Clinical trial NCT02814643
Conditions: Asthma
Keywords: Male and female adolescent patients severe asthma
Sponsor: AstraZeneca
Start date: 2016-07-01; Completion date: 2017-01-24
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, parallel group, placebo-controlled study designed to investigate the potential effect of a fixed dose of benralizumab administered subcutaneously (SC) on antibody responses following seasonal influenza virus vaccination

Detailed description:
This study is designed to investigate the potential effect of benralizumab on the antibody response to the seasonal influenza virus vaccine in patients 12-21 years of age with asthma. Benralizumab will be given subcutaneously (SC) at Weeks 0, 4, and 8 weeks, at which time benralizumab levels will reach steady state. Patients will then receive 1 dose of intramuscular (IM) seasonal influenza virus vaccine at Week 8 and samples drawn at Week 8 and Week 12 to measure the antibody response to the influenza virus

Arms: arm 1: 1 mL fill volume administered every 4 weeks for 3 doses (Weeks 0, 4, and 8). Patients will receive 1 dose of seasonal influenza virus vaccine Intramuscular (IM) at Week 8. arm 2: 1 mL fill volume administered every 4 weeks for 3 doses (Weeks 0, 4, and 8). Patients will receive 1 dose of seasonal influenza virus vaccine Intramuscular (IM) at Week 8.
Interventions: intervention 1: Benralizumab intervention 2: Benralizumab Placebo intervention 3: Seasonal influenza virus vaccine
Intervention descriptions: intervention 1: Benralizumab SC administered every 4 weeks for 3 doses (Weeks 0, 4, and 8). intervention 2: Placebo administered every 4 weeks for 3 doses (Weeks 0, 4, and 8). intervention 3: Patients will receive 1 dose of seasonal influenza virus vaccine Intramuscular (IM) at Week 8.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, 
Phase 3b Study to Evaluate the Potential Effect of Benralizumab on the 
Humoral Immune Response to the Seasonal Influenza Vaccination in 
Adolescent and Young Adult Patients with Severe Asthma (ALIZE)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
Administrative 
Change No.
Date of Administrative 
Change
Local Administrative 
Change No.
Date of Local Administrative 
Change
This submission document contains confidential commercial information, disclosure of which is prohibited without 
providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca Standard procedures.  The 
clinical study protocol is publicly registered and the results are disclosed and/or published according to the 
AstraZeneca Global Policy on Bioethics and in compliance with prevailing laws and regulations.


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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PROTOCOL SYNOPSIS
A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-
controlled, Phase 3b Study to Evaluate the Potential Effect of Benralizumab 
on the Humoral Immune Response to the Seasonal Influenza Vaccination in 
Adolescent and Young Adult Patients with Severe Asthma (ALIZE)
International Coordinating Investigator 
 
 
 
 
 
Study center(s) and number of patients planned
This study will be conducted in the United States in approximately 35 study centers. Target is to 
randomize approximately 100 patients.
Study period
Phase of development
Estimated date of first patient enrolled
Q3 2016
Phase 3b
Estimated date of last patient completed
Q1 2017


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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Objectives
(a)
Primary Objective
Objective
Endpoint(s)
To evaluate the potential effect of 
benralizumab on the humoral immune 
response following seasonal influenza 
virus vaccination in adolescent and young 
adult patients with severe asthma
!
Post-dose strain-specific 
hemagglutination-inhibition (HAI)
antibody geometric mean fold rises 
(GMFRs) from Week 8
!
Post-dose strain-specific serum HAI 
antibody geometric meant titers (GMTs)
obtained at Week 12
!
Proportion of patients who experience a 
strain-specific post-dose antibody
response at Week 12 with antibody
response defined as a ≥4-fold rise in HAI
antibody titer from Week 8
!
Proportion of patients who achieve a 
strain-specific post-dose HAI antibody 
titer ≥40 at Week 12
(b)
Secondary Objectives
Objective
Endpoint(s)
To further evaluate the potential effect of 
benralizumab on the humoral immune 
response following seasonal influenza 
virus vaccination in adolescent and young 
adult patients with severe asthma
!
Proportion of patients who achieve a 
strain-specific post-dose HAI antibody 
titer ≥320 at Week 12
!
Post-dose strain-specific 
microneutralization (MN) antibody 
GMFRs from Week 8
!
Post-dose strain-specific serum MN 
GMTs obtained at Week 12 
!
Proportion of patients who experience a 
strain-specific post-dose antibody 
response at Week 12 with antibody 
response defined as a ≥4-fold rise in MN 
antibody titer from Week 8
To assess the potential effect of 
benralizumab on asthma control
!
Change from baseline in mean Asthma 
Control Questionnaire-6 (ACQ-6) score
at Week 12


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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(c)
Safety Objective 
Objective
Endpoint
To assess the safety and tolerability of 
benralizumab 
!
Adverse events (AEs) and serious 
adverse events (SAEs)
!
Laboratory variables
!
Physical Examination
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
investigate the potential effect of a fixed dose of benralizumab (30 mg) administered 
subcutaneously (SC) on antibody responses following seasonal influenza virus vaccination. 
Approximately 100 patients 12-21 years of age with severe asthma will be randomized to receive 
SC benralizumab 30 mg or placebo administered at Weeks 0, 4, and 8. 
After enrolment and confirmation of entry criteria, patients will proceed to a screening period of 
a minimum of 2 weeks to allow adequate time for all of the eligibility criteria to be evaluated
before being randomized at Visit 3. Patients who continue to meet eligibility criteria will be 
randomized on Week 0 to receive 3 SC doses (at Weeks 0, 4, and 8) of benralizumab 30 mg or 
placebo. Patients will receive 1 dose of seasonal influenza vaccine intramuscularly (IM) at 
Week 8. Serum samples for evaluation of antibody response will be drawn at Week 8 and 
Week12. An End of Treatment (EOT) will also be conducted at Week 12 and a Follow-up visit 
will be conducted at Week 20.
Patients will be maintained on their currently prescribed ICS-LABA therapy(ies) without change 
from enrolment throughout the screening and treatment period.
Target patient population
Male and female adolescent patients 12 to 21 years of age, inclusive, with severe asthma will be 
enrolled. Fifty percent or more of the patients will be 12 to 17 years of age.
Investigational product, dosage and mode of administration
Benralizumab 30 mg/mL solution for injection in an accessorized pre-filled syringe (APFS) will 
be administered at the study center SC every 4 weeks for 3 doses (Weeks 0, 4, and 8).
Comparator, dosage and mode of administration
Matching placebo solution for injection in an APFS will be administered at the study center SC 
every 4 weeks for 3 doses (Weeks 0, 4, and 8).
Duration of treatment
Following enrolment, patients will enter a 2 to 3 week screening period followed by a 12-week
double-blind, randomized treatment period, with the last dose of benralizumab/placebo 


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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administered at Week 8. An End of Treatment (EOT) will be conducted at Week 12 and a
Follow-up visit will be conducted at Week 20.
The total planned study duration is a maximum of 23 weeks.
Statistical methods
The benralizumab versus placebo antibody response following seasonal influenza virus 
vaccination will be assessed by
!
Post-dose strain-specific HAI antibody geometric mean folder rises (GMFRs) from 
Week 8
!
Post-dose strain-specific HAI antibody geometric mean titers (GMTs) obtained at 
Week 12 
!
Proportion of patients who experience a strain-specific post-dose antibody response at 
Week 12 with antibody response defined as a ≥4-fold rise in HAI antibody titer from 
Week 8
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer ≥40 at 
Week 12   
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer ≥320 at 
Week 12
!
Post-dose strain-specific microneutralization (MN) antibody GMFRs from Week 8
!
Post-dose strain-specific serum MN antibody GMTs obtained at Week 12 
!
Proportion of patients who experience a strain-specific post-dose antibody response at 
Week 12 with antibody response defined as a ≥4-fold rise in MN antibody titer from 
Week 8
The analysis of the anti-influenza antibody response endpoints–strain-specific GMFRs and 
GMTs–will be performed on the immunogenicity analysis set, defined as all randomized patients 
who received at least 1 dose of planned investigational product (ie, 1 dose of influenza vaccine 
plus 1 dose of benralizumab or placebo), had pre- and post-dose HAI antibody measurements,
had pre- and post-dose MN antibody measurements, and had no protocol deviation judged to 
have the potential to interfere with the generation or interpretation of an humoral response to the 
influenza vaccine.  GMFRs and GMTs will be summarized by treatment group, and the group 
ratio of GMFRs (influenza vaccine divided by benralizumab and influenza vaccine) and GMTs 
and their corresponding 90% confidence intervals (CIs) will be constructed.
The antibody response to the influenza vaccine is defined as a ≥4-fold rise in HAI from Week 8.  
The proportion of patients who experience a post-dose HAI antibody response at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment group. 
The proportion of patients who achieve a post-dose HAI antibody titer ≥40 at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment group.


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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The proportion of patients who achieve a post-dose HAI antibody titer ≥320 at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment group.
The antibody response to the influenza vaccine is also defined as a ≥4-fold rise in MN antibody 
from Week 8.  The proportion of patients who experience a post-dose MN antibody response at 
Week 12 and corresponding 90% Clopper-Pearson exact CI will be summarized by treatment 
group. 
For GMFR and GMT, the geometric least square mean ratio between treatment groups 
(placebo/benralizumab) will be calculated via an analysis of covariance (ANCOVA) model on 
the log-transformed variable, adjusting for treatment group.  The least square geometric mean 
ratio will be provided with associated 90% CI.
No interim blinded review is planned.
No formal statistical hypotheses will be tested.  The sample size justification is based on the 
precision of the estimate of the GMTs (as GMTvaccine / GMTbenralizumab+vaccine).  With 50 patients 
per arm, the 90% CI for the GMT ratio would be 0.67 to 1.48, assuming an observed ratio of 1, 
and that the log (post-dose HAI antibody titer or post-dose MN antibody titer) is normally 
distributed with a standard deviation (SD) of 1.2 on the natural log scale (Langley et al 2013).
All safety parameters will be analyzed descriptively.  Safety analyses will be based on the safety 
analysis set, defined as all patients who received at least 1 dose of investigational product.


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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TABLE OF CONTENTS
PAGE
TITLE PAGE .......................................................................................................... 1
PROTOCOL SYNOPSIS........................................................................................ 2
TABLE OF CONTENTS........................................................................................ 7
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................... 12
1.
INTRODUCTION................................................................................................. 15
1.1
Background and rationale for conducting this study............................................. 15
1.2
Rationale for study design, doses and control groups........................................... 16
1.3
Benefit/risk and ethical assessment....................................................................... 17
1.4
Study design .......................................................................................................... 17
2.
STUDY OBJECTIVES......................................................................................... 20
2.1
Primary Objective.................................................................................................. 20
2.2
Secondary Objectives............................................................................................ 20
2.3
Safety Objective .................................................................................................... 21
3.
PATIENT SELECTION, ENROLLMENT, DISCONTINUATION, AND 
WITHDRAWAL CRITERIA................................................................................ 21
3.1
Inclusion criteria.................................................................................................... 21
3.2
Exclusion criteria................................................................................................... 23
3.3
Patient enrolment and randomization.................................................................... 25
3.4
Procedures for handling incorrectly enrolled or randomized patients .................. 26
3.5
Concomitant medications, restrictions during, and after the study....................... 26
3.5.1
Concomitant medication........................................................................................ 26
3.5.1.1
Background medication......................................................................................... 26
3.5.1.2
Rescue medication................................................................................................. 26
3.5.2
Restrictions............................................................................................................ 27
3.5.2.1
Asthma medication restrictions............................................................................. 27
3.5.2.2
Other medication restrictions ................................................................................ 27
3.5.2.3
Other restrictions................................................................................................... 28
3.6
Discontinuation from investigational product....................................................... 28
3.7
Withdrawal from the study.................................................................................... 29
3.7.1
Screen failures....................................................................................................... 29
3.7.2
Withdrawal of the Informed Consent.................................................................... 29
3.8
Withdrawal of informed consent for donated biological samples......................... 29


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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4.
STUDY PLAN AND PROCEDURES ................................................................. 31
4.1
Enrollment and screening period........................................................................... 33
4.1.1
Enrollment (Visit 1)............................................................................................... 33
4.1.2
Screening (Visit 2)................................................................................................. 33
4.1.3
Re-screening.......................................................................................................... 33
4.1.3.1
Procedures for patients who experience an exacerbation during screening/run-
in............................................................................................................................ 34
4.2
Randomized treatment period ............................................................................... 34
4.3
Follow-up period................................................................................................... 34
5.
STUDY ASSESSMENTS AND TIMING OF PROCEDURES........................... 34
5.1
Efficacy assessments ............................................................................................. 34
5.1.1
Humoral response to influenza vaccine................................................................. 34
5.1.2
Spirometry............................................................................................................. 34
5.1.2.1
Reversibility test and post-BD FEV1 assessment.................................................. 36
5.2
Safety assessments ................................................................................................ 37
5.2.1
Physical examination............................................................................................. 37
5.2.1.1
Complete physical examination ............................................................................ 37
5.2.1.2
Brief physical examination.................................................................................... 37
5.2.2
Vital signs.............................................................................................................. 37
5.2.3
Local electrocardiogram........................................................................................ 37
5.2.4
Safety laboratory tests ........................................................................................... 38
5.2.4.1
Pregnancy test........................................................................................................ 39
5.3
Other assessments and procedures ........................................................................ 39
5.3.1
Weight and height ................................................................................................. 39
5.3.2
Assessment of asthma exacerbations .................................................................... 39
5.3.3
Asthma Control Questionnaire (ACQ-6) .............................................................. 39
5.3.4
Other screening/run-in assessments ...................................................................... 40
5.3.4.1
Serology................................................................................................................. 40
5.3.5
Pharmacokinetics................................................................................................... 40
5.3.6
Pharmacodynamics................................................................................................ 40
5.3.7
Assessment of anti-benralizumab antibodies ........................................................ 41
5.3.8
Handling of biological samples............................................................................. 41
5.3.8.1
Labeling and shipment of biological samples....................................................... 41
5.3.8.2
Chain of custody of biological samples ................................................................ 41
6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS................................. 42
6.1
Identity of investigational product(s) .................................................................... 42
6.2
Labeling................................................................................................................. 42
6.3
Storage................................................................................................................... 42
6.4
Accountability ....................................................................................................... 43
6.5
Methods for assigning treatment groups ............................................................... 43


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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6.6
Methods for ensuring blinding .............................................................................. 43
6.7
Methods for unblinding......................................................................................... 44
6.8
Investigational product administration and treatment compliance........................ 45
6.9
Management of investigational product-related reactions .................................... 46
7.
SAFETY REPORTING ........................................................................................ 47
7.1
Adverse events ...................................................................................................... 47
7.1.1
Definition of adverse events.................................................................................. 47
7.1.2
Definitions of serious adverse event ..................................................................... 47
7.1.3
Recording of adverse events.................................................................................. 47
7.1.3.1
Time period for collection of adverse events ........................................................ 47
7.1.3.2
Follow-up of unresolved adverse events............................................................... 47
7.1.3.3
Variables................................................................................................................ 48
7.1.3.4
Causality collection............................................................................................... 48
7.1.3.5
Adverse events based on signs and symptoms...................................................... 48
7.1.3.6
Adverse events based on examinations and tests.................................................. 49
7.1.3.7
Symptoms of the disease under study ................................................................... 49
7.1.4
Hy’s Law............................................................................................................... 49
7.1.5
Reporting of serious adverse events...................................................................... 49
7.2
Overdose................................................................................................................ 50
7.3
Pregnancy.............................................................................................................. 50
7.3.1
Maternal exposure................................................................................................. 51
7.3.2
Paternal exposure .................................................................................................. 51
8.
EVALUATION AND CALCULATION OF VARIABLES ................................ 51
8.1
Statistical considerations....................................................................................... 51
8.2
Sample size estimate ............................................................................................. 52
8.3
Definitions of analysis sets.................................................................................... 52
8.3.1
All patients analysis set ......................................................................................... 52
8.3.2
Full analysis set ..................................................................................................... 52
8.3.3
Vaccine immunogenicity analysis set ................................................................... 52
8.3.4
Safety analysis set ................................................................................................. 52
8.3.5
Pharmacokinetic analysis set................................................................................. 53
8.4
Variables for analyses ........................................................................................... 53
8.4.1
Calculation or derivation of efficacy variables ..................................................... 53
8.4.1.1
Humoral immune response following seasonal influenza virus vaccination ........ 53
8.4.2
Calculation or derivation of safety variable(s)...................................................... 53
8.4.3
Calculation or derivation of patient reported outcome variables .......................... 54
8.4.3.1
Asthma Control Questionnaire (ACQ-6) .............................................................. 54
8.4.4
Calculation or derivation of pharmacokinetic variables........................................ 54
8.4.5
Calculation or derivation of benralizumab immunogenicity variables ................. 54
8.5
Methods for statistical analyses............................................................................. 54


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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8.5.1
Analysis methods for antibody endpoints ............................................................. 54
8.5.2
Analysis methods for non-immunogenicity endpoints.......................................... 55
8.5.3
Analysis methods for safety variables................................................................... 55
8.5.3.1
Asthma exacerbations............................................................................................ 55
8.5.3.2
Other safety variables............................................................................................ 55
8.5.3.3
Analysis methods for pharmacokinetic variables.................................................. 56
8.5.3.4
Analysis method for benralizumab immunogenicity variables............................. 56
8.5.4
Interim analysis ..................................................................................................... 56
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.......................... 56
9.1
Training of study center personnel........................................................................ 56
9.2
Monitoring of the study......................................................................................... 56
9.2.1
Source data ............................................................................................................ 57
9.2.2
Recording of data .................................................................................................. 57
9.2.3
Study agreements .................................................................................................. 57
9.2.4
Archiving of study documents .............................................................................. 58
9.3
Study timetable and end of study .......................................................................... 58
9.4
Data management by AstraZeneca........................................................................ 58
10.
ETHICAL AND REGULATORY REQUIREMENTS ........................................ 58
10.1
Ethical conduct of the study.................................................................................. 58
10.2
Patient data protection........................................................................................... 58
10.3
Ethics and regulatory review................................................................................. 59
10.4
Informed consent................................................................................................... 59
10.5
Changes to the protocol and informed consent form ............................................ 60
10.6
Audits and inspections........................................................................................... 60
11.
LIST OF REFERENCES ...................................................................................... 61
LIST OF TABLES
Table 1
Study Plan – Enrollment, screening period.............................................. 31
Table 2
Study Plan – Randomization, treatment period, and follow-up............... 32
Table 3
List of safety laboratory tests................................................................... 38
Table 4
Identity of investigational product........................................................... 42


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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LIST OF FIGURES
Figure 1
Study flow chart....................................................................................... 19
Figure 3
Injection sites and rotation scheme.......................................................... 45
LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 
Appendix C
IATA 6.2 Guidance document
Appendix D
Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law
Appendix E
Background Therapy Equivalence Table
Appendix F
Anaphylaxis: definition, signs and symptoms, management
Appendix G
Restricted and prohibited medications


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
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
ARE
Antibody Response Evaluation
AST
Aspartate aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
Beta-hCG
Beta- human chorionic gonadotropin
BMI
Body mass index
CI
Confidence interval
CO2
Carbon dioxide
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency department
EOT
End of treatment
EU
European Union
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
GMFR
Geometric mean fold rises


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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Abbreviation or 
special term
Explanation
GMP
Good Manufacturing Practice
GMT
Geometric mean titers
HAI
Hemagglutination-inhibition 
HCG
Human chorionic gonadotropin
HCP
Health care provider
HIV
Human immunodeficiency virus
IATA
International Air Transport Association
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICI
International Coordinating Investigator
ICS
Inhaled corticosteroids
IL
Interleukin
IL-5
Interleukin-5
IL-5R
Interleukin-5 receptor
IL-5Rα
Interleukin-5 receptor alpha subunit
IM
Intramuscular
IP
Investigational product
IPD
Premature IP Discontinuation
IRB
Institutional Review Board
ITT
Intent-to-Treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-acting β2 agonists
LTRA
Leukotriene receptor antagonists
MedDRA
Medical Dictionary for Regulatory Activities
MN
Microneutralization antibodies to influenza vaccine
PK
Pharmacokinetic(s)
Post-BD
Post-bronchodilator
Pre-BD
Pre-bronchodilator
PRO
Patient reported outcome
RBC
Red blood cell
SABA
Short-acting β2 agonists


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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Abbreviation or 
special term
Explanation
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SUSARs
Suspected Unexpected Serious Adverse Reactions
ULN
Upper limit of normal
WBC
White blood cell
WBDC
Web-based Data Capture
WOCBP
Women of childbearing potential


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
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 has become more common in both children and 
adults around the world in recent decades.  It 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 (GINA 201, 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 centered around inhaled corticosteroids (ICS) and 
leukotriene receptor antagonists (LTRA), with the addition of long-acting β2 agonists (LABA) in 
patients with more severe asthma (GINA 2015, NAEPP 2007). Despite treatment per 
management guidelines, up to 50% of patients have asthma that is not well controlled (Bateman 
et al 2010). This results in considerable impact on quality of life, disproportionate use of 
healthcare resources, and adverse reactions from regular systemic steroid use. Therefore, there 
remains an unmet medical need for patients whose asthma is not controlled by existing therapies.
The observed variability in clinical response to currently available asthma therapies appears to be 
related, in part, to distinctive inflammatory phenotypes (Wenzel 2012). In particular, asthma 
associated with eosinophilic inflammation in the airway (often referred to as eosinophilic 
asthma) is common (approximately 40% to 60% of asthmatics) with the degree of eosinophilia 
associated with clinical severity including the risk of asthma exacerbations (Bousquet et al 1990,
Louis et al 2000, Di Franco et al 2003, Scott and Wardlaw 2006, Simpson et al 2006, Zhang and 
Wenzel 2007). 
Interleukin-5 (IL-5) is a key cytokine essential for eosinophil trafficking and survival (Molfino et 
al 2011). Clinical trials of the anti-IL-5 antibodies mepolizumab and reslizumab in patients with 
uncontrolled eosinophilic asthma have shown benefit in reducing asthma exacerbation, 
improving lung function, and reducing symptoms (Castro et al 2015, Ortega et al 2014). These 
promising results support continued development of therapies targeting the IL-5 pathway in 
eosinophilic asthmatics.
Benralizumab (MEDI-563) is a humanized, afucosylated, monoclonal antibody that binds 
specifically to the human IL-5 receptor alpha subunit (IL-5Rα) on the target cell. The IL-5 
receptor (IL-5R) is expressed almost exclusively on the surface of eosinophils and basophils 
(Takatsu et al 1994, Toba et al 1999). Afucosylation confers enhanced antibody-dependent 
cellular cytotoxicity (ADCC) which results in highly efficient eosinophil depletion by apoptosis 
(Kolbeck et al 2012). Single and repeated doses of benralizumab in mild to severe asthma 
patients has resulted in depletion of blood and airway eosinophils (Busse et al 2010, Laviolette et 
al 2013).  Also, a recent dose-finding trial in severe asthma proved benralizumab to have benefit
across a range of asthma outcomes including reductions in asthma exacerbations, improvements 
in lung function, and reduction in symptoms (Castro et al 2014).


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
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Benralizumab is currently being studied in Phase 3 in severe asthmatics with a history of 
exacerbations, still symptomatic despite using medium-to-high dose ICS/LABAs with or without 
oral corticosteroids or additional controller medications.  
As benralizumab depletes eosinophils, it is important to determine if benralizumab affects 
functioning of the immune system, especially in adolescents and young adults.  In this study, a 
functional response of the immune system will be assessed by measuring antibody responses to 
the influenza vaccine.
1.2
Rationale for study design, doses and control groups
This study is designed to investigate the potential effect of benralizumab on the antibody
response to the seasonal influenza virus vaccine in patients 12-21 years of age with asthma.  
Benralizumab (30 mg) will be given subcutaneously (SC) at Weeks 0, 4, and 8 weeks, at which 
time benralizumab levels will reach steady state.  Patients will then receive 1 dose of 
intramuscular (IM) seasonal influenza virus vaccine at Week 8 and samples drawn at Week 8 
and Week 12 to measure the antibody response to the influenza virus
The immune response, as assessed by evaluation of antibody responses to the influenza vaccine 
in the group receiving benralizumab versus placebo will be assessed by
!
Post-dose strain-specific HAI antibody geometric mean folder rises (GMFRs) from 
Week 8
!
Post-dose strain-specific HAI antibody geometric mean titers (GMTs) obtained at 
Week 12 
!
Proportion of patients who experience a strain-specific post-dose antibody response at 
Week 12 with antibody response defined as a ≥4-fold rise in HAI antibody titer from 
Week 8
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer ≥40 at 
Week 12
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer ≥320 at 
Week 12
!
Post-dose strain-specific MN antibody GMFRs from Week 8
!
Post-dose strain-specific serum MN antibody GMTs obtained at Week 12 
!
Proportion of patients who experience a strain-specific post-dose antibody response at 
Week 12 with antibody response defined as a ≥4-fold rise in MN antibody titer from 
Week 8
The benralizumab dose (30 mg SC, fixed) is based on all available safety and efficacy data, as 
well as population exposure-response modeling and stochastic trial simulations from earlier 
phase benralizumab trials.  Other stable asthma therapies on top of inhaled corticosteroids/long-
acting β2 agonists (ICS/LABA) that are within expert guidance and not restricted per protocol are 
allowed in order to accommodate local standards of care.


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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1.3
Benefit/risk and ethical assessment
Benralizumab is principally being studied in severe asthmatics where there are few treatment 
options for patients whose asthma remains uncontrolled on high dose ICS/LABA and oral 
corticosteroids (GINA 2015).  In adult patients whose asthma was poorly controlled on medium-
to-high dose ICS/LABA therapy, benralizumab at 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 (Castro et al 2014).  
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).  To date, there have been no identified risks.  Also, 
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 
herein include exclusion of patients with untreated parasitic infection and active or recent 
malignancy, in conjunction with the performance of routine pharmacovigilance activities.
The purpose of this trial is to assess the effect of benralizumab on the humoral immune response
following seasonal influenza virus vaccination in patients 12-21 years of age with asthma.  Mild 
problems following inactivated flu vaccine may include soreness, redness, or swelling where the 
shot was given, as well as sore, red or itchy eyes, hoarseness, cough, fever, aches, headache,
itching, and fatigue (CDC 2014).  Very rarely, as with all vaccines, anaphylaxis may occur.  
Benefits would include probable protection against developing influenza in the upcoming flu 
season.
A more detailed assessment of the overall risk/benefit of benralizumab in patients with asthma is 
given in the Investigator’s Brochure.
1.4
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
investigate the potential effect of a fixed dose of benralizumab (30 mg) administered SC on the 
humoral immune response following seasonal influenza virus vaccination. 
Approximately 100 patients 12-21 years of age with severe asthma will be randomized to receive 
SC benralizumab 30 mg or placebo administered at Weeks 0, 4, and 8. Fifty percent or more of 
the patients will be 12 to 17 years of age.
Patients will receive 1 dose of seasonal influenza virus vaccine IM at Week 8.  Samples for 
evaluation of antibody response will be drawn at Week 8 and Week 12.
After enrolment and confirmation of entry criteria, patients will proceed to screening period of a 
minimum of 2 weeks to allow adequate time for all of the eligibility criteria to be evaluated.  
Patients who continue to meet the eligibility criteria will be randomized at Week 0 to receive 3


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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SC doses (at Weeks 0, 4, and 8) of benralizumab 30 mg or placebo.  Patients will receive 1 dose 
of seasonal influenza virus vaccine IM at Week 8. Samples for evaluation of antibody response
will be drawn at Week 8 and Week 12. The End of Treatment (EOT) will be conducted at Week 
12 and a Follow-up (FU) visit will be conducted at Week 20.
Patients will be maintained on their currently prescribed ICS-LABA therapy(ies) without change
from enrollment throughout the screening and treatment period.


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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Figure 1
Study flow chart
Visit 1
Visit 2
Visit 3 (Week 0)
Double-blind Randomized Treatment 
Period
Visits 3 – 5 
Visit 6
Antibody Response 
Evaluation/End of 
Treatment
Vaccination
Visit 5 (Week 8)
50 Subjects 
SC Benralizumab 30 mg
at Weeks 0, 4, 8, (3 doses) 
ARE/EOT 
Visit 
Week 12
Screening
2 – 3 weeks
Visit 7
Follow-up
FU Visit
Week 20
Randomization
100 Subjects
in 1:1 ratio
50 Subjects 
SC Placebo 
at Weeks 0, 4, 8 (3 doses) 
ARE/EOT 
Visit 
Week 12
FU Visit
Week 20


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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2.
STUDY OBJECTIVES
2.1
Primary Objective
Objective
Endpoint
To evaluate the potential effect of 
benralizumab on the humoral immune
response following seasonal influenza 
virus vaccination in adolescent and young 
adult patients with severe asthma
!
Post-dose strain-specific 
hemagglutination-inhibition (HAI) 
antibody geometric mean fold rises 
(GMFRs) from Week 8
!
Post-dose strain-specific serum HAI 
antibody geometric meant titers (GMTs) 
obtained at Week 12 
!
Proportion of patients who experience a 
strain-specific post-dose antibody 
response at Week 12 with antibody 
response defined as a ≥4-fold rise in HAI 
antibody titer from Week 8
!
Proportion of patients who achieve a 
strain-specific post-dose HAI antibody 
titer ≥40 at Week 12
2.2
Secondary Objectives
Objective
Endpoint
To further evaluate the potential effect of 
benralizumab on the humoral immune
response following seasonal influenza virus 
vaccination in adolescent and young adult 
patients with severe asthma
!
Proportion of patients who achieve a strain-
specific post-dose HAI antibody titer ≥320 
at Week 12
!
Post-dose strain-specific microneutralization 
(MN) antibody GMFRs from Week 8
!
Post-dose strain-specific serum MN 
antibody GMTs obtained at Week 12 
!
Proportion of patients who experience a strain-
specific post-dose antibody response at Week 12 
with antibody response defined as a ≥4-fold rise 
in MN antibody titer from Week 8
To assess the potential effect of 
benralizumab on asthma control 
!
Change from baseline in mean Asthma 
Control Questionnaire-6 (ACQ-6) score at 
Week 12


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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2.3
Safety Objective 
Objective
Endpoint
To assess the safety and tolerability of 
benralizumab
!
Adverse events (AEs) and serious adverse 
events (SAEs)
!
Laboratory variables
!
Physical Examination
3.
PATIENT SELECTION, ENROLLMENT, DISCONTINUATION, 
AND WITHDRAWAL CRITERIA
3.1
Inclusion criteria
For inclusion in the study patients must fulfill all of the following criteria:
1.
Written informed consent/assent as appropriate with local guidance for study 
participation must be obtained prior to any study related procedures being performed 
and according to international guidelines and/or applicable European Union (EU) 
guidelines. 
2.
Female and male patients aged 12 to 21 years, inclusive, at the time of Visit 1
3.
Women of childbearing potential (WOCBP) must use an effective form of birth 
control (confirmed by the Investigator). Effective forms of birth control includes: true
sexual abstinence, a vasectomized sexual partner, Implanon® , female sterilization by 
tubal occlusion, any effective IUD Intrauterine device/IUS Ievonorgestrel Intrauterine 
system, Depo-Provera™ injections, oral contraceptive, and Evra Patch ™ or 
Nuvaring™. WOCBP must agree to use an effective method of birth control, as 
defined above, from enrollment, throughout the study duration and until 16 weeks 
after last dose of investigational product (IP).  WOCBP must also have negative serum 
pregnancy test result on Visit 1.
4.
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.
5.
Weight of ≥40 kg
6.
Documented history of current treatment with ICS and LABA.  The ICS and LABA 
can be parts of a combination product or given by separate inhalers. The ICS dose 
must be greater than or equal to 500 μg/day fluticasone propionate dry powder 
formulation or equivalent daily.


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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∀
For ICS/LABA combination preparations, both the mid- and high-strength 
maintenance doses approved in the local country will meet this ICS criterion.  
∀
Additional asthma controller medications (eg, LTRAs, short- and long-acting anti-
muscarinics, theophylline, oral corticosteroids, etc) that have been used for at least 
30 days prior to Visit 1 are allowed (see Section 3.5.2.1 for restricted therapies)
7.
Morning pre-bronchodilator forced expiratory volume in 1 second (FEV1) of >50% 
predicted at Visit 1 or Visit 2.
8.
Evidence of asthma as documented by either:
–
Airway reversibility (FEV1 >12% and 200 ml) demonstrated at Visit 1 or Visit 2
using the Maximum Post-bronchodilator Procedure OR 
–
Airway reversibility documented in the previous 12 months prior to Visit 1 
Note: All patients must have reversibility testing performed before randomization 
to establish a baseline characteristic even if historical documentation is used to 
meet this criterion.
If historical reversibility is being used to meet this criterion, the relevant historical pre-
and post-bronchodilator results must be entered into the electronic case report form 
(eCRF). 
If patients do not demonstrate airway reversibility at either Visit 1 or Visit 2 and 
historical reversibility is not available for evidence of asthma, the patient must not 
enter the treatment period and must be rescreened, if appropriate.  If re-screened, the 
site should reiterate the need to withhold short- and long-acting bronchodilators as 
required in Section 5.1.2 prior to spirometry visits in an effort to meet this inclusion 
criterion.
Randomization criteria
9.
For WOCBP: have a negative urine pregnancy test prior to administration of the IP at 
Visit 3
10.
Not well controlled asthma as documented by either 
–
An ACQ-6 >1.5 OR
–
A peak flow of 60-80% predicted OR
–
An exacerbation, 1 or more, that required oral corticosteroids in the previous year 
OR
–
Any 1 of the following assessed by patient recall over the previous 2-4 weeks


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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o
Asthma symptoms >2 days/week; OR
o
Nighttime awakenings 1 or more/week; OR
o
Short acting β2-agonist use for symptom control (not for prevention of 
exercise-induced asthma) >2 days/week.
3.2
Exclusion criteria
Patients must not enter the study if any of the following exclusion criteria are fulfilled:
1.
Clinically important pulmonary disease other than asthma (eg, active lung infection, 
bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome 
associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary 
ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other 
than asthma, that are associated with elevated peripheral eosinophil counts (eg, allergic 
bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic 
syndrome)
2.
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
3.
Known history of allergy or reaction to the IP formulation or influenza vaccine
4.
Allergy to eggs
5.
History of anaphylaxis to any biologic therapy
6.
History of Guillain-Barré syndrome
7.
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent/assent is obtained that has not been treated with, or has failed to respond to 
standard of care therapy
8.
Any clinically significant abnormal findings in physical examination, vital signs, 
baseline ECG, hematology, clinical chemistry, or urinalysis during screening period, 
which in the opinion of the Investigator, may put the patient at risk because of his/her 
participation in the study, or may influence the results of the study, or the patient’s 
ability to complete entire duration of the study


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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9.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a 
positive medical history for hepatitis B or C. Patients with a history of hepatitis B 
vaccination without history of hepatitis B are allowed to enroll
10.
A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test
11.
Current smokers 
12.
History of cancer:
∀
Patients who have had basal cell carcinoma, localized squamous cell carcinoma of 
the skin, or in situ carcinoma of the cervix are eligible provided that the patient is 
in remission and curative therapy was completed at least 12 months prior to the 
date informed consent/assent was obtained
∀
Patients who have had other malignancies are eligible provided that the patient is 
in remission and curative therapy was completed at least 5 years prior to the date 
informed consent/assent was obtained
13.
Use of immunosuppressive medication (including but not limited to: oral 
corticosteroid [for reasons other than asthma], methotrexate, troleandomycin, 
cyclosporine, azathioprine, tacrolimus, mycofenolate mofetil, intramuscular long-
acting depot corticosteroid [for reasons other than asthma], or any experimental 
anti-inflammatory therapy) within 3 months prior to the date informed consent/assent
14.
History of alcohol or drug abuse within 12 months prior to the date of informed 
consent
15.
Receipt of immunoglobulin or blood products within 30 days prior to the date 
informed consent/assent is obtained
16.
Receipt of any marketed (eg, omalizumab) or investigational biologic within 4 months 
or 5 half-lives prior to the date informed consent/assent is obtained, whichever is 
longer
17.
Receipt of live attenuated vaccines 30 days prior to the date of randomization
18.
Receipt of an influenza vaccine within 90 days prior to randomization
19.
Receipt of any non-biologic investigational medication within 30 days or 5 half-lives 
prior to randomization, whichever is longer
20.
Previously received benralizumab (MEDI-563) 
21.
Change to allergen immunotherapy or initiation of new allergen immunotherapy is not 
allowed within 30 days prior to the date of informed consent/assent. Changes to 


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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allergen immunotherapy are not allowed during the conduct of the study.
Immunotherapy initiated prior to this period or as a routine part of the patient’s 
seasonal treatment is allowed.  If the immunotherapy is delivered as an injection, there 
should be a gap of 7 days between the immunotherapy and IP administration.
22.
Planned surgical procedures during the conduct of the study
23.
Currently breastfeeding or lactating women
24.
Concurrent enrollment in another drug-related interventional clinical trial
25.
AstraZeneca staff involved in the planning and/or conduct of the study
26.
Employees of the study center or any other individuals involved with the conduct of 
the study or immediate family members of such individuals
27.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times 
the upper limit of normal (ULN) confirmed during screening period
28.
Life threatening asthma defined as episodes requiring intubation associated with 
hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes
Exclusion criterion at randomization 
29.
Poorly controlled asthma during the screening period that requires treatment with oral 
corticosteroids or a hospitalization/emergency room visit for the treatment of asthma
30.
Acute illness or evidence of significant active infection or known influenza infection 
during the current flu season
For procedures for withdrawal of incorrectly enrolled or randomized patients see Section 3.4.
3.3
Patient enrolment and randomization
Investigator(s) should keep a record of patients considered for and included in the study. This 
pre-screening/screening log will be evaluated periodically by AstraZeneca or its delegates during 
routine monitoring visits.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
The Investigator will:
1.
Obtain signed informed consent/assent as appropriate with local guidance from the 
potential patient before any study specific procedures are performed
2.
Assign each potential patient a unique enrollment number beginning with E# via 
interactive web/voice response system (IWRS/IVRS)


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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3.
Determine patient eligibility
4.
Assign eligible patient unique randomization code via IWRS/IVRS
If a patient withdraws from participation in the study, then his/her enrolment/randomization code 
cannot be reused.
Patients will be allocated to treatment arms in a 1:1 ratio. Specific information concerning the 
use of the IWRS/IVRS will be provided in the separate manual. Randomized patients who 
discontinue from IP administration will not be replaced.
3.4
Procedures for handling incorrectly enrolled or 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 
and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the Study Physician immediately, and a 
discussion should occur between the Study Physician and the Investigator regarding whether to 
continue or discontinue the patient from treatment. The Study Physician must ensure all 
decisions are appropriately documented.
3.5
Concomitant medications, restrictions during, and after the study
3.5.1
Concomitant medication
Information about any treatment in the 3 months prior to the date of the informed consent/assent, 
and all the concomitant treatments given during the study with reason for the treatment will be 
collected by the Investigator/authorized delegate at each visit (as shown in Table 1 and Table 2) 
and recorded in the eCRF.
Note: To satisfy inclusion criterion 6 (Section 3.1), the history of treatment with asthma 
therapies at the protocol designated doses prior to Visit 1 should be documented in source and 
recorded in the eCRF (see Section 4.1.1).
3.5.1.1
Background medication 
Background asthma medications should be maintained at stable doses from Visit 1 until the end 
of the study.  If changing the ICS/LABA dose or any other controller medication is judged as 
necessary by the Investigator or the patient’s healthcare provider (HCP), the justification should 
be documented in the source and the change in the doses should be reflected in the eCRF.
3.5.1.2
Rescue medication 
Short-acting bronchodilators (SABAs) may be used as rescue medication during the study in the 
event of a worsening of asthma symptoms.


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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3.5.2
Restrictions
3.5.2.1
Asthma medication restrictions
(a)
Changes to the patient’s background controller regimen are discouraged during 
the study unless judged medically necessary by the Investigator or the patient’s HCP; 
ideally such changes should be discussed with the AstraZeneca Study Physician. All 
changes in the patient’s background medication should be documented in source along 
with rational for change and recorded in eCRF.
Asthma exacerbations can be treated with oral or other systemic corticosteroids or 
other asthma therapies according to standard practice.
(b)
Asthma medication restrictions on the days of scheduled spirometry visits
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 the patient’s background 
medication are required prior to the spirometry as described below (also see Section 
5.1.2).
Screening Visit 2: Patients will be asked to withhold their usual bronchodilator 
medications on the morning of scheduled spirometry measurements.  Twice daily 
therapies containing bronchodilators should be withheld for 12- 24 hours; once daily 
therapies containing bronchodilators should be withheld for ≥24 hours for eligibility 
assessment.  In addition, SABA should not be used within 6 hours of these spirometry 
assessments.  If the patient has taken rescue SABA within 6 hours of the planned 
center visit spirometry, they can remain at the center until the 6-hour withholding time 
has been reached or return on another day within the visit window.
The patient’s usual asthma medications may be administered following completion of 
the screening lung function procedures.
3.5.2.2
Other medication restrictions
(a)
Use of immunosuppressive medication or administration of live/attenuated vaccines is 
not allowed. Topical administration of immunosuppressive medication may be 
allowed at the discretion of the Investigator after discussion with the AstraZeneca 
Study Physician. Refer to Section 3.2 exclusion criterion 13 for examples and further 
details.
(b)
Receipt of live attenuated vaccines within 30 days prior to randomization, during the 
treatment period, and for 16 weeks (5 half-lives) after the last dose of the IP is not 
allowed
(c)
Patient should not receive allergen immunotherapy injection(s) within 7 days of  IP
administration


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Edition Number 1.0
Date 14 December 2015
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(d)
When enrolling a patient who is on theophylline or other drugs with a narrow 
therapeutic range, the Investigator should ensure the levels of each of these 
medications must not exceed the upper limit of therapeutic range.  The Investigator 
will also be responsible for ensuring that these levels are regularly checked and 
documented as per local practice (see Table 1)
(e)
Patients should not take any other excluded medications.  A table with medication-
related restrictions is presented in Appendix G.
3.5.2.3
Other restrictions
(a)
Fertile and sexually active patients or their partners should use highly effective 
contraceptive methods throughout the study and at least for 16 weeks (5 half-lives) 
after last administration of the IP. Male patients should refrain from fathering child or 
donating sperm from the time of informed consent/assent, and for 16 weeks (5 half-
lives) after last dose of IP (see Section 3.1, inclusion criteria 3 and 4; and Section 
7.3.2)
(b)
Patients must abstain from donating blood and plasma from the time of informed 
consent/assent, 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 free to discontinue treatment at any time, without 
prejudice (see Section 3.7)
2.
Adverse event (AE) that in the opinion of the Investigator or Sponsor contraindicates 
further dosing
3.
Risk to patient as judged by the Investigator or AstraZeneca
4.
Eligibility requirement found not to be fulfilled (see Section 3.4).  Risk to patient as 
judged by the Investigator or AstraZeneca.
5.
Severe non-compliance with study protocol
6.
Pregnancy
7.
Lost to follow-up1
8.
Development of any study specific criteria for discontinuation:
                                                
1 Patient is considered lost to follow up when any of the following attempts of contact are failed: 3 attempts of either 
phone calls, faxes or emails; having sent one registered letter/certified mail; or one unsuccessful effort to check the 
vital status of the patient using publicly available sources, if allowed by local regulations.


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Edition Number 1.0
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(a) Anaphylactic reaction to the investigational product requiring administration of 
epinephrine
(b) Development of helminth parasitic infestations requiring hospitalization
(c) An asthma-related event requiring mechanical ventilation
All patients who prematurely discontinue investigational product should return to the study 
center and complete the procedures described for the Premature IP Discontinuation (IPD) visit 
within 4 weeks ±3 days.  
The reasons for premature discontinuation of IP should be recorded in the eCRF.
3.7
Withdrawal from the study
3.7.1
Screen failures 
Screening failures are patients who do not fulfill the eligibility criteria for the study and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded as 
‘Incorrect Enrollment’ (ie, patient does not meet the required inclusion/exclusion criteria). This 
reason for study withdrawal is only valid for screen failures (not randomized patients).
3.7.2
Withdrawal of the Informed Consent
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice 
to further treatment.
A patient/parent or legal guardian who withdraws consent/assent will always be asked about the 
reason(s) and the presence of any AE.  The Investigator will follow up AEs outside of the 
clinical study. The enrollment/randomization code of the withdrawn patient cannot be reused.
3.8
Withdrawal of informed consent for donated biological samples 
Samples taken for the evaluation of PK and ADA will be retained for repeat analysis of PK and 
ADA at AstraZeneca or designee for a maximum of 1 year following completion of the clinical 
study report (CSR).  If a patient/parent or legal guardian withdraws consent/assent to the use of 
blood samples, the samples will be disposed of/destroyed and the action documented.  If samples
are already analyzed, AstraZeneca is not obliged to destroy the results of this research.
The Principal Investigator or designee:
!
Ensures the local laboratory(ies) holding the samples is/are informed about the withdrawn 
consent/assent immediately and that samples are disposed/destroyed.
!
Ensures that the patient and AstraZeneca or designated CRO are informed about the 
sample disposal.


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent/assent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study center.


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Edition Number 1.0
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4.
STUDY PLAN AND PROCEDURES
Table 1
Study Plan – Enrollment, screening period
Assessment/ activity
Refer to
Screening
V1 
V2a
(W -4 to W -2)
Informed consent/assent
10.4
X
Inclusion/exclusion criteria
3.1/3.2
X
X
Medical and asthma history b
4.1.1
X
Complete physical examination
5.2.1.1
X
Weight, Height, BMI
5.3.1
X
Vital Signs
5.2.2
X
X
Local ECG 
5.2.3
X
Serum chemistry
5.2.4
X
Hematology 
5.2.4
X
Urinalysis
5.2.4
X
Serum concentration 
(theophylline)c
3.5.2.2
X
Serology (hepatitis B,C; HIV-1; 
HIV-2)
5.3.4.1
X
Serum pregnancy test
5.2.4.1
X
Pre-bronchodilator FEV1
d
5.1.2.1
X
X
Post-bronchodilator FEV1
d
5.1.2.1
X
X
Adverse events
7.1
X
X
Concomitant medication
3.5
X
X
a
Visit 1 and Visit 2 can be combined if the patient has the time and they have not taken SABAs for 6 hours or 
their long-acting bronchodilator-containing therapy for 12-24 hours. If spirometry/reversibility procedures are 
actually planned at Visit 1 as a convenience, then the ICF/assent must be signed prior to Visit 1 and prior to 
instructing the patient to withhold any medication.  
b
To include influenza vaccination history.
c
For patients on theophylline (see Section 3.5.2.2)
d
Pre- and post-bronchodilator spirometry can be done at Visit 1 OR Visit 2.  If patients do not demonstrate 
airway reversibility at either Visit 1 or Visit 2 and this is needed to qualify the patient for randomisation, the 
site should screen fail the patient.
BMI  Body mass index; D  Days; ECG  Electrocardiogram; HIV  Human immunodeficiency virus; V Visit; W 
Week.


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Table 2
Study Plan – Randomization, treatment period, and follow-up
Assessment/ activity
Refer 
to
Treatment
ARE/EOT
IPD
FU
Unsch
V3
V4
V5
V6
V7
W0
W4
W8
W12
W20
Visit window (days) a
±0
±3
±3
±3
±3
±3
Inclusion/exclusion criteria
3.1/3.2
X
Randomization
3.3
X
Administration of investigational 
productc
6.8
X
X
X
Administration of influenza 
vaccinee
X
Complete physical examination
5.2.1.1
X
X
X
X
Brief physical examination
5.2.1.2
X
X
X
Vital Signs
5.2.2
X
X
X
X
X
X
X
ACQ-6
5.3.3
X
X
X
X
X
Asthma exacerbation assessment
5.3.2
X
X
X
X
X
X
X
Adverse events
7.1
X
X
X
X
X
X
X
Concomitant medication
3.5
X
X
X
X
X
X
X
Serum chemistry
5.2.4
X
X
X
X
Hematology 
5.2.4
X
X
X
X
Urinalysis
5.2.4
X
X
X
X
Urine pregnancy test (dipstick) b
5.2.4.1
X
X
X
X
X
X
PK
5.3.5
X
X
X
X
X
ADA
5.3.7
X
X
X
X
X
Serum antibodies to influenza 
virus
Xd
X
a
All visits are to be scheduled from the date of randomization, not from the date of previous visit, except in the 
case of early discontinuation from IP (see Section 3.6 for details).
b
For WOCBP only, urine HCG test to be done at center on each study visit (before IP administration on V3-5)
c
In case of anaphylaxis additional samples to be taken (see Appendix F)
d
Blood draw for serum antibodies to influenza vaccine should occur prior to administration of influenza 
vaccine.
e
Influenza vaccine is to be administered at a different site than IP and site of injection noted.  Patient is to be 
observed for 15 minutes after injection and before administering IP


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Edition Number 1.0
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ACQ-6  Asthma Control Questionnaire 6; ADA  Anti-drug antibodies; ARE  Antibody response evaluation; D  
Days; EOT  End-of-treatment; FU  Follow-up; IPD  Premature investigational product discontinuation; PK  
Pharmacokinetics; UNSCH  Unscheduled; V  Visit; W  Week
4.1
Enrollment and screening period
4.1.1
Enrollment (Visit 1)
Each potential patient will provide written informed consent/assent as appropriate with local 
guidance prior to any study specific procedures and undergo assessments applicable for the visit 
(see Table 1).
Informed Consent Form (ICF)/assent must also be obtained prior to any Visit 1 procedures and 
prior to instructing the patient to withhold any medication.  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 asthma disease state and
the requisite level of severity based on background medications.  A record of physician-
diagnosed asthma is required in source documentation. A patient’s verbal history suggestive of 
asthma symptoms, but without supporting documentation, is not sufficient to satisfy these 
inclusion criteria.
Pulmonary function tests and assessment of reversibility (maximum post-bronchodilator [post-
BD] value of lung function) may be done if short- and long-acting bronchodilators have not been 
used for the patient as per Section 5.1.2.1.
Current, regular use of ICS prior to enrolment must be documented in the source. This 
documentation may be in the form of a recent, active medication list as per a health care 
provider (HCP) note, or filled prescriptions based on a pharmacy record.
4.1.2
Screening (Visit 2)
The screening period should be a minimum of 2 weeks in duration. Assessments applicable for 
the period are listed in Table 1.
Pulmonary function tests and assessment of reversibility (maximum post-BD value of lung 
function may be repeated at this visit, if pre-BD FEV1 > 50% predicted and reversibility was not 
performed or achieved at Visit 1 and are needed to qualify the patient for randomization see 
Section 5.1.2.1).
4.1.3
Re-screening
Re-screening is allowed only once for the patient.
Re-screened patient/parent or legal guardian should re-sign informed consent/assent on the re-
screening Visit 1. All procedures from the screening period should be repeated


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4.1.3.1
Procedures for patients who experience an exacerbation during screening/run-in
Patients who experience an asthma exacerbation during screening should be treated according to 
local medical practice and will be considered a screen failure. 
4.2
Randomized treatment period
Inclusion criteria at randomization will be confirmed at Week 0. Patients confirmed to be 
eligible will be randomised to either placebo or benralizumab 30 mg administered every 4 weeks 
throughout the treatment period.
Patients will have scheduled visits at 4-week intervals to complete protocol-specific assessments 
and IP administration as listed in Table 2.  Restrictions as set out in Section 3.5.2 will continue to 
apply throughout the treatment period.  In case of asthma worsening/exacerbation (see Section 
5.3.2), patients should be evaluated at the study center, when feasible.
Patients will receive 1 dose of seasonal influenza virus vaccine IM at Week 8.  Samples for 
evaluation of antibody response will be drawn at Week 8 (prior to administration of the vaccine)
and Week 12.
The End of Treatment (EOT) visit will be at Week 12, following the ARE assessments.
All patients who prematurely discontinue IP should return to the study center and complete the
procedures described for the Premature IP Discontinuation (IPD) visit within 4 weeks±3 days.
Completion or early termination of the treatment will be registered via IWRS/IVRS for each 
patient.
4.3
Follow-up period
Patients who complete the double-blind randomized treatment period will be followed for 12
weeks after the last dose of IP for the Week 20 follow-up visit.
5.
STUDY ASSESSMENTS AND TIMING OF PROCEDURES
5.1
Efficacy assessments
5.1.1
Humoral response to influenza vaccine
Serum HAI and MN antibody testing for antibody responses will be performed at Week 8 and 
Week 12.  Methods for these analyses will be described in the laboratory manual.
5.1.2
Spirometry
General requirements
Lung function (reversibility, FEV1 and FVC) at the study center will be measured by spirometry 
using the sites own equipment.  Spirometry should be performed by the Investigator or 


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authorized delegate according to American Thoracic Society/European Respiratory Society 
(ATS/ERS) guidelines (Miller et al 2005).  
Important!  Patients should withhold their SABA medication(s) for at least 6 hours prior to 
Visit 2 (see Section 3.5.2.1).  If Visits 1 and 2 are combined, bronchodilator therapy(ies) with or 
without ICS should be withheld for 12-24 hours depending on whether the patient is using twice-
or once-daily bronchodilator-containing therapy.  
Options for handling patients who have inadvertently taken their asthma medication within the 
restricted window are described in Section 3.5.2.
Spirometry technique
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to spirometry 
measurements. Patients should avoid eating a large meal for at least 2 hours prior to spirometry 
measurements at the 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 
enrollment 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. Mouthpieces of the same dimension and shape should be used by the 
patient from enrollment throughout 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 
will be recorded using the local spirometer at the site with predicted values derived from the 
reference value of choice, eg, NHANES III 2010, Quanjer et al 2012, etc. 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-bronchodilator spirometry will be performed to satisfy reversibility inclusion criterion 8.
The post-BD spirometry procedure should commence within 30±15 minutes according to the 
regimen for reversibility testing outlined in Section 5.1.2.1.


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Order of administration of usual asthma controller medication and investigational product
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-BD spirogram is complete for the reasons discussed above; usual asthma 
controller may be given after the post-BD spirogram. 
5.1.2.1
Reversibility test and post-BD FEV1 assessment
The procedure described in this section refers to the reversibility testing at Visit 1 or Visit 2.  
Bronchodilatation can be induced using albuterol (90 μg metered dose), salbutamol (100 μg 
metered dose) or levalbuterol (45 μg metered dose) up to a maximum of 8 inhalations).  It is 
highly recommended to use a spacer device for this procedure.  The algorithm for reversibility 
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 or 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
If the patient has not met reversibility criteria, an 
additional 2 inhalations of albuterol, salbutamol, or 
levalbuterol can be administered as single inhalations, 30 
seconds apart (for a total of 6 inhalations).  Second post-BD 
spirometry should be performed 15-20 minutes later.
4
If the patient still has not met reversibility criteria, 
an additional 2 inhalations of albuterol, salbutamol, or 
levalbuterol can be administered as single inhalations, 30 
seconds apart (for a total of 8 inhalations).  Second 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 puffscan be used if there is 
a concern about any effect on the patient’s heart rate, tremor, or safety.  The bronchodilator 
algorithm can be stopped at any time once a patient has met reversibility criteria.
The highest pre- and post-BD FEV1 should be used to determine reversibility. 


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Reversibility is calculated as follows:
% Reversibility=(post-BD FEV1- pre BD FEV1)×100
pre-BD FEV1
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at the study center for 
source data verification. The printout must be marked with the study code, enrollment code, date 
and time of measurement, and visit number.
5.2
Safety assessments
5.2.1
Physical examination 
Physical examination will be done in accordance with the schedules provided in Table 1 and 
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.
5.2.1.1
Complete physical examination 
The complete physical examination includes 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. 
5.2.1.2
Brief physical examination
The brief physical examination includes an assessment of the general appearance, abdomen, 
cardiovascular, and respiratory system. For the brief physical examination only information on 
whether the assessment was performed or not is to be recorded. 
5.2.2
Vital signs 
Pre-dose vital signs (pulse, blood pressure, respiration rate, and body temperature) are to be 
obtained in accordance with schedule provided in Table 1 and Table 2.
Body temperature is to be recorded in degrees Celsius.
5.2.3
Local electrocardiogram
ECG are to be performed in accordance with the schedule provided in Table 1.  
A 12-lead ECG will be taken in supine position, after the patient has been resting for at least 5 
minutes. The assessment should be performed before interventions with the patient (eg, 
spirometry).


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A standard ECG with a recommended paper speed of 25 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 Investigators interpretation and that provided by the ECG 
machine (if applicable), the Investigator’s interpretation takes precedence and should be noted on 
the printout and recorded in the eCRF.  Two identical copies of the ECG will be produced, 
quality checked, and kept in case of further need for re-evaluation.  The ECG printouts will be 
signed and dated by the Investigator and stored at the study center.  
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.
5.2.4
Safety laboratory tests
Safety laboratory tests (list provided in Table 3) will be performed in a central laboratory.  For 
information on methods of collection, assessment, labeling, storage, and shipment of samples 
please refer to the separate Laboratory Manual. Safety samples will be collected in accordance 
with the schedules provided in Table 1 and Table 2.
Hematology and urinalysis will be assessed in line with the schedules provided in Table 1 and 
Table 2.
Laboratory results should be reviewed by the Investigator/authorized delegate and evaluated for 
abnormalities. Any laboratory abnormalities considered significant in the 
Investigator’s/authorized delegate’s judgment should be reported as described in Section 7.1.3.
The copy of laboratory result report should be signed and dated by the Investigator and retained 
at the study center.
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)
Color
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Glucose
Calcium
Sodium
Red blood cell (RBC) 
count
Ketones


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Chloride
Total bilirubin
White blood cell (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, except for 
Visit 1 (see Section 6.6).
b
For patients on theophylline see Section  3.5.2.2.
5.2.4.1
Pregnancy test 
The following tests are applicable to female patients only and will be conducted in accordance 
with the schedules provided in Table 1 and Table 2:
!
Serum beta-hCG: To be done at screening Visit 1 only, for WOCBP (analyzed at central 
laboratory)  
!
Urine HCG: To be performed at the study center for WOCBP at each treatment visit 
(before IP administration on V3-5) using a dipstick. A positive urine test result must be 
confirmed with serum beta HCG.
5.3
Other assessments and procedures
5.3.1
Weight and height
Weight and height will be measured, and BMI calculated in accordance with schedules provided 
in Table 1 and Table 2. 
The patient’s weight will be recorded in kilograms; height will be recorded in centimeters.
5.3.2
Assessment of asthma exacerbations
In this study, an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic 
corticosteroids (or an increase in oral steroid dose for those already on systemic corticosteroids) and/or an 
in-patient hospitalization, and/or an emergency department visit.
An asthma exacerbation that occurs ≤7 days following the last dose of systemic steroids (oral, 
IM, IV), prescribed for a prior exacerbation, will be recorded as the same exacerbation event.
Asthma exacerbation information will be collected with a recall period of ‘since the last 
scheduled visit’.
5.3.3
Asthma Control Questionnaire (ACQ-6)
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (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.


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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). 
The questionnaire will be completed at the study center in accordance with schedule provided in
Table 2.
The Investigator’s clinical acumen and ACQ-6 results should be used in concert to determine 
whether or not the patient is well enough to continue in the current clinical study.
5.3.4
Other screening/run-in assessments
5.3.4.1
Serology
Hepatitis B surface antigen, hepatitis C antibody: To be done only at enrolment (Visit 1); test 
to be performed at central laboratory.
HIV-1 and HIV-2 antibodies: To be done only at enrolment (Visit 1); test to be performed at 
central laboratory.
Instructions for sample collection, processing, storage, and shipment can be found in the separate 
laboratory manual provided to the study centers.
5.3.5
Pharmacokinetics
For the PK analysis it is important that the date and time of each SC injection is recorded for 
each patient.
Instructions for sample collection, processing, storage, and shipment can be found in the separate 
laboratory manual provided to the centers.
Serum will be collected pre-dose at Visit 3, as well as at Visits 5 and 7, and the ARE/EOT, IPD
and FU visits, according to the study plan (see 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 repeat analysis of PK at AstraZeneca or designee for a 
maximum of 1 year following completion of the CSR.  
5.3.6
Pharmacodynamics 
Samples for the analysis of peripheral blood eosinophils will be performed in a central laboratory 
as part of the routine hematology assessment (complete blood count [CBC]). 


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5.3.7
Assessment of anti-benralizumab antibodies
Instructions for anti-drug antibodies (ADA) sample collection, processing, storage, and shipment 
can be found in the separate laboratory manual provided to the centers.
The ADA samples will be retained for repeat analysis of ADA at AstraZeneca or a designee for a 
maximum of 1 year following completion of the CSR.
Serum will be collected pre-dose at Visit 3, as well as at Visit 5, Visit 7, and the ARE/EOT, IPD 
and FU visits, to measure presence of ADA.  Samples will be collected according to the study 
plan (see Table 2).
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods. 
5.3.8
Handling of biological samples
5.3.8.1
Labeling and shipment of biological samples
The Principal Investigator is to ensure that samples are labeled 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 labeling, 
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.
Samples retained for further use will be registered in the AstraZeneca biobank system during the 
entire life cycle.


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6.
MANAGEMENT OF INVESTIGATIONAL PRODUCTS
6.1
Identity of investigational product(s)
All investigational products will be manufactured in accordance with Good Manufacturing 
Practice (GMP).
Benralizumab and placebo administered in the study will be a clear to opalescent, colorless to 
yellow solution (Table 4).
Table 4
Identity of investigational product
Investigational product
Dosage form and strength
Manufacturer
Benralizumab
30 mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1 mL fill volume
Cook Pharmica LLC on behalf of 
MedImmune
Placebo
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1 mL fill volume
Cook Pharmica LLC on behalf of 
MedImmune
6.2
Labeling
Labeling 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
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 (refer 
to IWRS/IVRS manual for further details).


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The quadrivalent influenza vaccine used in this study should be stored and administered in 
accordance with the package insert.
6.4
Accountability
The study drug provided for this study will be used only as directed in the study protocol.
The study personnel will account for all study drugs dispensed to the patient.
The monitor will account for all study drugs received at the center, unused study drugs and for 
appropriate destruction. Certificates of delivery, destruction, and/or return should be signed.
In the case of a malfunctioning accessorized prefilled syringe (APFS), the center should contact 
the study monitor to initiate a product complaint process according to applicable guidelines. 
6.5
Methods for assigning treatment groups
Randomization codes will be assigned strictly sequentially in each stratum (adolescents [12-17 
years of age] and young adults [18-21 years of age]) as patients become eligible for 
randomization.
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
The study will be conducted in double-blind fashion. 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 treatment allocation.
Placebo solution will be visually matched with benralizumab solution. Both benralizumab and 
placebo will be provided in an accessorized pre-filled syringe (APFS).


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Maintaining the blind to the patient’s blood eosinophil counts
While not entirely specific, patients on active benralizumab treatment are expected to have lower 
blood eosinophil counts than patients on placebo. Procedures to mitigate unblinding on this 
basis include:
!
From Week 0 on, monocyte counts will be redacted from central laboratory reports to 
prevent the Principal Investigator/designee from possibly deducing the ‘eosinophil + 
basophil’ contribution to the complete blood count.
!
If the Investigator orders any local safety laboratory assessments, the requested tests 
should be restricted to the question at hand. For example, if a hemoglobin is desired, the 
Investigator should avoid ordering a complete blood cell count with differential.
!
Handling of labs obtained during the treatment period but ordered outside of the 
clinical trial. 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. 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.
!
In cases where the Investigator requires an eosinophil, basophil, or monocyte count for 
managing safety issues he/she may order these tests. AstraZeneca should be notified of 
all such cases.
6.7
Methods for unblinding 
Individual treatment codes, indicating the treatment 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 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 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.


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6.8
Investigational product administration and treatment compliance
The administration of all study drugs (including investigational products) should be recorded in 
the appropriate sections of the CRF.
The IP (benralizumab) and influenza vaccine will be administered at the study center on 
treatment visits and within visit windows as specified in Table 2.
Before IP administration
Prior to each IP administration and administration of influenza vaccine:
!
Investigator/authorized delegate will assess injection sites as per standards of medical 
care
!
For WOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 5.2.4.1)
IP and influenza vaccine administration
The IP and influenza vaccine 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). At Week 8, the influenza vaccine should be injected at a site different than 
that of the IP injection site and should be administered prior to IP.  The injection site(s) must be 
recorded in the source documents and the eCRF at each treatment visit.
Figure 3
Injection sites and rotation scheme
Further details on IP administration are provided in the IP Handling Instruction. IP 
administration must be carried out in line with the Instruction.
After influenza vaccine administration
After influenza virus administration, the patient should be observed for a minimum of 15 
minutes for the appearance of any acute drug reaction and prior to administration of IP.


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Edition Number 1.0
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After IP administration
After IP administration the patient should be observed for a minimum of 2 hours for the 
appearance of any acute drug reactions.
Conditions requiring IP administration rescheduling 
If any of the following 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 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 (eg, epinephrine, H1 and H2 antihistamines, and corticosteroids), and medical 
equipment to treat acute anaphylactic reactions must be immediately available. Study personnel 
must be trained to recognize and treat anaphylaxis (Kroger et al 2011, Lieberman et al 2010). 
Management of anaphylaxis must be in accordance with current standard of care and clinical 
guidelines.  Details on anaphylaxis management are provided in Appendix F.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Simpson et al 2006). Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1.
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both, and at least 1 of the following: a) respiratory compromise or b) reduced 
blood pressure or symptoms of end-organ dysfunction
2.
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms
3.
Reduced blood pressure after exposure
Patients will have had a pre-assessment (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. Patients should also be observed in the clinic for 15
minutes after vaccine administration.  
In order to help understand the potential drug-relatedness of any acute reaction, a blood sample 
should be drawn as close as possible to the event for possible 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, ECG). 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, screening/run-in, 
treatment, washout, follow-up), that fulfills 1 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 any of the outcomes listed above
For further guidance on the definition of a SAE, see Appendix B.
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, parent, or legal guardian 
signs the informed consent/assent throughout the treatment period and including the follow-up 
period (through Week 20).
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 


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right to request additional information for any patient with ongoing AE(s)/SAE(s) at the end of 
the study, if judged necessary.
The requirement to follow-up AEs is not intended to delay database lock or production of the 
Clinical Study Report (CSR). These activities should proceed as planned with ongoing AEs if 
necessary.
Any follow-up information of ongoing SAEs after database lock will be reported to AstraZeneca.
7.1.3.3
Variables 
The following variables will be collect 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 a 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 a SAE.
7.1.3.4
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
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 


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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 
CSR. Deterioration as compared with baseline in protocol-mandated laboratory values and vital 
signs should therefore only be reported as AEs if they fulfill 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, anemia versus low hemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
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.
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, 
dyspnea, breathlessness and phlegm, will be recorded as AEs only when:
!
The sign or symptom is serious according to definitions, see Section 7.1.2
!
The patient discontinues the study due to the sign or symptom 
!
The sign or symptom is new to the patient or not consistent with the patient’s pre-existing 
asthma history (defined as within 1 year of Visit 1) as judged by the Investigator.
7.1.4
Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3xULN together with total bilirubin ≥2xULN may need to be 
reported as SAEs. Refer to Appendix D for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
7.1.5
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.


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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 Web-based Data 
Capture (WBDC) system, an automated email alert will be sent to the designated AstraZeneca 
representative.
If the WBDC system is not available, then the Investigator or other study center personnel is to 
report a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study center personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
7.2
Overdose
!
An overdose with associated AEs will be recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module
!
An overdose without associated symptoms will be reported on the Overdose CRF module 
only
If an overdose on an AstraZeneca study drug occurs in the course of the study, then Investigators 
or other center personnel will inform appropriate AstraZeneca representatives within 1 day ie, 
immediately but no later than 24 hours from when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, standard reporting timelines apply, see Section 7.1.5. For 
other overdoses, reporting should be done within 30 days.
7.3
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.


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7.3.1
Maternal exposure
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 7.1.5) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
7.3.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 16 
weeks (5 half-lives) following the last dose.
Pregnancy of the patient’s partners will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) should be followed up and documented for conceptions occurring from 
the date of the first administration of IP until 16 weeks (5 half-lives) after the last administration 
of IP.
8.
EVALUATION AND CALCULATION OF VARIABLES
8.1
Statistical considerations
!
All personnel involved with the analysis of the study will remain blinded until database 
lock
!
Analyses will be performed by AstraZeneca or its representatives
!
The SAP will be prepared prior to first patient randomized and any subsequent 
amendments will be documented, with final amendments completed prior to unblinding 
of the data


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Edition Number 1.0
Date 14 December 2015
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8.2
Sample size estimate
The study will have an estimated sample size of 50 patients in each treatment group.  No formal 
statistical hypotheses will be tested.  The sample size justification is based on the precision of the 
estimate of the GMTs (as GMTvaccine / GMTbenralizumab+vaccine).  With 50 patients per arm, the 90% 
CI for the GMT ratio would be 0.67 to 1.48, assuming an observed ratio of 1, and that the log 
(post-dose HAI antibody titer or post-dose MN antibody titer) is normally distributed with a 
standard deviation (SD) of 1.2 on the natural log scale (Langley et al 2013).  No formal statistical 
hypotheses will be tested.  
8.3
Definitions of analysis sets
Antibody endpoints to the influenza vaccine—strain-specific HAI and MN antibody GMFRs and 
GMTs—will be analyzed using the vaccine immunogenicity analysis set.  All remaining efficacy 
analyses will be performed using an Intent-to-Treat (ITT) approach based on the full analysis set. 
For consistency, demographic and baseline characteristics will be presented using the full 
analysis set. Safety objectives and ADA will be analyzed based on the Safety analysis set.
8.3.1
All patients analysis set
This analysis set will comprise all patients screened for the study and will be used for reporting 
of disposition and screening failures.
8.3.2
Full analysis set
All patients randomized and receiving any IP will be included in the full analysis set, irrespective 
of their protocol adherence and continued participation in the study. Patients will be analyzed 
according to their randomized treatment, irrespective of whether or not they have prematurely 
discontinued, according to the ITT principle. Patients who withdraw consent to participate in the 
study will be included up to the date of their study termination.
8.3.3
Vaccine immunogenicity analysis set 
The vaccine immunogenicity analysis set will include all randomized subjects who received at 
least 1 dose of planned IP (ie, 1 dose of influenza vaccine, and plus 1 dose of benralizumab or 
placebo), had pre- and post-dose HAI and MN antibody measurements, and had no protocol 
deviation judged to have the potential to interfere with the generation or interpretation of an 
antibody response.  The analyses conducted using this analysis set will be based on the actual 
treatment received.  Protocol deviations will be reviewed by the study team before unblinding.
8.3.4
Safety analysis set
All patients who received at least 1 dose of IP will be included in the safety analysis set. Patients 
will be classified according to the treatment they actually received. A patient who has on one or 
several occasions received active treatment will be classified as active. All safety and ADA 
summaries will be based on this analysis set.


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8.3.5
Pharmacokinetic analysis set
All patients who received benralizumab and from whom PK blood samples were obtained are 
assumed not to be affected by factors such as protocol violations. Those patients who had at 
least 1 quantifiable serum PK 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 double-blind treatment period, defined as the 
period after administration of randomized IP at Week 0 and the conclusion of Week 12 (EOT)
visit, inclusive.
8.4.1.1
Humoral immune response following seasonal influenza virus vaccination
The benralizumab versus placebo humoral immune responses following seasonal influenza virus 
vaccination will be assessed by
Primary objective:
!
Post-dose strain-specific HAI antibody geometric mean folder rises (GMFRs) from 
Week 8
!
Post-dose strain-specific HAI antibody geometric mean titers (GMTs) obtained at 
Week 12 
!
Proportion of patients who experience a strain-specific post-dose antibody response at 
Week 12 with antibody response defined as a ≥4-fold rise in HAI antibody titer from 
Week 8
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer ≥40 at 
Week 12
Secondary objectives:
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer ≥320 at 
Week 12
!
Post-dose strain-specific microneutralization (MN) antibody GMFRs from Week 8
!
Post-dose strain-specific serum MN antibody GMTs obtained at Week 12 
!
Proportion of patients who experience a strain-specific post-dose antibody response at 
Week 12 with antibody response defined as a ≥4-fold rise in MN antibody titer from 
Week 8
8.4.2
Calculation or derivation of safety variable(s)
The following safety data will be collected: vital signs, physical examination, hematology, 
clinical chemistry, urinalysis, and reported AEs.


Clinical Study Protocol
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Edition Number 1.0
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Change from baseline (Week 0) 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 (ACQ-6)
The outcome variable for ACQ-6 will be the change in mean score from baseline (Week 0) to 
EOT (Week 12).
Asthma control responder status will be categorized according to the following limits (Juniper et 
al 2005):
!
ACQ-6 (EOT) ≤0.75 → Well controlled
!
0.75< ACQ-6 (EOT) <1.5 → Partly controlled
!
ACQ-6 (EOT) ≥1.5 → Not well controlled
8.4.4
Calculation or derivation of pharmacokinetic variables
Due to the limited sampling schedule, the PK assessment will be primarily based on the observed 
steady-state serum trough (pre-dose) concentrations, Ctrough. Empirical evaluation of potential 
impact of demographic covariates and ADA on Ctrough will be conducted. The PK data and 
parameters from this study will be reported in the CSR.
8.4.5
Calculation or derivation of benralizumab immunogenicity variables
ADA assessments will be conducted utilizing a tiered approach (screen, confirm, titer). 
8.5
Methods for statistical analyses
The analysis of the efficacy endpoints will include all data captured during the 16-week 
treatment period, including follow-up (where applicable), unless the patient or their parent/legal 
guardian withdraws consent/assent to study participation, regardless of whether study treatment 
was prematurely discontinued, or delayed, and/or irrespective of protocol adherence. 
Demography and baseline characteristics will be summarized by treatment group for the full 
analysis set. 
8.5.1
Analysis methods for antibody endpoints
Geometric mean fold rises for the HAI and MN antibody measurements are defined as: 
GMFR=antilogz (mean [logz x])
Where x is the post-dose HAI or MN antibody titer fold rise from Week 8 and z is the natural 
logarithm.
Geometric mean titers for the HAI and MN antibody measurements are defined as: 


Clinical Study Protocol
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Edition Number 1.0
Date 14 December 2015
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GMT=antilogz (mean [logz y]) 
Where y is the HAI or MN antibody titer and z is the natural logarithm. 
The analysis of the antibody endpoints—strain-specific GMFRs and GMTs—will be performed 
on the vaccine immunogenicity analysis set.  GMFRs and GMTs will be summarized by 
treatment group.  For GMFR and GMT, the geometric least square mean ratio between treatment 
groups (placebo/benralizumab) will be calculated via an ANCOVA model on the log-
transformed variable, adjusting for treatment group.  The least square geometric mean ratio will 
be provided with associated 90% CI. 
Antibody response is defined as a ≥4-fold rise in HAI or MN antibody from Week 8.  The 
proportion of patients who experience a post-dose antibody response at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment group. 
The proportion of subjects who achieve a post-dose HAI antibody titer ≥40 at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarised by treatment group. 
The proportion of patients who achieve a post-dose HAI antibody titer ≥320 at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment group.
No interim blinded review is planned.
8.5.2
Analysis methods for non-immunogenicity endpoints
Change from baseline in ACQ-6 score will be summarized by timepoint. ACQ-6 asthma control 
responder status will be summarized at Week 12 (EOT) by treatment group according to the 
following limits:
!
ACQ-6 (EOT) ≤0.75 → Well controlled
!
0.75< ACQ-6 (EOT) <1.5 → Partly controlled
!
ACQ-6 (EOT) ≥1.5 → Not well controlled
All analyses will be based on the full analysis set. 
8.5.3
Analysis methods for safety variables
8.5.3.1
Asthma exacerbations
The number of asthma exacerbations and total follow-up time will be presented for each 
treatment group.  This analysis will be based on the safety analysis set.
8.5.3.2
Other safety variables
AEs will be summarized by means of counts by study period (on-study, on-treatment, and 
follow-up period). AEs will be listed for each patient and summarised by System Organ Class 
(SOC) and Preferred Term (PT) assigned to the event by MedDRA.


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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 will be examined 
at each visit by endpoint and frequencies of clinically noteworthy values will also be presented. 
Shifts from normal to abnormal between baseline and follow-up will be evaluated for the 
physical examination.
8.5.3.3
Analysis methods for pharmacokinetic variables
The PK analyses will be performed at or under the guidance of AstraZeneca Research and 
Development.
Benralizumab serum concentrations will be summarized using descriptive statistics at each visit 
by treatment group. 
8.5.3.4
Analysis method for benralizumab immunogenicity variables
Anti-drug antibodies (ADA) to benralizumab will be summarized using descriptive statistics at 
each visit by treatment group. 
8.5.4
Interim analysis
There is neither an unblinded data review nor interim analysis planned for this study.
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 utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
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)


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Edition Number 1.0
Date 14 December 2015
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!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed
!
Perform source data verification (a comparison of the data in the CRFs with the patient’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating patients. This will require 
direct access to all original records for each patient (eg, clinic charts)
!
Ensure withdrawal of informed consent/assent 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
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 eCRF 
instructions. The eCRF instructions will also guide the study center in performing data entry.
Data entered in the WBDC system will be immediately saved to a central database and changes 
tracked to provide an audit trail. The data will then be source data verified, reviewed/queried 
and updated as needed. The data will be validated as defined in the Data Management Plan. The 
Investigator will ensure that data are recorded on the eCRFs as specified in the CSP and in 
accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the CSA. The Investigator will sign the 
completed eCRFs. A copy of the completed eCRFs will be archived at the study center.
9.2.3
Study agreements
The Principal Investigator at each/the study center should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement (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 CSA shall prevail.
Agreements between AstraZeneca or designated CRO and the Principal Investigator should be in 
place before any study-related procedures can take place, or patients are enrolled.


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9.2.4
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as the last visit of the last patient undergoing the study.
The study is expected to start in Q3 2016 and to end by Q1 2017.
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 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 Quintiles staff according to the Data Management Plan.
Adverse events 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 Quintiles.
The Inform 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 eCRFs 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 eCRFs. A copy of the completed eCRFs will be archived at the study center.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation/Good 
Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics 
and Human Biological Samples.
10.2
Patient data protection
The ICF/assent will incorporate or, in some cases, be accompanied by a separate document 
incorporating wording that complies with relevant data protection and privacy legislation.


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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10.3
Ethics and regulatory review
An Ethics Committee (EC) should approve the final study protocol, including the final version of 
the ICF/assent 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 EC and to the
study center staff.
The opinion of the EC should be given in writing. The Investigator should submit the written 
approval to AstraZeneca or designated CRO before enrollment of any patient into the study. 
The EC should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the ICF/assent that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the EC annually.
Before enrollment of any patient into the study, the final study protocol, including the final 
version of the ICF/assent is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca or designated CRO will handle the distribution of any of these documents to the 
national regulatory authorities.
AstraZeneca or designated CRO will provide Regulatory Authorities, ECs 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 ECs/Institutional Review Board 
(IRB) with reports of any serious and unexpected adverse drug reactions from any other study 
conducted with the investigational product. AstraZeneca or designated CRO will provide this 
information to the Principal Investigator so that he/she can meet these reporting requirements.
10.4
Informed consent
The Principal Investigator(s) at each study center will:
!
Ensure each patient 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 ICF/assent 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.


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Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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!
Ensure each patient, parent, or legal guardian provides signed and dated Informed 
Consent before conducting any procedure specifically for the study.
!
Ensure the original, signed Informed Consent(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 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 
coordinating Investigator and AstraZeneca or designated CRO.
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 CSP).
The amendment is to be approved by the relevant EC and if applicable, also the national 
regulatory authority approval, before implementation. Local requirements are to be followed for 
revised protocols.
AstraZeneca or designated CRO will distribute any subsequent amendments and new versions of 
the protocol to each Principal Investigator(s). For distribution to EC see Section 10.3.
If a protocol amendment requires a change to a study center’s ICF/assent, AstraZeneca and the 
study center’s EC are to approve the revised ICF/assent before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved by 
each EC.
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 , 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.


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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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 2014
Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an 
anti-interleukin-5 receptor alpha monoclonal antibody, for uncontrolled eosinophilic asthma. 
Lancet Respir Med. 2014 Oct 09 (online).
Castro et al 2015
Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al.  Reslizumab
for inadequately controlled asthma with elevated blood eosinophil counts: results from two 
multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir 
Med. 2015 May;3(5):355-66.
CDC 2014
Centers for Disease Control and Prevention (CDC). U.S. Department of Health and Human 
Services. Vaccine information statement: Influenza vaccine (Flu vaccine, inactivated or 
recombinant) 2014-2015. 2014 (19 Aug):42 U.S.C.§ 300aa-26. Available at: 
http://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.pdf.
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.
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.


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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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.
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.
Kroger et al 2011
Kroger AT, Sumay CV, Pickering LK, Atkinson WL. General recommendations on 
immunization: Recommendations of the Advisory Committee on Immunizations Practices 
(ACIP). Morbidity and Mortality Weekly Report (MMWR). 2011;60(RR02):1-60.
Langley et al 2013
Langley JM, Matinez AC, Chatterjee A, Halperin SA, McNeil S, Reisinger KS, et al. 
Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: A Phase 
III randomized controlled trial in children. J Infect Dis. 2013 (15 August);208:544-553.
Laviolette et al 2013
Laviolette, M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of 
benralizumab on airway eosinophils in asthma with sputum eosinophilia. J Allergy Clin 
Immunol. 2013 November; 132(5):1086-1096.
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.


Clinical Study Protocol
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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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. 
NHANES III 2010
Centers for Disease Control and Prevention. NHANES III. Spirometry Procedure Manual. Office 
of Information Service, CDC/National Center for Health Statistics. 2010 Nov. Available at: 
http://www.cdc.gov/nchs/nhanes/nh3rrm.htm.
Ortega et al 2014
Ortega HG, Liu MC, Pavord ID, Brusselle GG, Fitzgerald JM, Chetta A, et al. Mepolizumab 
treatement in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 
25;371(13):1198-207.
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 


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Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
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marrow, and the characterization of phenotype and peroxidase of human basophiles. Cytometry. 
1999 Mar 1;35(3):249-59.
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 A
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
Protocol Dated
14 December 2015
Appendix A 
Signatures










Clinical Study Protocol Appendix B
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
Appendix B
Additional Safety Information


Clinical Study Protocol Appendix B
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
2(3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of such events are:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse.


Clinical Study Protocol Appendix B
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
3(3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties?
!
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.


Clinical Study Protocol Appendix C
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance
Document


Clinical Study Protocol Appendix C
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
2(3)
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).  For transport purposes the classification of infectious substances according to risk
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable


Clinical Study Protocol Appendix C
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
3(3)
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.


Clinical Study Protocol Appendix D
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
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 D3250C00033
Edition Number 1.0
Date 14 December 2015
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 D3250C00033
Edition Number 1.0
Date 14 December 2015
3(7)
1.
INTRODUCTION
During the course of the study the Investigator will remain vigilant for increases in liver biochemistry.  
The investigator is responsible for determining whether a patient meets potential Hy’s Law (PHL) 
criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are met.  HL criteria 
are met if there is no alternative explanation for the elevations in liver biochemistry other than Drug 
Induced Liver Injury (DILI) caused by the Investigational Medicinal Product (IMP) (FDA Guidance 
2009).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting Adverse 
Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review and assessment 
in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of Normal 
(ULN) and Total Bilirubin (TBL) ≥ 2xULN at any point during the study irrespective of an increase in 
Alkaline Phosphatase (ALP).  The elevations do not have to occur at the same time or within a specified 
time frame.
Hy’s Law (HL)
AST or ALT ≥ 3x ULN and TBL ≥ 2xULN, where no other reason, other than the IMP, can be found to 
explain the combination of increases, eg, elevated ALP indicating cholestasis, viral hepatitis, another 
drug.  The elevations do not have to occur at the same time or within a specified time frame.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of laboratory data 
for any patient who meets any of the following identification criteria in isolation or in combination:
!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca representative).


Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
4(7)
The Investigator will also remain vigilant for any local laboratory reports where the identification 
criteria are met, where this is the case the Investigator will:
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator will 
without delay:
!
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an approach for 
the study patients’ follow-up and the continuous review of data.  Subsequent to this contact the 
Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures


Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
5(7)
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study Physician 
contacts the Investigator in order to review available data and agree on whether there is an alternative 
explanation for meeting PHL criteria other than DILI caused by the IMP.  The AstraZeneca Medical 
Science Director and Global Safety Physician will also be involved in this review together with other 
subject matter experts as appropriate.
According to the outcome of the review and assessment, the Investigator will follow the instructions 
below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a determination of 
whether the alternative explanation is an AE will be made and subsequently whether the AE meets the 
criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations other 
than the IMP:
!
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to assess 
whether or not the case meets the criteria for HL, then it is assumed that there is no alternative 
explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review


Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
6(7)
6.
ACTIONS REQUIRED WHEN POTENTIAL HY’S LAW
CRITERIA ARE MET BEFORE AND AFTER STARTING STUDY 
TREATMENT 
This section is applicable to patients who meet PHL criteria on study treatment having previously met 
PHL criteria at a study visit prior to starting study treatment.
At the first on study treatment occurrence of PHL criteria being, even if there has been no significant 
change the patient’s condition# compared with pre-study treatment visits, the Investigator will:
!
Notify the AstraZeneca representative who will inform the central Study Team. 
!
Follow the subsequent process described is Section 4.2 of this Appendix.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in combination, or 
a clinically relevant change in associated symptoms. The determination of whether there has been a 
significant change will be at the discretion of the Investigator, this may be in consultation with the Study 
Physician if there is any uncertainty.
7.
ACTIONS REQUIRED FOR REPEAT EPISODES OF 
POTENTIAL HY’S LAW
This section is applicable when a patient meets PHL criteria on study treatment and has already met PHL 
criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of PHL is based 
on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being met and 
answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met 
chronic or progressing malignant disease << or did the patient meet PHL criteria prior 
to starting study treatment and at their first on study treatment visit as described in 
Section 6 >>?
If No: follow the process described in Section 4.2 of this Appendix
If Yes:
Determine if there has been a significant change in the patient’s condition# compared with when PHL 
criteria were previously met
!
If there is no significant change no action is required


Clinical Study Protocol Appendix D
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
7(7)
!
If there is a significant change follow the process described in Section 4.2 of this 
Appendix
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this may 
be in consultation with the Study Physician if there is any uncertainty.
8.
REFERENCES
FDA Guidance 2009
Food and Drug Administration Guidance for Industry: Drug-induced liver injury: Premarketing clinical 
evaluation. US Department of Health and Human Services, FDA Center for Drug Evaluation and 
Research and Center for Biologics Evaluation and Research, July 2009.


Clinical Study Protocol Appendix E
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
Appendix E
Background Therapy Equivalence Table


Clinical Study Protocol Appendix E
Drug Substance Benralizumab (MEDI-563)
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
2(2)
Estimated daily dosage for inhaled corticosteroids *
Asthma Therapy 
Total Daily Dose (μg/day) 
Inhaled Corticosteroid
Medium
High
Beclomethasone dipropionate 
>500 - 1000
>1000 
Beclomethasone HFA
>200 - 400
>400
Beclomethasone dipropionate (Fostair)
>200 - 400
>400
Ciclesonide 
>160 - 320
>320
Triamcinolone acetonide 
>1000 - 2000
>2000
Flunisolide 
>1000 - 2000
>2000
Fluticasone propionate 
>250 - 500
>500
Fluticasone propionate HFA
>250 - 500
>500
Budesonide
Budesonide, if as delivered dose (eg 
Symbicort)
>400 to 800
>320 to <640
>800 
≥640
Mometasone furoate 
>220 - 440
>440


Clinical Study Protocol Appendix F
Drug Substance
Benralizumab (MEDI-563)
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
Appendix F
Anaphylaxis: signs and symptoms, management


Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
2(5)
1.
INTRODUCTION
As with any antibody, allergic reactions to dose administration are possible.  The World Health 
Organization has categorized anaphylaxis into 2 subgroups, which are clinically indistinguishable: 
immunologic [IgE-mediated and non-IgE-mediated (eg, IgG and immune complex mediated) and 
nonimmunologic (Johansson et al 2004).  The clinical criteria for defining anaphylaxis for this study are 
listed in section 2.  A guide to the signs and symptoms and management of acute anaphylaxis is provided 
in section 3.  Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical 
equipment to treat anaphylactic reactions must be immediately available at study sites, and study 
personnel should be trained to recognize and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the patient as soon as possible after 
the event, at 60 minutes ± 30 minutes after the event, and at discharge for analysis of serum tryptase.
2.
CLINICAL CRITERIA FOR DEFINING ANAPHYLAXIS AND 
IMMUNE COMPLEX DISEASE
Anaphylaxis
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-
uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a)
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(b)
Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence).
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
(a)
Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b)
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(c)
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence).
(d)
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).


Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
3(5)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
patient’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of antigen-antibody or 
antigen-antibody-complement complexes on cell surfaces, with subsequent involvement of breakdown 
products of complement, platelets, and polymorphonuclear leukocytes, and development of vasculitis; 
serum sickness and nephritis is common.
3.
SIGNS AND SYMPTOMS AND MANAGEMENT OF ACUTE 
ANAPHYLAXIS
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or all of the 
following signs and symptoms occur: 
!
Diffuse erythema
!
Pruritus
!
Urticaria and/or angioedema
!
Bronchospasm
!
Laryngeal edema
!
Hypotension
!
Cardiac arrhythmias
!
Feeling of impending doom
!
Unconsciousness
!
Shock
Other earlier or concomitant signs and symptoms can include:
!
Itchy nose, eyes, pharynx, genitalia, palms, and soles
!
Rhinorrhea
!
Change in voice
!
Metallic taste
!
Nausea, vomiting, diarrhea, abdominal cramps and bloating


Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
4(5)
!
Lightheadedness
!
Headache
!
Uterine cramps
!
Generalized warmth
4.
MANAGEMENT OF ACUTE ANAPHYLAXIS
4.1
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation.
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as necessary, 
depending on the presenting signs and symptoms of anaphylaxis, to control signs and symptoms 
and prevent progression to more severe symptoms such as respiratory distress, hypotension, 
shock and unconsciousness.
4.2
Possibly appropriate, subsequent measures depending on response to 
epinephrine
(a)
Place patient in recumbent position and elevate lower extremities.
(b)
Establish and maintain airway.
(c)
Administer oxygen.
(d)
Establish venous access.
(e)
Normal saline IV for fluid replacement.
4.3
Specific measures to consider after epinephrine injections, where 
appropriate
(a)
Consider epinephrine infusion.
(b)
Consider H1 and H2 antihistamines.
(c)
Consider nebulized β2 agonist [eg, albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
(d)
Consider systemic corticosteroids.
(e)
Consider vasopressor (e.g. dopamine).
(f)
Consider glucagon for patient taking b-blocker.
(g)
Consider atropine for symptomatic bradycardia.
(h)
Consider transportation to an emergency department or an intensive care facility.


Clinical Study Protocol Appendix F
Drug Substance Benralizumab (MEDI-563) 
Study Code D3250C00033
Edition Number 1.0
Date 14 December 2015
5(5)
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary.
Adapted from Kemp et al 2008.
5.
REFERENCES
Johansson et al 2004
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for 
allergy for global use: Report of the Nomenclature Review Committee of the World Allergy 
Organization, October 2003. J Allergy Clin Immunol. 2004 May;113(5):832-6.
Kemp et al 2008
Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc Committee on Epinephrine in 
Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy 
Organization. Allergy. 2008; 63(8):1061-70.


Clinical Study Protocol Appendix G
Drug Substance
Benralizumab (MEDI-563) 
Study Code
D3250C00033
Edition Number
1.0
Date
14 December 2015
Appendix G
Restricted and prohibited medications


Clinical Study Protocol Appendix G
Drug Substance Benralizumab (MEDI-563) Study
Code D3250C00033
Edition Number 1.0
Date 14 December 2015
2
PROHIBITED AND RESTRICTED MEDICATIONS
Medication restrictions
Table 1
Medication
Prohibited/restricted
Details
Live Attenuated Vaccines
Prohibited
Not allowed 30 days prior to
randomization; during treatment 
period, and 16 weeks (5 half-lives) 
after the last dose of IP.
Influenza vaccine
Restricted
Receipt of an influenza vaccine within 
90 days prior to randomization or during 
the study period (except for influenza 
vaccine at V5 per protocol).
Inactive/killed vaccinations
(not applicable for inactive
influenza vaccine)
Restricted
Allowed provided they are not
administered within within 1 week 
before/after any IP administration.
Any immunomodulators or
immunosuppressives
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 of IP.
Blood products or
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to date of
ICF, and 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, or
during treatment period.
Allergen Immunotherapy
Restricted
Allowed if on stable therapy for at
least 30 days prior to date of ICF; no 
anticipated changed during treatment.
period.

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D3250C00033
Edition Number
2.0
Date
06 March 2017
A Multicenter, Randomized, Double-blind, Parallel Group, 
Placebo-controlled, Phase 3b Study to Evaluate the Potential Effect of 
Benralizumab on the Humoral Immune Response to the Seasonal Influenza 
Vaccination in Adolescent and Young Adult Patients with Severe Asthma 
(ALIZE)


Statistical Analysis Plan 
D3250C00033
Edition Number 2.0
06 March 2017
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Statistical Analysis Plan 
D3250C00033
Edition Number 2.0
06 March 2017
3


Statistical Analysis Plan 
D3250C00033
Edition Number 2.0
06 March 2017
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Statistical Analysis Plan 
D3250C00033
Edition Number 2.0
06 March 2017
5
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
TABLE OF CONTENTS.........................................................................................5
LIST OF ABBREVIATIONS..................................................................................8
AMENDMENT HISTORY ...................................................................................10
1.
STUDY DETAILS.................................................................................................11
1.1
Study objectives.....................................................................................................11
1.1.1
Primary objectives .................................................................................................11
1.1.2
Secondary objectives .............................................................................................12
1.1.3
Safety objectives ....................................................................................................12
1.2
Study design...........................................................................................................12
1.2.1
Duration of the Study.............................................................................................13
1.2.1.1
Enrollment (Visit 1), Screening (Visit 2), and Re-screening.................................13
1.2.1.2
Randomization treatment period............................................................................13
1.2.1.3
Follow-up Period ...................................................................................................13
1.3
Number of subjects ................................................................................................13
2.
ANALYSIS SETS .................................................................................................14
2.1
Definition of analysis sets......................................................................................14
2.1.1
All patients analysis set..........................................................................................14
2.1.2
Full analysis set (FAS)...........................................................................................14
2.1.3
Vaccine immunogenicity analysis set....................................................................14
2.1.4
Safety analysis set..................................................................................................14
2.1.5
Pharmacokinetic analysis set .................................................................................14
2.2
Violations and deviations.......................................................................................15
2.2.1
Randomization issues.............................................................................................15
2.3
Visit window definitions........................................................................................15
3.
PRIMARY AND SECONDARY VARIABLES...................................................16
3.1
Efficacy variables...................................................................................................16
3.1.1
Humoral immune response following seasonal influenza virus vaccination.........16
3.1.1.1
Primary outcome variables.....................................................................................16
3.1.1.2
Secondary outcome variables.................................................................................16
3.1.2
Patient-reported outcome variables (PRO) ............................................................17
3.1.2.1
Secondary variable: Asthma Control Questionnaire (ACQ-6) ..............................17
3.2
Safety variables......................................................................................................17
3.2.1
Spirometry (Baseline and Historical).....................................................................17
3.2.2
Adverse Events (AE) .............................................................................................18


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3.2.3
Prior/concomitant medication................................................................................20
3.2.4
Safety assessments.................................................................................................21
3.2.4.1
Clinical laboratory safety assessments...................................................................21
3.2.4.2
Serology .................................................................................................................22
3.2.4.3
Vital signs ..............................................................................................................22
3.2.4.4
Physical examination .............................................................................................23
3.2.4.5
Local electrocardiogram ........................................................................................23
3.2.5
Other safety assessments........................................................................................23
3.2.5.1
Weight and height..................................................................................................23
3.2.5.2
Assessment of asthma exacerbation.......................................................................24
3.2.5.3
Benralizumab immunogenicity variables ..............................................................24
3.3
Pharmacokinetic variables .....................................................................................24
3.4
Pharmacodynamics ................................................................................................25
4.
ANALYSIS METHODS .......................................................................................25
4.1
General principles ..................................................................................................25
4.1.1
General methodology.............................................................................................25
4.1.2
Vaccine immunogenicity data................................................................................25
4.1.3
Patient-reported outcome data ...............................................................................25
4.1.4
Handling of safety data ..........................................................................................26
4.1.5
Handling of PK concentration data........................................................................26
4.1.6
Handling of missing data .......................................................................................26
4.2
Analysis methods...................................................................................................27
4.2.1
Analysis of patient characteristics..........................................................................27
4.2.1.1
Patient disposition..................................................................................................27
4.2.1.2
Important protocol deviations................................................................................27
4.2.1.3
Demographic and other baseline characteristics....................................................27
4.2.1.4
Concomitant treatments .........................................................................................28
4.2.1.5
Past and current medical conditions/diseases ........................................................28
4.2.2
Spirometry (baseline and historical) ......................................................................28
4.2.3
Efficacy analysis (primary and secondary variables) ............................................28
4.2.3.1
Primary and secondary variables: Humoral immune response following 
seasonal influenza virus vaccination......................................................................28
4.2.4
Patient-reported outcome (PRO) variables ............................................................30
4.2.4.1
Secondary variable: Asthma Control Questionnaire (ACQ-6) ..............................30
4.2.5
Safety and tolerability analysis ..............................................................................30
4.2.5.1
Adverse events.......................................................................................................30
4.2.5.2
Clinical laboratory .................................................................................................31
4.2.5.3
Vital signs ..............................................................................................................31
4.2.5.4
Assessment of asthma exacerbation.......................................................................31
4.2.5.5
Benralizumab immunogenicity variables analysis.................................................31
4.2.6
Pharmacokinetic variables analysis .......................................................................32
5.
INTERIM ANALYSES.........................................................................................32


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6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................32
7.
REFERENCES ......................................................................................................32
8.
APPENDIX............................................................................................................33
8.1
Appendix A: Important Protocol Deviations .........................................................33
8.2
Appendix B: Partial Date Conventions for Adverse Events..................................34
8.3
Appendix C: Algorithm for Prior/Concomitant Medications:...............................35
LIST OF TABLES
Table 1
Visit windows for assessments conducted every 4 weeks........................15
Table 2
Visit windows for laboratory assessments................................................15
Table 3
Vital signs reference ranges......................................................................23
Table 8.1.1
Definition of important protocol deviations.............................................33


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LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-drug antibodies
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANCOVA
Analysis of covariance
ARE
Antibody Response Evaluation
AST
Aspartate transaminase
ATS/ERS
American Thoracic Society/European Respiratory Society
Beta-HCG
Beta-human chorionic gonadotropin
BMI
Body mass index
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
CO2
Carbon dioxide
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
EOT
End of treatment
FAS
Full analysis set
FEV1
Forced expiratory volume in 1 second
FU
Follow-up
FVC
Forced vital capacity
Gamma-GT
Gamma-glutamyl transpeptidase
GMFR
Geometric mean fold rise
GMT
Geometric mean titer
GSD
Geometric standard deviation
HAI
Hemagglutination-inhibition
HCG
Human chorionic gonadotropin


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Abbreviation or 
special term
Explanation
HIV
Human immunodeficiency virus
HPF
High power field
ICF
Informed consent form
ICS
Inhaled corticosteroids
IM
Inter-muscular
IP
Investigational product
IPD
Premature IP Discontinuation
ITT
Intent-to-Treat
LABA
Long-acting β2 agonists
LSmeans
Least-square means
MedDRA
Medical Dictionary for Regulatory Activities
MN
Microneutralization antibodies to influenza vaccine
MVC
Mean corpuscular volume
PK
Pharmacokinetic
PT
MedDRA Preferred term
Post-BD
Post-bronchodilator
Pre-BD
Pre-bronchodilator
PRO
Patient-Reported Outcome
PT
Preferred term
RBC
Red blood cell
SABA
Short-acting β2 agonists
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SI
Standard international
SOC
System organ class
ULN
Upper limit of normal
WBC
White blood cell
WOCBP
Women of childbearing potential


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Edition Number 2.0
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AMENDMENT HISTORY
Date
Brief description of change
N/A
23Jan2017
Updated safety and tolerability analysis text based on updates to the table, 
listing, and figure mock shells. Updated the definition of the efficacy analysis 
set.


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1.
STUDY DETAILS
The study is a randomized, double-blind, parallel group, placebo-controlled study designed to 
investigate the potential effect of a fixed dose of benralizumab (30 mg) administered 
subcutaneously (SC) on humoral immune response following seasonal influenza virus 
vaccination.
This statistical analysis plan (SAP) is based on version 1.0 of the clinical study protocol 
(CSP – 14 December 2015) for the study D3250C00033.
1.1
Study objectives
1.1.1
Primary objectives
Objective
Endpoint
To evaluate the potential effect of 
benralizumab on the humoral 
immune response following 
seasonal influenza virus 
vaccination in adolescent and 
young adult patients with severe 
asthma
!
Post-dose strain-specific hemagglutination-
inhibition (HAI) antibody geometric mean fold 
rises (GMFRs) from Week 8
!
Post-dose strain-specific serum HAI antibody 
geometric meant titers (GMTs) obtained at Week 
12
!
Proportion of patients who experience a strain-
specific post-dose antibody response at Week 12 
with antibody response defined as a ≥4-fold rise 
in HAI antibody titer from Week 8
!
Proportion of patients who achieve a strain-
specific post-dose HAI antibody titer ≥40 at 
Week 12


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1.1.2
Secondary objectives 
Objective
Endpoint
To further evaluate the potential 
effect of benralizumab on the 
humoral immune response 
following seasonal influenza virus 
vaccination in adolescent and 
young adult patients with severe 
asthma
!
Proportion of patients who achieve a strain-
specific post-dose HAI antibody titer ≥320 at 
Week 12 
!
Post-dose strain-specific microneutralization 
(MN) antibody GMFRs from Week 8
!
Post-dose strain-specific serum MN antibody 
GMTs obtained at Week 12
!
Proportion of patients who experience a strain-
specific post-dose antibody response at Week 12 
with antibody response defined as a ≥4-fold rise 
in MN antibody titer from Week 8
To assess the potential effect of 
benralizumab on asthma control
!
Change from baseline in mean Asthma Control 
Questionnaire-6 (ACQ-6) score at Week 12
1.1.3
Safety objectives 
Objective
Endpoint
To assess the safety and 
tolerability of benralizumab
!
Adverse events (AEs) and serious adverse events 
(SAEs) 
!
Laboratory variables
!
Physical Examination
1.2
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
investigate the potential effect of a fixed dose of benralizumab (30 mg) administered SC on 
the humoral immune response following seasonal influenza virus vaccination.
Approximately 100 male and female adolescent and young adult patients between 12 to 21 
years of age with severe asthma will be randomized to receive SC benralizumab 30 mg or 
placebo administered at Weeks 0, 4, and 8. Randomization to the treatment groups will be 
assigned in each stratum (adolescents [12 to 17 years of age] and young adults [18 to 21 years 
of age]) as patients become eligible for randomization. Fifty percent or more of the patients 
will be in the adolescent age group (12 to 17 years of age). Patients will receive 1 dose of 
seasonal influenza virus vaccine inter-muscular (IM) at Week 8. Samples for evaluation of 
antibody response will be drawn at Week 8 and Week 12. An End of Treatment (EOT) visit 


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will be conducted at Week 12 and a Follow-up (FU) visit will be conducted at Week 20.  
Patients will be maintained on their currently prescribed inhaled corticosteroids (ICS)-long-
acting β2 agonists (LABA) therapy(ies) without change from enrollment throughout the 
screening and treatment period.
1.2.1
Duration of the Study
The total planned study duration is a maximum of 23 weeks.
1.2.1.1
Enrollment (Visit 1), Screening (Visit 2), and Re-screening
Each potential patient will provide written informed consent (ICF)/assent as appropriate with 
local guidance prior to any study specific procedures and undergo assessments applicable for 
the enrollment visit (Visit 1). After enrollment and confirmation of entry criteria, patients will 
proceed to screening period of a minimum of 2 weeks to allow adequate time for all of the 
eligibility criteria to be evaluated. Re-screening is allowed only once for the patient. Re-
screened patient/parent or legal guardian should re-sign ICF/assent on the rescreening Visit 1. 
All procedures from the screening period should be repeated. Patients who experience an 
asthma exacerbation during screening should be treated according to local medical practice 
and will be considered a screen failure.
1.2.1.2
Randomization treatment period
Patients confirmed to be eligible will be randomized at Week 0 to receive 3 SC doses (at 
Weeks 0, 4, and 8) of benralizumab 30 mg or placebo. Patients will receive 1 dose of seasonal 
influenza virus vaccine IM at Week 8. Samples for evaluation of antibody response will be 
drawn at Week 8 (prior to administration of the vaccine) and Week 12. The EOT visit will be 
at Week 12, following the antibody response evaluation (ARE) assessments. All patients who 
prematurely discontinue investigational product (IP) should return to the study center and 
complete the procedures described for the premature IP discontinuation (IPD) visit within 4 
weeks±3 days.
1.2.1.3
Follow-up Period 
Patients who complete the double-blind randomized treatment period will be followed for 12
weeks after the last dose of IP for the Week 20 FU visit.
1.3
Number of subjects
The study will have an estimated sample size of 50 patients in each treatment group.  No 
formal statistical hypotheses will be tested.  The sample size justification is based on the 
precision of the estimate of the geometric mean titers (GMTs) (as GMTvaccine / 
GMTbenralizumab+vaccine).  With 50 patients per arm, the 90% confidence interval (CI) for the 
GMT ratio would be 0.67 to 1.48, assuming an observed ratio of 1, and that the log (post-dose 
hemagglutination-inhibition [HAI] antibody titer or post-dose microneutralization antibodies 
to influenza vaccine [MN] antibody titer) is normally distributed with a standard deviation 
(SD) of 1.2 on the natural log scale (Langley et al 2013). 


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2.
ANALYSIS SETS
2.1
Definition of analysis sets
Antibody endpoints to the influenza vaccine, strain-specific HAI and MN antibody geometric 
mean fold rises (GMFRs) and GMTs, will be analyzed using the vaccine immunogenicity 
analysis set.  All remaining efficacy analyses will be performed using an Intent-to-Treat (ITT) 
approach based on the full analysis set (FAS).  For consistency, demographic and baseline 
characteristics will be presented using the FAS.  Safety objectives and anti-drug antibodies 
(ADA) will be analyzed based on the safety analysis set.
2.1.1
All patients analysis set
This analysis set will comprise all patients screened for the study and will be used for
reporting of disposition and screening failures.
2.1.2
Full analysis set (FAS)
All patients randomized and receiving any IP will be included in the FAS, irrespective of their 
protocol adherence and continued participation in the study.  Patients will be analyzed 
according to their randomized treatment, irrespective of whether or not they have prematurely 
discontinued, according to the ITT principle.  Patients who withdraw consent to participate in 
the study will be included up to the date of their study termination.
2.1.3
Vaccine immunogenicity analysis set
The vaccine immunogenicity analysis set will include all randomized patients who received at 
least 1 dose of planned IP (ie, 1 dose of influenza vaccine, plus 1 dose of benralizumab or 
placebo), had pre- (Visit 5/Week 8) and post-dose (Visit 6/Week 12) for HAI or MN antibody 
measurements, and had no protocol deviations judged to have the potential to interfere with 
the generation or interpretation of an antibody response.  The analyses conducted using this 
analysis set will be based on the actual treatment received.  Protocol deviations will be 
reviewed and finalized by the study team before unblinding.
2.1.4
Safety analysis set
All patients who received at least 1 dose of IP will be included in the safety analysis set.  
Patients will be classified according to the treatment they actually received.  A patient who 
has on one or several occasions received active treatment will be classified as active.  All 
safety and ADA summaries will be based on this analysis set.
2.1.5
Pharmacokinetic analysis set
All patients who received benralizumab and from whom pharmacokinetic (PK) blood samples 
were obtained are assumed not to be affected by factors such as protocol violations.  Those 
patients who had at least 1 quantifiable serum PK observation post-first dose will be included 
in the PK analysis dataset.  All PK summaries will be based on this analysis set.


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2.2
Violations and deviations
Important protocol deviations are a subset of protocol deviations that may significantly impact
the completeness, accuracy, and/or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being.  All patients who meet the definition of FAS and 
safety analysis set will be included in the FAS and safety analysis set, respectively, regardless 
of these important protocol deviations.  Definition of important protocol deviations based on 
inclusion and exclusion criteria are listed in Appendix A.
Important protocol deviations will be reviewed and finalized by the medical advisors and 
statisticians prior to database lock to help define the vaccine immunogenicity analysis set and 
PK analysis set.
2.2.1
Randomization issues
If the wrong treatment is administered to a patient, and the reason for the incorrect treatment is 
documented, this will be noted in the clinical study report (CSR).  All safety data will be 
analyzed and presented according to the actual treatment received.  Patients given the wrong 
medication to which they are randomized will not be included in the vaccine immunogenicity 
analysis set and PK analysis set.  
2.3
Visit window definitions
Visit windows for assessments (ie, Laboratories, ACQ-6) will be based on the following 
tables.
Table 1
Visit windows for assessments conducted every 4 weeks
Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
Week 0 Day 1
1
Study Day=1
Week 4
29
2 ≤ Study Days ≤ 56
Week 12
85
57 ≤ Study Days
Table 2
Visit windows for laboratory assessments
Adjusted Defined Windows Visit
Scheduled Study Day
Maximum Windows
Week 0 Day 1
1
Study Day=1
Week 12
85
2 ≤ Study Days ≤ 112
Week 20 (Follow-up)
141
113 ≤ Study Days 


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3.
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy variables
All efficacy objectives will be evaluated for the double-blind treatment period, defined as the 
period after administration of randomized IP at Week 0 and the conclusion of Visit 6 
(Week 12; ARE/EOT) visit, inclusive.
3.1.1
Humoral immune response following seasonal influenza virus vaccination
Serum HAI and MN antibody testing for antibody responses will be performed at Visit 5 
(Week 8) and Visit 6 (Week 12; ARE/EOT).  The benralizumab versus placebo humoral 
immune responses following seasonal influenza virus vaccination will be assessed.
3.1.1.1
Primary outcome variables
!
Post-dose strain-specific HAI antibody geometric mean folder rises (GMFRs) from 
Visit 5 (Week 8)
!
Post-dose strain-specific HAI antibody geometric mean titers (GMTs) obtained at 
Visit 6 (Week 12; ARE/EOT)
!
Proportion of patients who experience a strain-specific post-dose antibody response 
at Visit 6 (Week 12; ARE/EOT) with antibody response defined as a ≥4-fold rise in 
HAI antibody titer from Visit 5 (Week 8)
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer 
≥40 at Visit 6 (Week 12; ARE/EOT).
3.1.1.2
Secondary outcome variables
!
Proportion of patients who achieve a strain-specific post-dose HAI antibody titer 
≥320 at Visit 6 (Week 12; ARE/EOT)
!
Post-dose strain-specific microneutralization (MN) antibody GMFRs from Visit 5 
(Week 8)
!
Post-dose strain-specific serum MN antibody GMTs obtained at Visit 6 (Week 12; 
ARE/EOT)
!
Proportion of patients who experience a strain-specific post-dose antibody response 
at Visit 6 (Week 12; ARE/EOT) with antibody response defined as a ≥4-fold rise in 
MN antibody titer from Visit 5 (Week 8)


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3.1.2
Patient-reported outcome variables (PRO)
3.1.2.1
Secondary variable: Asthma Control Questionnaire (ACQ-6)
The questionnaire will be completed at the study center during the Treatment visits 
(Visit 3/Week 0, Visit 4/Week 4, and Visit 5/Week 8), Visit 6 (Week 12; ARE/EOT), and IPD
visit when applicable.
The Asthma Control Questionnaire (ACQ-6) is a shortened version of the ACQ that assesses 
asthma symptoms (nighttime waking, symptoms on waking, activity limitation, shortness of 
breath, wheezing, and short-acting β2 agonist use) omitting the forced expiratory volume in 
1 second (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 to the questions.  The 
outcome variable for ACQ-6 will be the change in mean score from baseline at Visit 3
(Week 0).
Asthma control status will be categorized according to the following limits of the score 
thresholds (Juniper et al 2006):
!
ACQ-6 (EOT) ≤0.75 → Well controlled
!
0.75< ACQ-6 (EOT) <1.5 → Partly controlled
!
ACQ-6 (EOT) ≥1.5 → Not well controlled
3.2
Safety variables
The following safety data will be collected: all reported adverse events (AEs) and serious 
adverse events (SAEs), concomitant medications, hematology, clinical chemistry, urinalysis, 
physical examination, vital signs, electrocardiogram (ECG), asthma exacerbation, and ADA to 
benralizumab.
3.2.1
Spirometry (Baseline and Historical)
Lung function (reversibility, FEV1, and forced vital capacity [FVC]) at the study center will 
be measured by spirometry at Visit 1 (Enrollment) or Visit 2 (Screening).  Spirometry should 
be performed by the Investigator or authorized delegate according to American Thoracic 
Society/European Respiratory Society (ATS/ERS) guidelines (Miller et al 2005).  Patients 
should withhold their Short-acting β2 agonists (SABA) medication(s) for at least 6 hours prior 
to Visit 2.  If Visits 1 and 2 are combined, bronchodilator therapy(ies) with or without ICS 
should be withheld for 12-24 hours depending on whether the patient is using twice or once-
daily bronchodilator-containing therapy.


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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 (FEV1 and FVC), the percentage of predicted normal value, and 
FEV1/FVC ratio will be recorded using the local spirometer at the site with predicted values 
derived from the reference value of choice, eg, NHANES III 2010and Quanjer et al 2012.  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-bronchodilator (BD) spirometry will be performed to satisfy reversibility inclusion 
criterion 8 as defined in the CSP.  The post-BD spirometry procedure should commence 
within 30±15 minutes according to the regimen for reversibility testing outlined in 
Section 5.1.2.1 of the CSP.  The patient’s usual morning asthma controller therapy must not 
be given until after the initial pre-medication, pre-BD spirogram is completed; usual asthma 
controller may be given after the post-BD spirogram.
The highest pre- and post-BD FEV1 should be used to determine reversibility.
Reversibility is calculated as follows:
% Reversibility = (post-BD FEV1- pre-BD FEV1) × 100
                                               pre-BD FEV1
3.2.2
Adverse Events (AE)
The AEs experienced by the patients will be collected throughout the entire study and will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) 
per the Data Management Plan.
Definition of adverse events 
An 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, ECG).  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.
Definitions of serious adverse event
A SAE is an AE occurring during any study phase (ie, screening/run-in, treatment, washout, 
and follow-up), that fulfills one or more of the following criteria:
!
Results in death


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!
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.
Recording of adverse events
All AEs, including SAEs, will be collected from the time the patient, parent, or legal guardian 
signs the ICF/assent throughout the treatment period and including the follow-up period 
(through Visit 7 [Week 20]).
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 
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.
The AE data will be categorized according to onset date:
!
The AEs collected during the on-study are defined as those with onset date between 
day of first dose of study treatment and the day of the scheduled FU visit. This 
includes the day of the scheduled EOT visit for patients who complete study 
treatment or IPD visit for patients who prematurely discontinue study treatment, 
inclusive. In the event that the EOT or IPD visit is beyond the protocol-defined visit 
window, AEs with onset after the last dose of study treatment date + 28 days + 3 
days (visit window) will be excluded from the summary analysis, but will still be 
presented in the data listings.
Any AEs with an onset date prior to the day of first dose of study treatment will only be 
presented in patient listings.
Rules for imputing AE start/stop dates which are completely or partially missing can be found 
in Appendix B.  Missing start/stop dates will appear as missing in the patient data listings, but 
will be imputed to permit proper tabulation of AE data.


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It is important to distinguish between SAEs and severe AEs.  Severity is a measure of 
intensity (mild, moderate, or severe), whereas seriousness is defined by the criteria stated 
above.  An AE of severe intensity need not necessarily be considered serious. If a patient 
reports multiple occurrences of the same AE within the same study period, the maximum 
intensity will be taken as the highest recorded maximum intensity (the order being mild, 
moderate, and severe).
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.  A guide to the interpretation of the causality question is found in 
Appendix B of the CSP.
Potential Hy’s Law
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
and occurrences of Aspartate transaminase (AST) or Alanine transaminase (ALT) ≥3xULN 
together with total bilirubin ≥2xULN may need to be reported as SAEs. Potential Hy’s law 
definition and case confirmation are given in Appendix D of the CSP.
Patients who meet any of the following criteria within a visit at any point during the study will 
be flagged:
!
AST
≥3 - <5x ULN
≥5 - <10x ULN
≥10x ULN
!
ALT
≥3 - <5x ULN
≥5 - <10x ULN
≥10x ULN
!
Total Bilirubin (Bilirubin)
≥2x ULN
3.2.3
Prior/concomitant medication
Prior medications are defined as those taken by the patients within 90 days and have stopped 
on or before the date of first dose of the IP at Visit 3 (Week 0).
Concomitant medications (allowed and disallowed) are defined:


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!
Medications that started prior to the date of first dose of the IP and continued after 
the first dose of the IP to study completion/discontinuation or stopped after the first 
dose of the IP.
!
Medications taken on or after the date of first dose of the IP to study 
completion/discontinuation or stopped after the first dose of the IP. 
Concomitant medications collected throughout the entire study and will be coded using the 
latest version of the WHO Drug Dictionary per the Data Management Plan.
3.2.4
Safety assessments
3.2.4.1
Clinical laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at Visit 1 (Enrollment), Visit 3 (Week 0), Visit 6 (Week 12; ARE/EOT), Visit 7
(Week 20; FU), and IPD visit when applicable.
The following laboratory variables will be measured:
Hematology 
Clinical Chemistry 
Urinalysis 
Hematocrit
Alkaline phosphatase (ALP)
Appearance
Hemoglobin
Alanine transaminase (ALT)
Blood
Mean corpuscular volume (MCV)
Aspartate transaminase (AST)
Color
Platelet count
BUN (blood urea nitrogen)
Glucose
Red blood cell (RBC) count
Calcium
Ketones
White blood cell (WBC) count with
Chloride
Microscopy including 
differentiala
CO2 (carbon dioxide)
WBC/high power field
Creatinine
(HPF), RBC/HPF
Gamma-GT (gamma-glutamyl 
pH
transpeptidase)
Specific gravity
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin
Total cholesterol
Uric acid
Theophyllineb


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a
In order to maintain blinding on treatment assignment, eosinophil, basophil and monocyte counts will be 
redacted from the central laboratory reports, except for Visit 1.
b
Samples only collected for patients on theophylline at Visit 1.
Blood and urine samples will be assessed in a central laboratory.  Laboratory data is to be 
reported in standard international (SI) units.  Observed values will be compared to the relevant 
reference range and classified as low (below range), normal (within range or on limits) or high 
(above range).  The central laboratory reference range will be used for laboratory parameters.  
If the laboratory reference range is missing, the missing range will be queried to the central 
laboratory to confirm the reference range is not required for the laboratory parameter.  All 
observed values falling outside the central lab reference ranges will be flagged.  Baseline will 
be defined as last available non-missing result collected prior to IP dosing on Visit 3 
(Week 0).
The following tests are applicable to female patients only:
!
Serum beta-human chorionic gonadotropin (HCG): To be done at Visit 1 only, for 
women of childbearing potential (WOCBP) (analyzed at central laboratory)
!
Urine HCG: To be performed at the study center for WOCBP at each treatment visit 
(before IP administration on Visits 3 to 5) using a dipstick.  A positive urine test 
result must be confirmed with serum beta HCG.
3.2.4.2
Serology
Hepatitis B surface antigen, hepatitis C antibody: To be done only at Visit 1; test to be 
performed at central laboratory.
HIV-1 and HIV-2 antibodies: To be done only at Visit 1; test to be performed at central 
laboratory.
3.2.4.3
Vital signs 
Pre-dose vital signs (pulse, blood pressure, respiration rate, and body temperature) are to be 
obtained at Visit 1 (Enrollment), Visit 2 (Screening), Treatment visits (Visit 3/Week 0, 
Visit 4/Week 4, and Visit 5/Week 8), Visit 6 (Week 12; ARE/EOT), Visit 7 (Week 20; FU), 
and IPD visit when applicable. 
Body temperature is to be recorded in degrees Celsius.
Baseline will be defined as last available non-missing result collected prior to IP dosing on 
Visit 3 (Week 0).
Absolute values will be compared to the reference ranges in Table 3 and classified as low 
(below range), normal (within range or on limits), or high (above range). All absolute values 
falling outside the reference ranges will be flagged.


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Table 3
Vital signs reference ranges
Parameter
Standard Units
Lower Limit
Upper Limit
Diastolic Blood Pressure
mmHG
60
120
Systolic Blood Pressure
mmHG
100
160
Pulse Rate
Beats/min
40
120
Respiratory Rate
Breaths/min
8
28
Body Temperature
Celsius
36.5
38
3.2.4.4
Physical examination
Complete physical examinations will be performed at Visit 1 (Enrollment), Visit 3 (Week 0), 
Visit 6 (Week 12; ARE/EOT), Visit 7 (Week 20; FU), and IPD visit when applicable.  The 
brief physical examinations will be done at Treatment visits (Visit 4/Week 4 and 
Visit 5/Week 8).
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.
The complete physical examination includes an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems.
The brief physical examination includes an assessment of the general appearance, abdomen, 
cardiovascular, and respiratory system.  For the brief physical examination only information 
on whether the assessment was performed or not is to be recorded.
3.2.4.5
Local electrocardiogram 
The ECGs are to be performed at Visit 1 (Enrollment).
A 12-lead ECG will be taken in supine position, after the patient has been resting for at least 
5 minutes.  The assessment should be performed before interventions with the patient (eg, 
spirometry).
3.2.5
Other safety assessments
3.2.5.1
Weight and height
Weight and height will be measured, and body mass index (BMI) calculated at Visit 1 
(Enrollment).
The patient’s weight will be recorded in kilograms; height will be recorded in centimeters.


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3.2.5.2
Assessment of asthma exacerbation
An asthma exacerbation is defined by a worsening of asthma requiring the use of systemic 
corticosteroids (or an increase in oral steroid dose for those already on systemic 
corticosteroids) and/or an in-patient hospitalization, and/or an emergency department visit.  
Asthma exacerbation will be assessed at Treatment visits (Visit 3/Week 0, Visit 4/Week 4, 
and Visit 5/Week 8), Visit 6 (Week 12; ARE/EOT), Visit 7 (Week 20; FU), and IPD visit 
when applicable.
An asthma exacerbation that occurs ≤7 days following the last dose of systemic steroids (oral, 
IM, IV), prescribed for a prior exacerbation, will be recorded as the same exacerbation event.
Asthma exacerbation information will be collected with a recall period of ‘since the last 
scheduled visit’.
3.2.5.3
Benralizumab immunogenicity variables
Serum samples for ADA assessments will be collected pre-dose at Treatment visits (Visit 
3/Week 0 and Visit 5/Week 8), Visit 6 (Week 12; ARE/EOT), Visit 7 (Week 20; FU), and 
IPD visit when applicable to measure presence of ADA to benralizumab. 
A 3-tiered testing plan, which consisted of validated screening, confirmatory, and titering
assays, was used to analyze clinical samples. The samples will be retained for repeat analysis 
of ADA at AstraZeneca or a designee for a maximum of 1 year following completion of the 
CSR.
ADA result from each sample will be reported as either positive or negative. A subject with a 
positive result will also be further defined as persistent or transient positive.  Persistent 
positive is defined as positive result at ≥2 post-baseline assessments (with ≥16 weeks between 
first and last positive) or positive at last post-baseline assessment.  Transient positive is 
defined as having at least one post baseline ADA positive assessment and not fulfilling the 
conditions of persistent positive. If the sample is positive, the ADA titer will be reported as 
well.
3.3
Pharmacokinetic variables
Benralizumab serum concentrations will be collected pre-dose at Treatment visits 
(Visit 3/Week 0 and Visit 5/Week 8), Visit 6 (Week 12; ARE/EOT), Visit 7 (Week 20; FU), 
and IPD visit when applicable.  For the PK analysis it is important that the date and time of 
each SC injection is recorded for each patient.
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (pre-dose) concentrations, Ctrough.  Empirical evaluation of 
potential impact of demographic covariates and ADA on Ctrough will be conducted.


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3.4
Pharmacodynamics
Samples for the analysis of peripheral blood eosinophils will be performed in a central 
laboratory as part of the routine hematology assessment (complete blood count [CBC]).  The 
data will be available after database lock. 
4.
ANALYSIS METHODS
4.1
General principles
4.1.1
General methodology
The data analyses will be conducted using the SAS® System (SAS Institute Inc., Cary, NC). 
All SAS® programs used to generate analytical results will be developed and validated 
according to AstraZeneca SAS® programming standards and validation procedures. 
Individual data will be presented in patient listings.  All patient data listings will be sorted by 
treatment group and patient number.
All efficacy, safety, and PK concentration variables will be summarized using descriptive 
statistics by treatment group. Graphs will be produced as appropriate.  Continuous variables 
will be summarized by descriptive statistics (sample size [n], arithmetic mean, SD, minimum, 
median and maximum).  Categorical variables will be summarized in frequency tables 
(frequencies and percentages).
Means and medians will be displayed with one more decimal place than the collected data, 
and SDs will have one more decimal place than the means and medians.  Minimums and 
maximums will be displayed with the same number of decimal places as the collected data.  
For discrete variables, population size (N for analysis set size and n for available data) and 
percentage will be presented.  Percentages will be displayed with one decimal place. 
Patient characteristics (eg, demographic and other baseline characteristics) and study 
medication information will be summarized by treatment group and overall.  Efficacy, safety, 
and PK concentration data will be summarized by treatment group and assessment visit, when 
applicable. 
4.1.2
Vaccine immunogenicity data
All observed vaccine immunogenicity values will be included in the primary and secondary
analyses.  Extra measurements (such as unscheduled or repeat assessments) will not be 
included in the descriptive statistics, but will be included in data listings.
4.1.3
Patient-reported outcome data
All PRO values will be included in the secondary analysis.  Extra measurements (such as 
unscheduled or repeat assessments) will not be included in the descriptive statistics, but will 
be included in data listings.


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4.1.4
Handling of safety data
All patients in the safety analysis set will be included in the safety analyses.  All safety 
measurements will use all available data for analyses, including data from unscheduled visits 
and repeated measurements. No safety data results will be imputed. 
Change from baseline to each post-treatment time point where scheduled assessments were 
made will be calculated for relevant measurements. AEs will be summarized by means of 
using descriptive statistics and qualitative summaries.
For laboratory values recorded with a leading greater than or less than (‘>’, ‘<’) symbol, the 
reported numeric value will be used for analysis and the value with the symbol will be 
included in the listings, unless otherwise specified. For example, a value of <0.01 will be 
analyzed as 0.01 and listed as <0.01.
4.1.5
Handling of PK concentration data 
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.
4.1.6
Handling of missing data
For the datasets used for summary of demographic and baseline characteristics, efficacy, 
safety, and PK concentration; each variable will be analyzed and/or summarized using the 
available data.  Patients with missing data will be excluded only from analyses for which data 
are not available.  
Unscheduled visit or retest measurements at a scheduled time point will be provided in subject 
listings.  If the retest measurement occurs prior to the first IP dosing, the retest measurement 
will be used in the summary statistics if it is the last non-missing measurement taken prior to 
the first dose.  The retest measurements will not be used in summary statistics for post-dose 
measurements.  If all scheduled measurements for a specific variable are missing for a patient, 
the unscheduled measurements will be included in the analysis and footnoted in the table.  The 
decision to use the unscheduled measurements will be determined prior to database lock.  
The PK analysis set will not include a PK measurement with important protocol 
deviations/violations or events thought to significantly affect the PK analysis as defined in
Section 2.1.5.  Data from patients excluded from the PK analysis set will be included in the 
data listings, but not in the descriptive or inferential statistics.  
Descriptive presentations will be based on observed cases.  No adjustment or imputation will 
be utilized for missing values or for patients who withdraw prior to completing the study after 
the enrollment visit, nor will analyses be restricted to patients with complete data.
AE and concomitant medication missing start/stop dates will appear as missing in the patient 
data listings, but will be imputed to permit the proper tabulation of AE and medication data.  
The imputation of missing AE and concomitant medication onset/start and end/stop dates will 


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be used to determine the status of each AE and the previous/concomitant status of each 
medication. Please refer to Appendix B for the method of imputation of missing AE 
onset/start and end/stop dates and Appendix C for the method of imputation of missing 
concomitant medication onset/start and end/stop dates.  
4.2
Analysis methods
4.2.1
Analysis of patient characteristics
Descriptive statistics on patient disposition will be summarized using the all patients analysis 
set defined in Section 2.1.1.  All descriptive statistics for demographic and other baseline 
characteristics, medical history, and prior and concomitant medications will be presented 
based on the FAS.
4.2.1.1
Patient disposition
The total number of patients will be summarized for the following groups: those who enrolled, 
and those who were not randomized (and reason). The number and percentage of patients 
within each treatment group and overall will be presented by the following categories; 
randomized, received treatment, did not receive treatment (and reason), completed treatment, 
discontinued treatment (and reason), discontinued treatment but completed study follow-up, 
completed study, and withdrawn from study (and reason).
Screen failure information will be listed for the all patients analysis set.
The number and percentage of patients included in each of the analysis sets; vaccine 
immunogenicity, PK, and safety, will be tabulated. Reasons for exclusion from analysis 
datasets will also be provided.
A listing will be presented to describe: study treatment, date treatment/study completed or 
terminated, and the reason for post-randomization discontinuation for each patient. 
4.2.1.2
Important protocol deviations
The number and percentages of patients with at least one important protocol deviation will be 
summarized for treatment group and overall. 
A listing of all patients with any important protocol deviations will be provided.
4.2.1.3
Demographic and other baseline characteristics
Demographic characteristics and other baseline characteristics such as age, sex, race, 
ethnicity, weight, height, BMI, and BMI groups will be summarized by treatment group and 
overall using descriptive statistics.  Age will be derived from the date of informed consent-
date of birth, rounded down to the nearest integer.  The BMI groups are Underweight (<18.5), 
Normal (≥18.5 to <25), Overweight (25 to 30), and Obese (>30).
Listings of all patients demographic and baseline characteristics will be provided.


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4.2.1.4
Concomitant treatments
All prior and concomitant medications will be classified according to the terminology of the 
latest of the WHO Drug Dictionary per the Data Management Plan.  The number and 
percentage of patients with disallowed and allowed concomitant medications will be tabulated 
by ATC Term and Drug Preferred Name by treatment group and overall.  
Patients taking the same medication multiple times will only be counted once for that ATC 
Term or drug preferred name.
Medications with start/stop dates that are partially/completely missing will be analyzed as 
described in Appendix C.
Listing of all prior and concomitant medications for each patient will be provided.
4.2.1.5
Past and current medical conditions/diseases 
All medical/surgical/respiratory disease history will be classified according to the terminology 
of the latest version of the MedDRA.  
Past medical conditions/diseases are those medical conditions/diseases that stopped prior to 
the study entry (Visit 1) while current medical conditions/diseases are those medical 
conditions/diseases that are still present at the study entry (Visit 1).
The number of patients with any relevant past and current medical conditions/diseases will be 
tabulated by MedDRA system organ class (SOC) and preferred term (PT) by treatment group.  
A patient will only be counted once within a particular SOC (or PT) even if he/she has 
multiple conditions/diseases in the same SOC (or PT).
Past and current medical history and surgical history will be presented as part of the patient 
data listings.
4.2.2
Spirometry (baseline and historical)
Lung function data for pre-BD, post-BD, and reversibility (Section 3.2.1) results will be 
summarized by treatment group and overall using descriptive statistics.
All lung function data will be provided in patient data listings.
4.2.3
Efficacy analysis (primary and secondary variables)
4.2.3.1
Primary and secondary variables: Humoral immune response following 
seasonal influenza virus vaccination
The analysis of the antibody endpoints will be summarized by descriptive statistics 
(strain-specific GMFRs and GMTs, geometric standard deviation [GSD] and geometric 
coefficient of variation [CV]).
GMFRs for the HAI and MN antibody measurements are defined as:


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GMFR = antilogz (mean [logz x])
Where x is the post-dose HAI or MN antibody titer fold rise from Visit 5 (Week 8) and z is 
the natural logarithm. The GMFR value for each subject will be calculated as the GMT ratio 
between Visit 6 (Week 12)/Visit 5 (Week 8), where GMT is calculated for each subject at 
each visit based on the definition below.
GMTs for the HAI and MN antibody measurements are defined as:
GMT = antilogz (mean [logz y])
Where y is the HAI or MN antibody titer and z is the natural logarithm.
The analysis of the HAI or MN antibody endpoints (Section 3.1.1.1), strain-specific GMFRs 
and GMTs, will be performed on the vaccine immunogenicity analysis set.
Number and percentage of patients with HAI or MN antibodies will be summarized by titer, 
visit, and treatment group. Incidence of negative and positive antibodies will also be 
summarized descriptively by visit and treatment group. 
The strain-specific HAI or MN antibody endpoints (GMFRs and GMTs) will be summarized 
by treatment group for each assessment visit.
For GMFR and GMT, the geometric least square mean (LSmean) ratio between treatment 
(placebo/benralizumab) along with the corresponding 90% CI will be calculated via an 
Analysis of covariance (ANCOVA) model on the log transformed variable (antibody titer fold 
rise from Week 8 or antibody titer at Week 12).  The linear model effects are treatment group 
as a fixed effect and age group (adolescents and young adults) as fixed categorical covariate.  
The model based natural log estimates of the LSmeans for each treatment and the differences 
of the LSmeans (placebo - benralizumab) along with the corresponding 90% CI will be 
exponentiated.  The geometric LSmeans for each treatment and geometric LSmean ratio with 
90% CI will be presented.
Antibody response is defined as a ≥4-fold rise in HAI or MN antibody from Week 8 to 
Week 12.  The proportion of patients who experience a post-dose antibody response at Week 
12 and corresponding 90% Clopper-Pearson exact CI will be summarized by treatment.
The proportion of patients who achieve a post-dose HAI antibody titer ≥40 at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment.
The proportion of patients who achieve a post-dose HAI antibody titer ≥320 at Week 12 and 
corresponding 90% Clopper-Pearson exact CI will be summarized by treatment.


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4.2.4
Patient-reported outcome (PRO) variables
4.2.4.1
Secondary variable: Asthma Control Questionnaire (ACQ-6)
The analysis of the ACQ-6 score data (Section 3.1.2.1) will be performed on the FAS.  The 
ACQ-6 score data actual and change from baseline results will be summarized by visit and
treatment group using descriptive statistics.  The frequency (number and percentage) of ACQ-
6 asthma control responder status will be summarized at Baseline and Week 12 (EOT) by 
treatment group according to the following limits:
!
ACQ-6 (EOT) ≤0.75 → Well controlled
!
0.75< ACQ-6 (EOT) <1.5 → Partly controlled
!
ACQ-6 (EOT) ≥1.5 → Not well controlled
4.2.5
Safety and tolerability analysis
All safety and tolerability variables will be summarized descriptively by treatment group 
using the safety analysis set.  
4.2.5.1
Adverse events
All AEs will be coded using the MedDRA. 
!
The number and percentages of patients who experienced at least 1 AE will be 
summarized by SOC and PT.  
!
SAEs and AEs leading to study discontinuation will be tabulated. 
!
AEs will be summarized by maximum intensity and causally-related to study 
medication. 
!
AEs, SAEs, and AEs leading to study discontinuation will be listed with time to 
onset of event from the recent IP dose and total dose of IP received prior to the 
event.
Unless otherwise specified, all percentages (%) will be calculated out of the number of 
patients per treatment group in the safety analysis set.
All summary tables will be sorted by decreasing order of frequency of MedDRA SOC (if 
applicable) and within each SOC by decreasing order of frequency of PT by overall number.
An overview of AEs will be given describing the total number patients with AEs during the
enrollment and during the randomized treatment period in each of the following categories:
!
Any AE


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!
Any AE with outcome = death
!
Any SAE (including outcome = death )
!
Any AE leading to discontinuation of investigational product
!
Any AE of maximum intensity
!
Any causally related AE as judged by the Investigator
All AEs and SAEs will be provided in patient data listings.
The frequency of maximum post-baseline ALT/AST values with respect to maximum post-
baseline bilirubin values for assessing potential Hy’s law criteria will be tabulated by 
treatment group. Patients that meet potential Hy’s Law criteria will be provided in patient data 
listings.
4.2.5.2
Clinical laboratory
Laboratory data for hematology and clinical chemistry (Section 3.2.4.1) actual and change 
from baseline results will be summarized by visit and treatment group using descriptive 
statistics.  The frequency of changes (shift from baseline) with respect to normal ranges
(high/low/normal findings) between baseline and minimum/maximum post-baseline values 
will be tabulated by treatment group.  Shifts from normal to out of range values between 
baseline and maximum post-baseline values will be evaluated for categorical urinalysis tests 
by treatment group.
All laboratory data will be provided in patient data listings.
4.2.5.3
Vital signs
Vital signs (Section 3.2.4.2) actual and change from baseline results will be summarized by 
visit and treatment group using descriptive statistics.  The frequency of changes (shift from 
baseline) with respect to normal ranges (high/low/normal findings) between baseline and 
minimum/maximum post-baseline values will be tabulated by treatment group.  
4.2.5.4
Assessment of asthma exacerbation
The frequency (number and percentage) of number of asthma exacerbations (Section 3.2.5.2) 
will be summarized by treatment group. The total follow-up time since the last exacerbation
will be summarized (median, minimum, and maximum) by treatment group.
4.2.5.5
Benralizumab immunogenicity variables analysis
The incidence of negative or positive ADA response to benralizumab (Section 3.2.5.3) will be 
summarized descriptively by visit. A table will present a listings of patients with persistent 
and transient positive ADA result at any time point, along with the corresponding PK 
concentration.


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4.2.6
Pharmacokinetic variables analysis
The analysis of the benralizumab serum concentrations data (Section 3.3) will performed on 
the PK analysis set.  Benralizumab serum concentrations will be summarized using descriptive 
statistics at each visit by treatment group.  Graphical assessments of steady-state for 
benralizumab will be performed using Ctrough concentration samples collected following 
multiple-dose administration.  Arithmetic mean predose concentrations (±SD) will be plotted 
against visit to visually evaluate attainment of steady-state for benralizumab.  
All benralizumab serum concentrations will be provided in patient data listings.
5.
INTERIM ANALYSES
There are no interim analyses planned for this study.
6.
CHANGES OF ANALYSIS FROM PROTOCOL
The definition of the vaccine immunogenicity analysis set was updated to include subjects in 
the analysis if the subjects have pre- and post-dose of HAI or MN antibody measurements.  
The CSP stated that subjects should have antibody measurements from both HAI and MN 
antibodies. 
The CSP stated that AEs will be summarized by study period (on-study, on-treatment, and 
follow-up period). Since the study duration time is short, the summary of the AEs was updated 
to summarize on-study AEs.
7.
REFERENCES
Juniper et al 2006
Juniper E.F, Bousquet J., Abetz L., Bateman E.D.,The GOAL Committee. Identifying 
‘wellcontrolled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire. 
Respir Med. 2006 100:616–21.
Langley et al 2013
Langley JM, Matinez AC, Chatterjee A, Halperin SA, McNeil S, Reisinger KS, et al.
Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: A 
Phase III randomized controlled trial in children. J Infect Dis. 2013 (15 August);208:544-553.
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.


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NHANES III 2010
Centers for Disease Control and Prevention. NHANES III. Spirometry Procedure Manual. 
Office of Information Service, CDC/National Center for Health Statistics. 2010 Nov. 
Available at: http://www.cdc.gov/nchs/nhanes/nh3rrm.htm.
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.
8.
APPENDIX
8.1
Appendix A: Important Protocol Deviations
Table 8.1.1
Definition of important protocol deviations
Visit
Number
Important deviation
Treatment
V1
Time from influenza vaccine (Visit 5) to antibody response assessment 
(Visit 6) is less than 14 days.
Enrollment and 
Randomization
V2
ICS dose <500 μg fluticasone propionate dry powder formulation or 
equivalent daily using separate inhaler for ICS.
ICS = Inhaled corticosteroids
Reference V1: https://www.cdc.gov/flu/protect/keyfacts.htm.
Reference V2: This is a subsection of inclusion criterion question 6 in the CSP.


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8.2
Appendix B: Partial Date Conventions for Adverse Events
Missing type
Action
If only the day part of the AE onset date is 
missing and occurs in the same month and year as 
the first dose of study medication, the missing day 
of onset of AE will be set to:
!
First day of the month that the event occurred, 
if the onset YYYY-MM is after the YYYY-
MM of first study treatment
!
The day of the first study treatment, if the 
onset YYYY-MM is the same as YYYY-MM 
of the first study treatment
!
The date of informed consent, if the onset 
YYYY-MM is before the YYYY-MM of the 
first treatment.
If the day and month parts of the AE onset date
are missing and occur in the same year as the first 
dose of study medication, the date of onset of AE 
will be set to:
!
January 1 of the year of onset, if the onset year 
is after the year of the first study treatment
!
The date of the first treatment, if the onset year 
is the same as the year of the first study 
treatment
!
The date of informed consent, if the onset year 
is before the year of the first treatment
If only the day part of the AE resolution date is 
missing and occurs before or in the same month 
and year as the first dose of study medication, the 
missing day of resolution of AE will be set to:
The last day of the month of the occurrence. If the 
patient died in the same month, then set the 
imputed date as the death date.
If the day and month parts of the AE resolution 
date are missing, the date of resolution of AE will 
be set to:
December 31 of the year of occurrence. If the 
patient died in the same year, then set the imputed 
date as the death date.  


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8.3
Appendix C: Algorithm for Prior/Concomitant Medications: 
START 
DATE
STOP 
DATE
ACTION
Known
Known
If stop date < study med start date, assign as prior 
If stop date ≥study med start date and start date ≤study med last date 
+30 days, assign as concomitant 
If stop date ≥study med start date and start date > study med last date 
+30 days, assign as post study
Partial
Impute stop date as latest possible date (ie, last day of month if day 
unknown or 31st December if day and month are unknown), then:
If stop date < study med start date, assign as prior
If stop date ≥study med start date and start date ≤study med last date 
+ 30 days, assign as concomitant
If stop date ≥study med start date and start date > study med last date 
+ 30 days, assign as post treatment
Missing
If stop date is missing could never be assumed a prior medication
If start date ≤study med last date + 30 days, assign as concomitant
If start date > study med last date + 30 days, assign as post treatment
Partial
Known
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown), then:
If stop date < study med start date, assign as prior
If stop date ≥study med start date and start date ≤study med last date 
+30 days, assign as concomitant
If stop date ≥study med start date and start date > study med last date 
+30 days, assign as post treatment
Partial
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown) and impute 
stop date as latest possible date (ie, last day of month if day unknown 
or 31st December if day and month are unknown), then:
If stop date < study med start date, assign as prior
If stop date ≥study med start date and start date ≤ study med last date 
+30 days, assign as concomitant
If stop date ≥study med start date and start date > study med last date 
+30 days, assign as post treatment
Missing
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown), then:
If stop date is missing could never be assumed a prior medication
If start date ≤study med last date +30 days, assign as concomitant
If start date > study med last date +30 days, assign as post treatment


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START 
DATE
STOP 
DATE
ACTION
Missing
Known
If stop date < study med start date, assign as prior
If stop date ≥study med start date, assign as concomitant
Cannot be assigned as ‘post treatment’
Partial
Impute stop date as latest possible date (ie, last day of month if day 
unknown or 31st December if day and month are unknown), then:
If stop date < study med start date, assign as prior
If stop date ≥study med start date, assign as concomitant
Cannot be assigned as ‘post treatment’
Missing
Assign as concomitant