;125(6):1344-53.

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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
46(47)
Lieberman et al 2010
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The 
diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin 
Immunol. 2010 Sep;126(3):477-80.e1-42.
Louis et al 2000
Louis R, Lau LC, Bron AO, Roldaan AC, Radermerker M, Djukanovic R. The relationship 
between airways inflammation and asthma severity. Am J Respir Crit Care Med. 2000 
Jan;161(1):9-16.
Masoli et al 2004
Masoli M, Holt S, Weatherall M, Beasley R. The dose-response relationship of inhaled
corticosteroids in asthma. Curr Allergy Asthma Rep. 2004 Mar;4(2):144-8.
Miller et al 2005
Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, et al. General 
considerations for lung function Testing. Eur Respir J 2005;26(1):153-61.
Molfino et al 2011
Molfino NA, Gossage D, Kolbeck R, Parker JM, Geba GP. Molecular and clinical rationale for 
therapeutic targeting of interleukin-5 and its receptor. Clin Exp Allergy. 2011;42;712-37.
Molfino et al 2012
Molfino NA, Nowak R, Silverman RA, Rowe BH, Smithline H, Khan F,et al Reductionin the 
number and severity of exacerbations following acute severe asthma: results of a placebo-
controlled, randomized clinical trial with benralizumab. Am J Respir Crit Care Med;2012: 
185:A2753.
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3:Guidelines for the Diagnosis and Management of Asthma. Available: 
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. 
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Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe 
eosinophilic asthma (DREAM):a multicentre, double-blind, placebo-controlled trial. Lancet. 
2012,Aug;380:651-59.
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Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, et al. Multi ethnic reference 
values for spirometry for the 3-95 year age range: the global lung function 2012 equations. 2012 
Dec;40(6):1324-43.
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Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and 
identification using induced sputum. Respirology 2006;11(1):54-61.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition 2.0
Date 14 October 2019
47(47)
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Scott KA, Wardlaw AJ. Eosinophilic airway disorders. Semin Respir Crit Care Med. 2006; 
27(2):128-33.
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Takatsu K, Takaki S, Hitoshi Y. Interleukin-5 and its receptor system: implications in the 
immune system and inflammation. Adv Immunol. 1994;57:145-90.
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Toba K, Koike T, Shibata A, Hashimoto S, Takahashi M, Masuko M, et al. Novel technique for 
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Wenzel S E. Asthma phenotypes: the evolution from clinical to molecular approaches. 2012 May 
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2007 Nov;27:623-32.

Clinical Study Protocol Appendix B
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00037
Edition Number
1.0
Date
11 January 2016
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
2(3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse.

Clinical Study Protocol Appendix B
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
3(3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?
!
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.

Clinical Study Protocol Appendix C
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00037
Edition Number
1.0
Date
11 January 2016
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance
Document

Clinical Study Protocol Appendix C
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
2(3)
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).  For transport purposes the classification of infectious substances according to risk
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Clinical Study Protocol Appendix C
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
3(3)
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.

Clinical Study Protocol Appendix D
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00037
Edition Number
1.0
Date
11 January 2016
Appendix D
Actions Required in Cases of Combined Increase of Aminotransferase and 
Total Bilirubin - Hy’s Law

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
2(7)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................................2
1.
INTRODUCTION...................................................................................................3
2.
DEFINITIONS ........................................................................................................3
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES ..................................3
4.
FOLLOW-UP ..........................................................................................................4
4.1
Potential Hy’s Law Criteria not met........................................................................4
4.2
Potential Hy’s Law Criteria met..............................................................................4
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW CRITERIA 
ARE MET BEFORE AND AFTER STARTING STUDY TREATMENT............6
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF POTENTIAL HY’S 
LAW ........................................................................................................................6
8.
REFERENCES ........................................................................................................7

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
3(7)
1.
INTRODUCTION
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry.  
The investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) 
criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  HL criteria 
are met if there is no alternative explanation for the elevations in liver biochemistry other than Drug 
Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP) (FDA Guidance 
2009).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse 
Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment 
in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) and Total Bilirubin (TBL) ≥ 2xULN at any point during the study irrespective of an increase in 
Alkaline Phosphatase (ALP).  The elevations do not have to occur at the same time or within a specified 
time frame.
Hy’s Law (HL)
AST or ALT ≥ 3x ULN and TBL ≥ 2xULN, where no other reason, other than the IMP, can be found to 
explain the combination of increases, eg, elevated ALP indicating cholestasis, viral hepatitis, another 
drug.  The elevations do not have to occur at the same time or within a specified time frame.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data 
for any patient who meets any of the following identification criteria in isolation or in combination:
!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca representative).

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
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The Investigator will also remain vigilant for any local laboratory reports where the identification 
criteria are met, where this is the case the Investigator will:
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator will 
without delay:
!
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an approach for 
the study patients’ follow-up and the continuous review of data.  Subsequent to this contact the 
Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
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5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study Physician 
contacts the Investigator in order to review available data and agree on whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP.  The AstraZeneca Medical
Science Director and Global Safety Physician will also be involved in this review together with other 
subject matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the instructions 
below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a determination of 
whether the alternative explanation is an AE will be made and subsequently whether the AE meets the 
criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations other 
than the IMP:
!
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
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6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW
CRITERIA ARE MET BEFORE AND AFTER STARTING STUDY 
TREATMENT 
This section is applicable to patients who meet PHL criteria on study treatment having previously met 
PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being, even if there has been no significant 
change the patient’s condition# compared with pre-study treatment visits, the Investigator will:
!
Notify the AstraZeneca representative who will inform the central Study Team. 
!
Follow the subsequent process described is Section 4.2 of this Appendix.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or 
a clinically relevant change in associated symptoms.  The determination of whether there has been a 
significant change will be at the discretion of the Investigator, this may be in consultation with the Study 
Physician if there is any uncertainty.
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW
This section is applicable when a patient meets PHL criteria on study treatment and has already met PHL 
criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based 
on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being met and 
answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease << or did the patient meet PHL criteria prior 
to starting study treatment and at their first on study treatment visit as described in 
Section 6 >>?
If No: follow the process described in Section 4.2 of this Appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with when PHL 
criteria were previously met
!
If there is no significant change no action is required

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
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!
If there is a significant change follow the process described in Section 4.2 of this 
Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.
8.
REFERENCES
FDA Guidance 2009
Food and Drug Administration Guidance for Industry: Drug-induced liver injury: Premarketing clinical 
evaluation. US Department of Health and Human Services, FDA Center for Drug Evaluation and 
Research and Center for Biologics Evaluation and Research, July 2009.

Clinical Study Protocol Appendix E
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00037
Edition Number
1.0
Date
11 January 2016
Appendix E
Anaphylaxis: signs and symptoms, management

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
2(5)
1.
INTRODUCTION
As with any antibody, allergic reactions to dose administration are possible.  The World Health 
Organization has categorized anaphylaxis into 2 subgroups, which are clinically indistinguishable: 
immunologic [IgE-mediated and non-IgE-mediated (eg, IgG and immune complex mediated) and 
nonimmunologic (Johansson et al 2004).  The clinical criteria for defining anaphylaxis for this study are 
listed in section 2.  A guide to the signs and symptoms and management of acute anaphylaxis is provided 
in section 3.  Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical 
equipment to treat anaphylactic reactions must be immediately available at study sites, and study 
personnel should be trained to recognize and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the patient as soon as possible after 
the event, at 60 minutes ± 30 minutes after the event, and at discharge for analysis of serum tryptase.
2.
CLINICAL CRITERIA FOR DEFINING ANAPHYLAXIS AND 
IMMUNE COMPLEX DISEASE
Anaphylaxis
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a)
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(b)
Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence).
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
(a)
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b)
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(c)
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence).
(d)
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
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3.
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
patient’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of antigen-antibody or 
antigen-antibody-complement complexes on cell surfaces, with subsequent involvement of breakdown 
products of complement, platelets, and polymorphonuclear leukocytes, and development of vasculitis; 
serum sickness and nephritis is common.
3.
SIGNS AND SYMPTOMS AND MANAGEMENT OF ACUTE 
ANAPHYLAXIS
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or all of the 
following signs and symptoms occur: 
!
Diffuse erythema
!
Pruritus
!
Urticaria and/or angioedema
!
Bronchospasm
!
Laryngeal edema
!
Hypotension
!
Cardiac arrhythmias
!
Feeling of impending doom
!
Unconsciousness
!
Shock
Other earlier or concomitant signs and symptoms can include:
!
Itchy nose, eyes, pharynx, genitalia, palms, and soles
!
Rhinorrhea
!
Change in voice
!
Metallic taste
!
Nausea, vomiting, diarrhea, abdominal cramps and bloating

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
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!
Lightheadedness
!
Headache
!
Uterine cramps
!
Generalized warmth
4.
MANAGEMENT OF ACUTE ANAPHYLAXIS
4.1
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation.
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as necessary, 
depending on the presenting signs and symptoms of anaphylaxis, to control signs and symptoms 
and prevent progression to more severe symptoms such as respiratory distress, hypotension, 
shock and unconsciousness.
4.2
Possibly appropriate, subsequent measures depending on response to 
epinephrine
(a)
Place patient in recumbent position and elevate lower extremities.
(b)
Establish and maintain airway.
(c)
Administer oxygen.
(d)
Establish venous access.
(e)
Normal saline IV for fluid replacement.
4.3
Specific measures to consider after epinephrine injections, where 
appropriate
(a)
Consider epinephrine infusion.
(b)
Consider H1 and H2 antihistamines.
(c)
Consider nebulized β2 agonist [eg, albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
(d)
Consider systemic corticosteroids.
(e)
Consider vasopressor (e.g. dopamine).
(f)
Consider glucagon for patient taking b-blocker.
(g)
Consider atropine for symptomatic bradycardia.
(h)
Consider transportation to an emergency department or an intensive care facility.

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00037
Edition Number 1.0
Date 11 January 2016
5(5)
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary.
Adapted from Kemp et al 2008.
5.
REFERENCES
Johansson et al 2004
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for 
allergy for global use: Report of the Nomenclature Review Committee of the World Allergy 
Organization, October 2003. J Allergy Clin Immunol. 2004 May;113(5):832-6.
Kemp et al 2008
Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc Committee on Epinephrine in 
Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy 
Organization. Allergy. 2008; 63(8):1061-70.

Clinical Study Protocol Appendix F
Drug Substance
Benralizumab (MEDI-563) 
StudyCode
D3250C00037
Edition Number
2.0
Date
18 July 2017
Appendix F
Restricted and prohibited medications

Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563) Study
Code D3250C00037
Edition Number 1.0
Date 11 January 2016
2
PROHIBITED AND RESTRICTED MEDICATIONS
Other medication restrictions
Table1
Other medication restrictions
Medication
Prohibited/restricted Details
Live Attenuated Vaccines
Prohibited
Not allowed 30 days prior to
randomization; during
treatment period, and 16 
weeks (5 half-lives) after
the last dose
Inactive/killed vaccinations
(e.g. inactive influenza)
Restricted
Allowed provided they are not
administered within 1 week 
before/after any IP
administration
Any immunomodulators or
immunosuppressives except systemic 
steroids used: 1) for the treatment of 
asthma exacerbations and 2) as 
intraarticular injections
Prohibited
Not allowed within 3 months
prior to the date informed
consent is obtained; during
treatment period; 3 months or     
5 half -lives (whichever is 
longer) after last dose
Blood products or
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to date
of ICF; during treatment period
Any marketed (e.g. omalizumab) or 
investigational biologic treatment
Prohibited
Not allowed 4 months or            
5 half-lives (whichever is longer) 
prior to Visit 1; during treatment 
period; 4 months or 5 half-lives 
(whichever is longer) after the 
last dose of the investigational 
product

Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563) Study
Code D3250C00037
Edition Number 1.0
Date 11 January 2016
3
Medication
Prohibited/restricted Details
Other investigational Products (including 
investigational use of an approved drug)
Prohibited
Not allowed 30 Days or              
5 half-lives (whichever is longer) 
prior to Visit 1; during treatment 
period
Allergen Immunotherapy
Restricted
Allowed if on stable therapy, or 
stable seasonal therapy, for at
least 30 days prior to date of 
ICF; no anticipated change 
during treatment period; 
immunotherapy injections must 
be separated from IP injections 
by at least 7 calendar days
Herbal remedies for the treatment of 
allergic, inflammatory, or respiratory 
diseases
Prohibited
Not allowed 30 days prior to 
Visit 1; during the treatment 
period
Non-selective oral  β-adrenergic antagonist 
(e.g. propranolol)
Prohibited
Patients currently using any
non-selective oral β-adrenergic 
antagonist at the time of 
enrolment are not eligible for
the study. Not allowed during 
treatment period.

Clinical Study Protocol Appendix G
Drug Substance
Benralizumab (MEDI-563) 
StudyCode
D3250C00037
Edition Number
2.0
Date
18 July 2017
Appendix G
Study Plan and Procedures – Years 2, 3, and 4

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
2
STUDY PLAN AND PROCEDURES
Q4W REGIMEN – YEAR 2
Table 1
Study Assessments Schedule – Q4W regimen – Year 2 
Assessment/ activity
Refer to
Treatment
  EOTe
  IPDf
   FUe,f
UNSg
V15
V16 
V17
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27
w56
w60
w64
w68
w72
w76
w80
w84
w88
w92
w96
w100
w104
4 wks 
after last 
dose
4 wks 
after last 
dose
12 wks 
after last 
dose
Visit window (days) a
+3
+3
+3
+3
+3
   +3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Hematology
5.2.1
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
Urine pregnancy test 
(dipstick) b
5.2.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
5.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA c,d
5.3.4
X
X
X
X
X
Assessment of asthma 
exacerbations and asthma-
related HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
3.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of IPf 
6.6
X
X
X
X
X
X
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
b
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
c
ADA samples to be collected before IP administration.
d
In case of anaphylaxis additional samples to be taken (see Section 6.7)

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
3
e
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval process in 
the local market.  For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in December 2018 with 
EOT and FU visits in 1Q 2019.
f
IPD visit to be conducted on early discontinuation of IP (see Section 3.6).  Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 weeks 
after the last dose of IP, for a final follow-up visit.
g
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
4
Q4W REGIMEN – YEAR 3
Table 2
Study Assessments Schedule – Q4W regimen – Year 3 
Assessment/ 
activity
Refer to
Treatment
EOTe
IPDf
FUe,f
UNSg
V28
V29
V30 
V31
V32
V33
V34
V35
V36
V37
V38
V39
V40
w108
w112
w116
w120
w124
w128
w132
w136
w140
w144
w148
w152
w156
4 wks 
after 
last 
dose
4 wks 
after 
last 
dose
12 
wks 
after 
last 
dose
Visit window (days) a
+3
+3
+3
+3
+3
+3
  +3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Hematology
5.2.1
X
X
X
X
X
Serum chemistryj
5.2.1
X
X
X
X
Urine pregnancy 
test (dipstick) b
5.2.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
5.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA c,d
5.3.4
X
X
X
X
X
Assessment of 
asthma 
exacerbations and 
asthma-related 
HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
3.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of 
IPf 
6.6
X
X
X
X
X
X
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
b
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
c
ADA samples to be collected before IP administration.
d
In case of anaphylaxis additional samples to be taken (see Section 6.7)

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
5
e
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval process in 
the local market.  For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in December 2018 with 
EOT and FU visits in 1Q 2019.
f
IPD visit to be conducted on early discontinuation of IP (see Section 3.6). Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 weeks 
after the last dose of IP, for a final follow-up visit.
g
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
6
Q4W REGIMEN – YEAR 4
Table 3
Study Assessments Schedule – Q4W regimen – Year 4 
Assessment/ 
activity
Refer to
Treatment
EOTe
IPDf
FUe,f
UNSg
V41
V42
V43
V44 
V45
V46
V47
V48
V49
V50
V51
V52
V53
w160
w164
w168
w172
w176
w180
w184
w188
w192
w196
w200
w204
w208
4 wks 
after 
last 
dose
4 wks 
after 
last 
dose
12 
wks 
after 
last 
dose
Visit window (days) a
+3
+3
+3
+3
+3
  +3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Hematology
5.2.1
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
Urine pregnancy 
test (dipstick) b
5.2.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
5.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADA c,d
5.3.4
X
X
X
X
X
Assessment of 
asthma 
exacerbations and 
asthma-related 
HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
3.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of 
IPf 
6.6
X
X
X
X
X
X
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
b
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
c
ADA samples to be collected before IP administration.
d
In case of anaphylaxis additional samples to be taken (see Section 6.7)

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
7
e
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval process in 
the local market. For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in December 2018 with 
EOT and FU visits in 1Q 2019.
f
IPD visit to be conducted on early discontinuation of IP (see Section 3.6). Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 weeks 
after the last dose of IP, for a final follow-up visit.
g
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
8
Q8W REGIMEN – YEAR 2
Table 4
Study Assessments Schedule – Q8W regimen – YEAR 2
Assessment/ activity
Refer to
Treatment
EOTe
IPDf
FUe,f
UNSg
V8
V9
V10
V11
V12
V13
V14
4 wks 
after last 
dose
4 wks 
after last 
dose
12 wks 
after last 
dose
W56
W64
W72
W80
W88
W96
W104
Visit window (days) b
+3
+3
+3
   +3
+3
+3
+3
+7
+7
+7
N/A
Hematology
5.2.1
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
Urine pregnancy test (dipstick) a
5.2.1.1
X
X
X
X
X
X
X
X
X
X
Vital signs  
5.2.2
X
X
X
X
X
X
X
X
X
X
X
ADAc,d
5.3.4
X
X
X
X
X
Assessment of asthma exacerbations 
and asthma-related HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
3.5
X
X
X
X
X
X
X
X
X
X
X
Administration of IP f
6.6
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
b
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
c
ADA samples to be collected before IP administration.
d
In case of anaphylaxis additional samples to be taken (see Section 6.7)
e
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval process in 
the local market. For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in December 2018 with 
EOT and FU visits in 1Q 2019.
f
IPD visit to be conducted on early discontinuation of IP (see Section 3.6). Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 weeks 
after the last dose of IP, for a final follow-up visit.
g
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
9
Q8W REGIMEN – YEAR 3
Table 5
Study Assessments Schedule – Q8W regimen – YEAR 3
Assessment/ activity
Refer to
Treatment
EOTe
IPDf
FUe,f
UNSg
V15
V16
V17
V18
V19
V20
4 wks after last 
dose
4 wks after last 
dose
12 wks after last 
dose
W112
W120
W128
W136
W144
W152
Visit window (days) a
+3
+3
+3
   +3
+3
+3
+7
+7
+7
N/A
Hematology
5.2.1
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
Urine pregnancy test (dipstick) b
5.2.1.1
X
X
X
X
X
X
X
X
X
Vital signs  
5.2.2
X
X
X
X
X
X
X
X
X
X
ADAc,d
5.3.4
X
X
X
X
X
Assessment of asthma exacerbations 
and 
asthma-related HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
Concomitant medication
3.5
X
X
X
X
X
X
X
X
X
X
Administration of IP f
6.6
X
X
X
X
X
X
a
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
b
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
c
ADA samples to be collected before IP administration.
d
In case of anaphylaxis additional samples to be taken (see Section 6.7)
e
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval process in 
the local market. For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in December 2018 with 
EOT and FU visits in 1Q 2019.
f
IPD visit to be conducted on early discontinuation of IP (see Section 3.6). Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 weeks 
after the last dose of IP, for a final follow-up visit.
g
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week

Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00037
Edition Number 1 0
Date 11 January 2016
10
Q8W REGIMEN – YEAR 4
Table 6
Study Assessments Schedule – Q8W regimen – YEAR 4
Assessment/ activity
Refer to
Treatment
EOTe
IPDf
FUe,f
UNSg
V21
V22
V23
V24
V25
V26
V27
4 wks after 
last dose
4 wks after 
last dose
12 wks after 
last dose
W160
W168
W176
W184
W192
W200
W208
Visit window (days) a
+3
+3
+3
+3
   +3
+3
+3
+7
+7
+7
N/A
Hematology
5.2.1
X
X
X
X
X
Serum chemistry
5.2.1
X
X
X
X
Urine pregnancy test (dipstick) b
5.2.1.1
X
X
X
X
X
X
X
X
X
X
Vital signs  
5.2.2
X
X
X
X
X
X
X
X
X
X
X
ADAc,d
5.3.4
X
X
X
X
X
Assessment of asthma 
exacerbations and 
asthma-related HRU
5.3.1/5.3.2
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication
3.5
X
X
X
X
X
X
X
X
X
X
X
Administration of IP f
6.6
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of enrolment, not from the date of previous visit
b
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
c
ADA samples to be collected before IP administration.
d
In case of anaphylaxis additional samples to be taken (see Section 6.7)
e
EOT visit will occur when benralizumab has been approved and is available in the local market or the candidate drug is withdrawn from the approval process in 
the local market. For countries in which a marketing application is not submitted, patients will receive their last dose of benralizumab in December 2018 with 
EOT and FU visits in 1Q 2019.
f
IPD visit to be conducted on early discontinuation of IP (see Section 3.6). Patients who complete an IPD visit will return 8 weeks (±7 days) later, ie, 12 weeks 
after the last dose of IP, for a final follow-up visit.
g
Perform any assessments considered clinically relevant.
D  Days; EOT  End of treatment; FU  Follow-up; HRU  Healthcare resource utilization; V  Visit; W  Week