A Multicentre, Double-blind, Randomized, Parallel Group, Phase 3 Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus Long-acting β2 Agonist (BORA)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca



Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 4.0
Date 16 December 2016
3(85)
Objectives
(a)
Primary Objective
Objective
Endpoint
1.
To assess the safety and tolerability of 2 
dosing regimens of benralizumab for adult 
patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To assess the safety and tolerability of 2 
dosing regimens of benralizumab for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
Number of AEs/SAEs
!
Laboratory variables
!
Physical examination
(b)
Secondary Objectives
Objective
Endpoint
1.
To evaluate the effect of 2 dosing regimens 
of benralizumab on asthma exacerbations 
in adult patients during the 56-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
2.
To evaluate the effect of 2 dosing regimens 
of benralizumab on asthma exacerbations 
in adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
Annual asthma exacerbation rate, where an 
asthma exacerbation is defined by a worsening 
of asthma requiring the use of systemic 
corticosteroids for at least 3 days, and/or an 
in-patient hospitalization, and/or an emergency 
department or urgent care visit.
1.
To evaluate the effect of 2 dosing regimens 
of benralizumab on health care utilization 
and work and productivity loss for adult 
patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To evaluate the effect of 2 dosing regimens 
of benralizumab on health care utilization 
and work and productivity loss for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
WPAI+CIQ
!
Hospitalizations, ED visits, urgent care visits 
and all other outpatient visits due to asthma

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 4.0
Date 16 December 2016
4(85)
Objective
Endpoint
1.
To assess the effect of 2 dosing regimens 
of benralizumab on asthma related and 
general health-related quality of life for 
adult patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To assess the effect of 2 dosing regimens 
of benralizumab on asthma related and 
general health-related quality of life for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
AQLQ(S)+12
!
EQ-5D-5L
1.
To assess the effect 2 dosing regimens of 
benralizumab on asthma control for adult 
patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To assess the effect 2 dosing regimens of 
benralizumab on asthma control for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
ACQ-6
1.
To evaluate the pharmacokinetics and 
immunogenicity of 2 dosing regimens of 
benralizumab for adult patients during the 
56-week treatment period and through the 
follow-up period (16 weeks from day of 
last dose)
2.
To evaluate the pharmacokinetics and 
immunogenicity of 2 dosing regimens of 
benralizumab for adolescent patients 
during the 108-week treatment period and 
through the follow-up period (16 weeks 
from day of last dose)
!
PK parameters
!
Anti-drug antibodies (ADA)
1.
To assess the effect of 2 dosing regimens 
of benralizumab on pulmonary function for 
adult patients during the 56-week treatment 
period (16 weeks from day of last dose)
2.
To assess the effect of 2 dosing regimens 
of benralizumab on pulmonary function for 
adolescent patients during the 108-week 
treatment period (16 weeks from day of last 
dose)
!
Pre-bronchodilator FEV1 and post-
bronchodilator FEV1 at the study center

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 4.0
Date 16 December 2016
5(85)
Objective
Endpoint
1.
To assess the impact of 2 dosing regimens 
of benralizumab on blood eosinophil levels 
for adult patients during the 56-week 
treatment period and through follow-up 
period (16 weeks from day of last dose)
2.
To assess the impact of 2 dosing regimens 
of benralizumab on blood eosinophil levels 
for adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
Blood eosinophils
Study design
This is a double-blind, randomized, parallel group, extension study designed to evaluate the 
safety and tolerability of a fixed 30 mg dose of benralizumab administered subcutaneously (SC).  
Patients who complete 1 of the predecessor studies D3250C00017, D3250C00018, or 
D3250C00020 on investigational product may be eligible to enrol into this study.
After a minimum of 1200 patients have been enrolled in this study, subsequent patients (up to a 
maximum of 2200 total for the study), who complete a minimum of 16 weeks, and no more than 
40 weeks, in this study, will be given the option to transition to an open-label safety extension 
study, Study D3250C00037 (MELTEMI), which retains patients on the same treatment regimen 
as in this study and contains a simplified set of study assessments.  
Patients choosing to enter Study D3250C00037 will complete an end-of-treatment (EOT) visit in 
this study before transitioning.  Adolescent patients, patients from Japan and South Korea, and 
any patient who chooses not to enter Study D3250C00037 will remain in this study through IPD 
or EOT and FU.
Once the blind is broken in the predecessor studies, this study (BORA) becomes a single-blind 
design for those patients who had been on active treatment in the predecessor studies. The study 
will become single-blind for all remaining patients at the time of the Japanese EOT analysis. 
While the Sponsor will be unblinded to regimen for analysis purposes, study conduct and 
blinding at the site and patient level will remain unchanged. 
Adults
Patients previously assigned to an active treatment arm in the predecessor study
Patients previously randomized to the every 4 weeks (Q4W) regimen of benralizumab will 
continue injections of active drug every 4 weeks.  

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 4.0
Date 16 December 2016
6(85)
Patients previously randomized to the every 8 week (Q8W) regimen will continue to receive 
active drug every 8 weeks with placebo (dummy) injections administered at the 4-week interim 
treatment visits in order to maintain the blind.  
Patients previously assigned to the placebo arm in the predecessor study
All adult patients previously assigned to the placebo arm in the predecessor study will be 
re-randomized to either the Q4W or Q8W regimen (first 3 doses administered every 4 weeks 
followed by every 8 weeks thereafter).  Patients on the Q4W regimen will receive active drug 
every 4 weeks.  Patients on the Q8W regimen will receive active drug at Visit 1 (Week 0), Visit 
2 (Week 4), Visit 3 (Week 8), followed by alternating monthly SC injections of placebo and 
active drug, eg, placebo at Visit 4 (Week 12), active drug at Visit 5 (Week 16), placebo at Visit 6 
(Week 20), and so on in order to maintain the blind relative to the Q4W regimen.  
Adolescents outside the European Union1
Adolescents previously assigned to an active treatment arm in the predecessor study
Adolescents previously randomized to the Q4W regimen of benralizumab will continue 
injections of active drug every 4 weeks.  Patients previously randomized to the Q8W regimen 
will continue to receive active drug every 8 weeks with placebo (dummy) injections 
administered at the 4-week interim treatment visits in order to maintain the blind.  
Adolescents previously assigned to the placebo arm in the predecessor study
Adolescents previously assigned to the placebo arm in the predecessor study will be 
re-randomized to either the Q4W or Q8W regimen (first 3 doses administered every 4 weeks 
followed by every 8 weeks thereafter).  Patients on the Q4W regimen will receive active drug 
every 4 weeks.  Patients on the Q8W regimen will receive active drug at Visit 1 (Week 0), Visit 
2 (Week 4), Visit 3 (Week 8), followed by alternating monthly SC injections of placebo and 
active drug, eg, placebo at Visit 4 (Week 12), active drug at Visit 5 (Week 16), placebo at Visit 6 
(Week 20), and so on in order to maintain the blind relative to the Q4W regimen.   
Adolescents within the European Union 
Adolescents previously assigned to an active treatment arm in the predecessor study
Adolescents within the European Union (EU) will continue to receive only the Q8W dosing 
regimen as per the predecessor study.  In order to maintain the blind of the predecessor study, 
this group will receive injections every 4 weeks for the first 3 doses (active drug at Visits 1 and 
3, placebo administered at Visit 2) followed by every 8 weeks thereafter.  
Adolescents previously assigned to the placebo arm in the predecessor study
                                                
1 For the purposes of this study the European Union (EU) is defined as consisting of the following countries: 
Bulgaria, Czech Republic, France, Germany, Italy, Poland, Romania, Spain, Sweden and the United Kingdom.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 4.0
Date 16 December 2016
7(85)
Adolescents within the EU who were randomized to placebo in the predecessor study will be 
assigned to benralizumab 30 mg Q8W in this study (every 4 weeks for the first 3 doses followed 
by every 8 weeks thereafter).  
After the first 3 doses, adolescent patients within the EU will be receiving open-label treatment 
with IP administered at their bimonthly visit; however, they will still follow an every 4 weeks 
study visit schedule (see Table of Assessments, Table 2).
Target patient population
Patients who complete Study D3250C00017, D3250C00018, or D3250C00020 on 
investigational product may be eligible for this study.  
Investigational product and mode of administration
Benralizumab 30 mg/mL solution for injection in an accessorized pre-filled syringe (APFS) OR 
matching placebo in an APFS will be administered SC at the study site according to the dosing 
regimens described below.
Dosage 
Refer to Study Design section above.
Duration of treatment
Adults: This is a 68-week study with the last dose of study drug administered at Week 52.  An 
end of treatment (EOT) visit will be conducted at Week 56.  A final follow-up visit will be 
conducted at Week 68, which is 16 weeks after the last dose of study drug.
The total planned study duration is 68 weeks.
Adolescents: This is a 120-week study with the last dose of study drug administered at Week 
104.  An EOT visit will be conducted at Week 108.  A final follow-up visit will be conducted at 
Week 120, which is 16 weeks after the last dose of study drug.
The total planned study duration is 120 weeks.
Statistical methods 
All safety and efficacy parameters will be analyzed descriptively based on the full analysis set.  
The full analysis set includes all randomized patients who received any dose of IP.
Patients that enter the predecessor study as an adolescent (at Visit 1 of the predecessor study) 
will continue to be considered as an adolescent throughout this study, and will thus be assigned 
to treatment regimen and assessments of an adolescent, irrespective of when they reach 18 years 
of age.  
Data from adult patients choosing to enter the safety extension study, D3250C00037, will be 
summarized separately from those remaining in this study.  

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 4.0
Date 16 December 2016
8(85)
The adult completion analysis of BORA will be conducted when all adult patients have 
completed the study, and all adolescent patients have completed the first 56 weeks of treatment 
within BORA.  A subsequent analysis in adolescent patients will be completed when all 
adolescent patients have completed the study.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
9(85)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................14
1.
INTRODUCTION .................................................................................................18
1.1
Background............................................................................................................18
1.2
Rationale for conducting this study .......................................................................19
1.3
Rationale for study design, doses, and control groups...........................................19
1.4
Benefit/risk and ethical assessment........................................................................19
1.5
Overall study design ..............................................................................................20
2.
STUDY OBJECTIVES..........................................................................................24
3.
PATIENT SELECTION CRITERIA AND WITHDRAWAL CRITERIA...........26
3.1
Inclusion criteria ....................................................................................................26
3.2
Exclusion criteria ...................................................................................................27
3.3
Patient enrolment and randomization ....................................................................28
3.4
Procedures for handling incorrectly randomized patients .....................................29
3.5
Concomitant medications, restrictions during and after the study.........................29
3.5.1
Concomitant medication ........................................................................................29
3.5.1.1
Background medication .........................................................................................29
3.5.1.2
Rescue medication .................................................................................................29
3.5.2
Restrictions ............................................................................................................29
3.5.2.1
Asthma medication restrictions..............................................................................29
3.5.2.2
Other medication restrictions.................................................................................30
3.5.2.3
Other restrictions....................................................................................................31
3.6
Discontinuation from investigational product .......................................................31
3.7
Withdrawal from the study ....................................................................................32
3.7.1
Withdrawal of Informed Consent ..........................................................................32
3.8
Withdrawal of informed consent for donated biological samples .........................32
4.
STUDY PLAN AND PROCEDURES ..................................................................34
4.1
Enrolment period ...................................................................................................42
4.1.1
Randomization (Visit 1).........................................................................................42
4.2
Randomized treatment period................................................................................42

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
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4.2.1
Patients that continue for duration of BORA.........................................................42
4.2.2
Patients that will transition into MELTEMI ..........................................................42
4.2.3
Dosing regimens ....................................................................................................43
4.2.3.1
Adults.....................................................................................................................43
4.2.3.2
Adolescents outside the European Union ..............................................................43
4.2.3.3
Adolescents within the European Union................................................................44
4.2.3.4
Randomized treatment period assessments............................................................44
4.3
Follow-up period....................................................................................................45
5.
STUDY ASSESSMENTS AND PROCEDURES.................................................45
5.1
Efficacy assessments..............................................................................................45
5.1.1
Assessment of asthma exacerbations.....................................................................45
5.1.2
Spirometry..............................................................................................................46
5.1.2.1
Post-bronchodilator FEV1 efficacy assessment .....................................................48
5.2
Safety assessments.................................................................................................49
5.2.1
Medical and asthma history ...................................................................................49
5.2.2
Physical examination .............................................................................................49
5.2.2.1
Complete physical examination.............................................................................49
5.2.2.2
Brief physical examination ....................................................................................49
5.2.3
Vital signs ..............................................................................................................49
5.2.4
Electrocardiogram..................................................................................................49
5.2.5
Safety laboratory tests............................................................................................50
5.2.5.1
Pregnancy test ........................................................................................................52
5.3
Other assessments and procedures.........................................................................52
5.3.1
Weight and height..................................................................................................52
5.3.2
Patient reported outcomes......................................................................................52
5.3.2.1
Asthma Control Questionnaire ..............................................................................53
5.3.2.2
Standardised Asthma Quality of Life Questionnaire for 12 years and older.........53
5.3.2.3
Work Productivity and Activity Impairment questionnaire plus Classroom 
Impairment Questions............................................................................................54
5.3.2.4
EQ-5D-5L ..............................................................................................................54
5.3.3
Health care resource utilization..............................................................................54
5.3.4
Other assessments ..................................................................................................55
5.3.4.1
Immunoglobulins for adolescents..........................................................................55
5.3.5
T cell, B cell, and NK cell flow cytometry for adolescents...................................55
5.3.6
Pharmacokinetics ...................................................................................................55
5.3.7
Pharmacodynamics ................................................................................................55
5.3.7.1
Immunogenicity.....................................................................................................55
5.3.8
Handling of biological samples .............................................................................56
5.3.8.1
Labelling and shipment of biological samples.......................................................56
5.3.8.2
Chain of custody of biological samples.................................................................56
6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS .................................57
6.1
Identity of investigational product(s).....................................................................57

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
11(85)
6.2
Labelling ................................................................................................................57
6.3
Storage ...................................................................................................................57
6.4
Accountability........................................................................................................58
6.5
Methods for assigning treatment groups................................................................58
6.6
Methods for ensuring blinding...............................................................................58
6.7
Methods for unblinding..........................................................................................59
6.8
Investigational Product administration and treatment compliance........................59
6.9
Management of Investigational Product related reactions.....................................61
7.
SAFETY REPORTING.........................................................................................62
7.1
Adverse events.......................................................................................................62
7.1.1
Definition of adverse events ..................................................................................62
7.1.2
Definitions of serious adverse event......................................................................62
7.1.3
Recording of adverse events ..................................................................................62
7.1.3.1
Time period for collection of adverse events.........................................................62
7.1.3.2
Follow-up of unresolved adverse events................................................................63
7.1.3.3
Variables ................................................................................................................63
7.1.3.4
Causality collection................................................................................................63
7.1.3.5
Adverse events based on signs and symptoms.......................................................64
7.1.3.6
Adverse events based on examinations and tests...................................................64
7.1.3.7
Symptoms of the disease under study....................................................................64
7.1.4
Reporting of serious adverse events.......................................................................65
7.2
Overdose ................................................................................................................65
7.3
Pregnancy...............................................................................................................66
7.3.1
Maternal exposure..................................................................................................66
7.3.2
Paternal exposure...................................................................................................66
8.
EVALUATION AND CALCULATION OF VARIABLES.................................67
8.1
Statistical considerations........................................................................................67
8.2
Sample size estimate..............................................................................................67
8.3
Definitions of analysis sets ....................................................................................67
8.3.1
Full analysis set......................................................................................................67
8.3.2
Pharmacokinetic analysis set .................................................................................67
8.4
Variables for analyses............................................................................................68
8.4.1
Calculation or derivation of efficacy variables......................................................68
8.4.1.1
Exacerbation rate....................................................................................................68
8.4.1.2
Time to first exacerbation ......................................................................................68
8.4.1.3
Forced expiratory volume in 1 second...................................................................69
8.4.2
Calculation or derivation of safety variable(s).......................................................69
8.4.2.1
Safety variables......................................................................................................69
8.4.3
Calculation or derivation of patient reported outcome variables...........................69

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
12(85)
8.4.3.1
Asthma Control Questionnaire ..............................................................................69
8.4.3.2
Standardised Asthma Quality of Life Questionnaire for 12 years and older.........70
8.4.3.3
Health Care Utilization and Work Productivity and Activity Impairment............70
8.4.3.4
EQ-5D-5L ..............................................................................................................71
8.4.3.5
Health Care Utilization ..........................................................................................72
8.4.4
Calculation or derivation of pharmacokinetic variables ........................................72
8.4.5
Calculation or derivation of immunogenicity variables.........................................72
8.5
Methods for statistical analyses .............................................................................72
8.5.1
Efficacy endpoints analysis method(s) ..................................................................72
8.5.1.1
Analysis methods for safety variables ...................................................................73
8.5.1.2
Analysis methods for pharmacokinetic variables ..................................................73
8.5.1.3
Analysis method for immunogenicity variables ....................................................73
8.5.1.4
Analysis methods for healthcare utilization and patient reported outcomes .........73
8.5.2
Subgroup analysis ..................................................................................................75
8.5.3
Sensitivity analysis.................................................................................................75
8.5.4
Interim analysis......................................................................................................75
8.6
Independent adjudication committee .....................................................................76
8.7
Data Safety Monitoring Board...............................................................................76
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................76
9.1
Training of study center personnel ........................................................................76
9.2
Monitoring of the study .........................................................................................77
9.2.1
Source data.............................................................................................................77
9.2.2
Recording of data...................................................................................................77
9.2.3
Study agreements...................................................................................................78
9.2.4
Archiving of study documents...............................................................................78
9.3
Study timetable and end of study...........................................................................78
9.4
Data management by AstraZeneca ........................................................................78
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................79
10.1
Ethical conduct of the study...................................................................................79
10.2
Patient data protection............................................................................................79
10.3
Ethics and regulatory review..................................................................................79
10.4
Informed consent ...................................................................................................80
10.5
Changes to the protocol and informed consent form.............................................80
10.6
Audits and inspections ...........................................................................................81
11.
LIST OF REFERENCES.......................................................................................82

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
13(85)
LIST OF TABLES
Table 1
Study Assessments Schedule – Adults.....................................................34
Table 2A
Study Assessments Schedule – Adolescents: Weeks 0 to 64...................37
Table 2B
Study Assessments Schedule – Adolescents: Weeks 68 to 120...............39
Table 3
List of safety laboratory tests....................................................................51
Table 4
Serum chemistry tests schedule................................................................51
Table 5
Identity of investigational product............................................................57
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................23
Figure 2
Reversibility testing algorithm .................................................................48
Figure 3
Injection sites and rotation scheme...........................................................60
LIST OF APPENDICES
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

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
14(85)
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
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
APFS
Accessorized pre-filled syringe
AQLQ(S)+12
Standardised Asthma Quality of Life Questionnaire for 12 Years and Older
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
Beta-hCG
Beta- human chorionic gonadotropin
BP
Blood pressure
BUN
Blood urea nitrogen
Cmax
Maximum drug concentration
CO2
Carbon dioxide
COPD
Chronic obstructive pulmonary disease
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency department
EC90
Benralizumab serum concentration corresponding to 90% of maximum 
efficacy
ED90
Benralizumab dose corresponding to 90% of maximum efficacy
EOT
End of treatment
EU
European Union

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
15(85)
Abbreviation or 
special term
Explanation
EXACA
Exacerbation eCRF
FEV1
Forced expiratory volume in 1 second
FSH
Follicle-stimulating hormone
FVC
Forced vital capacity
Gamma-GT
Gamma-glutamyl transpeptidase
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice
GLI 
The Global Lung Function Initiative
HCP
Health care provider
HCU
Healthcare Utilization
HDL cholesterol
High density lipoprotein cholesterol 
HIV
Human immunodeficiency virus
IATA
International Air Transport Association
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
Ig
Immunoglobulin
IL
Interleukin
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IL-5Rα
Interleukin-5 receptor alpha subunit
IM
Intramuscular
ICI
International Coordinating Investigator
IP
Investigational product
IPD
Premature Investigational Product Discontinuation
IRB
Institutional Review Board
ISF
Investigator Study File
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-acting β2 agonists

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
16(85)
Abbreviation or 
special term
Explanation
LAMA
Long-acting anti-muscarinic
LDH
Lactate dehydrogenase
LDL cholesterol
Low density lipoprotein cholesterol
LFT
Liver function test
LTRA
Leukotriene receptor antagonists
MED
Medication
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
Messenger ribonucleic acid
nAb
Neutralizing antibodies
NAEPP
National Asthma Education Prevention Program
OAE
Other significant adverse event
OCS
Oral corticosteroids
PEF
Peak expiratory flow
PFS
Pre-filled syringe
PK
Pharmacokinetic(s)
PN
Predicted normal
Post-BD
Post-bronchodilator
Pre-BD
Pre-bronchodilator
PRO
Patient-reported outcome
ROW
Rest of World (countries outside European Union)
RBC
Red blood cell
SABA
Short-acting β2 agonists
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
TBNK
T cell, B cell and Natural Killer cell
TEAE
Treatment Emergent Adverse Event
TH2
T helper 2
TLC
Total lung capacity
ULN
Upper limit of normal

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
17(85)
Abbreviation or 
special term
Explanation
UNS
Unscheduled
US
United States of America
WBC
White blood cell
WBDC
Web-based Data Capture
WOCBP
Women of childbearing potential
WPAI+CIQ
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
18(85)
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.  Symptom control in children and adolescents with asthma can be similarly 
challenging, due in part to the limitations of current therapeutic modalities.  Longer treatment 
courses, over a period of months or years, and higher medication doses may be required to 
achieve the maximum possible improvement in lung function in children older than 5 years 
(GINA 2015).  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; Di Franco et al 2003; Scott and Wardlaw 2006, 
Simpson et al 2006; Zhang and Wenzel 2007).  Adjusting conventional ICS-based asthma 
therapy according to the degree of elevated sputum eosinophils as a marker of disease activity 
resulted in a reduction in the frequency of asthma exacerbations in prospective trials (Green et 
al 2002; Jayaram et al 2006).
Interleukin-5 (IL-5) is a cytokine factor essential for eosinophil trafficking and survival 
(Molfino et al 2011).  Clinical trials of neutralizing anti-IL-5 antibodies (mepolizumab and 
reslizumab) in patients with uncontrolled eosinophilic asthma resulted in an improvement in 
key asthma control metrics, including asthma exacerbations (Castro et al 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 

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Edition 4.0
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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 
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 extremely 
limited.
In previous clinical studies, benralizumab administration resulted in rapid and prolonged 
depletion of eosinophils in the peripheral blood and in the asthmatic airway with associated 
improvements in multiple metrics of asthma control.  The purpose of this study is to continue 
to characterize the safety profile of benralizumab administration in asthma patients who have 
completed 1 of the 3 predecessor studies: D3250C00017, D3250C00018, or D3250C00020. 
1.3
Rationale for study design, doses, and control groups
This is a global study designed to continue to investigate the safety of benralizumab in severe 
asthma patients on ICS-LABA therapy with or without chronic oral corticosteroids (OCS) 
and/or other asthma controllers.  All patients who were assigned to the placebo regimen 
during the predecessor study will be reassigned to receive active drug, while those who 
received active drug during the predecessor study will continue on that same regimen.  This 
will allow for the collection of safety and efficacy information in some patients for up to 2 
continuous years in adults and 3 continuous years in adolescents. 
Once the blind is broken in the predecessor studies, this study (BORA) becomes a single-blind 
design for those patients who had been on active treatment in the predecessor studies. The 
study will become single blind for all remaining patients at the time of the Japanese EOT 
analysis (see Section 8.5.4). While the Sponsor will be unblinded to regimen for analysis 
purposes, study conduct and blinding at the site and patient level will remain unchanged.
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.

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Drug Substance Benralizumab (MEDI-563)
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Edition 4.0
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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 
eosinophil count below which benralizumab is generally not effective remains unclear at this 
point in time.
The efficacy and safety of benralizumab in asthmatic patients is being evaluated in studies 
D3250C00017, D3250C00018, and D3250C00020.  In this study, additional risk/benefit 
information will be generated with regard to the impact of benralizumab on asthma 
exacerbations, lung function, asthma control metrics, AEs and SAEs, and laboratory data.  
Additional information with regard to peripheral blood eosinophil levels and benefit/risk will 
be collected. 
Eosinophils are a prominent feature of the inflammatory response to helminthic parasitic 
infections, and the presence of infiltrating eosinophils has been circumstantially associated 
with a positive prognosis in certain solid tumors.  Therefore, there is a theoretical risk that 
prolonged eosinophil depletion may diminish the ability to defend against helminthic 
parasites, or negatively impact the natural history of certain malignant tumors.  Risk 
minimization measures include exclusion of patients with untreated parasitic infection and 
active or recent malignancy, in conjunction with the performance of routine 
pharmacovigilance activities.  In addition, the development of anti-drug antibodies (ADA) to 
benralizumab has been documented.  Theoretical risks of developing ADA include decreased 
drug efficacy and hypersensitivity reactions (eg, anaphylaxis or immune complex disease).
A detailed assessment of the risk/benefit of benralizumab in patients with asthma is provided 
in the Investigator’s Brochure.
1.5
Overall study design
This is a double-blind, randomized, parallel group, study designed to evaluate the safety and 
tolerability of a fixed 30 mg dose of benralizumab administered subcutaneously (SC).  
Eligible patients will transition from the predecessor study into this follow-on study at the 
End-of-Treatment (EOT) visit of the predecessor study.  Visit 1 of this extension study will be 
scheduled on the same day as the EOT visit of the predecessor study (see Section 4.1.1).  
Duplicate assessments will not be required.
Patients will be maintained on their currently prescribed ICS-LABA therapy(ies), throughout 
the treatment period, unless any changes are considered necessary/appropriate at the discretion 
of the Investigator.
In this study, patients will receive 56 weeks of study treatment (108 weeks for adolescents).  
Patients who enter the predecessor study as an adolescent (at Visit 1 of the predecessor study) 
will continue to be considered  an adolescent throughout this study, and will thus be assigned 

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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
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to the treatment regimen and assessments of an adolescent, irrespective of when they reach 18 
years of age.
A follow-up visit will be conducted at Week 68 (Week 120 for adolescents), which is 16 
weeks after the last dose of study drug.
The total patient population for this study will be approximately 2200 patients, comprising 
patients from Studies D3250C00017, D3250C00018, and D3250C00020.  Approximately 
1200 adult patients will remain in this study through IPD or EOT and FU.  The remaining 
approximately 700-1000 adult patients will stay in BORA for at least 16 weeks and not more 
than 40 weeks, and will then be asked to transition to an open-label safety extension study, 
Study D3250C00037 (MELTEMI).  Investigators will be provided with the list of patients 
who will be asked to participate in Study D3250C00037.  
A minimum of 1200 patients is considered sufficient to address the primary objective of safety 
and tolerability in the on-treatment and 16-week safety follow-up period of this study.  The 
safety extension study, MELTEMI, will allow remaining patients to continue to receive 
benralizumab until it is available in their local market, until it has been withdrawn from the 
approval process in their local market, or until the end of December 2018 in those countries in 
which a marketing application will not be submitted.  The minimum 16-week treatment period 
prior to transition to MELTEMI ensures that any patients previously randomized to placebo 
have completed monthly study visits and assessments for the first 3 active doses within this 
study before transitioning to MELTEMI.
Patients will begin to transition from BORA into this study only after the database lock of the 
initial study into which the individual patient was recruited has been reached, and a positive 
risk/benefit evaluation of the results from CALIMA & SIROCCO has taken place.  In order to 
maintain the blind of ZONDA, transition of patients that originate from that study will 
commence only after the database lock of ZONDA.  To ensure this strategy is followed, study 
sites will be instructed by the Sponsor at which point transition of individual patients may 
begin.
To meet certain health authority obligations, adolescent patients and patients from Japan and 
South Korea will remain in this study through IPD or EOT and FU.  Patients choosing not to 
transition into MELTEMI will be allowed to remain in this study through IPD or EOT and 
FU.
Adults
Patients previously assigned to an active treatment arm in the predecessor study
Patients previously randomized to the every 4 weeks (Q4W) regimen of benralizumab will 
continue injections of active drug every 4 weeks.

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Edition 4.0
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Patients previously randomized to the every 8 week (Q8W) regimen will continue to receive 
active drug every 8 weeks with placebo (dummy) injections administered at the 4-week 
interim treatment visits in order to maintain the blind.
Patients previously assigned to the placebo arm in the predecessor study
All adult patients previously assigned to the placebo arm in the predecessor study will be 
re-randomized to either the Q4W or Q8W regimen (first 3 doses administered every 4 weeks 
followed by every 8 weeks thereafter).  Patients on the Q4W regimen will receive active drug 
every 4 weeks.  Patients on the Q8W regimen will receive active drug at Visit 1 (Week 0), 
Visit 2 (Week 4), Visit 3 (Week 8), followed by alternating monthly SC injections of placebo 
and active drug, eg, placebo at Visit 4 (Week 12), active drug at Visit 5 (Week 16), placebo at 
Visit 6 (Week 20), and so on in order to maintain the blind relative to the Q4W regimen.  
Adolescents outside the European Union (EU)2
Adolescents previously assigned to an active treatment arm in the predecessor study
Adolescents previously randomized to the Q4W regimen of benralizumab will continue 
injections of active drug every 4 weeks.  
Patients previously randomized to the Q8W regimen will continue to receive active drug every 
8 weeks with placebo (dummy) injections administered at the 4-week interim treatment visits 
in order to maintain the blind.
Adolescents previously assigned to the placebo arm in the predecessor study
Adolescents previously assigned to the placebo arm in the predecessor study will be 
re-randomized to either the Q4W or Q8W regimen (first 3 doses administered every 4 weeks 
followed by every 8 weeks thereafter).  Patients on the Q4W regimen will receive active drug 
every month.  Patients on the Q8W regimen will receive active drug at Visit 1 (Week 0), Visit 
2 (Week 4), Visit 3 (Week 8), followed by alternating monthly SC injections of placebo and 
active drug, eg, placebo at Visit 4 (Week 12), active drug at Visit 5 (Week 16), placebo at 
Visit 6 (Week 20), and so on in order to maintain the blind relative to the Q4W regimen.  
Adolescents within the European Union (EU)
Adolescents previously assigned to an active treatment arm in the predecessor study
Adolescents within the EU will continue to receive only the Q8W dosing regimen as per the 
predecessor study.  In order to maintain the blind of the predecessor study, this group will 
receive injections every 4 weeks for the first 3 doses (active drug at Visits 1 and 3, placebo 
administered at Visit 2) followed by every 8 weeks thereafter (to match the regimen of the 
adolescents who were on placebo in the predecessor study).
                                                
2 For the purposes of this study the European Union (EU) is defined as consisting of the following countries: 
Bulgaria, Czech Republic, France, Germany, Italy, Poland, Romania, Spain, Sweden and the United Kingdom.

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Edition 4.0
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Adolescents previously assigned to the placebo arm in the predecessor study
Adolescents within the EU who were randomized to placebo in the predecessor study will be 
assigned to benralizumab 30 mg Q8W in this study (every 4 weeks for the first 3 doses 
followed by every 8 weeks thereafter).
After the first 3 doses, adolescent patients within the EU will be receiving open-label 
treatment with IP administered at their bimonthly visit; however, they will still follow an 
every 4 weeks study visit schedule (see Table of Assessments, Table 2).
Figure 1
Study flow chart
IP administration will be managed via an IVRS call at every dosing visit to ensure correct dosing schedule as 
follows:
!
Previously on active treatment: benralizumab Q4W or Q8W.  For the Q8W regimen, placebo will be given at 
the interim visits.
!
Previously on placebo: benralizumab at Visits 1-3 (ie, Q4W for first 3 doses), followed by benralizumab 
Q4W or Q8W.  For the Q8W regimen, placebo will be given at the interim visits.
NOTE: Adolescents on active treatment in the EU will continue on the Q8W regimen and will not receive 
placebo at the interim visits, except for Visit 2 (in order to maintain the blind).  Adolescents in the EU on 
placebo will receive benralizumab at Visits 1-3 (ie, Q4W for first 3 doses), then continue on the Q8W 
regimen and will not receive placebo at the interim visits.

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Edition 4.0
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2.
STUDY OBJECTIVES
(a)
Primary Objective
Objective
Endpoint
1.
To assess the safety and tolerability of 2 
dosing regimens of benralizumab for adult 
patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose) 
2.
To assess the safety and tolerability of 2 
dosing regimens of benralizumab for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
Number of AEs/SAEs
!
Laboratory variables
!
Physical examination
(b)
Secondary Objectives
Objective
Endpoint
1.
To evaluate the effect of 2 dosing regimens 
of benralizumab on asthma exacerbations 
in adult patients during the 56-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
2.
To evaluate the effect of 2 dosing regimens 
of benralizumab on asthma exacerbations 
in adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
Annual asthma exacerbation rate, where an 
asthma exacerbation is defined by a worsening 
of asthma requiring the use of systemic 
corticosteroids for at least 3 days, and/or an 
in-patient hospitalization, and/or an emergency 
department or urgent care visit.
1.
To evaluate the effect of two dosing 
regimens of benralizumab on health care 
utilization and work and productivity loss 
for adult patients during the 56-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose) 
2.
To evaluate the effect of two dosing 
regimens of benralizumab on health care 
utilization and work and productivity loss 
for adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
WPAI+CIQ
!
Hospitalizations, ED visits, urgent care visits 
and all other outpatient visits due to asthma

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Objective
Endpoint
1.
To assess the effect of 2 dosing regimens 
of benralizumab on asthma related and 
general health-related quality of life for 
adult patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To assess the effect of 2 dosing regimens 
of benralizumab on asthma related and 
general health-related quality of life for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
AQLQ(S)+12
!
EQ-5D-5L
1.
To assess the effect two dosing regimens of 
benralizumab on asthma control for adult 
patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To assess the effect two dosing regimens of 
benralizumab on asthma control for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
ACQ-6
1.
To evaluate the pharmacokinetics and 
immunogenicity of 2 dosing regimens of 
benralizumab for adult patients during the 
56-week treatment period and through the 
follow-up period (16 weeks from day of 
last dose)
2.
To evaluate the pharmacokinetics and 
immunogenicity of 2 dosing regimens of 
benralizumab for adolescent patients 
during the 108-week treatment period and 
through the follow-up period (16 weeks 
from day of last dose)
!
PK parameters
!
Anti-drug antibodies (ADA)

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Edition 4.0
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Objective
Endpoint
1.
To assess the effect of 2 dosing regimens 
of benralizumab on pulmonary function for 
adult patients during the 56-week treatment 
period and through the follow-up period 
(16 weeks from day of last dose)
2.
To assess the effect of 2 dosing regimens 
of benralizumab on pulmonary function for 
adolescent patients during the 108-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
!
Pre-bronchodilator FEV1 and post-
bronchodilator FEV1 at the study center
1.
To assess the impact of 2 dosing regimens 
of benralizumab on blood eosinophil levels 
for adult patients during the 56-week 
treatment period and through the follow-up 
period (16 weeks from day of last dose)
2.
To assess the impact of 2 dosing regimens 
of benralizumab on blood eosinophil levels 
for adolescent patients during the 108-
week treatment period and through the 
follow-up period (16 weeks from day of 
last dose)
!
Blood eosinophils
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 (and/or assent as applicable locally) for study participation must 
be obtained prior to any study related procedures being performed (local regulations 
are to be followed in determining the assent/consent requirements for children and 
parent(s)/guardian(s)) and according to international guidelines and/or applicable 
European Union guidelines.
2.
Female and male patients who completed the double-blind treatment period in a 
predecessor study on benralizumab or matching placebo.
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 
Intrauterine device/IUS Ievonorgestrel Intrauterine system, Depo-Provera™ 

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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 postemenopausal if 
they have been amenorrheic for 12 months prior to the planned date of randomization 
without an alternative medical cause.  The following age-specific requirements apply:
∀
Women <50 years old would be considered postmenopausal if they have been 
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 studies 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 
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 a predecessor study which in 
the opinion of the investigator may put the patient at risk because of his/her 

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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 a 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 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 major protocol deviations in any of the predecessor studies at the 
discretion of the Sponsor
For procedures for withdrawal of incorrectly enrolled or randomized patients see Section 3.4.
3.3
Patient enrolment and randomization
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.
The Investigator will:
1.
Obtain signed informed consent and/or assent as applicable locally (hereafter 
referred to collectively as ‘consent’) from the patient, and/or parent or legal
guardian, before any study specific procedures are performed at Visit 1
2.
Assign each potential patient a unique enrolment number beginning with ‘E# via 
interactive web/voice response system (IWRS/ IVRS)
3.
Determine patient eligibility
4.
Assign eligible patient a unique randomization code via IWRS/IVRS
For all adult patients and non-EU adolescent patients previously assigned to the placebo arm 
in the predecessor study, randomization in this safety extension study will be stratified by the 

Revised Clinical Study Protocol
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Edition 4.0
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predecessor study.  For patients from the predecessor studies D3250C00017 and 
D3250C00018, the randomization will be further stratified by age group (adults/adolescents).  
In addition, the adult patients will be also stratified by country.  Specific information 
concerning the use of the IWRS/IVRS will be provided in the separate manual. 
3.4
Procedures for handling incorrectly randomized 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 randomized 
or initiated on study treatment and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized 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.
3.5
Concomitant medications, restrictions during and after the study
3.5.1
Concomitant medication
All the concomitant treatments given during the study, with reason for the treatment, will be 
collected by the Investigator/authorized delegate at each visit (as shown in Table 1 and Table 
2) and recorded in the eCRF.  AstraZeneca will link the records for concomitant medications, 
medical and asthma history and adverse events from the predecessor study to those collected 
for this study to create a continuous record.  
3.5.1.1
Background medication 
Patients are required to remain on the same stable dose of background asthma medication as in 
the predecessor study in order not to confound the objectives of the study.  If changing the 
background asthma medication is judged necessary by the Investigator, the study physician 
should be contacted for approval, the justification should be documented in the source, and the 
change of drugs or doses should be reflected in the eCRF.  
3.5.1.2
Rescue medication 
Salbutamol, albuterol, or levalbuterol may be used as rescue medication during the study in 
the event of a worsening of asthma symptoms.  Patients who are already on nebulized SABA 
as rescue medication can continue their use throughout the study.
3.5.2
Restrictions
3.5.2.1
Asthma medication restrictions
(a)
Asthma medication restrictions on the days of scheduled spirometry visit 
Pre- and/or post-dose spirometry assessments will be performed at the study center 
at scheduled visits (see Table 1 and Table 2): restrictions to patient’s background 

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asthma medication are required prior to the spirometry as described below (also see 
Section 5.1.2):
Treatment Visits 1–14 (Visits 1-27 for adolescents): 
Twice daily ICS and LABA therapies should be withheld for 12- 24 hours; once 
daily therapies containing ICS, LABA, or LAMA therapies should be withheld for 
≥24 hours before scheduled center visit spirometry as this will affect the pre-BD 
FEV1 value; they may be taken subsequently, at the center.  For the same reason 
patients should not use their rescue SABA medication 
(albuterol/salbutamol/levalbuterol) within 6 hours of a scheduled center visit 
spirometry.  This restriction is particularly critical for efficacy measures taken 
during the treatment period.  
If the patient has taken their usual ICS-LABA asthma controller medication on the 
morning of the scheduled spirometry visit, the Investigator/authorized delegate 
should remind the patient of the importance of withholding their usual morning 
asthma medication, and reschedule the visit for another day within the allowed 
window. 
If the patient has taken rescue SABA within 6 hours of the planned center visit 
spirometry they should ideally 
1) remain at the center until such time that the 6 hour withholding time has 
been reached if it does not exceed the 1.5 hour spirometry window or 
2) return on another day, within the visit window.  
(b)
Asthma medication restrictions on unscheduled visits
Asthma medication restrictions on unscheduled visits may not be feasible and may 
be applied at the discretion of the Investigator.  Timing of recent controller and 
rescue SABA use relative to the unscheduled spirometry should be noted in the 
record.
3.5.2.2
Other medication restrictions
(a)
Use of immunosuppressive medication (other than prior stable oral corticosteroids 
for the maintenance treatment of asthma or bolus systemic steroids for the treatment 
of an asthma exacerbation) or administration of live/attenuated vaccines is not 
allowed.  Topical administration of immunosuppressive medication and local 
corticosteroid injections may be allowed at the discretion of the Investigator after 
discussion with the AstraZeneca Study Physician. 
(b)
Patient should not receive an allergen immunotherapy injection on the same day as 
IP administration

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
31(85)
(c)
Patients who are on theophylline or digoxin; the Investigator should ensure the 
levels of each of these medications does not exceed the upper limit of therapeutic 
range.  The Investigator will also be responsible for ensuring that these levels are 
regularly checked, assessed, and documented as per local practice 
(d)
Patients should not take any other excluded medications:
∀
Five-lipoxygenase inhibitors (eg, Zileuton)
∀
Oral or ophthalmic non-selective β-adrenergic antagonist (eg, propranolol)
A table with medication-related restrictions is presented in Appendix F.
3.5.2.3
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 contraindicates further 
dosing
3.
Risk to patient as judged by the Investigator or AstraZeneca
4.
Severe non-compliance to study protocol
5.
Eligibility requirement found not to be fulfilled (see Section 3.4)
6.
Pregnancy
7.
Lost to follow-up3
8.
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 or more than 2 scheduled doses of IP are 
missed during course of the study
                                                
3 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.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
32(85)
(d) An asthma-related event requiring mechanical ventilation
All patients who prematurely discontinue IP should return to the study center and complete 
the procedures described for the Premature Investigational Product Discontinuation Visit 
(IPD) within 4 weeks +7 days after the last dose of IP and for the final Follow-up visit at 
16 weeks (±7 days) after the last dose of IP (see Table 1 and Table 2).  
Reasons for premature discontinuation of IP should be recorded in the eCRF.
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. Patients who discontinue IP will be discontinued from the 
study.  
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 AEs outside of the clinical study.  
The enrolment/randomization code of the withdrawn patient cannot be reused.
If patient agrees, he/she will be asked to return to the study center and complete procedures 
described for the IPD and FU visits within 4 weeks (+7 days) and 16 weeks (±7 days) after the 
last dose of IP, respectively.
3.8
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological 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.
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.
If the patient only withdraws consent for the retention of samples for future exploratory use, 
the patient will not be withdrawn from the study.
The Principal Investigator or designee:
!
Ensures patients’ withdrawal of informed consent for the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that patient, if stored at the study center, are 
immediately identified, disposed of /destroyed, and the action documented
!
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 are informed about the sample disposal.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
33(85)
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.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
34(85)
4.
STUDY PLAN AND PROCEDURES
Table 1
Study Assessments Schedule – Adults 
Assessment/ activity
Refer 
to
Treatment
EOT
m
IPD 
j
FU
UNS i
V1
V2 
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
w0
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w68 
Visit window (days) c
+0
+2
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Inclusion/exclusion 
criteria
3.1/3.2
X
Informed consent
10.4
X
Medical and asthma 
history 
5.2.1
X a
Comprehensive CV 
history k
5.2.1
X
Height
5.3.1
X b
X
X
X
FSH g
5.2.5.1
X
Complete physical 
examination
5.2.2.1
X b
X
X
Brief physical 
examination
5.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
5.3.1
X b
X
X
X
Vital Signs
5.2.3
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Local ECG 
5.2.4
X b
X
X
X
Serum chemistry d
5.2.5
X b
X
X
X
X
X
Hematology 
5.2.5
X b
X
X
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
35(85)
Table 1
Study Assessments Schedule – Adults 
Assessment/ activity
Refer 
to
Treatment
EOT
m
IPD 
j
FU
UNS i
V1
V2 
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
w0
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w68 
Visit window (days) c
+0
+2
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Urinalysis
5.2.5
X b
X
X
X
X
X
Urine pregnancy test 
(dipstick) e
5.2.5.1
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK f
5.3.6
X b
X
X
X
X
X
X
X
X
ADA/nAb f
5.3.7.1
X b
X
X
X
X
X
X
X
X
ACQ-6 
5.3.2.1
X b
X
X
X
X
X
X
X
AQLQ(S)+12 
5.3.2.2
X b
X
X
X
X
X
X
X
WPAI+CIQ 
5.3.2.3
X b
X
EQ-5D-5L 
5.3.2.4
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Health care resource 
utilization
5.3.3
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
asthma exacerbations 
5.1.1
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre- BD spirometryl
5.1.2
X b
X
X
X
X
X
X
Post- BD spirometryl
5.1.2
X b
X
X
Randomization 
(where applicable)
6.5
X
Administration
of IP h
6.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7
X a
X
X
X
X
X
X
X
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
X
X
X
X
X
X 
X

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
36(85)
a
Medical and asthma history, AEs and concomitant medications will be linked to the predecessor study to create a complete and continuous record for the 
patient.
b
Assessments done at the EOT visit of the predecessor study do not need to be repeated at Visit 1 of this study, as the data will be duplicated between study 
databases (see Section 4.1.1).
c
All visits are to be scheduled from the date of randomization but not from the date of previous visit
d
Detailed schedule for serum chemistry tests provided in Section 5.2.5, Table 3 and Table 4
e
For WOCBP, urine HCG test to be done at center on each treatment visit before IP administration.
f
PK, ADA and nAb samples to be collected before IP administration.
g
FSH test done only for female patients <50 years who have been amenorrheic for >12 months to confirm postmenopausal status 
h
In case of anaphylaxis additional samples to be taken (see Section 6.9)
i
Unscheduled visits may be initiated as needed, and additional assessments performed at these visits, at the discretion of the Investigator
j
IPD visit should be completed within 4 weeks (+7 days) after last scheduled site visit
k
Refer to CRF for specific CV history to be collected
l
All patients transitioning from ZONDA into this study are exempt from performing the post-BD assessments.  The pre-BD measurement from EOT for 
ZONDA patients will serve as the first pre-BD measurement for these patients in BORA.
m
Patients transitioning into Study D3250C00037 will complete EOT assessments for this study at the same visit during which they transition.  Patients who 
are asked to transition into this study by the Investigator must do so at the next odd-numbered visit (ie, Visit 5, 7, 9, or 11) once the study has started at their 
site (see Section 4.2).  
D  Days; EOT  End-of-treatment; FU  Follow-up; R  Randomization; V  Visit; UNS  Unscheduled; W  Week; IPD Premature IP Discontinuation

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
37(85)
Table 2A
Study Assessments Schedule – Adolescents: Weeks 0 to 64
Assessment/ 
activity
Refer
to
Treatment
IPD
i
UNS
h
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
w0
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w60
w64 
Visit window (days) c
+0
+2
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
Inclusion/exclusion 
criteria
3.1/3.2
X
Informed 
consent+assent
10.4
X
Medical and asthma 
history 
5.2.1
X a
Height
5.3.1
X b
X
X
X
Complete physical 
examination
5.2.2.1
X b
X
X
X
Brief physical 
examination
5.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TBNK Flow 
Cytometry
5.3.5
X b
X
X
X
X
X
Immunological 
Assessments
5.3.4.1
X b
X
X
X
X
X
Weight
5.3.1
X b
X
X
X
Vital Signs
5.2.3
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Local ECG 
5.2.4
X b
X
X
X
X
Serum chemistry d
5.2.5
X b
X
X
X
X
X
Hematology 
5.2.5
X b
X
X
X
X
X
Urinalysis
5.2.5
X b
X
X
X
X
X
Urine pregnancy 
5.2.5.1
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
38(85)
Table 2A
Study Assessments Schedule – Adolescents: Weeks 0 to 64
Assessment/ 
activity
Refer
to
Treatment
IPD
i
UNS
h
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
w0
w4
w8
w12
w16
w20
w24
w28
w32
w36
w40
w44
w48
w52
w56
w60
w64 
Visit window (days) c
+0
+2
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
+7
N/A
test (dipstick) e
PK f
5.3.6
X b
X
X
X
X
X
X
X
ADA/nAb f
5.3.7.1
X b
X
X
X
X
X
X
X
ACQ-6 
5.3.2.1
X b
X
X
X
X
X
X
AQLQ(S)+12 
5.3.2.2
X b
X
X
X
X
X
X
WPAI+CIQ 
5.3.2.3
X b
X
X
EQ-5D-5L 
5.3.2.4
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Health care 
resource utilization
5.3.3
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
asthma 
exacerbations 
5.1.1
X b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre- BD spirometry
5.1.2
X b
X
X
X
X
X
X
Post- BD 
spirometry
5.1.2
X b
X
X
Randomization
6.5
X
Administration
of IP ,j
6.8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
7
X a
X
X
X
X
X
X
X
X
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
X
X
X
X
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
39(85)
a
Medical and asthma history, AEs and concomitant medications will be linked to the predecessor study to create a complete and continuous record for the 
patient.
b
Assessments done at the EOT visit of the predecessor study do not need to be repeated at Visit 1 of this study, as the data will be duplicated between study 
databases (see Section 4.1.1).
c
All visits are to be scheduled from the date of randomization but not from the date of previous visit
d
Detailed schedule for serum chemistry tests provided in Section 5.2.5, Table 3 and Table 4
e
For all adolescent females, urine HCG test to be done at center on each treatment visit before IP administration.
f
PK, ADA and nAb samples to be collected before IP administration.
g
In case of anaphylaxis additional samples to be taken (see Section 6.9)
h
Unscheduled visits may be initiated as needed, and additional assessments performed at these visits, at the discretion of the Investigator
i
IPD visit should be completed within 4 weeks (+7 days) after last scheduled site visit
j
For adolescent patients in the EU, IP administration is Q4W for the first 3 doses (dummy injection of placebo for those patients on benralizumab in the 
predecessor studies) and then Q8W thereafter, with no injection of placebo at the 4 week interim visits.
D  Days; EOT  End-of-treatment; FU  Follow-up; R  Randomization; V  Visit; UNS  Unscheduled; W  Week; IPD Premature IP Discontinuation
Table 2B
Study Assessments Schedule – Adolescents: Weeks 68 to 120
Assessment/ activity
Refer 
to
Treatment
EOT
IPD i
FU 
UNS h
V18
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
w68
w72
w76
w80
w84
w88
w92
w96
w10
0
w10
4
w108
w120
Visit window (days) c
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
Height
5.3.1
X
X
X
X
Complete physical 
examination
5.2.2.1
X
X
X
X
Brief physical 
examination
5.2.2.2
X
X
X
X
X
X
X
X
X 
X
TBNK Flow 
Cytometry
5.3.5
X
X
X
X
X
Immunological 
Assessments
5.3.4.1
X
X
X
X
X
Weight
5.3.1
X
X
X
X
Vital Signs
5.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X 
X

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
40(85)
Table 2B
Study Assessments Schedule – Adolescents: Weeks 68 to 120
Assessment/ activity
Refer 
to
Treatment
EOT
IPD i
FU 
UNS h
V18
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
w68
w72
w76
w80
w84
w88
w92
w96
w10
0
w10
4
w108
w120
Visit window (days) c
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
Local ECG 
5.2.4
X
X
X
X
Serum chemistry d
5.2.5
X
X
X
X
Hematology 
5.2.5
X
X
X
X
X
Urinalysis
5.2.5
X
X
X
X
Urine pregnancy test 
(dipstick) e
5.2.5.1
X
X
X
X
X
X
X
X
X
X
X
X
X
PK f
5.3.6
X
X
X
X
X
ADA/nAb f
5.3.7.1
X
X
X
X
X
ACQ-6 
5.3.2.1
X
X
X
X
X
X
AQLQ(S)+12 
5.3.2.2
X
X
X
X
X
X
WPAI+CIQ 
5.3.2.3
X
X
EQ-5D-5L 
5.3.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
Health care resource 
utilization
5.3.3
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
asthma exacerbations 
5.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
Pre- BD spirometry
5.1.2
X
X
X
X
X
Post- BD spirometry
5.1.2
X
X
Administration
of IP g, j
6.8
X
X
X
X
X
X
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
41(85)
Table 2B
Study Assessments Schedule – Adolescents: Weeks 68 to 120
Assessment/ activity
Refer 
to
Treatment
EOT
IPD i
FU 
UNS h
V18
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
w68
w72
w76
w80
w84
w88
w92
w96
w10
0
w10
4
w108
w120
Visit window (days) c
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
+7
N/A
Adverse events
7
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
a
Medical and asthma history, AEs and concomitant medications will be linked to the predecessor study to create a complete and continuous record for the 
patient.
b
Assessments done at the EOT visit of the predecessor study do not need to be repeated at Visit 1 of this study, as the data will be duplicated between study 
databases (see Section 4.1.1)
c
All visits are to be scheduled from the date of randomization but not from the date of previous visit
d
Detailed schedule for serum chemistry tests provided in Section 5.2.5, Table 3 and Table 4
e
For all adolescent females, urine HCG test to be done at center on each treatment visit before IP administration.
f
PK, ADA and nAb samples to be collected before IP administration.
g
In case of anaphylaxis additional samples to be taken (see Section 6.9)
h
Unscheduled visits may be initiated as needed, and additional assessments performed at these visits, at the discretion of the Investigator
i
IPD visit should be completed within 4 weeks (+7 days) after last scheduled site visit
j
For adolescent patients in the EU, IP administration is Q8W with no injection of placebo at the 4 week interim visits.
D  Days; EOT  End-of-treatment; FU  Follow-up; R  Randomization; V  Visit; UNS  Unscheduled; W  Week; IPD Premature IP Discontinuation

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4.1
Enrolment period
4.1.1
Randomization (Visit 1)
Each potential patient or parent/legal guardian (as applicable) will provide written informed 
consent prior to any study specific procedures and undergo assessments applicable for the visit 
(see Table 1 or Table 2).
In order to provide sufficient time for patients to consider participation in this study, and to 
ensure an uninterrupted dosing regimen as patients transition between the predecessor study and 
this study, patients will be provided with the ICF at/after the visit at which they receive their last 
dose of IP in the predecessor study and will be asked to sign the ICF at Visit 1 of this study, prior 
to any study-specific procedures being performed.  
Visit 1 of this study will be scheduled to ensure an uninterrupted dosing regimen as patients 
transition between the predecessor study and this safety extension study.  Therefore, if the actual 
EOT visit in the predecessor study occurs more than 7 days from the scheduled EOT visit, the 
patient will not be eligible to enrol in this study.  The End-of-Treatment (EOT) visit for the 
predecessor study and Visit 1 for this study will occur on the same day and will include the first 
dose of IP for this study.  If IP cannot be administered at this visit, the patient will not be eligible 
for enrolment in this study.  
As Visit 1 coincides with the EOT visit of the predecessor study, repeated assessments (see 
Table 1 and Table 2) are not required, as data will be duplicated programmatically between the 2 
study databases, as applicable  As electronic patient-reported outcome (PRO) devices were used 
to capture ACQ6, AQLQ(S)+12, WPAI+CIQ, EQ-5D-5L in the predecessor studies, the patient 
does not need to complete the paper versions of these at Visit 1 of this safety extension study.
Registration of patient’s enrolment via IWRS/IVRS should occur on day when other Visit 1 
procedures are done.
Visit 1 assessments are primarily concerned with confirmation of the patient eligibility for the 
extension study 
4.2
Randomized treatment period
4.2.1
Patients that continue for duration of BORA
Patients that will continue for the duration of BORA (comprising the first approximately 1200 
adult patients enrolled in BORA), all patients in Japan and South Korea, and all adolescents will 
follow the procedures described below until completion of the study, or early withdrawal, as 
applicable.
4.2.2
Patients that will transition into MELTEMI
Patients who enter BORA after approximately 1200 adults have enrolled will be asked to 
transition into the separate safety extension study, MELTEMI, after completing a minimum of 

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16 weeks and a maximum of 40 weeks in BORA (ie, patients may transition at Visit 5, 7, 9, or 
11).
Patients must transition from BORA into MELTEMI 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 is reached).  Patients may transition into MELTEMI only at Visits 5, 
7, 9, or 11 of this study.
4.2.3
Dosing regimens
4.2.3.1
Adults
Patients previously assigned to an active treatment arm in the predecessor study
Patients previously randomized to the Q4W regimen of benralizumab will continue injections of 
active drug every 4 weeks.  
Patients previously randomized to the Q8W regimen will continue to receive active drug every 8 
weeks with placebo (dummy) injections administered at the 4-week interim treatment visits in 
order to maintain the blind.
Patients previously assigned to the placebo arm in the predecessor study
All adult patients previously assigned to the placebo arm in the predecessor study will be 
re-randomized to either the Q4W or Q8W regimen (first 3 doses administered every 4 weeks 
followed by every 8 weeks thereafter).  Patients on the Q4W regimen will receive active drug 
every month.  Patients on the Q8W regimen will receive active drug at Visit 1 (Week 0), Visit 2 
(Week 4), Visit 3 (Week 8), followed by alternating monthly SC injections of placebo and active 
drug, eg, placebo at Visit 4 (Week 12), active drug at Visit 5 (Week 16), placebo at Visit 6 
(Week 20), and so on in order to maintain the blind relative to the Q4W regimen.
4.2.3.2
Adolescents outside the European Union 
Adolescents previously assigned to an active treatment arm in the predecessor study
  Adolescents previously randomized to the Q4W regimen of benralizumab will continue 
injections of active drug every 4 weeks.  
Patients previously randomized to the Q8W regimen will continue to receive active drug every 8 
weeks with placebo (dummy) injections administered at the 4-week interim treatment visits in 
order to maintain the blind.
Adolescents previously assigned to the placebo arm in the predecessor study
Adolescents previously assigned to the placebo arm in the predecessor study will be 
re-randomized to either the Q4W or Q8W regimen (first 3 doses administered every 4 weeks 
followed by every 8 weeks thereafter).  Patients on the Q4W regimen will receive active drug 

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every 4 weeks.  Patients on the Q8W regimen will receive active drug at Visit 1 (Week 0), Visit 
2 (Week 4), Visit 3 (Week 8), followed by alternating monthly SC injections of placebo and 
active drug, eg, placebo at Visit 4 (Week 12), active drug at Visit 5 (Week 16), placebo at Visit 6 
(Week 20), and so on in order to maintain the blind relative to the Q4W regimen.
4.2.3.3
Adolescents within the European Union 
Adolescents previously assigned to an active treatment arm in the predecessor study
Adolescents within the European Union (EU) will continue to receive only the Q8W dosing 
regimen as per the predecessor study.  In order to maintain the blind of the predecessor study, 
this group will receive the injections every 4 weeks for the first 3 doses (active drug at Visits 1 
and 3, placebo administered at Visit 2) followed by every 8 weeks thereafter (to match the 
regimen of the adolescents who were on placebo in the predecessor study).
Adolescents within the EU will thereafter be receiving open label treatment.  These adolescent 
patients will follow an every 4 weeks Study Visit schedule; however, investigational product (IP) 
will only be administered at every other visit after the first 3 doses as described above.
Adolescents previously assigned to the placebo arm in the predecessor study
Adolescents within the EU who were randomized to placebo in the predecessor study will be 
assigned to benralizumab 30 mg every 8 weeks in this safety extension study (every 4 weeks for 
the first 3 doses followed by every 8 weeks thereafter).
After the first 3 doses, adolescent patients within the EU will be receiving open label treatment 
with IP administered at their bimonthly visit.
With no placebo arm in this safety extension study, adolescent patients within the EU will thus 
be receiving open label treatment.  These adolescent patients will follow an every 4 weeks Study 
Visit schedule; however, IP will only be administered at every other visit after the first 3 doses as 
described above.
4.2.3.4
Randomized treatment period assessments
For Visits 2 -16 (Visit 2 - 29 for adolescents), spirometry and blood sampling (for hematology, 
serum chemistry, PK, ADA/nAb) may be performed 1 day prior to the scheduled date of IP 
injection, at the discretion of the investigator.  All other study procedures must be done on the 
scheduled day of IP injection.  Urine pregnancy tests must be done prior to IP administration.  
The patient will receive 56 weeks treatment (108 weeks for adolescents), with the last dose of 
benralizumab administered at Visit 14 (Visit 27 for adolescents).  Adolescent patients in EU will 
be administered IP according to open-label schedule.
Patients will have scheduled visits at 4-week intervals 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 an asthma 
worsening/exacerbation (see Section 5.1.1), patients should be evaluated at the study center, 

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when feasible, at an unscheduled visit, or ordinary visit if the worsening happens to fall within a 
scheduled visit window.
Patients’ lung function will be monitored at the site, as well as responses to questionnaires (see 
Section 5.3.2 for details).
At Week 56 (Week 108 for adolescents) patients will come to the center for the End of 
Treatment (EOT) visit.
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 16 
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 Visit 15, Week 56 (Visit 28, Week 108 for adolescents) will return at 
Week 68 (Week 120 for adolescents) for a final follow-up visit.
5.
STUDY ASSESSMENTS AND PROCEDURES
5.1
Efficacy assessments
5.1.1
Assessment of asthma exacerbations
Although this is a safety study, asthma exacerbations will be assessed to characterize the 
exacerbation rate with longer maintenance treatment.  In this study, an asthma exacerbation is 
defined as a worsening of asthma which requires use of systemic corticosteroids for at least 3 
days, and/or an in-patient hospitalization, and/or emergency department or urgent care 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 counted as the same exacerbation event.
The patient may remain in the study after an exacerbation and continue to receive IP if the 
Investigator judges that it is medically appropriate for the patient to do so.
Study center evaluations for asthma worsening may occur as an unscheduled visit or as part of an 
ordinary center visit if the worsening happens to be coincident with a scheduled visit window. A 
copy of the medical record should be obtained for exacerbations evaluated and treated at non-
study centers (eg, by the primary care HCP or at an emergency department/hospital) and details 
entered into the exacerbation eCRF in a timely fashion.  Changes in concomitant medication due 
to exacerbation must be recorded in the appropriate module of the eCRF.

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5.1.2
Spirometry
General requirements
Lung function (FEV1 and FVC) at the study center will be measured by spirometry using the 
site’s own equipment.  Spirometry will be performed by the Investigator or authorized delegate 
according to American Thoracic Society/European Respiratory Society (ATS/ERS) 
guidelines.(Miller et al 2005).
The Investigator is responsible for assuring that the spirometer used at the site meets ATS/ERS 
recommendations and that the study center personnel performing the testing are properly trained 
and certified.  In order to minimize variability, the same spirometer should be used for all 
assessments of spirometry on patients in this study, wherever possible.  If there is any need to 
change the device, AstraZeneca should be notified. Calibration of spirometers must be 
performed in accordance with the instructions of the manufacturer and should be performed 
every time a study subject visits the study center.  All calibration reports must be signed, dated 
and filed in the Investigator Study File (ISF).
Important!  Patients should withhold their usual ICS and long-acting bronchodilator containing 
medications on the morning of the Visit 1 FEV1 measurement and post-bronchodilator 
testing. Twice daily ICS and long-acting bronchodilator therapies should be withheld for 12- 24 
hours; once daily therapies containing ICS, LABA, or LAMA therapies should be withheld for 
≥24 hours before scheduled center visit spirometry as this will affect the pre-BD FEV1 value; 
they may be taken subsequently, at the center.  For the same reason patients should not use their 
rescue SABA medication (albuterol/salbutamol/levalbuterol) within 6 hours of a scheduled 
center visit spirometry.  This restriction is particularly critical for efficacy measures taken during 
the treatment period. 
Options for handling patients who have inadvertently taken their asthma medication within the 
restricted window are described in Section 3.5.2.
All patients transitioning from the OCS-sparing study (ZONDA) into this study are exempt from 
performing the post-BD assessments.  The pre-BD measurement from EOT for ZONDA patients 
will serve as the first pre-BD measurement for these patients in BORA.
Time of day for scheduled center visit spirometry
Spirometry testing should be done according to the schedule provided in Table 1 or Table 2.  All 
spirometry assessments should be performed within ±1.5 hours of the time that the first 
spirometry in the study (Visit 1) was performed.  For example, if the first spirometry was started 
at 8:00 AM, then all subsequent spirometry testing should be initiated between 6:30 AM and 
9:30 AM.  Ideally, these assessments should be conducted at the same time of day as in the 
predecessor study, wherever possible.
Spirometry technique
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to spirometry 
measurements.  Patients should avoid eating a large meal for at least 2 hours prior to spirometry 

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measurements at the center.  Forced expiratory maneuvers should be performed with the patient 
seated in an upright position.  If this is not comfortable for the patient, standing is permitted.  
The same position should be used by the patient for each forced expiratory maneuver from 
enrolment throughout the study.  The head must not be tilted during maneuvers and the thorax 
should be able to move freely; hence tight clothing should be loosened.  A nose-clip should be 
used for the maneuver.  Disposable mouthpieces of the same dimension and shape should be 
used as far as possible for the duration of the study.
The forced expiratory maneuver (FEV1 and FVC) should start with a maximal inspiration and 
then followed by a fast and forceful expiration that should last for at least 6 seconds.  It is 
important to encourage the patient to continue the expiration to be fast and forceful throughout 
the maneuver.  Ensure that none of the following has occurred: coughing during the first second, 
glottis closure, leak or obstruction of the mouthpiece (by the tongue).
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
center spirometry session and the 2 best efforts that meet the ATS/ERS acceptability and 
reproducibility criteria will be recorded.  The best efforts will be based on the highest FEV1.  The 
absolute measurement (for FEV1 and FVC), and the percentage of predicted normal value 
(Quanjer et al 2012) will be recorded.  The highest FVC will also be reported regardless of the 
effort in which it occurred (even if the effort did not result in the highest FEV1).
Post-bronchodilator spirometry
Post-BD spirometry will be performed as an efficacy measure on designated center visits during 
the treatment period as listed in Table 1 and Table 2.
Order of administration of usual asthma controller medication and IP relative to scheduled 
pre- and post-bronchodilator spirograms
The patient’s usual morning asthma controller therapy must not be given until after the initial 
pre-medication, pre-bronchodilator spirograms are complete for the reasons discussed above; 
usual asthma controller may be given after final post-bronchodilator spirograms.
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at study center for 
source data verification.  The printout must be marked with the study code, enrolment code, date 
and time of measurement, and visit number.
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the patient’s 
predicted normal (PN) values (Quanjer et al 2012).
FEV1 expressed as percent of the PN value will be calculated as follows:
FEV1% of PN = FEV1 measured/FEV1PN x 100

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5.1.2.1
Post-bronchodilator FEV1 efficacy assessment
Post-bronchodilator (post-BD) spirometry will be performed as an efficacy measure on 
designated center visits during the treatment period as listed in Table 1 or Table 2.  Maximal 
bronchodilatation should be induced using albuterol (90 μg metered dose), salbutamol (100 μg 
metered dose), or levalbuterol (45μg metered dose) up to a maximum of 8 inhalations (Sorkness 
et al 2008).  It is highly recommended to use a spacer device for this procedure.  The algorithm 
for testing is outlined in Figure 2.
Figure 2
Reversibility testing algorithm
1
Verify with the patient that the medication 
restrictions to allow the reversibility assessment have been 
met (Section 3.5.2).
2
After a gentle and complete expiration, 
albuterol/salbutamol/ levalbuterol is inhaled in one breath to 
TLC from a spacer device.  The breath is then held for 5–10 
seconds before the patient exhales.  Four separate 
inhalations are delivered at approximately 30- second 
intervals.  Post-BD spirometry should be performed 15-20 
minutes later.
3
Following this, an additional 2 inhalations of 
albuterol/salbutamol/ levalbuterol should be administered as 
single inhalations, 30 seconds apart (for a total of 6 
inhalations).  Second post-BD spirometry will be performed 
15-20 minutes later.
4
If the incremental change in FEV1 after 6 
inhalations of albuterol/salbutamol/ levalbuterol is ≤5% of 
the FEV1 value after 4 inhalations, the procedure is 
complete.  If the change is >5% an additional 2 inhalations 
of albuterol/salbutamol/ levalbuterol should be administered 
in single inhalation 30 seconds apart and a third and final 
post-BD spirometry should be performed 15-20 minutes 
later.
A lower total dose, eg, 2 inhalations instead of 4 
in the first round of puffs, and/or a total of less than 8 puffs, can be used if there is a concern 
about any effect on the patient’s heart rate, tremor, or safety.  Please note that the same 
procedure (ie, the same bronchodilator, device, number of puffs, etc.) should be used at all visits 
throughout the study.
The % difference comparing FEV1 after 6 puffs to the FEV1 after 4 puffs will be calculated as 
follows:
% Difference=FEV1(6 puffs)-FEV1(4 puffs)/FEV1(4 puffs)×100

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5.2
Safety assessments
5.2.1
Medical and asthma history
Medical and asthma history will be retrieved from predecessor studies.  Any new occurrence(s) 
or change(s) from previous status will be documented and if judged as clinically significant by 
the Investigator will be reported as an AE as described in Section 7.  In addition, a detailed CV 
history will be taken at Visit 1.
5.2.2
Physical examination 
Physical examination will be done in accordance with schedule provided in Table 1 or Table 2.
Baseline data will be collected at Visit 1.  Any new finding(s) or aggravated existing finding(s) 
judged as clinically significant by the Investigator will be reported as an AE as described in 
Section 7.1.
5.2.2.1
Complete physical examination 
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems. 
5.2.2.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, abdomen, 
cardiovascular and respiratory systems.  For the brief physical examination, only information on 
whether the assessment was performed or not is to be recorded. 
5.2.3
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 if possible, blood drawing and usual 
asthma controller medication.  Vital signs should also be taken prior to per protocol 
bronchodilator administration if applicable for that visit.
Pulse rate, respiration rate, and blood pressure should be measured after the patient has been 
resting for at least 5 minutes.  The measurement should be taken in sitting position.  
Body temperature will be measured in Celsius before IP administration in accordance with local 
standards.
5.2.4
Electrocardiogram 
An electrocardiogram (ECG) will be performed in accordance with schedule provided in Table 1
or Table 2.

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In all patients, the printouts of the ECG will be collected and signed, dated, and stored at the 
study center along with a signed and dated copy (if the printouts are not on archive-quality 
paper).
A 12-lead ECG will be taken in supine position, after the patient has been resting for at least 5 
minutes.  
A standard ECG with a recommended paper speed of either 25 mm/second or 50 mm/second 
covering at least 6 sequential beats will be used.  The Investigator or authorized delegate will be 
responsible for the overall interpretation and determination of clinical significance of any 
potential ECG findings.  In case of discrepancy between the Investigator’s interpretation and that 
provided by the ECG machine (if applicable), the Investigator’s interpretation will take 
precedence and should be noted on the printout and recorded in the eCRF.  Two identical copies 
of the ECG will be produced and quality checked and kept in case of further need for re-
evaluation.
It is highly recommended that the same machine is used for assessment throughout the patient’s 
participation in the study.
ECG data and evaluation will be recorded in the eCRF.
5.2.5
Safety laboratory tests
Safety laboratory tests (list provided in Table 3 and Table 4) will be performed in a central 
laboratory.  For information on methods of collection, assessment, labelling, storage and 
shipment of samples, please refer to the separate Laboratory Manual.  Safety samples will be 
collected in accordance with the schedules provided in Table 1 or Table 2.
Hematology and urinalysis will be assessed in line with the schedules provided in Table 1 or 
Table 2.  A detailed schedule of the chemistry tests is presented in Table 3 and Table 4.  Visit 1 
of this study is to be combined with the EOT visit of the predecessor study (see Section 4.1.1), 
therefore safety laboratory tests performed at the EOT visit in the predecessor study will be 
considered as baseline for this safety extension study.  NB: As the required list of safety 
laboratory tests at Visit 1 of this safety extension study differs from those collected at EOT of the 
predecessor studies, the additional parameters required for this study (ie, those not required at the 
EOT visit of the predecessor study) will only be reported in this study to avoid duplicate 
reporting.  Refer to the separate Laboratory Manual for more details.
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.
The copy of the laboratory results report should be signed and date by Investigator and retained 
at the study center.

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Table 3
List of safety laboratory tests
Serum chemistry
Hematology
Urinalysis
Alkaline phosphatase
Gamma-GT (gamma-
glutamyl 
transpeptidase)
Hematocrit
Appearance
ALT (alanine 
aminotransferase)
Glucose
Hemoglobin
Blood
AST (aspartate 
aminotransferase)
Phosphorus
Mean corpuscular 
volume (MCV)
Colour
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Glucose
Calcium
Sodium
Red blood cell (RBC) 
count
Ketones
Chloride
Total bilirubin
WBC count with 
differentiala
Microscopy including 
WBC/high power field 
(HPF), RBC/HPF
CO2 (carbon dioxide)
Total cholesterol
pH
Creatinine
Uric acid
Specific gravity
Serum concentration b
a
Eosinophil, basophil and monocyte counts will be redacted from the central laboratory reports
b
For patients who are on theophylline or digoxin (see Section 3.5.2.2)
Table 4
Serum chemistry tests schedule
VISIT
V1
V4
V8
V12 
V15
V20 a
V24 a
V28 a
Alkaline phosphatase
X
X
X
X
X
X
X
X
ALT
X
X
X
X
X
X
X
X
AST
X
X
X
X
X
X
X
X
BUN
X
X
X
X
X
X
X
X
Calcium, serum
X
X
X
X
Chloride, serum
X
X
X
X
CO2 (carbon dioxide)
X
X
X
X
Creatinine
X
X
X
X
X
X
X
X
Gamma-GT
X
X
X
X
X
X
X
X
Glucose 
X
X
X
X
Phosphorus, serum
X
X
X
X

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Table 4
Serum chemistry tests schedule
VISIT
V1
V4
V8
V12 
V15
V20 a
V24 a
V28 a
Potassium, serum
X
X
X
X
Sodium, serum
X
X
X
X
Total bilirubin
X
X
X
X
X
X
X
X
Total cholesterol
X
X
X
X
Uric acid
X
X
X
X
a
Adolescents only
5.2.5.1
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 for all females (excluding adolescents) <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 including all 
adolescent females (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.  
5.3
Other assessments and procedures
5.3.1
Weight and height
Weight and height will be measured in accordance with schedules provided in Table 1 or Table 
2.
The patient’s weight will be recorded in kilograms; height in centimetres.
Weight and height measurements will be performed in light clothing and with shoes off.
5.3.2
Patient reported outcomes
As part of routine monitoring of the patients’ condition, patients will be asked about their asthma 
symptoms, rescue medication usage, nocturnal awakenings, and maintenance medication use at 
each visit or by phone between visits if they feel it is necessary.  Patient reports will be verbal 
and no PRO instruments will be used for these assessments. 
Background medication
Background asthma medication use will be recorded in the eCRF accordingly.

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Patients will be requested to complete 4 simple questionnaires during particular visits as per 
Table 1 or Table 2, accordingly.  Data will be collected using a paper form provided to the 
patient by the Investigator or designee at the time of visit.
5.3.2.1
Asthma Control Questionnaire 
The Asthma Control Questionnaire (ACQ-6) is a shortened version of the ACQ that assesses 
asthma control (nighttime waking, symptoms on waking, activity limitation, shortness of breath, 
wheezing, and short-acting β2 agonist use) omitting the FEV1 measurement from the original 
ACQ score.
Patients are asked to recall how their asthma has been during the previous week by responding to 
1 bronchodilator use question and 5 symptom questions.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled).  The mean ACQ-6 score is the mean of the responses.  Mean scores of ≤0.75 
indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled asthma, 
and a score >1.5 indicates not well controlled asthma (Juniper et al 2006).  Individual changes of 
at least 0.5 are considered to be clinically meaningful.
The questionnaire will be completed by the patient at the site using a paper questionnaire.
Patients will be asked to complete the ACQ-6 at Visit 1 and then every 12 weeks thereafter 
throughout the treatment period including the EOT visit.
The Investigator/authorized delegate will check the patient’s adherence to the ACQ-6, as shown 
in Table 1 or Table 2.
5.3.2.2
Standardised Asthma Quality of Life Questionnaire for 12 years and older 
The Standardised Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(S)+12) is 
a questionnaire that measures the health-related quality of life experienced by asthma patients.
The questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional 
function, and environmental stimuli).
Patients are asked to recall their experiences during the previous 2 weeks and to score each of the 
questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment).  The 
overall score is calculated as the mean response to all questions.  The 4 individual domain scores 
(symptoms, activity limitations, emotional function, and environmental stimuli) are the means of 
the responses to the questions in each of the domains.  Individual improvement in both the 
overall score and individual domain scores changes of ≥0.5 are considered clinically meaningful.
The questionnaire will be completed by patient at the site using a paper questionnaire. 
Patients will be asked to complete the AQLQ(S)+12 at Visit 1 and then every 12 weeks 
thereafter throughout the treatment period including the EOT visit.

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The Investigator/authorized delegate will check patient adherence to the AQLQ(S)+12 at each 
visit as shown in Table 1 or Table 2.
5.3.2.3
Work Productivity and Activity Impairment questionnaire plus Classroom 
Impairment Questions 
The Work Productivity and Activity Impairment questionnaire plus Classroom Impairment 
Questions (WPAI+CIQ) questionnaire is a 10-item questionnaire that assesses productivity and 
activity impairment over the previous week.  The questionnaire includes hours missed from 
work/school due to asthma, degree health affected productivity while at work/school, as well as 
the degree to which health affected regular activities other than work or school.  The 
questionnaire relates to the previous 7 days.
The questionnaire will be completed by patients at the site using a paper questionnaire
Patients will be asked to complete the WPAI+CIQ at Visit 1 and at the EOT visit.
The Investigator/authorized delegate will check patient adherence to the WPAI+CIQ as shown in 
Table 1 or Table 2.
5.3.2.4
EQ-5D-5L
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty.
The patient will be asked to indicate his/her current health state by selecting the most appropriate 
level in each of the 5 dimensions.  The questionnaire also includes a visual analogue scale, where 
the patient will be asked to rate current health status on a scale of 0-100, with 0 being the worst 
imaginable health state
The EQ-5D-5L will be completed at every scheduled visit.  
The Investigator/authorized delegate will check patient adherence to the EQ-5D-5L at every 
scheduled visit as shown in Table 1 or Table 2.
5.3.3
Health care resource utilization
Information on the number of in-patient hospitalizations, number of days in the hospital, 
emergency department visits, urgent care visits and all other outpatient visits due to asthma 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.
Healthcare Resource Utilization (HRU) information will be collected with a recall period of 
‘since the last scheduled visit’. 
Healthcare Resource Utilization information will be completed at every scheduled visit.

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Note: Cases of in-patient hospitalization also must be reported as an SAE (see Section 7.1.2 and 
7.1.4).
5.3.4
Other assessments
5.3.4.1
Immunoglobulins for adolescents
The levels of total IgG, IgA, IgM, and IgE will be evaluated by a central laboratory.  These tests 
will be performed at time points as specified in Table 2).
Instructions for sample collection, processing, storage, and shipment can be found in the separate 
laboratory manual provided to the centers.
5.3.5
T cell, B cell, and NK cell flow cytometry for adolescents
T cell, B cell, and NK cell (TBNK) flow cytometry of whole blood will be evaluated by a central 
laboratory.  This test will be performed at the visits as described in Table 2.
Instructions for sample collection, processing, storage, and shipment can be found in a separate 
laboratory manual provided to the centers.
5.3.6
Pharmacokinetics
For the PK analysis, it is important that the date and time of each SC injection is recorded for 
each patient.
Instructions for sample collection, processing, storage, and shipment can be found in the separate 
laboratory manual provided to the centers.
Serum will be collected pre-dose according to the schedule of study procedures (see Table 1 or 
Table 2).
Samples for determination of benralizumab concentration in serum will be analyzed by a central 
laboratory on behalf of AstraZeneca using a validated bioanalytical method.  Details of the 
analytical method used will be described in a bioanalytical report.
The PK samples will be retained for future use at AstraZeneca or designee for a maximum of 15 
years following Last Patient’s Last Visit.
A summary of PK analysis results will be reported in the Clinical Study Report (CSR).
5.3.7
Pharmacodynamics
5.3.7.1
Immunogenicity 
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment can be found in the separate laboratory manual provided to the centers.
The immunogenicity samples will be retained at AstraZeneca or a designee for a maximum of 
15 years following the Last Patient’s Last Visit.

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A summary of the analysis will be presented in the CSR.
ADA and nAb will be assessed using validated bioanalytical methods.  Details of the analytical 
methods used will be described in separate bioanalytical reports.
Anti-benralizumab antibodies and neutralizing antibodies:
The pre-dose serum samples to measure presence of anti-benralizumab antibodies (ADA) will be 
collected according to the schedule of study procedures (see Table 1 or Table 2).
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods. 
Neutralizing antibodies (nAb) are to be assessed at the time points as specified in Table 1 and 
Table 2.  Samples that are ADA-negative will not be tested for nAb. 
Astrazeneca will retain remaining serum supplies from samples designated for PK and ADA 
analyses for future asthma-related research.  Any exploratory research performed after study 
completion will be asthma-related research only and may be limited by local restrictions.  Serum 
samples will be retained for a maximum of 15 years following the Last Patient’s Last Visit.
5.3.8
Handling of biological samples
5.3.8.1
Labelling and shipment of biological samples
The Principal Investigator is to ensure that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix 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.
5.3.8.2
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.

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Samples retained for further use 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 and placebo administered in the study will be a clear to opalescent, colourless to 
yellow solution (Table 5).
Table 5
Identity of investigational product
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
30mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1mL fill volume
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1mL fill volume
MedImmune
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/placebo 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
!
Damaged kit upon receipt
!
Damaged syringe/cartridge

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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 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 adults globally, and adolescents outside the EU who were randomized to benralizumab in the 
predecessor study will be assigned to the same dosing regimen in this safety extension study as 
they received in the predecessor study.  Patients who were randomized to the placebo arm in the 
predecessor study will be randomized at Visit 1 of this safety extension study to 1 of the 2 
benralizumab dose regimens (in a ratio of 1:1).  Randomization codes will be assigned strictly 
sequentially as patients become eligible for randomization in accordance with stratification in 
this study.  All adolescents within the EU will be assigned to the 30mg every 8 weeks dose 
regimen regardless of the treatment assignment in the lead-in study.
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study medication.  There can be no exceptions to this rule.
6.6
Methods for ensuring blinding
AstraZeneca staff involved in the study, the patients, and the investigators involved in the 
treatment of the patients, or in their clinical evaluation, will not be aware of the dosing regimen 
allocation, except in the case of adolescents within EU (who only receive the every 8 weeks 
dosing regimen, and who therefore will be on open label treatment in this study).
Placebo solution will be visually matched with benralizumab solution.  Both benralizumab and 
placebo will be provided in an accessorized pre-filled syringe.
Center staff who are directly involved in the patient’s management should remain blinded to any 
eosinophil, basophil, and monocyte results included as part of outside lab reports up to and 
including Visit 2 in order to maintain the blind of the predecessor study.  To help ensure this, 
each investigational center will designate an individual (eg, administrator or another ancillary 
person) not directly involved in patient management, to receive and blind any eosinophil, 
basophil, and monocyte results prior to the report being handed over to the center staff involved 
in the patient’s management and prior to filing as a source document.  Similarly, eosinophil and 
basophil results must be redacted from all communications with the Sponsor.

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After database lock has been declared in each of the predecessor studies (CALIMA, SIROCCO, 
and ZONDA), the treatment codes will be broken and the data from these studies will be 
analyzed and reported. Once the blind is broken in these studies, this study (BORA) becomes a 
single-blind design for those patients who had been on active treatment in the predecessor 
studies. The study will become single blind for all remaining patients at the time of the Japanese 
EOT analysis (see Section 8.5.4). While the Sponsor will be unblinded to regimen for analysis 
purposes, study conduct and blinding at the site and patient level will remain unchanged.
To prevent complete unblinding of this study, treatment-revealing information will not be shared 
with the study site or patients (patient-level listings, as well as other treatment-revealing 
information will be redacted from the Clinical Study Reports).
6.7
Methods for unblinding 
Individual treatment codes indicating the treatment dosing regimen randomization for each 
randomized patient will be available to the Investigator(s) or pharmacists at the study center from 
the IWRS/IVRS.  Further detail on how to unblind a patient’s treatment dosing regimen 
allocation will be described in the IWRS/IVRS user manual provided to each study center.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment dosing regimen randomization.  
The Investigator is to document and report the action to AstraZeneca without revealing the 
treatment given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for serious adverse events (SAEs) that are 
unexpected and are suspected to be causally related to an IP and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual patient 
have been made and documented.
To protect the blind of this study and of the predecessor studies (CALIMA, SIROCCO, and 
ZONDA), patients who transition from this study into Study D3250C00037 (MELTEMI) will be 
unblinded to treatment regimen only after signing the ICF for MELTEMI, at which point they 
will have exited BORA.
6.8
Investigational Product administration and treatment compliance
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the CRF.
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 or 
more than 2 of the scheduled doses of IP are missed during course of the study the patient should 
be discontinued; please refer to Section 3.6.

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If an Investigator decides to skip the IP administration due to exacerbations, the above rule does 
not apply.
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, including all adolescent females, a urine pregnancy test will be done.  
IP must only be administered when the result of the test is negative (see 
Section 5.2.5.1)
IP administration
The IP will be administered by the Investigator/authorized delegate.  It is advised that the site of 
injection of the IP be rotated such that the patient receives IP at a different anatomical site at 
each treatment visit.  Suggested injection site rotation sequence is presented below (see Figure 
3).  The injection site must be recorded in the source documents and the eCRF at each treatment 
visit.
Figure 3
Injection sites and rotation scheme
In the case when rotation of the injection site is not favourable for the patient and/or Investigator, 
the reason should be recorded in the source documents.  The injection site of the IP should be 
recorded in the source documents and eCRF at each treatment visit.
Further details on IP administration are provided in the IP Handling Instruction.  IP 
administration must be carried out in line with the Instruction.
After investigational product administration
After IP administration, the patient should be observed for a minimum of 2 hours for the 
appearance of any acute drug reactions.

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Conditions requiring investigational product administration rescheduling 
If any of the following should occur, the Investigator should reschedule the visit and the IP 
should not be administered until the rescheduled visit:
!
The patient has an intercurrent illness, that in the opinion of the Investigator may 
compromise the safety of the patient in the study (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
6.9
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 will have had a pre-assessment (ie, vital signs and lung function) prior to IP 
administration) and should 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 the 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.

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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.
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 and including the follow-up period (Visit 16, Week 68 
(Visit 29, Week 120 for adolescents).  AEs, including SAEs that started during the predecessor 

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study and are ongoing at the start of this safety extension study, will be followed up for the 
duration of the study and as long as medically indicated.
7.1.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at follow-up in the study will be followed up by the Investigator for 
as long as medically indicated, but without further recording in the CRF.  AstraZeneca retains the 
right to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of 
the study, if judged necessary.
The requirement to follow-up AEs is not intended to delay database lock or production of the 
Clinical Study Report (CSR).  These activities should proceed as planned with ongoing AEs if 
necessary.
Any follow-up information of ongoing SAEs after database lock will be reported to AstraZeneca 
(see Section 7.1.4).
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’.

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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 
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 examinations and tests
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
clinical study report.  Deterioration as compared with baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information.  Wherever possible, the reporting Investigator will use 
the clinical, rather than the laboratory term (eg, anaemia versus low hemoglobin value).  In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE.
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.

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After randomization, asthma exacerbations should be recorded in the exacerbation eCRF 
(EXACA; see Section 5.1.1). If the exacerbation fulfils any of the above criteria, the sign or 
symptom should also be recorded as an AE.
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
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.

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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.
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 

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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 randomized.  Subsequent amendments will be 
documented ahead of database lock for the planned analyses (Section 8.5.4) if necessary.     
8.2
Sample size estimate
Patients who complete the double-blind treatment period on IP in 1 of the predecessor studies, 
D3250C00017, D3250C00018, and D3250C00020, may be eligible to enrol into this study.  
With an estimated rollover rate of >90% from these preceding studies, this safety extension study 
will enrol approximately 1800 to 2000 patients, up to a maximum of 2200 patients worldwide.  
The first 1200 adult patients will remain in this study through IPD or EOT and FU.  The 
remaining 700-1000 adult patients will be asked to transition into a safety extensions study, 
Study D3250C00037.  Adolescent patients and patients from Japan and South Korea will remain 
in this study through IPD or EOT and FU.
A minimum of 1200 patients is considered sufficient to address the primary objective of safety 
and tolerability in the on-treatment and 16-week safety follow-up period of this study.  The 
safety extension study, MELTEMI, will allow remaining patients to continue to receive 
benralizumab until it is available in their local market or until it has been withdrawn from the 
approval process in their local market.  The minimum 16-week treatment period prior to 
transition to MELTEMI ensures that any patients previously randomized to placebo have 
completed monthly study visits and assessments for the first 3 active doses within this study 
before transitioning to MELTEMI.
The study is not designed to power the statistical testing of any null hypothesis.
8.3
Definitions of analysis sets
In the analysis sets outlined below, data from adult patients choosing to enter the safety 
extension study, D3250C00037, will be summarized separately from those remaining in this 
study (BORA) unless otherwise noted in the SAP.  
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 randomized or assigned.  
8.3.2
Pharmacokinetic analysis set
All patients who received benralizumab, from whom PK blood samples are assumed not to be 
affected by factors such as protocol violations, and who had at least 1 quantifiable serum PK 

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observation post first dose will be included in the PK analysis dataset.  All PK summaries will be 
based on this analysis set.
8.4
Variables for analyses
8.4.1
Calculation or derivation of efficacy variables
All efficacy objectives will be evaluated for the treatment period, defined as the period after 
administration of IP at Visit 1 to the conclusion of the EOT visit, inclusive.
8.4.1.1
Exacerbation rate
The annual asthma exacerbation rate will be used as an efficacy variable.
An asthma exacerbation is defined in Section 5.1.1.
In order to calculate the number of exacerbations experienced by a patient during the treatment 
period, the following rule will be applied.
The start of an exacerbation is defined as the start date of systemic corticosteroids or start date 
of a temporary increase in a stable oral corticosteroid background dose, or start date of hospital 
admission, whichever occurs earlier.  The end date is defined as the last day of systemic
corticosteroids or the last day of a temporary increase in a stable oral corticosteroid 
background dose, or the date of discharge from a hospital, whichever occurs later.  In the 
primary analysis, the number of exacerbations observed for a patient during the 56-week 
treatment period (108-weeks in adolescents) will be used as response variable.
Additional systemic corticosteroid treatments, emergency room /urgent care visits requiring use 
of systemic corticosteroids for at least 3 days, or in-patient hospitalization due to asthma 
occurring during an exacerbation should not be regarded as a new exacerbation.  In order to be 
counted as a new exacerbation, it must be preceded by at least 7 days in which neither criterion is 
fulfilled.
Maximum on-treatment follow-up time for exacerbations for a patient is approximately 56 weeks 
(108 weeks for adolescents); defined as the time from first dose to the date of EOT.  For a patient 
lost to follow-up, this will be defined as the time from randomization to the time point after 
which an exacerbation could not be assessed.
For the production of summary statistics, the annual exacerbation rate in each treatment group 
will be calculated using the time-based approach.
Annual Exacerbation Rate=Total Number of Exacerbations*365.25/ Total duration of
follow-up within the treatment group (days).
8.4.1.2
Time to first exacerbation 
Time to first exacerbation will only be calculated for the patients who were randomized to 
placebo in the lead-in study and is calculated as follows:

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Start Date of first asthma exacerbation - Date of First Dose of Benralizumab + 1.
The time to first asthma exacerbation for patients who do not experience an asthma exacerbation 
during the treatment period will be censored at the date of their last visit for the treatment period, 
or at the time point after which an exacerbation could not be assessed (for lost-to-follow-up 
patients).
8.4.1.3
Forced expiratory volume in 1 second 
The change from baseline to each of the post-randomization visits (post Visit 1 up to and 
including the EOT visit) will be used as secondary efficacy variables.  
The last measurement recorded prior to the first dose (Visit 1) will be used as baseline FEV1. 
8.4.2
Calculation or derivation of safety variable(s)
8.4.2.1
Safety variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
hematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline to each post-treatment time point where scheduled assessments were made 
will be calculated for relevant measurements.  Adverse events will be summarized by means of 
descriptive statistics and qualitative summaries.
8.4.3
Calculation or derivation of patient reported outcome variables
8.4.3.1
Asthma Control Questionnaire 
In the ACQ-6 questionnaire the subjects are asked to recall the status of their asthma during the 
previous week with regards to symptom and BD.  The questionnaire includes questions on
!
Awakened at night by symptoms
!
Limitation of normal daily activities
!
Waking in the morning with symptoms
!
Dyspnoea
!
Wheeze
!
Daily rescue medication
The questions of the ACQ-6 are measured on a 7-point scale scored from 0 (totally controlled) to 
6 (severely uncontrolled).  The ACQ-6 score is computed as the un-weighted mean of the 
responses.
Asthma control responder status (Improved, No change, Deterioration) will be categorized 
according to the following limits (Juniper et al 2005):
!
ACQ-6 (End of treatment – baseline) ≤-0.5 → Improvement
!
-0.5< ACQ-6 (End of treatment– baseline) <0.5 → No change

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!
ACQ-6 (End of treatment– baseline) ≥0.5 → Deterioration
Asthma control status will be categorized according to their ACQ-6 end of treatment score as 
follows (Juniper et al 2006):
!
ACQ-6 (End of treatment) ≤0.75 → Well controlled
!
0.75< ACQ-6 (End of treatment) <1.5 → Partly controlled
!
ACQ-6 (End of treatment) ≥1.5 → not well controlled
The primary outcome for those not previously treated with benralizumab in the predecessor 
study will be improvement from baseline (Visit 1) in asthma control as defined above.  The 
primary outcome for those previously treated with benralizumab in the predecessor study will be 
maintenance of asthma control defined as either improvement or no change from baseline (Visit 
1).
8.4.3.2
Standardised Asthma Quality of Life Questionnaire for 12 years and older 
The AQLQ(s)+12 is a 32 question health-related quality of life assessment.  Respondents are 
asked to recall their experiences during the previous 2 weeks and to score each of the 32 
questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment).
The overall score is calculated as the mean response to all questions.  The 4 individual domain 
scores (4 domains assessing 1) symptoms, 2) activity limitations, 3) emotional function, and 4) 
environmental stimuli) are the means of the responses to the questions in each of the domains.
All patients will be categorized according to the following definitions:
!
AQLQ(S)+12 (End of treatment – baseline) ≥0.5 → Improvement
!
-0.5 < AQLQ(S)+12 (End of treatment – baseline) <0.5 → No change
!
AQLQ(S)+12 (End of treatment – baseline) ≤-0.5 → Deterioration
The primary outcome for those not previously treated with benralizumab in the predecessor 
study will be improvement from baseline (Visit 1) as defined above.  The primary outcome for 
those previously treated with benralizumab in the predecessor study will be maintenance of 
health-related quality of life defined as either improvement or no change from baseline (Visit 1).
8.4.3.3
Health Care Utilization and Work Productivity and Activity Impairment 
The ten questions included in the WPAI+CIQ are as follows:
1 = currently employed (yes/no) 
2 = hours missed work due to health problems 
3 = hours missed work due to other reasons 
4 = hours actually worked 
5 = degree health affected productivity while working (0-10 scale, with 0 meaning no effect)
6 = attends class in an academic setting (yes/no)

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7 = hours missed class due to health problems
8 = hours actually attended class
9 = degree health affected productivity while attending class (0-10 scale, with 0 meaning no 
effect)
10 = degree health affected regular activities (other than work or class) (0-10 scale, with 0 
meaning no effect)
For the work related questions, the following calculations should be used to create the variables 
of interest:
!
Number of work hours missed = Q2
!
Absenteeism = Q2/(Q2+Q4) 
!
Presenteeism = Q5/10 
!
Work Productivity Loss = Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)] 
!
Activity Impairment = Q10/10 
For the class-related questions, the following calculations should be used to create the variables 
of interest: 
!
Number of class hours missed = Q7
!
Absenteeism = Q7/(Q7+Q8) 
!
Presenteeism = Q9/10 
!
Absenteeism+Presenteeism = Q7/(Q7+Q8)+[(1-Q7/(Q7+Q8))x(Q9/10)]
!
Activity Impairment = Q10/10 
The primary outcome for those not previously treated with benralizumab in the predecessor 
study will be reductions in the variables of interest described above (number of work/class hours 
missed, absenteeism, presenteeism, and work productivity loss and activity impairment) when 
comparing the values at the EOT to baseline (Visit 1).  The primary outcome for those 
previously treated with benralizumab in the predecessor study will be no change in the variables 
of interest when comparing values at the EOT visit to baseline (Visit 1).
8.4.3.4
EQ-5D-5L
The distribution of responses for each of the five dimensions will be summarized by visit.  The 
change from baseline (Visit 1) on the visual analogue scale will also be evaluated.  The primary 
outcome for those not previously treated with benralizumab in the predecessor study will be a 
higher mean score on the visual analogue scale at the EOT visit compared with the baseline visit 
(Visit 1).  The primary outcome for those previously treated with benralizumab in the 
predecessor study will be no change in mean scores on the visual analogue scale at the EOT visit 
compared to the baseline visit (Visit 1).

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8.4.3.5
Health Care Utilization
The annual rates of health care utilization by type of health care encounter will be calculated for 
in-patient hospitalizations, emergency department visits/urgent care visits combined, 
unscheduled outpatient visits, and all of these healthcare encounters combined.  The rates of 
health care encounters will be calculated in a manner similar to the calculation of the annual 
exacerbation rates defined in Section 5.1.1.  The primary outcome for those previously treated 
with benralizumab in the predecessor study will be no change in the mean rate of healthcare 
encounters by type in this safety extension study compared to the mean rates of healthcare 
encounters by type among the benralizumab treated patients in the predecessor studies.  The 
primary outcome for those not previously treated with benralizumab in the predecessor study 
will be mean rates of healthcare encounters by type comparable to the mean rates of healthcare 
encounters for those previously treated with benralizumab in the predecessor study.
8.4.4
Calculation or derivation of pharmacokinetic variables
Due to the limited sampling schedule, the PK assessment will be primarily based on the observed 
steady-state serum trough (predose) concentrations, Ctrough.
8.4.5
Calculation or derivation of immunogenicity variables
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer).  The 
presence of neutralizing antibodies (nAb) will be tested in all ADA-positive samples using a 
ligand binding assay.  
8.5
Methods for statistical analyses
Data from adult patients choosing to enter the safety extension study, D3250C00037, will be 
summarized separately from those remaining in this study (BORA), unless otherwise noted in the 
SAP. Presentations will be provided for the overall population, adults, and adolescents 
separately. The details will be specified in the SAP. 
8.5.1
Efficacy endpoints analysis method(s)
The efficacy endpoints in this study are:
!
Change from baseline in pre-bronchodilator/post-bronchodilator FEV1
!
Annual exacerbation rate
!
Time to the first asthma exacerbation 
!
Health care resource utilization
!
ACQ-6
!
AQLQ(S)+12
!
WPAI+CIQ
!
EQ-5D-5L
All efficacy endpoints will be summarized by treatment group and other group variables, which 
will be specified in the SAP.

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8.5.1.1
Analysis methods for safety variables
AEs will be summarized by means of counts summaries by study period (treatment period and 
follow-up period).  AEs will be listed for each patient and summarized by System Organ Class 
(SOC) and Preferred Term (PT) assigned to the event by MedDRA.  Laboratory safety variables 
will be summarized using standard summary statistics and plots as appropriate.  Other safety 
variables will be summarized as appropriate.  Further details will be provided in the SAP.
Laboratory data for hematology and clinical chemistry will be summarized.  The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point will 
be tabulated.  Frequencies of clinically noteworthy values (defined in the SAP) occurring during 
the clinical study will also be given.  Shifts from normal to abnormal between baseline and each 
post-baseline time point will be evaluated for urinalysis.  Changes in vital signs and ECGs will 
be examined at each visit and at endpoint.  Frequencies of clinically noteworthy values (defined 
in the SAP) occurring during the clinical study will be presented.  Shifts from normal to 
abnormal between baseline and follow-up will be evaluated for the physical examination.
8.5.1.2
Analysis methods for pharmacokinetic variables
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development.
Benralizumab serum concentrations will be summarized using descriptive statistics at each visit 
by treatment group and other group variables.
8.5.1.3
Analysis method for immunogenicity variables
Anti-drug antibodies (ADA) to benralizumab will be summarized using descriptive statistics at 
each visit by treatment group and other group variables.  ADA titers-time profiles of 
benralizumab by treatment group and other group variables will be generated. 
8.5.1.4
Analysis methods for healthcare utilization and patient reported outcomes
The ACQ-6 and AQLQ(s)+12 outcome variables for those not previously randomized to 
benralizumab in prior studies will be the change in scores (ACQ-6/AQLQ(s)+12 and domains) 
from baseline to Week 56/EOT (Week 108/EOT in adolescents).  Baseline is defined as the 
Visit 1 observation in this study (pre-treatment for these patients).  Additionally, subjects not 
previously randomized to benralizumab will be categorized by responder and control status at 
Week 56/EOT (Week 108/EOT in adolescents) (Juniper et al 2005; Juniper et al 2006).
The outcome variable for those previously treated with benralizumab in the predecessor study 
will be maintenance of asthma control status (ACQ-6) and health-related quality of life
(AQLQ(s)+12) at Week 56/EOT (Week 108/EOT in adolescents). Maintenance of control status 
in these patients previously treated with benralizumab will be evaluated several ways: 
(i)
The proportion of those with improvement or no change in ACQ-6 score from baseline 
to Week 56/EOT (Week 108/EOT in adolescents) will be compared with the 

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proportion of those with deterioration from baseline at Week 56/EOT (Week 108/EOT 
in adolescents).  
(ii)
The proportion of those patients with improvement or no change in ACQ-6 score from 
baseline to Week 56/EOT (Week 108/EOT in adolescents) will be calculated for each 
baseline state (well, partially, not well controlled).  
(iii)
The proportion of post-baseline ACQ-6 observations indicating well controlled asthma 
will be calculated for those patients who are well controlled at baseline. Likewise, the 
proportion of post-baseline ACQ-6 observations indicating well or partially controlled 
asthma will be calculated for patients in those states at baseline and separately for 
those not well controlled at baseline.  
Asthma control responder status (Improved, No change, Deterioration) will be categorized 
according to the following limits (Juniper et al 2005):
!
ACQ-6 (End of treatment – baseline) ≤-0.5 → Improvement
!
-0.5< ACQ-6 (End of treatment– baseline) <0.5 → No change
!
ACQ-6 (End of treatment– baseline) ≥0.5 → Deterioration
Asthma control status will be categorized according to their ACQ-6 end of treatment score as 
follows (Juniper et al 2006):
!
ACQ-6 (End of treatment) ≤0.75 → Well controlled
!
0.75< ACQ-6 (End of treatment) <1.5 → Partly controlled
!
ACQ-6 (End of treatment) ≥1.5 → not well controlled
To evaluate maintenance of HRQoL the proportion of those with improvement or no change in 
AQLQ(s)+12 total and domain scores from baseline to Week 56/EOT (Week 108/EOT in 
adolescents) will be calculated, as will the proportion of those with deterioration from baseline at 
Week 56/EOT (Week 108/EOT in adolescents).  These descriptive statistics will be calculated 
for each ACQ-6 control category as defined previously.  
Health-related quality of life responder status will be defined as (Juniper et al 1994):
!
AQLQ(S)+12 (End of treatment – baseline) ≥0.5 → Improvement
!
-0.5 < AQLQ(S)+12 (End of treatment – baseline) <0.5 → No change
!
AQLQ(S)+12 (End of treatment – baseline) ≤-0.5 → Deterioration
For the ACQ-6, the distribution of patients who are well-controlled, partly controlled, and not 
well-controlled will be summarized descriptively for each of the visits in which the assessment 
was completed.  The level of improvement based on the ACQ-6 and the AQLQ(S)+12 will also 
be summarized descriptively for each of the visits in which the assessment was completed.

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For the EQ-5D-5L, the distribution of responses for each of the 5 dimensions assessed will be 
summarized by visit.  The change from baseline (Visit 1) on the visual analogue scale will also 
be evaluated.  The primary outcome for those not previously treated with benralizumab in the 
predecessor study will be a higher mean score on the visual analogue scale at the EOT visit 
compared to the baseline visit (Visit 1).  The primary outcome for those previously treated with 
benralizumab in the predecessor study will be no change in mean scores on the visual analogue 
scale at the EOT visit compared to the baseline visit (Visit 1). 
The mean rates of healthcare utilization by type of event (in-patient hospitalizations, emergency 
department visits/urgent care visits combined, unscheduled outpatient visits, and all unscheduled 
healthcare encounters will be summarized over the treatment period.  The primary outcome for 
those previously treated with benralizumab in the predecessor study will be no change in the 
mean rate of healthcare encounters by type in this safety extension study compared with the 
mean rates of healthcare encounters by type among the benralizumab treated patients in the 
predecessor studies.  The primary outcome for those not previously treated with benralizumab in 
the predecessor study will be mean rates of healthcare encounters by type comparable to the 
mean rates of healthcare encounters for those previously treated with benralizumab in the 
predecessor study.
The number and percentage of patients employed and attending classes will be summarized for 
Visit 1 and the EOT visit.  The number of work hours missed and the number of class hours 
missed due to asthma as well as the 4 summary scores of absenteeism, presenteeism, absenteeism 
+ presenteeism combined, and activity impairment will also be summarized for Visit 1 and the 
EOT visit.  The primary outcome for those not previously treated with benralizumab in the 
predecessor study will be reductions in the variables of interest (number of work/class hours 
missed, absenteeism, presenteeism, and work productivity loss and activity impairment) when 
comparing the values at the EOT to baseline (Visit 1).  The primary outcome for those 
previously treated with benralizumab in the predecessor study will be no change in the variables 
of interest when comparing values at the EOT visit to baseline (Visit 1).
8.5.2
Subgroup analysis
Details of the subgroup analyses will be provided in the SAP.
8.5.3
Sensitivity analysis
N/A
8.5.4
Interim analysis
Following analyses will be performed:
!
Japanese patients EOT analysis (Japanese patients only): Data cutoff for this analysis 
will be determined by the date at which the final Japanese patient completes the EOT 
visit.
!
Adult completion analysis of BORA: This analysis will be conducted when all adult 
patients within BORA have completed the study, and the final adolescent patient has 

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completed the first 56 weeks of treatment within BORA.  At this time, all of the study 
objectives related to adults will be fully addressed.
!
Adolescent completion analysis: This analysis will be conducted when the final 
adolescent patient has completed BORA, and will be reported in an addendum report 
to the BORA CSR.
Full details of each analysis will be outlined in separate SAPs.  
8.6
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.
8.7
Data Safety Monitoring Board
The Data Safety Monitoring Board (DSMB) is an independent expert advisory group 
commissioned and charged with the responsibility of evaluating cumulative safety and other 
clinical trial data at regular intervals and making appropriate recommendations based on the 
available data.  The DSMB will function independently of all other individuals associated with 
the conduct of the studies, including the study sponsor, AstraZeneca.  The committee will 
operate in accordance with a DSMB Charter.
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, PROs, 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).

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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 
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.

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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.
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 Q4 2014 and to end by Q3 2018.
The study may be terminated at individual study centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  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 AstraZeneca Drug Dictionary.  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.

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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent/Assent 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/Assent 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/Assent 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/Assent 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.

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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
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10.4
Informed consent
The Principal Investigator(s) at each study center will:
!
Ensure each patient, parent, or legal guardian is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study 
(before any study procedures are performed) as per local requirements.  The Informed 
Consent/Assent Form needs to be adjusted as per local requirements.
!
Ensure each patient, parent, or legal guardian is notified that they are free to 
discontinue from the study at any time
!
Ensure that each patient, parent, or legal guardian is given the opportunity to ask 
questions and allowed time to consider the information provided 
!
Ensure each patient, parent or legal guardian provides signed and dated Informed 
Consent/Assent before conducting any procedure specifically for the study.  Local 
regulations are to be followed in determining the assent/consent requirements for 
children of different age groups.
!
Ensure the original, signed Informed Consent/Assent Form(s) is/are stored in the 
Investigator’s Study File and kept for a period that is complaint with GCP/local 
regulatory requirements, whichever is longer
!
Ensure a copy of the signed Informed Consent/Assent Form is given to the patient
!
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the Informed Consent/Assent Form that is approved by an Ethics Committee
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, and 
assent where applicable, AstraZeneca and the study center’s Ethics Committee are to approve the 
revised Informed Consent/Assent Form before the revised form is used. 

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
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If local regulations require, any administrative change will be communicated to or approved by 
each Ethics Committee.
10.6
Audits and inspections
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 
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.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
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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.
Di Franco et al 2003
Di Franco 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.
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.
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.
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.

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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
83(85)
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.
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.

Revised Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
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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.
NAEPP 2007
NAEPP 2007, National Asthma Education Prevention Program. Expert Panel Report 
3:Guidelines for the Diagnosis and Management of Asthma. Available: 
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. 
Pavord et al 2012
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.
Quanjer et al 2012
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.
Simpson et al 2006
Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and 
identification using induced sputum. Respirology 2006;11(1):54-61.
Scott and Wardlaw 2006
Scott KA, Wardlaw AJ. Eosinophilic airway disorders. Semin Respir Crit Care Med. 2006; 
27(2):128-33.
Sorkness et al 2008
Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, et al. Lung function 
in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with 
bronchodilation. J Appl Physiol, 2008;104:394–403,.
Takatsu et al 1994
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.
Toba et al 1999
Toba K, Koike T, Shibata A, Hashimoto S, Takahashi M, Masuko M, et al. Novel technique for 
the direct flow cytofluorimetric analysis of human basophiles in unseparated blood and bone 
marrow, and the characterization of phenotype and peroxidase of human basophiles. Cytometry. 
1999 Mar 1;35(3):249-59.

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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition 4.0
Date 13 January 2016
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Wenzel 2012
Wenzel S E. Asthma phenotypes: the evolution from clinical to molecular approaches. 2012 May 
4;18(5):716-25.
Zhang and Wenzel 2007
Zhang JY, Wenzel SE. Tissue and BAL based biomarkers in asthma. Immunol Clin North Am. 
2007 Nov;27:623-32.

Clinical Study Protocol Appendix B
Drug Substance
Benrzalizumab (MEDI-563)
Study Code
D3250C00021
Edition Number
1
Date
20 June 2014
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance Benrzalizumab (MEDI-563) 
Study Code D3250C00021
Edition Number 1
Date 20 June 2014
2
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 immediatelylife 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 Benrzalizumab (MEDI-563) 
Study Code D3250C00021
Edition Number 1
Date 20 June 2014
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
D3250C00021
Edition Number
1
Date
20 June 2014
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance
Document

Clinical Study Protocol Appendix C
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00021
Edition Number 1
Date 20 June 2014
2
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 D3250C00021
Edition Number 1
Date 20 June 2014
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 I containment materials at all times.  The lATA 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
D3250C00021
Edition Number
1
Date
18 July 2014
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 D3250C00021
Edition Number 1
Date 18 July 2014
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 D3250C00021
Edition Number 1
Date 18 July 2014
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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).
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

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 18 July 2014
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When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative).
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see 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

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 18 July 2014
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!
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
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:

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 18 July 2014
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!
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
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 

Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 18 July 2014
7(7)
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
!
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 for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf

Clinical Study Protocol (CSP) Appendix X Generic, GEL, ed 1.0
Template Active Date: 5 February 2009
Parent SOP LDMS_001_00061249
Clinical Study Protocol Appendix E
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00021
Edition Number
1
Date
9 July 2014
Appendix E
Anaphylaxis: signs and symptoms, management

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 9 July 2014
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).

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 9 July 2014
3 (5)
(c) 
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope,
incontinence).
(d) 
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3. 
Reduced BP after exposure to known allergen for that patient (minutes to several
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from
that patient’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of 
antigenantibody 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:

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 9 July 2014
4 (5)
!  
Itchy nose, eyes, pharynx, genitalia, palms, and soles
!  
Rhinorrhea
            !  
Change in voice
!  
Metallic taste
!  
Nausea, vomiting, diarrhea, abdominal cramps and bloating
!  
Lightheadedness
!  
Headache
!  
Uterine cramps
            !          Generalized warmth
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.

Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 1
Date 9 July 2014
5 (5)
(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.
(i) 
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary.
Adapted from: 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)
Study Code
D3250C00021
Edition Number
2
Date
16 December 2016
Appendix F
Restricted and prohibited medications

Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 2
Date 16 December 2016
2 (4)
PROHIBITED AND RESTRICTED MEDICATIONS
Asthma medication restrictions
Table 1           Asthma medication restrictions
Medication
Prohibited/restricted
Details
Maintenance asthma
controller medications 
containing a LABA and/or 
LAMA
Restricted only on days of 
scheduled clinic visits
Usual ICS-LABA/LAMA 
should not
be taken prior to scheduled
spirometry and ECG 
assessments (to be
administered once 
assessments are
completed)
Short acting beta-agonists
(SABA)
Restricted only on days of 
scheduled clinic visits
SABA should not be used 
within 6
hours prior to scheduled 
spirometry and
ECG 
assessments.
Zileuton
Prohibited
Not allowed 30 days prior to 
Visit
1;during treatment period
Other medication restrictions
Table 2              Other medication restrictions
Medication
Prohibited/restricted
Details
Live Attenuated Vaccines
Prohibited
Not allowed 30 days prior to
randomization; during 
treatment
period, and 16 weeks
after the Last Dose
Inactive/killed vaccinations
(e.g. inactive influenza)
Restricted
Allowed provided they are 
not
administered within within 1 
week

Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 2
Date 16 December 2016
3 (4)
before/after any IP 
administration.
Any immunomodulators or
Immunosuppressives except 
systemic steroids used: 1) for 
the treatment of asthma 
exacerbations and 2) as intra-
articular 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
Any immunomodulators or
immunosuppressives –
topical
Restricted
Topical administration of
immunosuppressive 
medication may
be allowed at the discretion 
of the
Investigator after discussion 
with the
AstraZeneca Study Physician
Blood products or
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to 
date of
ICF; during treatment period
Any marketed (eg
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
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,

Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00021
Edition Number 2
Date 16 December 2016
4 (4)
for at
least 30 days prior to date of 
ICF; immunotherapy 
injections must be separated 
from IP injections by at least 
7 calendar days
Herbal remedies for the
treatment of allergic,
inflammatory, or respiratory
diseases
Prohibited
Not allowed 30 days prior to 
Visit 1; during treatment 
period
Non-selective oral or 
ophthalmic β-
adrenergic antagonist (e.g.
propranolol)
Prohibited
Patients currently using any 
non-selective oral or
ophthalmic β-adrenergic 
antagonist at
the time of enrolment are not 
eligible
for the study.
Not allowed during treatment 
period.